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SENESCENCE AND REJUVENESCENCE

THE UNIVERSITY OF CHICAGO PRESS
CHICAGO, ILLINOIS

Agents

THE CAMBRIDGE UNIVERSITY PRESS
LONDON AND EDINBURGH

THE MARUZEN-KABUSHIKI-KAISHA
TOKYO, OSAKA, KYOTO

KARL W. HIERSEMANN
LEIPZIG

THE BAKER & TAYLOR COMPANY
NEW YORK

SENESCENCE

AND

REJUVENESCENCE

By
CHARLES MANNING CHILD

Of the Department of Zoology
The University of Chicago

THE UNIVERSITY OF CHICAGO PRESS
CHICAGO, ILLINOIS

ra

QH

fis8S3

“a
NYG (a
CopyRIGHT 1915 By

Tue UNIVERSITY OF CHICAGO

All Rights Reserved

Published October 1915

2

Composed and Printed By
The University of Chicago Press
Chicago, Illinois, U.S.A.

PREFACE

The following study of senescence and rejuvenescence is pri-
marily a register of progress along certain lines of a research program
on which I have been engaged during the last fifteen years. This
program began with the attempt to analyze experimentally the
simpler reproductive processes, but it at once became evident that
the whole problem of the organic individual, its origin, development,
physiological character, and limiting factors, was involved. In
the study of the organic individual the importance of the physio-
logical age changes soon became apparent and it was found neces-
sary to devote considerable time to their analysis, for the origin of
new individuals by reproduction is in many cases very closely
associated with physiological aging. And since the conclusions
reached concerning the age cycle finally attained a definite, positive
form, differing to some extent from commonly accepted views,
but seeming to throw some light upon various other biological
problems, it has seemed desirable to attempt a general considera-
tion and synthesis of the subject of age changes from the point of
view which has grown out of the research program mentioned
above.

It will appear clearly in the following pages that the problems
of individuation, reproduction, and age are all closely connected.
For that reason it has been necessary to devote a chapter—chap. ix
—to the problem of individuation and reproduction. This chapter
is merely a brief statement of some of the more important evidence
and the conclusions reached concerning the nature of the organic
individual, a full consideration of the subject being left to another
time.

About half the book is a presentation of results of my own
investigations and the larger part of these have not been published
elsewhere. Consequently the book stands as a record of research
as well as an attempt at a general survey. No attempt has been
made to present a complete bibliography of the subject of age. The
references are to a large extent intended to serve rather as guides
or aids in obtaining further knowledge of the literature than as an

Vv

vi PREFACE

exhaustive bibliography. The matter of selection has often been
a difficult one and doubtless references have been omitted which
should have been included. For such errors of judgment or of
ignorance I must accept the full responsibility.

At various points in the book it has seemed necessary to extend
the consideration into fields more or less remote from those with
which I am most familiar. I must frankly acknowledge, however,
that some of these ventures into other fields have been attended by
the feeling that discretion would perhaps have been the better part
of valor, for any venture very far outside one’s own little garden plot
of scientific thought is likely to be attended by a very decided feeling
of strangeness; one realizes that one is not at home. Nevertheless
such ventures are necessary if different lines of investigation and
thought are to be co-ordinated and synthesized into a harmonious
whole. I can only hope that in this particular case the excursions
into neighboring gardens and fields have not been wholly fruitless
or mistaken. As regards actual errors of statement or reference
and other similar matters which may have escaped correction, I
can only plead human fallibility.

It has been necessary, particularly in those chapters which are
concerned with the various reproductive processes and with the
morphology of the gametic cells, to use figures from various other
authors and I wish to acknowledge my obligations for such figures.
Figs. 102, 103, 104, 105, 106, 107, A-C, 108, 125, 128, 132, 133, 134,
135, 136, 137, 138, 139, 141, A-E#, are reproduced from A Text-
book of Botany by Coulter, Barnes, and Cowles, by permission of
the American Book Company, publishers, and Dr. Coulter, the
senior author. I am greatly indebted both to the publishers and
to Dr. Coulter for permission to use these figures of characteristic
morphological and reproductive features of plant life. Figs. 111
and 112 are reproductions in slightly modified form from Minot’s
The Problem of Age, Growth and Death, by permission of the pub-
lishers, Messrs. G. P. Putnam’s Sons. For other figures which are
not original acknowledgment is made in the legends, and since it
is often highly desirable to know, not only the author of a particular
figure, but the publication in which it originally appeared, a refer-
ence number, as well as the author’s name, is given and the full

PREFACE vii

reference is included in the list at the end of the chapter in which
the figure appears.

For permission to cite unpublished data I am indebted to
Dr. S. Tashiro, of the Department of Biochemistry, to Miss L. H.
Hyman, of the Department of Zodlogy, and to Mr. M. M. Wells,
formerly of the Department of Zodlogy, of the University of Chicago.
For the redrawing of all figures from other authors and for a num-
ber of original drawings from preparations I am indebted to Mr.
Kenji Toda, the artist of the Department of Zodlogy, and I wish to
express my appreciation of his work. For the reading of parts of
the manuscript and proofs and for various suggestions and criti-
cisms my thanks are due to my colleagues, Dr. A. P. Mathews
and Dr. C. J. Herrick. To my wife, Lydia Van Meter Child, I
am deeply indebted for her unfailing co-operation and assistance
in the preparation of the manuscript and proofs. And, lastly, I
wish to express my appreciation of the manner in which the Uni-
versity of Chicago Press has done its part as publisher.

C. M. Cuitp

Hutt Zo6tocicat LABORATORY
UNIVERSITY OF CHICAGO
May, 1915

TABLE OF CONTENTS

INTRODUCTION .

CHAPTER

I.

II.

PART I. THE PROBLEM OF ORGANIC CONSTITUTION

VARIOUS THEORIES OF THE ORGANISM

Neo-vitalistic Theory; Corpuscular Theories; Chemical Theory;
Physico-chemical Theory; The Colloid Substratum of the Organism;
The Relation between Structure and Function; References.

Tue LIFE CYCLE

Growth and Reduction: Definitions of Growth and Reduction, The
Nature of Growth and Reduction; Differentiation and Dedifferentia-
tion: Differentiation, Dedifferentiation; The Basis of Senescence and
Rejuvenescence; References.

Pace

34

PART II. AN EXPERIMENTAL STUDY OF PHYSIOLOGICAL SENES-

III.

IV.

VI.

CENCE AND REJUVENESCENCE IN THE LOWER ANIMALS

THE PROBLEM AND METHODS OF INVESTIGATION

The Nature of the Problem; Susceptibility in Relation to Rate of Metab-
olism; The Direct Method; The Indirect Method; Other Methods;

References.

AGE DIFFERENCES IN SUSCEPTIBILITY IN THE LOWER ANIMALS .

The Experimental Material; Age Differences in Susceptibilty in Pla-
naria maculata; Age Differences in Susceptibility in Planaria
dorotocephala; Age Differences in Susceptibility in Other Forms;
Conclusion; References.

THE RECONSTITUTION OF ISOLATED PIECES IN RELATION TO RE-
JUVENESCENCE IN Planaria AND OTHER ForMs .

The Reconstitution of Pieces in Planaria; Changes in Susceptibility
during the Reconstitution of Pieces; The Increase in Susceptibility in
Relation to the Degree of Reconstitution; The Susceptibility of Ani-
mals Resulting from Experimental Reproduction and Sexually Pro-
duced Animals; Repeated Reconstitution; References.

THE RELATION BETWEEN AGAMIC REPRODUCTION AND REJU-
VENESCENCE IN THE LOWER ANIMALS .

The Process of Agamic Reproduction in Planaria dorotocephala and Re-
lated Forms; The Occurrence of Rejuvenescence in Agamic Reproduc-
tion in Planaria dorotocephala and P. maculata; Agamic Reproduction
and Rejuvenescence in P. velata; Agamic Reproduction and Re-
juvenescence in Stenostomum and Certain Annelids; The Relation be-
tween Agamic Reproduction and Rejuvenescence in Protozoa; Agamic
Reproduction and Rejuvenescence in Coelenterates; References.

ix

63

g2

103

I22

x

CHAPTER

VI.

VIII.

TABLE OF CONTENTS

THE ROLE OF NUTRITION IN SENESCENCE AND REJUVENESCENCE
in Planaria

Reduction by Starvation in Planaria; Changes in Susceptibility during
Starvation in P. dorotocephala and P. velata; The Production
of Carbon Dioxide by Starved Animals; The Rate of Decrease
in Size during Starvation; The Capacity of Starved Animals for Accli-
mation; Partial Starvation in Relation to Senescence; The Character
of Nutrition in Relation to the Age Cycle; References.

SENESCENCE AND REJUVENESCENCE IN THE LIGHT OF THE PRE-
CEDING EXPERIMENTS

Review and Analysis of the Experimental Data; The Nature of Senes-
cence and Rejuvenescence; Periodicity in Organisms in Relation to
the Age Cycle; Senescence and Rejuvenescence in Evolution;
References.

PAGE

155

178

PART III. INDIVIDUATION AND REPRODUCTION IN RELATION TO

Ix.

XI.

XII.

THE AGE CYCLE

INDIVIDUATION AND REPRODUCTION IN ORGANISMS .

The Problem; The Axial Gradient; Dominance and Subordination of
Parts in Relation to the Axial Gradients; The Nature and Limits of
Dominance; Degrees of Individuation; Physiological Isolation and
Agamic Reproduction; References.

Tue AGE CYCLE IN PLANTS AND THE LOWER ANIMALS

Individuation and Agamic Reproduction in the Life Cycle of Plants;
The Vegetative Life of Plants in Relation to Senescence; The Occur-
rence of Dedifferentiation and Rejuvenescence in Plant Cells; The Rela-
tion of the Different Forms of Agamic Reproduction in Plants to the
Age Cycle; Individuation, Agamic Reproduction, and the Age Cycle
in the Lower Animals; Senescence as a Condition of Reproduction and
Rejuvenescence; Conclusion; References.

SENESCENCE IN THE HIGHER ANIMALS AND MAN

Individuation and Reproduction in the Higher Forms in Relation to
the Age Cycle; The Process of Senescence in the Higher Forms; The
Rate of Metabolism; The Rate of Growth; Nutrition, Growth, and
Senescence; Changes in Water-Content and Chemical Constitution;
The Morphological Changes; Conclusion; References.

REJUVENESCENCE AND DEATH IN THE HIGHER ANIMALS AND MAN

Rejuvenescence in the Life History; Length of Life and Death from
Old Age; Some Theories of Length of Life; Conclusion; References.

199

237

266

203

CHAPTER

XII.

XIV.

XV.

XVI.

XVII.

INDEX .

TABLE OF CONTENTS

PART IV. GAMETIC REPRODUCTION IN RELATION
TO THE AGE CYCLE

ORIGIN AND MORPHOLOGICAL AND PHYSIOLOGICAL CONDITION
OF THE GAMETES IN PLANTS AND ANIMALS

The Theoretical Significance of Gametic Origin; The Origin of the
Gametes in Plants; The Origin of the Gametes in Animals; The Mor-
phological Condition of the Gametes; The Physiological Condition of
the Gametes; The Significance of Maturation; Conclusion; Refer-
ences.

CONDITIONS OF GAMETE FORMATION IN PLANTS AND ANIMALS

Conditions of Gamete Formation in the Algae and Fungi; Conditions of
Gamete Formation in Mosses and Ferns; Conditions of Gamete Forma-
tion in the Seed Plants; Conditions of Conjugation in the Protozoa;
Conditions of Gamete Formation in the Multicellular Animals;
Parthenogenesis and Zygogenesis; Conclusion; References.

REJUVENESCENCE IN EMBRYONIC AND LARVAL DEVELOPMENT

The Effect of Fertilization; Parthenogenesis; The Experimental Ini-
tiation of Development; Oxygen Consumption and Heat Production
during Early Stages of Development; Changes in Susceptibility dur-
ing Early Stages; The Morphological Changes during Early Develop-
ment; Larval Stages and Metamorphosis; Embryonic Development in
Plants; The Degree of Rejuvenescence in Gametic and Agamic Repro-
duction; Conclusion; References.

PART V. THEORETICAL AND CRITICAL

Some THEORIES OF SENESCENCE AND REJUVENESCENCE

Senescence as a Special or Incidental Feature of Life; Senescence as a
Result of Organic Constitution; The Conception of Growth as an Auto-
catalytic Reaction and the Resulting Theory of Senescence; Refer-
ences.

Somez GENERAL CONCLUSIONS AND THEIR SIGNIFICANCE FOR
BIOLOGICAL PROBLEMS

364

403

433

459

469

INTRODUCTION

The succession of generations and the repetition of the life cycle
in the individual are the two great facts about which biological
thought centers. The problems of reproduction, growth, develop-
ment, inheritance, and evolution, as well as many other special
problems, are concerned with one aspect or another of these funda-
mental characteristics of life. Life as we know it exists only in the
form of individuals of various degrees and kinds which pass through
a definite series of changes and give rise to other individuals, and
these in turn repeat the process more or less exactly.

At the beginning of a new generation the size of the organism is
usually only a fraction of that to which it finally attains. Various
substances are taken up by the organism as food and transformed
in part into the energy of its activity and in part into the material
substratum in which the dynamic activities occur. Under the
usual conditions this material substratum which constitutes the
visible organism increases in amount or grows during a large part
of the life of the organism.

In all except perhaps the very simplest organisms another series
of changes occurs which we call morphogenesis or differentiation.
Localized differences in constitution, form, or structure appear,
and we say that the organism undergoes differentiation. Under
natural conditions this process of differentiation is very commonly
associated with growth, but the fact that it may occur in the com-
plete absence of growth shows that the association is by no means
a necessary one.

Sooner or later and in one way or another the organism gives
rise to one or more new organisms, which like their parent are at
first relatively small and simple, and like it also undergo a process
of growth and differentiation. This is reproduction. In some of
the simpler forms of reproduction the parent organism divides
into two or more parts which constitute the new generation, and
there is nothing which corresponds to death in the usual sense.
The old individuality is replaced by new individualities, but nothing

I

2 SENESCENCE AND REJUVENESCENCE

is left behind. In such cases there is, as Weismann has aptly put
it, no death because there is no corpse.

We see, however, that in certain other forms of reproduction, as
in various types of sporulation in plants and budding in lower
animals, and in sexual reproduction also if we take the facts at
their face value without reference to the germ-plasm theory, only
a circumscribed part of the parent organism is directly involved in
reproduction. In such cases the parent organism either remains
alive for a longer or shorter time, perhaps with periodic or con-
tinuous reproduction, or it dies almost at once. In short, death
of the non-reproductive or somatic parts of the organism is ap-
parently the final result in at least most of these cases.

In the higher animals which reproduce only sexually, and in at
least many of the higher plants, certain physiological and morpho-
logical changes accompany growth and development of the somatic
parts. The rate of growth decreases, in many cases irritability
and the rate of metabolism have also been found to decrease, a
relative and later an absolute decrease in the percentage of water
occurs, the structural elements become less plastic and in some
cases undergo more or less atrophy in later stages, and the organism
in general appears to be gradually losing its vigor. In many plants
these changes occur rapidly in certain parts and may be long, perhaps
indefinitely, delayed in others, and it will be shown in Part III
that the same is true for many of the lower animals; but in the
higher animals the whole of the body is apparently involved, though
even here the facts indicate that these changes may occur more
rapidly in one part or another according to various conditions.

These changes, which constitute a gradual deterioration of the
organism, a gradual decrease in the intensity of its living, are com-
monly designated as aging or senescence. The question whether
certain changes are properly to be regarded as senescence or not
may often be raised with respect to particular cases, but in general
there can be no doubt that in at least many organisms a process
of senescence does occur: the organism grows old. Moreover,
there is no doubt that in at least many forms this process of senes-
cence leads to the cessation of the processes of life, i.e., to what
we call death.

INTRODUCTION 3

The occurrence of senescence in the organic world raises many
questions of great interest and importance, not only for the scientist,
but in certain aspects for the human race in general. How do young
and old organisms differ from each other, and what is the nature
of senescence? Is it a feature of the fundamental processes of life
or the result of incidental conditions? Does it occur in all organ-
isms or only in the more complex, more highly differentiated forms ?
Does it inevitably lead sooner or later to death, or is a rejuvenes-
cence of old organisms or parts possible? Is the process of senes-
cence in a given organism always of the same character, or does it
depend upon the environmental conditions? Is the rate of senes-
cence always the same in a particular species, or does it differ in
different individuals according to the action of internal or external
factors. Many of these questions can be summed up in the one,
Can we control senescence ?

In nature the organism resulting from the union of the two
sexual cells is young. This fact raises another series of questions.
Does rejuvenescence occur somewhere in the course of sexual re-
production, or does the germ plasm from which the sex cells arise
not grow old? Are the organisms which result from asexual re-
production also young, or is sexual reproduction the only process
which gives rise to young organisms? If rejuvenescence occurs,
upon what does its occurrence depend and what is its nature?
Does it occur in all organisms, or only in certain of them? Is com-
plete rejuvenescence possible, or is the species and the organic world
in general undergoing a senescence which will lead to extinction ?

These are a few of the most important questions which the
occurrence of senescence and the processes of reproduction lead us
to ask. In the following chapters these and some other questions
will be considered in the light of the experimental and observational
evidence which we possess. To some of these questions we shall
be able to give a definite answer, to some others the answer must
be provisional, and some we must leave open for the future to
answer, though even here we can indicate the direction in which
the facts point.

The problem of senescence has been discussed many times in
the history of biology, and many hypotheses as to its nature have

4 SENESCENCE AND REJUVENESCENCE

been elaborated. Unfortunately by far the greater part of the
work along this line has dealt chiefly with the process of senescence
as it appears in man and the higher mammals. Only now and
then has an attempt been made even to formulate a general theory
of senescence, and analytic investigation of senescence in the
lower organisms has scarcely been attempted. This limitation in
the investigation of the problem of senescence is due to the fact
that in the past interest in the problem has been very largely con-
fined to the medical profession.

It is of course true that we are most familiar with the phenomena
of senescence in man and other mammals, the most complex of all
organisms. But man is a member of the organic world and a prod-
uct of evolution, and, as we have traced the development of his
structure from lower forms, so we must look to the lower forms for
adequate knowledge of his physiological processes. Before we
can understand senescence in man we must determine what it is in
its simplest terms.

The present book finds its chief reason for existence in the fact
that it has been possible with the aid of certain experimental
methods of investigation to obtain some definite knowledge con-
cerning the processes of senescence and rejuvenescence in the lower
animals. The facts discovered afford, as I believe, a basis for the
further investigation of senescence and rejuvenescence in general,
and for an analytic consideration and interpretation of various
phenomena in plants and animals which are more or less closely
associated with these processes. Since the most important result
of these investigations is, in my opinion, the demonstration of the
occurrence of rejuvenescence quite independently of sexual repro-
duction, the book differs to some extent from most previous
studies of senescence in that it attempts to show that in the
organic world in general rejuvenescence is just as fundamental
and important a process as senescence. In the higher forms
the possibilities of rejuvenescence are apparently very narrowly
limited, but in the simpler organisms it is a characteristic feature
of life, and the nature of the process here enables us to under-
stand more clearly certain changes which occur in the higher
forms.

INTRODUCTION 5

My investigation of senescence and rejuvenescence has been
closely connected with an attempt to determine the physiological
nature of the reproductive processes in organisms, and I believe
that some such conception of senescence and rejuvenescence as
that presented here is essential for the physiological analysis of
reproduction, since senescence, reproduction, and rejuvenescence
are very closely connected. But while some discussion of the
nature of various reproductive processes will be necessary in the
course of the present study, a full consideration of the problem of
reproduction is postponed to another time.

Our conception of the nature of these various processes, growth,
differentiation, senescence, reproduction, and rejuvenescence, must
depend upon our conception of the organism. It seems necessary,
therefore, to consider briefly in certain of its aspects the problem
of the constitution of the organism by way of clearing the ground
for consideration of the particular features of organic constitution
which form the subject of the book.

PART I

THE PROBLEM OF ORGANIC CONSTITUTION

CHAPTER I
VARIOUS THEORIES OF THE ORGANISM
NEO-VITALISTIC THEORY

To the primitive man all the phenomena of nature were de-
termined and controlled by some agent or agents essentially similar
to himself, but as his knowledge of the world increased, the con-
trast between living and non-living things forced itself upon him
and the idea of a special vital principle of some sort arose. In the
mind of different thinkers this principle has taken various forms,
and the attempt has been made again and again in the history of
thought to show that some such principle is absolutely indispen-
sable for any adequate conception of life. A century ago the idea
of vital force dominated biological thought.

Within recent years the same idea has reappeared in a somewhat
changed though not essentially different form. Particularly in
Germany a group of investigators has arisen who believe that they
have found new evidence in the facts of experimental biology for
the existence of a vital principle. The chief exponent of these ideas
is Driesch (’08) who has developed the Aristotelian idea of entele-
chies in a somewhat modified form. The entelechy is something
which acts in a purposive way and constructs the organism for a
definite end and controls its functioning after it is constructed.
The physico-chemical processes are simply means to the end.

Since the neo-vitalistic hypotheses profess to find their founda-
tion to a greater or less extent in the facts of experimental biological
investigation, they have a claim on the attention of biologists which
purely speculative hypotheses do not have. Buta critical examina-
tion of the works of Driesch and other neo-vitalists discloses the
fact that their hypotheses actually rest, not upon facts, but upon
certain undemonstrated and at present undemonstrable assump-
tions. Driesch’s so-called ‘‘proofs of the autonomy of vital pro-
cesses’’ are not proofs at all, because each of them involves in one
way or another the assumption of what it is supposed to prove. At
present it is as impossible to prove as to disprove the existence of a

9

Io SENESCENCE AND REJUVENESCENCE

vital principle, because our knowledge of the organism is insufficient.
Only when we have exhausted physico-chemical possibilities and
found them to be inadequate shall we be justified in searching else-
where for the basis of life.

But there is one point of particular interest in connection with
the neo-vitalistic hypotheses. They are a logical consequence of
the corpuscular theories of heredity and organic constitution and
development, such as the theory of Weismann. These theories
were widely current at the time when the neo-vitalistic school
arose. They themselves are fundamentally “vitalistic” in char-
acter, whatever their assertions to the contrary. An orderly pro-
gressive development of a definite character is inconceivable in an
organism composed of a very large number of independent ultimate
units each capable of growth and reproduction, except under the
influence of some controlling and directing principle distinct from
the ultimate units themselves. If such theories represent the last
word of science concerning the physico-chemical constitution of
the organism, then we must all be vitalists, whether we admit it
ornot. But if the controlling and determining principle, entelechy
or whatever we choose to call it, is indispensable, why must we
complicate matters by assuming the existence of a multitude of
discrete ultimate units of one kind or another? Why not give the
entelechy a task worthy of it and assume that all parts of the organ-
ism are essentially alike and equipotential? This is practically
what Driesch has done. The entelechy determines localization
and development and uses physico-chemical processes to effect its
ends.

The trend of biological thought has undergone change during
the past twenty years. The development of experimental methods
on the one hand and the development of the physical sciences on
the other have contributed to alter our conception of the organism
and today there is less basis for vitalistic theory than ever before.
Even the theory of Weismann and other morphological theories of
the organism are giving place to theories of a different type, and
while many other attempts will undoubtedly be made in future to
demonstrate the indispensability of some sort of vital principle,
the analysis and synthesis of science, proceeding step by step, test-

VARIOUS THEORIES OF THE ORGANISM II

ing and retesting the supposed facts, adopting and discarding hy-
potheses, will continue to be the basis of our advance in knowledge.

CORPUSCULAR THEORIES

During the latter half of the nineteenth century, biology, and
particularly zodlogy, was to a large extent dominated by the cor-
puscular theories of heredity and organic constitution. These
theories postulate some sort of a material particle or corpuscle
consisting of more than one molecule as the ultimate basis of life.
The organism is built up in one way or another from a number,
often very large, of such corpuscles, and the corpuscles are the
“bearers of heredity.” The gemmules of Darwin, the pangenes
of DeVries, the physiological units of Spencer, the biophores and
determinants of Weismann, and various other hypothetical units
have played an important part in biological thought during almost
half a century.

This group of theories may be called the morphological or
static group. They all postulate a complex morphological struc-
ture as the basis of inheritance and development, and they are all
attempts to answer the question as to how the characteristics of
the species are maintained from one generation to another. Among
them the theory of Weismann has been more completely developed
and has influenced biological thought and investigation to a greater
extent than any other.

All of these theories possess certain characteristic features in
common. The ultimate elements, whatever they may be called,
are not alike, but each possesses certain definite characteristics and
plays a definite part in the development of the individual. The
organism is in short essentially a colony of such units. According
to Weismann, DeVries, and others, the ultimate units are each
capable of growth, and each reproduces its own kind.

It is scarcely necessary to call attention to the fact that these
theories do not help us in any way to solve any of the fundamental
problems of biology; they merely serve to place these problems.
beyond the reach of scientific investigation. The hypothetical
units are themselves organisms with all the essential characteristics
of the organisms that we know; they possess a definite constitution,

12 SENESCENCE AND REJUVENESCENCE

they grow at the expense of nutritive material, they reproduce
their kind. In other words, the problems of development, growth,
reproduction, and inheritance exist for each of them and the assump-
tion of their existence brings us not a step nearer the solution of
any of these problems. These theories are nothing more nor less
than translations of the phenomena of life as we know them into
terms of the activity of multitudes of invisible hypothetical or-
ganisms, and therefore contribute nothing in the way of real ad-
vance. No valid evidence for the existence of these units exists,
but if their existence were to be demonstrated we might well
despair of gaining any actual knowledge of life.

But these theories possess another fundamental defect in that
they do not provide any adequate mechanism for the control
-and co-ordination or dominance and subordination of the activity
of the ultimate units. It is absolutely inconceivable that a mul-
titude of these units, such as is assumed to constitute the basis
of the cell or the organism, should always in a given species
arrange themselves in a perfectly definite manner so as to pro-
duce always essentially the same total result. In other words,
these theories do not account satisfactorily for the peculiarly con-
stant course and character of development and morphogenesis.
If we follow them to their logical conclusion, which their authors
have not done, we find ourselves forced to assume the existence of
some sort of controlling and co-ordinating principle outside the
units themselves, and superior to them. If the units constitute the
physico-chemical basis of life, as their authors maintain, then this
controlling principle, since it is an essential feature of life, must of
necessity be something which is not physico-chemical in nature.
In short, these theories lead us in the final analysis to the same
conclusion as that reached by the neo-vitalists. If we are not
content to accept this conclusion we must reject the theories.

The development within recent years of the experimental
method of investigation and the consequent approach of mor-
phology and physiology toward a common ground have accom-
plished much in inducing biologists to turn their attention in other
directions for interpretation and synthesis of the facts. But the
Weismannian germ plasm as an entity distinct from the soma and

VARIOUS THEORIES OF THE ORGANISM 13

governed by different laws still plays no small part in interpretation
and speculation, and we have heard much of unit characters within
the last few years. The chromosomes and their hypothetical
constituent elements still serve their purpose as safe repositories
of unsolved problems, and doubtless will long continue to do so.
And in Rignano’s theory of centro-epigenesis (’06) we have a cor-
puscular theory in a new dress, but still with the same characteristic
features.

But all of these theories and conceptions bear the stamp of the
study rather than of the laboratory. Many of them show great
ingenuity, but they all fail to show us how the things are done that
they assume to be done: they ignore almost entirely the dynamic
side of life. At present we can neither prove nor disprove them,
for they are entirely beyond the reach of science. No facts can-
overthrow them, for it is always possible to make the hypothetical
units behave as the facts demand. But we can at least look in
other directions for a more satisfactory basis for interpretation of
the facts of observation and experiment and for guidance in our
thinking.

CHEMICAL THEORY

The synthesis in the laboratory of organic substances which
began in 1828 with the synthesis of urea by Wohler led to the
overthrow of the doctrine of vital force current before that time.
The formulation of the law of conservation of energy by Robert
Mayer, its establishment by Helmholtz, and its application to
organisms by both of these investigators as well as by others, con-
tributed still further to the belief that the dynamic processes in
organisms, instead of being unique and governed by special laws,
are not fundamentally different from those which occur inde-
pendently of life. And, finally, the acceptance of the theory of
evolution gave a breadth of outlook never before attained, in that
it permitted us not only to regard the organic world as one great
whole, but also afforded a firm foundation for the belief that the
living must have arisen from the lifeless and that the fundamental
laws governing both are the same.

With the attainment of this point of view the problem of the
nature of the processes in the living organism was fully established

14 SENESCENCE AND REJUVENESCENCE

as a scientific problem. And since it was evident that chemical
reactions play a very large part in life processes it became essen-
tially a chemical problem. From this time on our knowledge of
the chemistry of organisms increased rapidly, and certain investi-
gators have been so sanguine as to believe that we were on the
threshold of the synthesis in the laboratory of living matter. Dur-
ing the same period the visible structural basis of life was being
studied under the microscope. In 1837-39 the cell theory was
formulated by Schleiden and Schwann, and in the half-century
following the problems of cellular and protoplasmic structure
claimed the attention of biologists to a large extent.

These investigations soon made it evident that life is closely
associated in some way with the substances which we call proteids.
These are found in all organisms and so far as we know nowhere
else. Excepting water, they are the chief constituent of the visible
substance characteristic of organisms, i.e., protoplasm. It was also
demonstrated that life is associated with a complex of chemical
activities. Certain substances are taken up by the organism and
others are eliminated. Between ingestion and elimination a com-
plex series of chemical reactions was found to occur, and the whole
process was called metabolism.

The conception of the metabolic process and its relation to
protoplasm, which was most widely accepted during this period of
chemical and morphological investigation in the latter half of the
nineteenth century, was that metabolism consisted fundamentally
of two parts. Of these one, the anabolic or assimilative process,
was in its essential features the recombination and synthesis of the
nutritive substances into extremely complex proteid molecules
which constituted the “living substance.” These proteid mole-
cules were regarded as highly labile chemically, or “‘explosive,’’ so
that they were able to respond to stimulation of various kinds by
decomposition and the very rapid liberation of energy. The various
steps in the decomposition of these living proteid molecules consti-
tuted the process of katabolism or dissimilation. Investigation
showed that the molecular weight of the proteids was in general
very high, and this was believed to indicate very great complexity
of the molecules. The highly unstable or labile character of the

VARIOUS THEORIES OF THE ORGANISM 15

living proteid was believed to be connected with its great com-
plexity. Of course many differences of opinion existed with respect
to the details of the process, but the essential feature of this con-
ception of the organism is that life consists in the building up and
the breaking down of proteid molecules. The energy developed
by living forms is the energy contained in these molecules.

The necessity for the distinction between living and dead proteid
was pointed out by Pfliiger (’75), and in later years Verworn (’03)
has developed the idea further in his ‘‘ biogene hypothesis,”’ of which
the essential feature is that certain complex labile proteid mole-
cules are the biogenes, the ‘‘producers of life.’”” These molecules
are not necessarily entirely decomposed in metabolism, but the
source of energy probably lies in certain chemical groups which
break down and are replaced by synthesis from the nutritive sub-
stances. According to this hypothesis the dynamic processes in
the organism are connected with the breakdown and synthesis of
these labile molecules. The molecule is not itself ‘‘alive,” but its
constitution is the basis of life and life results from the chemical
transformations which its lability makes possible. The “living
substance” is then not a substance of uniform definite molecular
constitution: such a substance would not be alive. It is rather a
substance in which some of the labile molecules are continually
undergoing transformation, i.e., life itself consists in chemical
change, not in chemical constitution.

This theory of the organism leaves us very much in the dark on
many points. In the first place, most of the proteids as we know
them in the laboratory are relatively stable and inert chemically
and show no traces of the extreme lability or explosiveness which
the theory postulates as their most important characteristic in the
living organism. This difficulty was solved theoretically by assum-
ing that the lability is a property of living proteids only and dis-
appears with death. Death in fact was regarded as resulting from
this change from lability to stability. The proteids im vitro are
of course dead proteids, therefore we should not expect to find them
possessing the property of lability. This assumed distinction be-
tween living and dead substance has the further disadvantage of
practically removing the “living substance’ from the field of

16 SENESCENCE AND REJUVENESCENCE

investigation, for as soon as we attempt to determine how it differs
from dead substance death occurs.

Moreover, if death results from change from extreme lability
to relatively high stability we should expect at least many of the
proteids of the body to undergo marked changes in appearance and
physical properties at the time of death. Some changes of this
sort, such as coagulation, do occur, but coagulation does not neces-
sarily involve chemical transformation, and in general the visible
changes in the proteids with death are not very great. Certainly
they are not as great as would be expected if such a profound
chemical change occurs.

If the energy of the organism is due to the explosive trans-
formation of highly labile molecules into more stable conditions
and if death also results from a more extreme change of the same
sort in the substance of the organism, we should expect to find a
very large amount of energy developed at the time of death. If
all the living substance changes into dead substance in the course
of a few moments or a few hours, or even a few days, what becomes
of the energy liberated? The amount of energy developed by such
a change would necessarily be greater than that resulting from the
most extreme stimulation which did not kill, for such stimulations
are supposed always to leave some part of the hypothetical living
substance intact. Such a liberation of energy could scarcely fail
. to produce profound changes of some sort, either mechanical,
electrical, or thermic, but death is not necessarily accompanied by
any energetic changes of such magnitude as might be expected to .
occur according to the hypothesis.

How, we must also ask, are we to account for growth on this
basis? What peculiar property of the living substance determines
not only that the molecules which break down shall again be built
up or replaced, but that other new molecules shall be added?
Various highly hypothetical answers have been given to this ques-
tion, but the fact remains that so far as we know no similar process
exists elsewhere in the world. The growth of crystals has often
been compared with that of organisms, but the resemblance is at
best only very remote, for growth in the organism is certainly closely
associated with chemical reaction of a complex character, while in
the crystal it results from a physical relation between like molecules.

VARIOUS THEORIES OF THE ORGANISM 17

The solution of the problem of differentiation has scarcely been
attempted. It is manifestly closely associated with the metabolic
process, but what is the origin and significance of the different
kinds of proteid substance and how is their localization at different
points of the organism accomplished? If the “‘labile’’ biogene
molecules all possess the same constitution, then they must undergo
different transformations in different parts of the organism; if
they differ in constitution in different parts we must find some
basis for the difference. It is an established fact that the basis of
differentiation exists within the organism and not in environmental
factors: it must then depend in some way upon the labile proteid
molecule which according to the hypothesis is the basis of life.
But it is difficult to understand how such molecules can serve as a
foundation for localization and differentiation.

If we accept this hypothesis we must after all conclude that the
processes in the living organism differ very widely from those in
the inorganic world, for nowhere except where there is life do we
find anything approaching in any degree the synthesis of so com-
plex and highly labile a substance as the living substance is assumed
to be. But even if we should ever succeed in producing in the
laboratory a proteid with the degree of lability postulated for the
living substance, it would be likely, in the absence of the delicate
mechanism regulating its transformation in the organism, to die
or “‘explode”’ at once.

From this point of view it is also difficult to account for the
capacity of organisms to continue alive when subjected to the
never-ceasing changes in the world about them. We should
scarcely expect such extremely delicate and sensitive mechanisms
as these highly labile molecules to withstand the shocks to which
organisms in nature are constantly subjected. The facts indicate
that organisms have existed continuously for millions of years and
during this time have given rise to inconceivable amounts of
“living substance.’’ How could such a labile substance ever have
persisted long enough in the first instance to form an organism ?

The only way in which we can account for these facts without
discarding the hypothesis of a highly labile living substance is by
the assumption that in some way a part of the energy liberated by
the breakdown of these labile molecules must serve for the synthesis

18 SENESCENCE AND REJUVENESCENCE

of new molecules from the nutritive substances. In other words,
the living substance once produced is self-perpetuating, at least
within a very wide range of external conditions. But if the ability
to perpetuate itself in this way is a property of the living substance,
then it is in this respect also very different from any other sub-
stance with which we are acquainted.

It appears then that when we analyze this hypothesis of a labile
proteid substance which gives rise to the manifestations of life by
its chemical transformations we find that it does not help us to
any great extent in bridging the gap between the organism and the
inorganic world. The self-perpetuating substance or substances
which constitute the basis of life remain unique in character.
They are highly labile, yet persist under a great variety of con-
ditions, and “‘die”’ in most cases without the liberation of any very
great amount of energy. During life they regulate their own
chemical changes in some way, they determine the formation of
new molecules like themselves, and they are responsible somehow
for an orderly sequence of differentiation of parts of the organism.
Evidently they are very different from other chemical substances,
even highly labile ones, with which we are familiar.

The numerous difficulties which arise in connection with hy-
potheses of this character must at least raise the question whether
the point of view on which they are based is fundamentally correct.
Is life at bottom simply a complex of chemical reactions or is there
some other factor involved which the hypothesis of a labile mole-
cule as the basis of life fails to take into account? In the following
sections an attempt is made to answer this question.

PHYSICO-CHEMICAL THEORY

A few years ago the existence of a living substance as a more or
less definite chemical compound was very generally accepted, and
only rarely were criticisms and questionings heard."

« See for example A. P. Mathews, ’99, ’05; Driesch, ’o1 (pp. 140-52). Mathews
pointed out that living matter must be a mixture of many substances among which
various chemical reactions occur. Driesch denies very positively the existence of a
definite living substance, but for him this is merely one point in the argument for the
autonomy of vital processes.

VARIOUS THEORIES OF THE ORGANISM 19

In his book on the physical chemistry of the cell and tissues,
Hober (’11, pp. 553-55) asserts that we have absolutely no grounds
for believing that the metabolic process is based on the lability of a
complex organic component of the protoplasm. When we attempt
to solve the problems of metabolism with the aid of this hypothetical
labile molecule, we find ourselves in a cul de sac from which the
only possible way out is retreat. According to Héber, and most
authorities now agree with him, there is no kind of proteid essen-
tially different from that with which we are familiar in the labora-
tory. If proteids are readily broken up in the organism, it is not
because in some way they have acquired a peculiar property of
lability which they do not possess elsewhere, but for very different
reasons; the conditions in the organism are different from those in
the test-tube. Héber maintains that the fundamental charac-
teristic of the process of metabolism is to be found in the combined
and correlated activity of certain definite substances in certain
definite quantitative relations.

This conception of metabolism has gained ground rapidly of
late and for various reasons. In the first place, evidence in its
favor has been rapidly accumulating, and there is not a shred of
experimental evidence in support of the labile molecule hypothesis.
It is all the time becoming more evident that life does not consist
in any one process nor depend on a particular kind of molecule,
but that it is the result of many processes occurring under con-
ditions of a certain kind and influencing each other. Moreover,
such a conception has a logical advantage over the hypothesis of
the labile molecule in that it does not involve assumptions which .
are outside the range of scientific investigation and which we can
therefore never hope to prove or disprove.

If we accept this idea we must abandon the assumption of a
living substance in the sense of a definite chemical compound.
Life is a complex of dynamic processes occurring in a certain field
or substratum. Protoplasm, instead of being a peculiar living sub-
stance with a peculiar complex morphological structure necessary
for life, is on the one hand a colloid product of the chemical reac-
tions, and on the other a substratum in which the reactions occur
and which influences their course and character both physically and

20 SENESCENCE AND REJUVENESCENCE

chemically. In short, the organism is a physico-chemical system
of a certain kind.

One point should perhaps be emphasized. The importance of
the proteids for life is no less according to this theory than on the
assumption of the labile proteid molecule. But the proteids are
physical as well as purely chemical factors in the result. We know
also that metabolism is not simply a process of building up and
breaking down of proteids, and that the proteids of the protoplasm
are only one of the products of the reaction-complex and may or
may not play an important chemical réle after their formation.
Since the investigations of recent years point more and more clearly
to some such physico-chemical conception of the organism as
this as the only satisfactory working hypothesis, it is necessary
to consider certain features of the organism in the light of
this conception.

THE COLLOID SUBSTRATUM OF THE ORGANISM

The classical investigations of Kossel and Emil Fischer have
established a firm foundation for the belief that the complexity of
the proteid molecule is not as great as was formerly believed. The
proteids are apparently built up from certain relatively simple
chemical compounds, the amino-acids and their derivatives, to-
gether with certain other substances, and the proteid molecule,
though very large, apparently consists essentially of a number of
these components linked together. Of course such a constitution
affords the possibility of a very great variety of chemical reactions,
but it does not afford a basis for the assumption of extreme lability
in the proteids of the living organism. On the contrary the results
of chemical as well as of morphological investigation indicate that
at least many of the proteids are relatively stable in the living
organism as well as in the test-tube.

The proteids exist in the colloid condition. Graham (’61)
distinguished two groups of substances, the colloids and crystal-
loids, and although we now know that no sharp distinction exists
between the two groups and that any substance may, at least
theoretically, exist in the colloid condition, certain substances
usually appear as colloids and others as crystalloids. In general

VARIOUS THEORIES OF THE ORGANISM aI

the more complex the constitution of a substance the more likely
it is to exist in the colloid condition.

The colloids are disperse heterogeneous systems, i.e., they
consist essentially of particles larger than molecules of a substance
or substances in a medium of dispersion which may be water or
some other fluid. In the colloid solution, or “sol,” the particles
are suspended and separated from each other by the medium,
while in the coagulated condition, or ‘‘gel,’”’ they are more or less
aggregated. As regards the size of the particles, the colloid may
range from a suspension or emulsion in which the particles are
visible to the naked eye to the molecular true solution at the oppo-
site extreme. The colloids are usually divided into two groups,
the suspensoids, in which the particles are solid, and the emul-
soids, in which they are fluid or, more properly, contain a high per-
centage of fluid.

The suspensoids are comparatively unstable as regards the
colloid condition, are readily precipitated or coagulated by salts,
carry a constant electric charge of definite sign, are not viscous,
usually do not swell, do not show a lower surface tension than the
pure medium of dispersion, and are mostly only slightly reversible.

The emulsoids, however, are comparatively stable as colloids,
less readily coagulated by salts, may become either positively or
negatively charged, are usually viscous and possess a lower surface
tension than the medium of dispersion, form membranes at their
limiting surfaces, and are reversible to a high degree."

Most of the organic colloids together with some other sub-
stances belong to the second group, the emulsoids, and it is demon-
strated beyond a doubt that many of the characteristic features of
living organisms are due to the presence of a substratum composed
of these colloids. The viscosity, the reversible changes in aggre-
gate condition through all gradations from sol to gel and back
again, the ability to take up water and swell, and the formation of
membranes as well as the other properties are of great significance

t Books on colloids are rapidly becoming numerous. See for example Freund-
lich, ’09, and Wolfgang Ostwald, ’r2, as general works on the subject. Bechhold,
*12, Hober, ’11, and Zanger, ’o8, consider the significance of the colloids for the living
organism.

22 SENESCENCE AND REJUVENESCENCE

for the phenomena of life. The organic colloids are chiefly proteid
or fatty in nature, and the present state of our knowledge indicates
that the properties of these substances as colloids are no less im-
portant for the living organism than their chemical constitution.

In every living organism known to us the chemical processes
of metabolism take place in a complex colloid field or substratum,
and many of the peculiarities of the metabolic processes are unques-
tionably due to this fact. Within recent years the significance of
colloids for the phenomena of life has been pointed out again and
again. Bechhold in his recent book (’12) goes so far as to assert
that life is inconceivable except in a colloid system. Doubtless
“colloid chemistry” is at present the fashion, but it is also true that
this fashion has a certain justification. The study of the behavior
and properties of colloids has thrown new light, not only on many
problems of chemistry and physics, but on many problems of biology
as well. Attention may briefly be called to a few of these biological
problems.

The problems of localization and morphogenesis assume a new
form in the light of our knowledge of colloids. In the course of
development of the organism certain processes become localized
at certain points and morphological structure and differentiation
result. The visible basis of morphogenesis is the protoplasm, and
in it the structural features arise. The definiteness and persistence
of organic structure in a substance like protoplasm which presents
all conditions between a concentrated and a very dilute gel or a sol
has always presented many difficulties, and the problem is at
present by no means solved. The attempt has been made repeat-
edly to find in the process of crystallization and the definiteness of
form in the crystal a basis for organic form and structure, but with-
out any very satisfactory results. The resemblance between the
physical process of crystallization in a substance of uniform consti-
tution and the development of form and structure in connection
with chemical reaction in the complex organism is certainly not
very close.

Under proper conditions it is possible to produce more or less
definite forms by means of chemical reaction, but in all such cases
we find that the form is not directly dependent upon the reaction

VARIOUS THEORIES OF THE ORGANISM 23

but upon particular osmotic or other physical conditions which are
present in the experiment. Structures so produced are often
evanescent and disappear as the conditions in the medium change,
for the chemical processes do not remain localized in the ordinary
media of chemical reaction, though where the substance of the
structure is insoluble they may persist.

Within recent years it has been shown that the production of
form and structure in connection with chemical reaction is much
more readily accomplished when the reaction occurs in the presence
of colloids. The colloids in such cases are not necessarily involved
in the chemical reaction in any way, but act primarily as a physical
substratum in which the reaction occurs. By altering the course
and rate of diffusion they serve to establish or maintain differences
of concentration; in consequence of the great amount of surface of
the colloid particles adsorption may play an important part, and
the formation of membranes may also affect the course of the re-
action. The effect of the colloid as a localizing factor, as a means
of producing form and structure, is greater in the gel than in the
sol state of aggregation.”

Many have not been slow to call attention to the resemblance
between form and structure thus produced and organic form and
structure, and more or less adventurous hypotheses of the nature
of life have been one result of such researches. On the other hand,
many biologists have been inclined to regard experimentation of
this sort as of little value for the problem of morphogenesis, but
this attitude seems to arise in part from a misconception. The most
important point in connection with such experiments is not the
resemblance between .the forms and structures produced and those
of living organisms. Actually of course the resemblances are in
many cases very remote and superficial and of minor importance.
But the fact that morphological form and structure can be made
to arise in such physico-chemical systems is of great importance
for biology, for it affords at least a basis for the scientific investiga-
tion and interpretation of morphogenesis in the organism. LEarlier
attempts to formulate theories of morphogenesis have consisted in

t Examples of investigation along this line are the work of Leduc, ’08, ’oga, ’o9b,
*ro; Liesegang, ’o9, ’11, ’14, and other earlier papers, and Kiister, ’13.

24 SENESCENCE AND REJUVENESCENCE

most cases simply in the postulation of a complex invisible morpho-
logical structure of one kind or another as the basis of the visible
structure which develops; with such theories the problem of struc-
ture remains and is less accessible than before.

The experiments mentioned above demonstrate that such a com-
plex invisible structure is quite unnecessary as a basis for visible
morphogenesis. In the case of many of the artificial structures the
determining conditions are not at all complex and the process is
readily analyzed. It is certainly not too much to say that these
experiments in the production of form constitute a real and impor-
tant step toward the solution of the problem of organic morpho-
genesis. From them we can at least see the possibility and even
the probability of reducing the problem of structure to other and
simpler terms, that is to say, terms of dynamic processes, and that
must be reckoned as no slight advance.

But the colloid substratum in the organism is of importance in
many other ways. The capacity of many of the organic colloids
for taking up water is of very great importance in determining and
maintaining the water content of organisms. A certain water
content is indispensable for the normal activity of every organism
and every part. We know, moreover, that various inorganic
substances alter the capacity of colloids to take up or hold water
and evidence is rapidly accumulating that many normal and patho-
logical variations in water-content are at least in part determined
by changes in the colloids which in turn result from changes in the
content of certain inorganic salts and other substances.

The content and distribution of the salts themselves is also
influenced by the colloids. Changes in the colloids alter the salt-
content, as regards either amount or kind. The permeability of
colloid membranes to the ions of salts and other substances and the
changes which they undergo with changes in conditions is believed
by many to be of great importance for many of the processes of
life. Authorities are not fully agreed as to the part played by
colloid surface membranes in organisms. While the theory of semi-
permeable membranes and of changes in permeability has been
very widely accepted, there are some facts which indicate that
other factors besides membranes are concerned in the penetration

VARIOUS THEORIES OF THE ORGANISM 25

of substances, and that differences in the aggregate condition of
different parts are important factors in the process.

But even if membranes play the important part which the
membrane theory assigns to them, there is no general agreement as
to the nature of the conditions which determine permeability,
semi-permeability, and impermeability. Some maintain that these
properties of membranes depend upon their chemical constitution,
and that most substances to enter the cell must combine chemically
with the substance of the membrane. Others believe that the
entrance of substances into the cell is a matter of solubility in the
membrane-substance. According to the familiar theory of Overton
and Meyer, the chief constituents of the cell membrane are lipoids,
and the passage of at least many substances depends on their
solubility in these lipoids. There is, however, considerable evi-
dence against this view that lipoids are in all cases the chief or only
factors concerned. Still another hypothesis is that the selective
capacity of the membrane depends in one way or another upon
its colloid condition. It may well be that many different factors
are involved in the permeability of membranes in living organisms,
but it seems certain that whatever the nature of these factors may
prove to be, the peculiarities of the so-called living substance in
this respect are very closely connected with its colloid condition.
And when we recall the slight diffusibility of colloids through each
other, it becomes evident that the colloid condition of the sub-
stratum is an important factor in determining the accumulation
and localization of colloids themselves.

It has been shown that various inorganic colloids, such for
example as colloid platinum, resemble to some extent in their action
as catalyzers the enzymes or ferments of the organism. All the
known organic enzymes are apparently colloids, and while there is
still difference of opinion as to the nature of their action, yet the
resemblance between them and inorganic catalyzers is at least
highly suggestive.t We know that enzymes are absolutely essential
factors in the processes of life, and if enzyme action is in any way
associated with the, colloid condition the significance of this con-
dition for organic life will be still further demonstrated.

t See Bredig, ’o1; Hober, ’11, pp. 553-614.

26 SENESCENCE AND REJUVENESCENCE

The transmission of stimuli in living tissues is also very com-
monly regarded as dependent in some way upon the colloid con-
dition, although here again there are differences of opinion as to
the exact nature of the process.

Our knowledge of the colloids and particularly of the organic
colloids is far from complete; undoubtedly the future will clear up
many points which are now obscure, but even now it is clear that
the colloid substratum in which the chemical reactions of metab-
olism occur is an essential factor in making the phenomena of life
what they are. Bechhold (’12), referring to the possibility of life
on other planets, asserts that whatever the substances may be which
make up such organisms they must be colloids. In fact, the more
we know concerning colloids the less possible it becomes to con-
ceive of anything similar to what we regard as life apart from them.
Whatever else it may be, it seems certain that the organism is a
colloid system. From this point of view our definition of a living
organism must be somewhat as follows: A living organism is a
specific complex of dynamic changes occurring in a specific colloid
substratum which is itself a product of such changes and which
influences their course and character and is altered by them.

THE RELATION BETWEEN STRUCTURE AND FUNCTION

The definition of the organism given above leads us to very
definite conclusions concerning the relation between structure and
function.

The dynamic processes which occur in organisms do not and
cannot constitute life in the absence of the colloid substratum, nor
is the colloid substratum alive without the dynamic processes.
But since the colloids characteristic of the organism are among the
products of the dynamic processes, it is also evident that the pro-
cesses cannot go on in their entirety without producing the colloid
substratum. In other words, neither structure nor function is
conceivable except in relation to each other.

‘The beginning of life is to be sought neither in a particular
complex of chemical reactions nor in a special morphological struc-
ture. Both the reactions and the colloid substratum are necessary
for life. But since the substratum is formed in the course of the

VARIOUS THEORIES OF THE ORGANISM 27

reactions, it is evident that the association between the reaction-
complex and the substratum must continue as long as the reaction-
complex continues. It is probable that if we could duplicate the
reaction-complex in the laboratory it would be impossible to
designate any particular point in the process as the point where
life begins. Life is not any particular reaction nor any particular
substance, but a great system of processes and substances. Struc-
ture and function are then indissociable. And yet in the broad
sense function produces structure and structure modifies function.
At first glance it may appear that this relation is quite unique, that
nothing like it exists in the inorganic world. As a matter of fact,
however, the same relation exists everywhere in dynamic systems
in nature.

Various authors have from time to time compared the organism
with one or another inorganic system. Roux (’os), for example,
has carried out in some detail the comparison between the organism
and the flame. Although this analogy contains much that is valu-
able, especially on the chemical side, it is imperfect morphologically
because the morphology of the flame is much less stable and per-
sistent than that of the organism. Some years ago (Child, ’11) I
found the analogy between the organism and a flowing stream
useful for purposes of illustration. While as regards metabolism
the river is much more widely different from the organism than
the flame, yet as regards the relation between structure and func-
tion there are certain resemblances between the two which are of
value for the present purpose. Such analogies serve merely to
call attention to certain points. The flow of water—the current
of the stream—is the dynamic process and is comparable in a
general way to the current of chemical energy flowing through the
organism. On the other hand, the banks and bed of the stream
represent the morphological features. Wherever such a system
exists, certain characteristic developmental changes occur which,
though much less definite and fixed in localization and character
than in the organism, are nevertheless of such a nature that we
can predict and control them.

Neither water alone nor the banks and bed alone constitute
the system which we call a river; and in nature the banks and bed

28 SENESCENCE AND REJUVENESCENCE

and the current have been associated from the beginning. Here
also structure and function are connected as in the organism: the
configuration of the channel modifies the intensity and course of
the current and the current in turn modifies the morphology of
the channel by deposition at one point, giving rise to structures
such as bars, islands, flats, and by erosion at another. And besides
this, the river possesses a considerable capacity for self-regulation.
Where the channel is narrower the rate of flow is higher, and vice
versa. A dam raises the level until equilibration results and the
flow continues. It is of course true that only in the lower reaches
does the river resemble the organism in the accumulation of
structural material: over most of its course it is primarily an
erosive agency. It does, however, exhibit what we may call a
physical metabolism on which its morphogenesis depends. The
current carries certain materials and the character of these differs
with the current. When the energy of the current is no longer
able to carry them they are deposited and take part in the building
up of structure. Certain materials are more readily carried by
the stream than others, and these may be eliminated from the river
and take no part in its morphogenesis.

But the most important point for present purposes is that in
the river, as in the organism, structure and function are indis-
sociable and react upon each other. From the moment the current
begins to flow it is a constructing agent, ie., it determines form
along its channel, and from the same moment the structure already
existing affects the flow of the current. It is evident then that the
relation between structure and function in the living organism is
not fundamentally different from that in the flowing stream.
Structure and function are indissociable and mutually determining
as long as the river exists and the organism lives. In a very inter-
esting series of papers Warburg" has recently demonstrated the
close interrelation between function and structure for the oxidation
processes and the fundamental structure of the cell, the occur-
rence of the oxidations being very directly dependent upon the
existence of the cell structure.

1 Warburg, ’12a, ’12b, ’13, 14a, 14).

VARIOUS THEORIES OF THE ORGANISM 20

The living organism has often been compared to a machine made
by man, such as the steam engine, which converts a part of the
energy of the fuel into function as the organism transforms the
energy of nutrition into functional activity. This analogy is a
very imperfect one, for in the steam engine and in all other machines
constructed by man structure and function are separable. More-
over, the man-made machine does not construct itself by its func-
tional activity, but is completely passive as regards its construction,
being built up by an agent external to itself for a definite purpose,
and being unable to function until its structure is completed. The
organism, on the other hand, functions from the beginning and con-
structs itself by its own functional activity; and the structure
already present at any given time is a factor in determining the
function, and the function at any given time is a factor in determin-
ing the future structure. The organism is then a very different
thing from a man-made machine, and comparisons between the
two are likely to lead to incorrect conclusions concerning the organ-
ism. The machine corresponds more closely to a fully developed
morphological part of the organism which constitutes a definite
functional mechanism. But the structure and function of such a
part give us no conception of the organism as a whole and of its
action as a constructive and activating agent.

The comparison between the living organism and the man-
made machine completely ignores the relation between structure
and function in the former. And any conception of the organism
which does not take into account its ability to construct its own
mechanism is very far from adequate. The whole living organism
may be compared with the machine plus the constructing and
activating agent, the intelligence that makes and runs it. It may
appear at first glance that this view leads necessarily to the assump-
tion that an intelligence more or less like that of man is concerned
in the development of every organism. This, however, is far from
being the case. In the broad sense, the man building and running
a machine is an organism constructing a part with a definite func-
tional mechanism which functions under the control of the whole.

If intelligence is a function of the human or any other organism,
then the same laws must hold for its activity as for that of organisms

30 SENESCENCE AND REJUVENESCENCE

in general. The facts show clearly enough that different degrees
of intelligence exist in different organisms, and we cannot deny
that even the simple organisms show something remotely akin
to intelligence. On the other hand, many of the supposed funda-
mental differences between the organism and the inorganic world
have disappeared in the light of scientific investigation. But
even supposing that we shall some day demonstrate the essential
unity of the universe from the simplest inorganic system to the
highest organism, when that is done there is no reason to believe
that the real problem of teleology will be eliminated; it will doubt-
less still be before us as a problem concerned, not with any single
group of organisms, nor with all organisms, but with the world as a
whole. In other words, on the basis of such a conception there is
not merely an analogy but a fundamental similarity between the
river with its current and channel, the organism constructing itself
by its own functional activity, and the man constructing and
running a machine. And this remains true whatever the final
solution of the teleological problem.

But as the complex structure of the human organism and also
the machine which it has constructed have constituted essential
factors in the development of human intelligence, so also in other
organisms the approach to anything like intelligence in the broadest
sense is manifestly associated with the development of structure.
The more complex the structure, particularly of the nervous sys-
tem, the closer the approach to intelligence. This is again merely
a special case under the general relation between structure and
function: the more complex the structure the greater the possi-
bilities of function. Moreover, even in man a very complex
structure is developed before we can find any evidence of intelli-
gence. In short, all the evidence along this line indicates that
anything which we are able to recognize as intelligence is not a
primary function of the organism, but one which becomes apparent
only in a highly complex structure. Just as clearly does the evi-
dence indicate that there is no real break in the series between the
simplest morphogenetic activity of the organism and the man
building and controlling the machine. But because the man builds
and runs the machine with a definite purpose in mind, it does not

VARIOUS THEORIES OF THE ORGANISM 31

at all follow that a similar idea of purpose underlies morphogenesis,
even though the dynamic processes may be more or less similar in
both cases. The foundations from which purposive action arises
must be sought in the constitution of the world in general, but it
does not follow that purposive action is everywhere present.

The various attempts made within recent years to interpret
the organism in terms of memory (Semon, ’o4), behavior (Schultz,
’10, ’12), entelechy (Driesch, ’08), or other more or less psycho-
logical or teleological terms, are interesting to every biologist, if
only as indications of a reaction from theories current a few years
ago, but they rather obscure than illuminate the problem. More-
over, purposive action and intelligence in various degrees of com-
plexity are all features of organic life, but any attempt to show
that they are fundamental or universal features is, to say the least,
premature and merely a matter of personal opinion. The close
association between complexity of structure and complexity of
behavior in organisms should lead us to search for terms common
to both, rather than to attempt to translate either into terms of
the other.

REFERENCES

BrEcHHOLD, H.
1912. Die Colloide in Biologie und Medezin. Dresden.

BrevIG, G.
tgo1. Anorganische Fermente. Leipzig.
Cuitp, C. M.

ror. ‘A Study of Senescence and Rejuvenescence Based on Experiments
with Planarians,” Arch. f. Entwickelungsmech., XXXI.
Driescu, H.
1901. Die organischen Regulationen. Leipzig.
1908. The Science and Philosophy of the Organism. London.
FREUNDLICH, H.
1909. Kapillarchemie. Leipzig.
GranaM, T.
1861. “Liquid Diffusion Applied to Analysis,” Phil. Trans., CLI.
HOBER, R.
1911. Physikalische Chemie der Zelle und der Gewebe. Dritte Auflage.
Leipzig.
Kuster, E.
1913. Uber Zonenbildung in kolloidalen Medien. Jena.

32 SENESCENCE AND REJUVENESCENCE

LEpwc, S.
1908. ‘‘Essais de biologie synthétique,” Biochem. Zeitschr., Festband fiir
H. J. Hamburger.
rooga. Les Croissances osmotiques et lorigine des étres vivantes. Bar-
le-Duc.
1g09b. “Les bases physiques de la vie et la biogenése,” Presse medicale,
VII.
1910. Théorie physico-chimique de la vie. Paris.
LIESEGANG, R. E.
1909. Beitrdge zu einer Kolloidchemie des Lebens. Dresden.
tgtr. ‘Nachahmung von Lebensvorgingen: I, Stoffverkehr, bestimmt
gerichtetes Wachstum; II, Zur Entwicklungsmechanik des Epi-
thels,” Arch. f. Entwickelungsmech., XXXII.
1914. “Eine neue Art gestaltender Wirkung von chemischen Aus-
scheidungen,” Arch. f. Eniwickelungsmech., XX XIX.
MatTuHews, A. P.
1899. ‘The Changes in Structure of the Pancreas Cell,” Jour. of Morph.,
XV (Supplement).
1905. “A Theory of the Nature of Protoplasmic Respiration and
Growth,” Biol. Buil., VIII.

OsSTWALD, WOLFGANG.
1912. Grundriss der Kolloidchemie. Dresden.
PFiiscEr, E. F. W.
1875. ‘‘Uber die physiologische Verbrennung in den lebendigen Organ-
ismen,” Arch. f. d. ges. Physiol., X.
RiIcGNANO, E.
1906. Sur la Trasmissibilité des caractéres acquis: Hypothése d’une cen-
troépigénése. Paris.
Roux, W.
1905. ‘‘Die Entwickelungsmechanik: ein neuer Zweig der biologischen
Wissenschaft,” Vorir. und Aufs. ii. Entwickelungsmech., I.
ScHULTZ, E.
1910. Prinzipien der rationellen vergleichenden Embryologie. Leipzig.
1gt2. “Uber Periodizitét und Reize bei einigen Entwicklungsvor-
gingen,” Vortr. und Aufs. i. Entwickelungsmech., XIV.
Semon, R.
1904. Die Mneme als erhaltendes Prinzip im Wechsel des organischen
Geschehens. Leipzig.
VeErRworn, M.
1903. Die Biogenhypothese. Jena.

VARIOUS THEORIES OF THE ORGANISM 33

WARBURG, O.
1g12a. ‘Untersuchungen tiber die Oxydationsprozesse in Zellen. II,”
Miinchener med. Wochenschr., LVIII.
19126. “Uber Beziehungen zwischen Zellstruktur und biochemischen
Reaktionen,” Arch. f. d. ges. Physiol., CXLV.
1913. Uber die Wirkung der Struktur auf chemische Vorginge in Zellen.
Jena.
1914. “Uber die Empfindlichkeit der Sauerstoffatmung gegeniiber in-
differenten Narkotika,” Arch. f. d. ges. Physiol., CLVIII.
1914). “Beitrige zur Physiologie der Zelle, insbesondere tiber die Oxyda-
tionsgeschwindigkeit in Zellen,” Ergebn. d. Physiol., XIV.
ZANGGER, H.
1908. “Uber Membranen und Membranfunktion,”’ Ergebn. d. Phy-
siol., VII.

CHAPTER IT
THE LIFE CYCLE
GROWTH AND REDUCTION

Definitions of growth and reduction.—One of the most charac-
teristic and striking features of the living organism is its ability to
add to its own substance. In most organisms an enormous increase
in size and weight occurs during the earlier part of the life cycle.
This is commonly known as growth. But different authorities are
not entirely agreed as to what constitutes growth. The differ-
ences of opinion seem to center chiefly about the question whether
growth consists simply in increase in size, or whether change in
form is the essential feature. Davenport,’ following Huxley and
others, defines organic growth as increase in volume. The plant
physiologist Pfeffer (or), on the other hand, says that in general
all formative processes which lead to a permanent change of form
are to be regarded as growth. Most authorities have regarded the
addition of material, or of certain kinds of material, or the increase
in size as the essential feature of growth. To make change of form
the basis of growth is certainly a wide departure from the com-
monly accepted meaning of the word, and also fails, I think, to
recognize the significance of accumulation of material in the organ-
ism. Increase in size or the addition of material may occur without
appreciable change in form, and change in form may occur without
increase in size or amount of material, and most of those who
have attempted to define growth have recognized this fact. The
capacity of the organism to add to its own substance and to in-
crease in size is evidently closely connected with the fundamental
processes of metabolism, and even organisms which do not undergo
appreciable changes of form do nevertheless grow in the usual
sense of the word.

But any consideration of the problem of growth which does
not take into account the process of reduction isincomplete. Under
the usual conditions of existence the healthy active organism is not

tIn Davenport’s Experimental Morphology (’97, pp. 281-82) a number of the
definitions of growth which have been given are cited.

34

THE LIFE CYCLE 35

only adding new material, but is at the same time breaking down
and eliminating material previously accumulated. The total
result as regards size or bulk is simply the difference between the
two processes. Some of the substances accumulated within the
organism break down less rapidly than others, but even such sub-
stances may be more or less completely removed. In the more
complex organisms also some of the substances of the substratum
are apparently more stable, i.e., inactive chemically, under physio-
logical conditions, and the processes of breakdown are therefore
less conspicuous as a factor in the total result than in the simpler
forms. Under conditions where the breakdown of material over-
balances the increment, as for example in starvation, the higher
organisms soon die with a considerable portion of their substance
intact, but in many of the simpler forms the material previously
accumulated serves to a large extent as a source of energy and the
organism remains alive and active, but undergoes reduction until
it represents only a minute fraction of its original size. Various
species of the flatworm Planaria may undergo reduction from
a length of twenty-five or thirty millimeters (Fig. 1) to a length
of three or four millimeters (Fig. 2) with a corresponding change
in other proportions before they die, and many others among
the simpler organisms are capable of undergoing great reduc-
tion without death. Since the addition of material and
increase in size play a much more conspicuous part in the life of
organisms in nature, and particularly in the higher organisms,
than do the reductional processes, it has come about that the term
growth has usually been applied to the incremental, or productive,
factors, and the significance of reduction in the life cycle has
scarcely been considered.

Various authors have laid stress upon the permanency of the
changes involved in growth. As a matter of fact, these changes
are not necessarily permanent, although they are more stable in
the higher than in the lower organisms. To say that growth con-
sists in permanent increase in volume or change of form is to ignore
entirely the phenomena of reduction which are, it is true, most
striking in the lower organisms, but which may occur to some
extent in all.

36 SENESCENCE AND REJUVENESCENCE

Logically our definition of growth might well
include both positive and negative growth, or
00 production and reduction, but since the word
growth has come to be so generally associated
with an increase in substance it is perhaps
inadvisable to attempt to change its meaning.
We may then retain the word growth for posi-
tive growth or production, and use the term
reduction for negative growth. But in so doing
we must not forget that both these processes
are in the broad sense, though not necessarily in
the chemical sense, reversible, and that any
adequate conception of the relation between
the substratum and the dynamic processes in
the organism must be based, not on growth
alone, but upon both growth and reduction.
In other words, the activity of the organism
may either increase or decrease the amount of
its substance according to conditions.

The question has often been raised whether
the increase in the water-content of the organism
is to be regarded as growth, or only the increase
in the structural substance. Some definitions
of growth have taken the one view, some the
other, but if water is included among the sub-
stances concerned in growth we have then
to determine whether increase in water-
content is in all cases to be regarded as
growth, or whether we shall make a dis-

1 tinction between growth and passive dis-

tension due to external factors. Here

2 again views differ. As a matter of fact,

Fics.3,2—Planaria Various investigators have shown that the

dorotocephala: Fig. 1,a imbibition of water is a very characteristic

well-fed animal 25mm. in feature during at least certain stages of
length; Fig. 2, an animal

what we are accustomed to call growth:

reduced by starvation from :
25 to4 mm. on the other hand, loss of water is a

THE LIFE CYCLE 37

characteristic feature of certain other stages of the life cycle.
Moreover, there is evidence that water is produced by chemical
action in the organism (Babcock, ’12), and it is a familiar fact
that water is absolutely essential to life.

But an adequate definition of organic growth must also take
account of the fact that it is a process of the living organism. A
passive distension of the organism or any part of it by water
or other substances, or a passive loss of water, is not properly
growth or reduction, because it is not due to the activity of the
organism or part.

If we admit then, first, that organic growth and reduction con-
sist essentially in changes in the amount of substance, secondly,
that water as well as other substances may be involved in growth,
and thirdly, that growth is a process of the living organism, our
definitions of growth and reduction must read somewhat as follows:
organic growth is an increase, organic reduction a decrease, in the
amount of the substance of a living organism or part, resulting
directly or indirectly from its specific metabolic activity. This
definition does not any more than others avoid all difficulties, for
sharp lines of distinction do not necessarily exist in natural phe-
nomena. Whether we call a certain process growth or not must
often depend upon whether we are considering the whole organism
or a part; moreover, it is impossible to separate the activity of the
organism completely from external factors.

Although growth in its simplest terms consists in large measure
in the synthesis of proteid molecules, it is evident that growth is
not always the same chemical process. Under different conditions
different proteid molecules may be formed, and very often growth
results from the synthesis of various substances other than proteids.
Recent investigations seem to indicate that from the point of view
of nutrition growth in recovery from starvation is not the same as
developmental growth with continuous feeding and that growth in
adult life is not the same as growth during youth.t Doubtless
many other differences will appear as investigation proceeds, but
there seems at present to be no adequate reason for limiting the

See the papers by Osborne and Mendel, in the references appended to chap. xi,
particularly the recent general discussion of the subject by Mendel (’14).

38 SENESCENCE AND REJUVENESCENCE

term growth to one or the other of the particular processes as some
authors incline to do. Growth results primarily from the ability
of the cell to synthesize certain substances which, once formed,
remain as relatively permanent constituents of the cell. Under
different conditions the nutritive substances necessary, the course
of synthesis, and the substances formed must differ widely, but
growth is a complex organic process rather than this or that par-
ticular chemical reaction.

The nature of growth and reduction—The question why the
organism grows is one of great interest, and while we cannot at
present answer it fully, we can at least reach certain provisional
conclusions. On the basis of the chemical hypothesis of the labile
proteid molecule, growth remains a mystery. We cannot conceive
how these labile molecules are able to build up others like them-
selves. Reduction, however, is readily enough accounted for
as the result of breakdown of the labile molecules. But if we
regard the organism as a complex of reactions in a colloid sub-
stratum, the problem of growth assumes a different form and is
open to attack. Certain aspects of the problem require brief con-
sideration from this point of view.

The reversibility of the growth process leads us at once to ask
whether or to what extent reversible chemical reactions are con-
cerned. If we could regard growth and reduction as the two
terms of a reversible chemical reaction it would simplify our con-
ceptions very greatly. Unfortunately, however, this seems to be
impossible. Reversible chemical reactions are undoubtedly con-
cerned in the synthesis and breakdown of the various molecules
which make up protoplasm, but the growth-reduction process is
something more than such a reaction. Apparently the course of
synthesis and of breakdown and the character of the end products
may differ widely. Many or all of the component reactions in
growth and reduction may be reversible, but it does not by any
means follow that reduction is a reversal in the chemical sense of
growth. During a considerable part of life under the usual condi-
tions the synthesis of certain substances overbalances their break-
down, they accumulate in the organism, and growth occurs.
Evidently conditions in the organism are such that certain sub-

THE LIFE CYCLE 30

stances once formed are not as readily or as rapidly decomposed
and eliminated.

It is evident that synthesis of proteid molecules is a factor of
great importance in growth, since proteids form the chief constitu-
ents of protoplasm, but there is no reason to believe, as various
authorities have maintained, that the metabolic process consists
wholly or chiefly in the synthesis and decomposition of proteid
molecules. All the facts indicate that much of the energy of the
organism comes from substances other than proteids, and that pro-
teid synthesis is only one of many chemical transformations occur-
ring in the organism.

Moreover, according to physico-chemical laws, the accumulation
of colloids and other substances as a substratum in the organism or
in the cell must depend upon what we may call their physiological
stability. A physiologically stable substance is one which, when
once formed, cannot readily escape from the living cell or organism
under the existing conditions, unless it undergoes chemical change,
and which, under the usual physiological conditions, does not under-
go this change or undergoes it less readily than other substances.
Physiological stability depends then, not only on the constitution
of the substance concerned, but also and probably to a large extent
on the conditions to which it is subjected. Different substances
differ in stability under the same conditions, and the same substance
may differ very greatly in stability under different conditions.
Moreover, physiological stability does not necessarily imply com-
plete chemical stability. There is good reason to believe that
many substances in the cell are undergoing more or less continuous
partial chemical breakdown and reconstitution, but so long as they
do not undergo complete breakdown and elimination they consti-
tute parts of the cell which are relatively stable physiologically.
In most plants, for example, proteid molecules once formed never
undergo decomposition to the point where the nitrogen which they
contain is eliminated in any form, yet there can be no doubt that
these proteids, or some of them, take part in the chemical reactions
within the cell and that their molecules are often partially decom-
posed and reconstituted. They are then physiologically, though
not necessarily chemically, stable constituents of the plant cell.

40 SENESCENCE AND REJUVENESCENCE

The visible substratum of the organism, i.e., the protoplasm,
must consist fundamentally of such physiologically stable sub-
stances, for if this were not the case we should have merely a system
of chemical reactions, and no permanency of form or structure
could exist. Theoretically, at least, a distinction must be made
between the substratum of the cell or organism and the substances
which are decomposed and eliminated and which constitute the
source of energy. Practically, however, such a distinction cannot
be clearly made in most cases, for physiological stability is relative
rather than absolute and it is impossible to say in a given case to
what extent the substratum is itself involved in the chemical re-
actions. Still it is evident that the substances which accumulate
within the cell under given conditions as its visible or structural
substratum must be in general and under the existing conditions
less subject to decomposition into eliminable form than those sub-
stances which undergo breakdown and elimination.

The organic colloids are in general physiologically stable sub-
stances. When once formed within the cells they do not diffuse
readily and cannot ordinarily escape except as they are decomposed
into eliminable substances. We know from studies of the metabo-
lism of the higher animals and from the amount of nitrogen-
containing food which is necessary for maintenance that in these
forms at least the breakdown of proteid molecules into completely
eliminable form constitutes only a fraction of the metabolic process
at any given time. Moreover, some of the nitrogenous substances
excreted may come from proteids of the food which have been
decomposed without forming a part of the substratum of the cells.
Undoubtedly also many chemical changes occur in the colloid
substratum which involve merely the transformation or exchange
of certain chemical groups and not the complete disruption of the
molecule. Chemical changes of this sort do not necessarily involve
the disintegration of the substratum as a whole, and it is probable
that cellular structures are often the seat of such changes without
undergoing any conspicuous morphological change.

The fact that emulsoid colloids and particularly proteids are
the fundamental constituents of the substratum of living organisms
is a necessary consequence, first, of the formation of these substances

THE LIFE CYCLE 4I

in the course of the reactions which constitute metabolism, and,
secondly, of their physico-chemical properties. The substratum
once formed in the course of chemical reactions affords a basis for
the continuation of the reactions and for the further addition of
colloids. So far as the metabolic reactions are enzyme reactions,
the structural substratum of the organism must consist of the sub-
stances which for one reason or another are less susceptible to
enzyme action than other substances which are transformed without
forming a part of the structure.

According to this view the colloid substratum and the morpho-
logical structure of the organism represent, so to speak, the sedi-
ment from the metabolic process. They are, in short, by-products
of the reactions which do not readily escape from the cell unless
they undergo decomposition and which are relatively stable.
Therefore they must constitute the more permanent constituents
of the cell and appear as a visible substratum or more or less perma-
nent structure of some sort. The constitution of the structural
substratum developed in different organisms differs because the
metabolic processes and the substratum already existing at the
beginning of development differ. The visible organism is then
the sediment left behind by the metabolic current: it consists of
the substances which the current is unable to carry farther. It does
not represent life any more than the sand-bar represents the river;
it is simply a product of past activity which may influence future
activity. Sixty years ago Huxley said concerning the cells: ‘They
are no more the producers of the vital phenomena than the shells
scattered along the sea-beach are the instruments by which the
gravitative force of the moon acts upon the ocean. Like these,
the cells mark only where the vital tides have been and how they
have acted”? (Huxley, ’53). And yet since Huxley’s words were
written how many attempts have been made either to show that
this or that structural element of the organism represents some-
thing fundamental to life or to translate the phenomena of life
into terms of an invisible hypothetical structure!

The visible structural features of the organic substratum possess
very different degrees of stability: some are evanescent, while
others persist throughout the life of the cell in which they arise.

42 SENESCENCE AND REJUVENESCENCE

This is true, not only as regards the different structures in a cell,
but also as regards different cells of an organism, and the cells of
different organisms. Many of the more or less evanescent struc-
tural appearances in protoplasm are perhaps nothing more than
visible indications of differences in the aggregations of the colloid.
The more highly aggregated portions, which form more or less
dense colloid gels, appear as more or less definite structures, the less
aggregated portions as indefinitely granular, alveolar, or fluid. But
even in such cases the denser portions of the protoplasm are probably
for the time being less subject to chemical change than the more
fluid portions because of their physical condition. It is evident,
however, that many of the more permanent structural features
result from the accumulation in the cell of specific substances
which possess a relatively high degree of physiological stability
under the existing conditions. But there is little doubt that in at
least most organic structures which are not mere inclosures in the
protoplasm or extra-cellular secretions a greater or less degree of
chemical breakdown, of degradation of the structural substance, is _
more or less constantly occurring while life continues. In some
_cases this may be very slight in amount or may involve only certain
components, in others it may involve the whole structural basis
of the organ or organism. When the conditions are such that the
new material added exceeds in amount that undergoing breakdown,
growth occurs, but when the rate of breakdown exceeds that of
accumulation, reduction is the result.

According to the theory of the labile proteid molecule, func-
tional activity results primarily from the breakdown of the struc-
tural substratum itself, or at least of its proteid constituents.
But if the substratum consists of comparatively stable by-products
of metabolism, as the facts seem to indicate, then it is clear that

_the energy of functional activity must ordinarily come chiefly from
other sources, i.e., from the breakdown of other substances which
do not constitute an essential structural part of the protoplasm.
Under the usual conditions the structural substratum is probably
to a large extent a field in which the reactions occur rather than
the reacting substance or substances, but in the absence of other
nutritive substances, i.e., in starvation, it may itself become the

THE LIFE CYCLE 43

chief source of energy, especially in the lower animals. As already
pointed out, different constituents of the substratum show very
different degrees of stability, some being evanescent and disappear-
ing at once with slight change in conditions, while others once
formed persist for a long time or through life. It is therefore
impossible to distinguish sharply between what constitutes the
substratum and what does not. We can only say that the sub-
stratum consists in general of more stable substances than those ©
which do not appear in it.

As our knowledge of the great complex of reactions which we
call metabolism increases, it becomes more and more evident that
the different reactions of the complex are not entirely independent
of each other, but constitute a reaction system. In this system the
oxidations appear to be the most important or dominant factor, the
independent variable, as Loeb and Wasteneys (’11) express it, upon
which the other reactions depend more or less closely. Rate of
oxidation is a more fundamental factor in growth than the amount
of nutritive material in excess of a certain minimum. From this
point of view the term “metabolism” loses some of its vagueness.
It is not simply a hodgepodge of chemical reactions in which now
one, now another, component is most conspicuous, as external con-
ditions change, but rather an orderly correlated series of events in
which certain reactions play the leading réles. The rate or char-
acter of component reactions may change very widely with external
conditions, but nevertheless the reaction system retains in general
certain definite characteristics and the relation between its com-
ponent reactions persists. Anabolism and katabolism, the synthesis
and the breakdown of the substance of organisms, are not independ-
ent processes, but the syntheses are apparently associated with,
and in greater or less degree dependent in some way upon, the
oxidations.

From this point of view functional hypertrophy loses its peculiar
character. It is not in any sense a “‘regeneration in excess’”’ or an
“over-compensation,”’ as it is so generally assumed to be, but is
simply the result of increased metabolism in the presence of an
adequate nutritive supply. Increased metabolism under these
conditions means increased production of structural substances.

44 SENESCENCE AND REJUVENESCENCE

The organism does not construct itself for function as the vitalistic
and chemical theories maintain: it constructs itself by function.

When the supply of nutritive material from without is insuffi-
cient, the previously accumulated structural material may serve
as a source of energy to a much greater extent than when nutritive
material is present in excess, and under these conditions the new
structural material, if any is formed, may be insufficient to cover
the loss and reduction results. Such reduction may involve the
whole organism to a greater or less extent, as in the flatworms and
other simple animals, or it may involve only or chiefly certain parts,
but in all cases we find that some parts or substances are involved
to a greater extent than others. In a starving flatworm, for
example, certain organs may disappear entirely before death occurs,
while others retain more nearly their usual proportions. Much
has been made of this fact in a teleological sense (see, for example,
E. Schultz, ’o4), and it has been repeatedly pointed out that the
organs least affected are those most essential to the life of the
organism. But a teleological interpretation seems to be quite
unnecessary. In general it is very evidently the case that those
organs which are most constantly, most frequently, or most in-
tensely active in the life of the organism undergo least reduction
during starvation. There is some reason to believe that the
structural substratum of the cells of such organs is more stable than
that of cells which possess in general a low rate of metabolism. The
nervous system undergoes least reduction during starvation, and
during the earlier stages of development it certainly has the highest
metabolic rate of any part of the body, and in many cases, if not
in all, this condition persists throughout life. Furthermore, during
the later stages of life its special functional activity is certainly
almost if not quite continuous. In such organs energy must be
derived to a much greater extent from nutritive substances than
from the substratum of the cells itself. Consequently, during
starvation their losses are less and are more completely repaired
than in organs where the substratum is less stable. Thus the more
active and therefore the more persistent organs maintain them-
selves largely at the expense of other less active parts in which the
degradation of the structural substratum occurs more readily.

THE LIFE CYCLE 45

And it is these more continuously or more intensely active organs
which are more essential to life. But according to this view they
undergo less reduction in starvation, not because they are more
essential in life, but because they are more active.

Reduction in an organ or part may also occur when conditions
change so that a decrease in the average rate of its metabolism below
a certain level occurs and synthesis of structural substances does not
compensate the gradual loss. The atrophy of organs from disuse
is a case in point. And, finally, reduction may occur in a part
when the correlative conditions which were an essential factor for
its continued existence as a part undergo change. In such cases
it is difficult to determine whether the change in metabolism is
primarily qualitative or quantitative. In the lower organisms
extensive reduction of this kind occurs when pieces are isolated
and undergo reconstitution. Previously existing organs may be
reduced and disappear and others be formed anew. In the higher
organisms such processes of reduction are narrowly limited.

If we accept the general conception of growth and reduction
here outlined, then it is no longer necessary to assume the existence
of a mysterious growth-impulse which gradually decreases in inten-
sity during development, for growth is primarily the accumulation
of certain substances formed in the course of the metabolic reactions
which are physiologically more stable than other substances that
break down, furnish energy, and are eliminated. Reduction
occurs when the breakdown and elimination of the cell substance
is not balanced by the synthesis of new substance. Some such
conception of growth and reduction seems to be forced upon us by
the facts, for certainly there is every reason to believe that the
different constituent substances of the cell show very different
degrees of stability and that the stability of a given substance may
differ with different conditions. Organic growth remains a com-
plete mystery unless certain fundamental constituents of proto-
plasm are relatively stable under the conditions of their production
in the cell.

DIFFERENTIATION AND DEDIFFERENTIATION

Differentiation —The process of development in the organism
is also a process of differentiation, of apparent complication, but

46 SENESCENCE AND REJUVENESCENCE

we find that differences in reaction or in capacity to react very
commonly exist in different parts even before visible differentiation
occurs, or in cases where it never occurs. The term ‘‘specifica-
tion” is often used for these differences which appear only in
physiological activity, and ‘‘differentiation” for the visible struc-
tural differences. The distinction is of course arbitrary, for the
visible differences result from differences in physiological activity.
An orderly sequence of differentiation during development is
characteristic of at least all except the very simplest organisms and
probably in these also some degree of differentiation exists.

In its biological sense the term “‘differentiation” is purely
descriptive: broadly speaking, differentiation includes all per-
ceptible changes in structure or behavior from the primitive embry-
onic or ‘‘undifferentiated’”’ condition, which occur either in the
cells or parts of an organism during its developmental history, or
in different organisms in the course of evolution. It is, in short,
a becoming different, but since the process of becoming different
in cells and organisms is a change from a generalized to a specialized
condition—a progressive development of particular kinds of struc-
ture and activity in different parts of the whole—differentiation in
organisms is a process of specialization.

The problem of differentiation has long been one of the great
biological problems. Biological thought has always been divided
upon the question of preformation versus epigenesis. To what
extent does the differentiation of the fully developed organism
actually exist as something preformed in the germ, so that develop-
ment is strictly an unfolding, a becoming visible, of what already
exists, and to what extent is there a real increase in complexity
during development? The corpuscular theories are an attempt
to answer the question from the point of view of preformation, but
they, like the vitalistic theories, succeed merely in placing the prob-
lem beyond the reach of investigation. It is evident that if the
organism is a physico-chemical system, at least some differentiations
must arise in the course of development. The adult organism is
represented, not in the morphological structure nor in the physical
and chemical changes of the reproductive cell or cell-mass, but
rather in its capacities. The experimental investigation of recent

THE LIFE CYCLE 47

years has shown that different degrees of differentiation exist in
different reproductive cells, but has not afforded any real support
to the view that the morphological characters of the adult are
represented in some way by distinct entities in the germ.’ But
even if we admit that organic differentiation is, at least to a large
extent, an epigenetic process, the real problem still remains. The
orderly and definite character of the process, the variety of struc-
tural features, and their apparent adaptation to the function which
they are to perform, all combine to render the problem one of the
greatest interest and significance.

At present, however, it must suffice to call attention only to
certain aspects of the problem. In the first place, in so far as
differentiation is really a progressive or epigenetic process, it must
depend on changes of some sort in the dynamic processes in different
regions of the developing organism. We know that differentiation
in its specific features is to a large extent independent of external
conditions; therefore the internal conditions must determine these
changes. And this brings us to the important question: How
can such localized differences in the dynamic processes arise in the
developing organism? The corpuscular theories have accustomed
us to regard different morphological parts of the organism as
qualitatively different, and it is evident that in many cases they
are, but it does not necessarily follow that the qualitative differences
are primary, or that all differentiations are qualitative. It isa well-
known fact that quantitative differences in the conditions existing
in a chemical reaction may result in qualitatively different products,
and this is demonstrated for many reactions which occur in the
metabolic complex. It cannot then be doubted that qualitative
differences may result from quantitative differences in the processes
occurring in the organism. We also know that many morpho-
logical differences are differences of size, shape, or quantity of some

1In view of the present vogue of the factorial hypothesis among investigators
in the field of genetics, and particularly of certain attempts to apply it to the chromo-
somes, such a statement may appear to many as at least unwarranted, if not incorrect.
The factorial hypothesis, however, does not necessarily involve the assumption of
factors as distinct entities in the germ, and the attempts to connect particular factors
with particular chromosomes or parts of chromosomes are not at present, properly
speaking, scientific hypotheses.

48 SENESCENCE AND REJUVENESCENCE

other kind, which are not necessarily qualitative in any sense.
And, finally, we are able to determine experimentally the devel-
opment of very different morphological characters by changes in
conditions which affect primarily the rate and not the character
of the metabolic reactions (Child, ’11). To what extent quantita-
tive differences in the dynamic processes actually serve as a basis
for specialization and differentiation we do not know, although it
is certain that they are a much more important factor than most
biologists have been accustomed to believe.

But, supposing that quantitative or qualitative differences
arise or exist in different regions of the developing organism, how
can they persist in a substance of the physical consistency of pro-
toplasm? It is here that the colloid condition of the substratum
plays a very important part. The organic colloids with their
slight diffusibility, their effect on the diffusion of other substances,
their viscosity and differences of aggregate condition, afford possi-
bilities for the localization as well as the origination of different
processes which do not exist in any other known medium. The
experiments on the production of form and structure by means of
chemical reactions in a colloid substratum outside the organism
demonstrate how readily even complex morphological features
may arise under such conditions, and in such cases we are often
able to analyze the process of differentiation. We have then in the
colloid substratum a real basis for differentiation, and the problem
of morphogenesis becomes accessible to scientific investigation and
analysis, instead of being merely restated in terms of some “vital-
istic”? principle or of determinants or other ultimate units.

The embryonic or undifferentiated cell is distinguishable from
the specialized or differentiated cell rather by the absence than by
the presence of definite morphological features. It represents the
cell of the species reduced to its simplest morphological terms,
consisting essentially of nucleus and relatively homogenous cyto-
plasm." It is of course true that cells which are not morphologically

* Embryonic cells are shown in Fig. 113 (p. 285), and in the smaller cells of Fig.
187 (p. 347), and in Fig. 194, em (p. 348). Cells which are embryonic in appear-
ance are represented more or less diagrammatically in various other figures, e.g.,
Figs. 71-74 (pp. 206, 208) and Fig. 192, pc (p. 348).

THE LIFE CYCLE 49

different in any visible way may show themselves by their behavior
to be physiologically different, so that the absence of visible differ-
entiation in the cell is not proof that the cell is completely unspecial-
ized.

The substance of the undifferentiated cell is the general meta-
bolic substratum of the organism, and it is the chemical or physical
transformations of this substratum, or the addition of substances
to it, that constitutes morphological differentiation. Physiological
differentiation consists in the progressive development of certain
activities at the expense of others.

While we know too little at present of the nature of the various
metabolic processes and of the relation between metabolism and
the cellular substratum to permit us to reach positive conclusions
concerning the nature of differentiation, the facts at hand suggest
certain probabilities. In the first place the embryonic cell very
evidently has in general a higher metabolic rate, or capacity for
a higher rate, independent of external stimulation, than do differ-
entiated cells. Apparently the mere continuation of life in the
cell without cell division brings about changes which decrease
the metabolic rate. Such changes may conceivably result from
gradual atomic rearrangements or from changes in aggregate con-
dition of the colloids. It is a well-known fact that emulsoid sols
outside the organism undergo slow changes in the direction of
coagulation, even when kept under as nearly as possible constant
conditions, and there is good reason to believe that similar changes
occur in the colloids of the living organism. In the coagulation
of proteids by high temperatures time is a factor, i.e., the occurrence
of coagulation depends, not only upon the actual temperature, but
on the time of exposure to it: the lower the temperature, the longer
the time necessary to bring about perceptible coagulation. From
the character of this relation between time of exposure and tem-
perature it is inferred that, theoretically, coagulation must occur
at all temperatures above the freezing-point of the sol, its rate being
infinitely slow at low temperatures and increasing rapidly as the
temperature rises. The fact that coagulation changes do occur
slowly in colloid sols at ordinary room temperatures supports this
view. Lepeschkin (’12) has found that the relation between

50 SENESCENCE AND REJUVENESCENCE

temperature, time of exposure, and occurrence of coagulation as
indicated by death is the same in living plant cells as in proteid
sols outside the organism, and he therefore concludes that the pro-
toplasmic sol is slowly undergoing changes in the direction of coagu-
lation even at temperatures where continued life is possible. If
this view is correct, then a slow increase in aggregation is occurring
continuously in protoplasm, but the formation of new sol and the
gradual chemical breakdown of the older partially coagulated sub-
stance may serve to delay the final result for a long time, or indefi-
nitely.

The accumulation and apparent gelification of protoplasm in
the course of growth and differentiation suggest that changes of
this sort are characteristic of the developmental history of all
organisms. If this is true, they must result in increasing physio-
logical stability of the protoplasm or parts of it, and so lead to
decrease in the rate of metabolism, and the decrease in metabolic
rate may in time lead to changes in the character of the metabolic
complex and so to further changes in structure which may again
alter metabolic conditions, and so on.

It is probable then that mere continued existence may in many
cases result in gradual progressive changes in protoplasm which
become evident sooner or later as some degree and kind of differ-
entiation. Such a process is a self-differentiation in the strictest
sense. Its occurrence or non-occurrence must depend upon the
absence or presence of changes which balance or compensate in
some way the progressive changes, and these are the changes which
lead to dedifferentiation (see following section).

Where all cells or parts are alike, self-differentiation must pro-
duce the same result in all, but where differences of any sort exist,
such, for example, as differences in metabolic rate between external
surface and interior or between other parts, then the different parts
may influence each other and differentiation becomes a correlative
process which may result in the production of many different parts.
In correlative differentiation the parts may influence each other in
various ways. Dynamic changes of one kind or another may be
transmitted from one part to another; quantitative or qualita-
tive differences in the chemical substances produced by different

THE LIFE CYCLE 51

parts may affect the course of metabolism in other parts, and
differences in the rate of growth of different parts may produce
mechanical effects. Since the action of external factors is variable,
both in time and in space, it is impossible for a cell or cell-mass to
exist for any considerable length of time under natural conditions
without local differences of some sort, temporary or permanent,
quantitative or qualitative, appearing in it in consequence of the
differential action of external factors.

Differentiation of some degree and kind is then a necessary and
inevitable result of continued existence except where the progressive
changes are balanced or compensated in some way, and we must
distinguish self-determining, correlative, and external factors in
the process. In general, as I have pointed out above, the gradual -
accumulation and increase in physiological stability of the proto-
plasm, either through change in chemical constitution or aggregate
condition or both, is self-determined and results from the nature
of metabolism and the constitution of protoplasm, while the correl-
ative and external factors play a part in determining the character
of the structural substratum thus produced.

The process of differentiation once initiated, each step becomes a
factor bringing about further changes. For example, the character
of the substances accumulated in a cell seems to depend to a greater
or less extent upon the conditions in the cell which affect metabolic
rate, such as aggregate condition of protoplasm, enzyme activity,
etc. In embryonic, undifferentiated cells, where the internal
conditions permit a high metabolic rate, only those substances
which form the general metabolic substratum, i.e., protoplasm,
remain as constituents of the cell, but as the self-determined meta-
bolic rate decreases, other substances begin to appear and remain
in the cell. Undifferentiated protoplasm is protoplasm reduced
morphologically to its lowest terms. Apparently the metabolic
rate in the cell, or the internal conditions on which the metabolic
rate depends, are factors in determining the physiological stability of
substances. Substances which are either not formed or are broken
down and eliminated after formation in cells with a high metabolic
rate appear as more or less permanent structural components
in cells with a lower rate. As the self-determined metabolic

52 SENESCENCE AND REJUVENESCENCE

rate decreases, new features appear as relatively stable com-
ponents of the structural substratum, and these become factors in
further changes. Probably also substances which were sufficiently
stable physiologically to become components of the structural sub-
stratum at the higher metabolic rate become more stable as the
metabolic rate decreases, not necessarily because of changes in
themselves, but because of the decrease in rate, or the conditions
which determine it. Thus the visible substratum of the cells
becomes more and more altered from its original condition, and
apparently the farther these changes go the less the ability of the
cell to synthesize protoplasm—i.e., the general metabolic sub-
stratum of the organism—and the less “protoplasmic” does its
structure become.

The non-protoplasmic substances which appear in the cell,
either in definite morphological form or as granules, droplets, or
inclosures in the protoplasm, have very commonly been grouped
together under the head of metaplasm. Kassowitz (’99), for ex-
ample, makes a sharp distinction between protoplasm and meta-
plasm and believes that only the accumulation of the latter is
responsible for decrease in metabolic rate in the cell. The distinc-
tion is doubtless of value theoretically, but practically it is impos-
sible to say what is protoplasm and what is metaplasm. And
there can be no doubt that the so-called metaplasmic substances
often take more or less part in the metabolic activity of the
cell instead of being inactive, as Kassowitz and others have
maintained. It seems therefore more in accord with the facts
to regard the cellular substratum as showing all gradations from
the purely protoplasmic condition of the embryonic cell to the
highly differentiated cell which may be loaded with substances
obviously non-protoplasmic in nature.

Differentiation is very generally, though not necessarily, as-
sociated with growth. It is probable that growth cannot proceed
very far without bringing about some degree of differentiation, for
the accumulation in the metabolic substratum of substance, what-
ever its nature, must result sooner or later in altering metabolic
conditions. On the other hand, change in conditions external to a
cell or part may bring about differentiation without growth.

THE LIFE CYCLE 53

According to the theory of differentiation developed here, the
self-determined rate of metabolism of the cell must be to some
extent an index of its degree of differentiation. This is to be ex-
pected, since the metabolic rate must depend upon the condition
of the metabolic substratum. It is important to note that it is
the metabolic rate, as determined by conditions existing within
the cell independently of external stimulation, which is thus related
to the degree of differentiation. Many highly differentiated cells
with a low, self-determined metabolic rate are capable temporarily
of a very high rate when stimulated from external sources. Such
increases in rate are evidently the result of changes in the cellular
substratum which are largely or wholly reversible. What their
nature is we do not know certainly, although various theories of
stimulation have been advanced. As differentiation proceeds
beyond a certain stage, even the metabolic rate following stimu-
lation decreases and the cell becomes less and less capable of per-
forming its special function as a differentiated cell.

In general, a greater degree of differentiation of cells is one of
the features which distinguish the so-called higher organisms from
the lower. A comparison of the cells of higher and lower forms
and of their course of differentiation seems to indicate very clearly
that the physiological stability of the substratum must be greater
even in the embryonic cells of the higher than in those of the lower
forms in order to serve as a basis for the more rapid and greater
differentiation which the higher forms show. Whether the rate of
metabolism per unit of weight and under similar conditions of tem-
perature, etc., is lower in the higher than in the lower forms is not
at present known, but there is some evidence that itis. If increase
in physiological stability of the cellular substratum has occurred
during the course of evolution, it must have been an essential
factor in determining the increase in structural complexity which
is so characteristic a feature of evolution, and structural evolution
must then be regarded as in some degree an equilibration process,
a change from a less stable to a more stable condition.

The orderly sequence of the process of organic differentiation
and the constancy of the results in a given species must result from
certain definite characteristics of the organic individual. My

54 SENESCENCE AND REJUVENESCENCE

own experimental investigations have forced me to the conclusion
that the organic individual consists of a dominant and of sub-
ordinate parts and that dominance and subordination in their
simplest terms depend upon rate of metabolism (see chap. ix).
Not only does the evidence indicate that this is the case, but it is
impossible to conceive of a definite, orderly process of differentia-
tion attaining a definite constant result in a complex physico-
chemical system without some sort of dominance and subordination
in the processes involved. In a complex system consisting of co-
ordinate parts the process of differentiation must differ widely in
character according to conditions, and the orderly character of
development and constancy of result which we find in organisms
would be impossible.

Most theories of the constitution of the organism have failed to
recognize the necessity for such a relation of dominance and sub-
ordination between parts as a fundamental feature; consequently
they have failed to account satisfactorily for the orderly course and
definite result of differentiation. Driesch is one of the few who
have seen clearly that the organic individual is impossible without
a controlling and ordering principle of some sort, and not finding
any physico-chemical basis for such a principle, he has vested the
control in entelechy. As regards plants, the dominance of the
vegetative tip over other parts has been clearly demonstrated,
but no such relation of parts in animal development has been
generally recognized by zodlogists. Nevertheless such a relation
exists and must exist, for without it development, as we know it,
is impossible.

Dedifferentiation—Dedifferentiation is a process of loss of
differentiation, of apparent simplification, of return or approach to
the embryonic or undifferentiated condition. Zodlogists have been
slow to admit its occurrence. According to Weismann—and many
agree with him—development proceeds always in one direction
and dedifferentiation is impossible. Whenever a new development
of a part or a whole occurs, it originates from cells or parts of cells
which have not undergone differentiation beyond the stage at which
the new development begins. Whenever cells which are visibly
differentiated give rise to new wholes or parts, as they often do in

THE LIFE CYCLE 55

cases of regeneration, it is assumed that they contain either some
of the undifferentiated germ plasm or those elements of the germ
plasm which are necessary for the formation of the new part. Such
assumptions are not only unsatisfactory because they cannot be
proved or disproved, but they are wholly unnecessary. We have
seen that the organism can not only accumulate structural material
of various kinds, but under other conditions can remove to a
greater or less extent the material previously accumulated. Since
reduction occurs in organisms, we must at least admit the possi-
bility of dedifferentiation. Consideration of the data of observa-
tion and experiment is postponed to later chapters:* at present
only certain general features of the process need be considered.

In the case of self-differentiation (see pp. 50, 51) the gradual
changes in the substratum may be reversed in direction under
altered conditions; the gel may again become a sol. But the
synthesis of new colloid molecules and the formation of new sol,
on the one hand, and the gradual breakdown and elimination of
the old gel, on the other, is also possible. Apparently nuclear and
cell division are or may be factors in dedifferentiation. With the
occurrence of division the progressive changes in the cell, since the
preceding division, disappear more or less completely and the cell
returns to or approaches its original condition. An increase in
metabolic rate is also apparently associated with division. If
the changes in one direction balance those in the other, cells which
divide may remain indefinitely embryonic, like the vegetative tissues
of plants and the growing regions of certain animals. But if the
nucleus or cell does not divide, or if division does not bring the
cell back to its original condition, then a progressive change must
occur in the cell or from one cell generation to another, and this
change appears sooner or later as differentiation and may go so
far that the cell finally becomes incapable of division. Where
differentiation has been a correlative process, isolation of a part
from the influence of the correlative factors which have determined
the course of its differentiation may result, if the part is capable of
teacting to the altered conditions, in metabolic changes of such a

1 See particularly chap. v, and chap. x, pp. 245-47.

2 See chap. vi, pp. 141-42, and also Lyon, ’o2,’04; Spaulding, ’04; Mathews, ’o6.

56 SENESCENCE AND REJUVENESCENCE

character that substances previously accumulated as structural
components of the part are now broken down and eliminated, and
this is dedifferentiation.

If the cell is a physico-chemical system and not an entity su
generis, the occurrence of dedifferentiation is no more difficult to
account for than the reappearance of a certain kind of chemical
reaction in a non-living chemical system when conditions which
altered the character of the reaction have ceased to act. The
occurrence of both differentiation and dedifferentiation is exactly
what we should expect from the physico-chemical point of view.
The assumptions of the germ-plasm theory merely complicate and
befog the whole problem, and not only that, but, as pointed out in
the preceding chapter, the theory is essentially ‘“‘vitalistic”’ and
even pluralistic in its logical implications.

Within the last few years, however, many cases of dedifferen-
tiation have been recorded and various authors, among them
Lillie, Loeb, Driesch, Schultz, and others, have suggested that
development in animals is a reversible process. But reversibility
of development, so called, is not necessarily reversibility in the
chemical sense. Dedifferentiation may conceivably result from
the breakdown and elimination of the differentiated substratum
or certain components of it, and the synthesis of new undifferen-
tiated substances from nutritive material, as well as by the reversal
of the reactions which occurred in the differentiation. As in the
case of growth and reduction, it would certainly simplify our con-
ception of the process of development if we could regard it as a
reversible chemical reaction, but such a conception can only lead
us astray. Undoubtedly many reversible reactions are concerned
in development, but development itself is not a reversible reaction.
In fact, it is not simply a chemical reaction of any kind, but an
exceedingly complex series of interrelated physical and chemical
changes. Reversal of development may result from relative
changes in the rate of certain reaction components of the meta-
bolic complex as well as from reversal of reaction. In fact, it is
probable that reversal of development occurs at least as frequently
in this way as by reversal of reaction. A change in metabolism,
for example, such that a substance which has previously been

THE LIFE CYCLE. 57

accumulated as a structural component of the cell is now broken
down, oxidized, and eliminated, may bring about dedifferentiation,
but it is not necessarily a reversal of reaction in the chemical sense,
for the breakdown and elimination of the substance may be a
different process dependent upon different factors from its syn-
thesis out of nutritive substances.

In order then to avoid the possibility of confusion, it is prefer-
able to regard development, not as reversible, but as regressible.
Differentiation is a progression from one condition to another,
dedifferentiation a regression, but perhaps through stages very
different from the stages of progression.

Apparently not all differentiated cells are capable of dediffer-
entiation to the embryonic condition; at least dedifferentiation
fails to occur in many cases under any conditions with which we
are familiar. In general, less highly differentiated cells undergo
dedifferentiation more readily and more completely than more
highly differentiated; consequently dedifferentiation is much
more conspicuous in the lower than in the higher forms, although
even in man some cells are capable of more or less dedifferentiation.
This limitation of dedifferentiation, as well as the advance of differ-
entiation, in the course of individual development and evolution,
suggests again an increase in the physiological stability of the
cellular substratum.

Dedifferentiation may be brought about in cells capable of it
either by forcing the cell to use up its own substance as a source
of energy and so undergo reduction, as in starvation, or by isolating
the cell from the action of the correlative factors which have
brought about differentiation, and in some cases, and to a certain
degree, simply by increasing the rate of metabolism of the cell by
stimulation or otherwise. Reduction, except perhaps in embryonic
cells, is probably impossible without some degree of dedifferentia-
tion, but dedifferentiation may occur without reduction. Since the
differentiated cell has in general a low rate of metabolism as com-
pared with the embryonic cell, and since the decrease in rate is
associated with differentiation, we should expect that an increase
in rate would occur during dedifferentiation, and this, as will appear,
is apparently the case.

58 SENESCENCE AND REJUVENESCENCE

If the suggestions of the preceding section concerning the nature
of differentiation are correct, we should expect the most recently
developed morphological features of the cell to disappear first in
dedifferentiation, since these are, under the conditions existing in
the cell, the least stable of the substratal constituents. As these
are removed the rate of metabolism rises and other parts of the
substratum become relatively unstable and disappear, and so on,
until the cell once more approaches the embryonic condition. So
far as the course of morphological dedifferentiation has been fol-
lowed, it seems in general to proceed in this way and so to reverse the
course of differentiation. But this does not necessarily involve a
reversal of reaction any more than the removal of a previously
deposited sand-bar, by acceleration or change of course of the cur-
rent of a river, involves a reversal of its flow.

The dedifferentiating cell is apparently capable at any stage
of resuming the process of differentiation, and if dedifferentiation
proceeds far enough it may, under altered correlative conditions,
begin a new course of differentiation and become a different kind
of a cell from that which it was originally. As the sand-bar formed
in the stream under certain conditions may under others be re-
moved and its place taken by a deep channel, and again the channel
may give place to a mud flat or a beach, so the original morpho-
logical differentiation of the cell may disappear and give place to
other kinds of differentiation as the physiological conditions change.

THE BASIS OF SENESCENCE AND REJUVENESCENCE

The association of a colloid substratum with a chemical reaction-
system and the occurrence of growth and reduction and of differ-
entiation and dedifferentiation lead us to a conception of senescence
and rejuvenescence which, as will appear in following chapters,
seems to be the only one which is in full agreement with the facts
of experiment and observation. According to this view, senescence
is primarily a decrease in rate of dynamic processes conditioned by
the accumulation, differentiation, and other associated changes of
the material of the colloid substratum. Rejuvenescence is an
increase in rate of dynamic processes conditioned by the changes
in the colloid substratum in reduction and dedifferentiation.

THE LIFE CYCLE 59

Senescence is then a necessary and inevitable feature of growth
and differentiation, while rejuvenescence is associated with reduc-
tion and with the various reproductive processes in which more
or less differentiated parts of the organism undergo dedifferentia-
tion. Even as regards gametic or sexual reproduction, the facts
indicate that the gametes or sex cells are very highly specialized
and differentiated cells and that early embryonic development is
essentially a period of dedifferentiation and rejuvenescence.

Viewed from this standpoint, life is then really a cyclical pro-
cess as it appears to be. The organism grows, differentiates, and
ages, and these processes lead, usually in nature through reproduc-
tion of one kind or another, to reduction, dedifferentiation, and
rejuvenescence. No part of the organism remains perpetually
undifferentiated and perpetually young. The young organism
arises from the old, not from a self-perpetuating source of youth,
which is itself always young, and the young becomes old again.

REFERENCES

Bascock, S. M.
1912. ‘Metabolic Water: Its Production and Réle in Vital Phenomena,”
Univ. of Wisconsin Agric. Expt. Sta. Research Bull. No. 22.

Curtp, C. M.
tg11. ‘Experimental Control of Morphogenesis in the Regulation of
Planaria,” Biol. Bull., XX.

DAVENporT, C. B.
1897. Experimental Morphology. New York.

Hoxtey, T. H.
1853. ‘Review of the Cell Theory,” British and Foreign Med. Chir.
Rev., XII.

Kassowrtz, M.
1899. Allgemeine Biologie. Wien.

LEPESCHEIN, W. W.
to1z. ‘Zur Kenntnis der Einwirkung suppramaximaler Temperaturen
auf die Pflanze,” Berichte d. deutsch. bot. Ges., XXX.

Logs, J., and WasTENEYS, H.
1g11. “Sind die Oxydationsvorginge die unabhangige Variable in den
Lebenserscheinungen ?”? Biochem. Zeitschr., XXXVI.

60 SENESCENCE AND REJUVENESCENCE

Lyon, E. P. ;
1902. “Effects of Potassium Cyanide and of Lack of Oxygen upon the
Fertilized Eggs and the Embryos of the Sea Urchin (Arbacia
punctulata),” Am. Jour. of Physiol., VII.

1904. ‘Rhythms of Susceptibility and of Carbon Dioxide Production
in Cleavage,” Am. Jour. of Physiol., XI.

Matuews, A. P.
1906. ‘‘A Note on the Susceptibility of Segmenting Arbacia and A sterias

Eggs to Cyanides,” Biol. Bull., XI.

PFEFFER, W.
1901. Pflanzenphysiologie, Band II. Leipzig.

SCHULTZ, E.
1904. “Uber Reduktionen: I, Uber Hungererscheinungen bei Planaria
lactea,” Arch. f. Entwickelungsmech., XVIII.

SPAULDING, E. G.
1904. ‘The Rhythm of Immunity and Susceptibility of Fertilized Sea
Urchin Eggs to Ether, to HCl and to Some Salts,” Biol. Bull., VI.

PART IIT

AN EXPERIMENTAL STUDY OF PHYSIOLOGICAL SENESCENCE
AND REJUVENESCENCE IN THE LOWER ANIMALS

CHAPTER III
THE PROBLEM AND METHODS OF INVESTIGATION
THE NATURE OF THE PROBLEM

Both morphological and physiological changes are involved in
the processes of senescence and rejuvenescence, and we may attack
the problems from either the morphological or the physiological
side. On the morphological side we may determine the changes
in physical properties, form, and structure of the substratum which
occur during senescence and rejuvenescence, and on the physio-
logical side we may investigate the changes in functional activity
and in metabolism.

Concerning the morphological changes associated with senes-
cence, particularly in the higher animals and man, we already
possess a considerable body of facts. As regards the physiological
changes, we know that in the higher animals and man the rate of
metabolism per unit of substance undergoes in general a decrease
with advancing age from very early stages onward, and that
sooner or later a decrease in functional activity and a general
deterioration of the organism occurs. Our knowledge concerning
the lower animals is less complete. We are familiar with the general
course of development and differentiation in most forms, but the
morphological differences between young and old adults have
received comparatively little attention. Of the physiological
aspect of senescence in the lower forms we have little positive
knowledge. We know that in most forms growth is more rapid
in earlier stages and that in many plants and animals the length
of life under the usual conditions is more or less definite, and in
some forms we can observe a decrease in functional activity with
advancing age. On the other hand, some organisms live and
remain active for an indefinite period and apparently do not grow
old. Few attempts have been made, however, to determine by
analytic investigation the significance of these various facts and to
find a common basis for them.

63

64 SENESCENCE AND REJUVENESCENCE

As regards rejuvenescence, biologists are not even agreed that
it is of general occurrence. The belief that the germ plasm,
which is assumed not to grow old, except as it gives rise to a soma,
is the only source of young organisms has been so general that the
possibility of rejuvenescence has received but little consideration.
Maupas’ classical investigations upon the infusoria (Maupas, ’88,
’8q) seemed to indicate that a process of rejuvenescence leading to
a larger size of individuals and a higher rate of division resulted
from conjugation in these forms, but the recent work of Jennings
(13) makes it evident that this is certainly not always the case.
The work of E. Schultz (o4, ’08) and others on reduction and
dedifferentiation in the lower forms, the suggestions of a number
of others that development is “‘reversible,”’ Minot’s view (Minot,
’08) that the egg before fertilization is an old cell and undergoes
rejuvenescence during the early stages of embryonic development,
and the well-known fact that in plants differentiated cells may lose
their differentiation and give rise to new plants—these are the chief
data and conclusions which we possess concerning rejuvenescence.

The various facts have led to the formulation of various theories
and suggestions as to the nature of senescence, but these are mostly
based rather upon observational than experimental evidence, and
some of them take account only of man and the higher animals
and so do not apply to organisms in general, while others are
more or less speculative in character and cannot readily be tested.
There is at present no generally accepted theory of senescence,
and as for rejuvenescence it can scarcely be said that any theory
exists.

The real problem before us is then that of finding a general
basis for these phenomena which is applicable to all cases, not
merely to those in which the organism manifestly grows old, repro-
duces, and dies, but also to those in which, instead of dying, the
whole organism breaks up or divides into new individuals, which
repeat the cycle of growth, development, and reproduction, and
finally, to those cases in which the whole organism or parts of it
appear not to grow old, but live on indefinitely.

The first step toward accomplishing this is to find some means
of determining whether an individual organism in a given case is

THE PROBLEM AND METHODS OF INVESTIGATION 65

young or old, not merely morphologically but physiologically. We
can of course distinguish embryonic, larval, and juvenile forms from
adults by their morphological characters, and in many cases by
their physiological characters as well, but it is not always easy to
distinguish younger and older individuals of the same general stage
of the life cycle. In the higher animals certain morphological
changes which are apparently characteristic of senescence have
been observed in some cells, but the morphological features of the
cells of different organisms are so different and the visible changes
so slight in many cases that, though it is usually possible to dis-
tinguish embryonic from definitely differentiated cells, it is very
often impossible to distinguish old and young individuals of the
same general stage by the morphological characters of their cells.
Measurements of the metabolism or of the rate of growth in man
and the mammals show that the rates of both per unit of weight
decrease as age advances, but the methods employed for such forms
are not readily applicable in many other cases, because of the con-
ditions of existence, the small size, the low rate of metabolism,
etc. In the course of my investigation of the process of reproduc-
tion in the lower invertebrates a method based on the physiological
resistance or susceptibility of the animals to certain conditions has
been developed, which has proved to be of great value in distin-
guishing physiologically young from old organisms as well as for
various other purposes.

SUSCEPTIBILITY IN RELATION TO RATE OF METABOLISM

It is a familiar fact that the susceptibility or physiological
resistance of man and the higher animals to various external factors,
and particularly to those which depress, changes with advancing
age, and I have found that this is also true for the lower animals, as
far as they have been tested. On the basis of this relation between
susceptibility and physiological age, it has been possible to develop
a method which not only enables us to distinguish differences in
age, but affords a means of comparing in a general way the rates
of the metabolic processes, or of certain fundamental metabolic
reactions in different animals. This method, which may be called
the susceptibility, physiological resistance, or survival-time method,

66 SENESCENCE AND REJUVENESCENCE

consists essentially in determining the length of life of different
individuals or lots under certain ‘standardized conditions which kill
by making impossible in one way or another the continuation of
metabolism.

The substances used in my determinations of susceptibility
include the cyanides, and ethyl alcohol, ethyl ether, chloroform,
chloretone, acetone-chloroform, and in some cases various other
narcotics. Carbon dioxide and water in which large stocks of the
species under examination have been kept and which therefore
contain soluble products of metabolism have also been used in a
few cases with essentially similar results. Certain conditions, such
as lack of oxygen, low temperature, and high temperature, act in
much the same way, at least in certain cases and when properly
controlled. In my experiments the cyanides have proved most
convenient and satisfactory, because the concentrations required
are very low and osmotic and other complications are negligible,
and because in the lower animals, which have been chiefly used,
irritability and movement persist to some extent almost to the
death point, while in alcohol, ether, and other narcotics they dis-
appear earlier. There is no doubt that a relation exists between
the general metabolic condition of organisms, or their parts, and
their susceptibility to a very large number of substances which act
as poisons, i.e., which in one way or another make metabolism
impossible, and that differences ‘n susceptibility may be used with
certain precautions and within certain limits as a means of distin-
guishing differences in metabolic condition and, more specifically,
differences in metabolic rate.

Concerning the nature of the action of poisons such as hydro-
cyanic acid, the cyanides, and the great group of substances com-
monly called narcotics, opinions at present differ widely. As
regards the cyanides, it has been very generally believed since
Geppert’s experiments that they decrease or inhibit cell respiration
directly or indirectly." Recent experiments by Vernon, Warburg,

* Carlson, ’07; Gasser and Loevenhart, ’14; Geppert, ’89; Grove and Loevenhart,
’11; Kastle and Loevenhart, ’01; Loeb and Wasteneys, ’13a, ’13b; Mathews and
Walker, ’09; Richards and Wallace, ’08; Vernon, ’06, ’09, ’10; Warburg, ’roc, ’14¢.
Further references will be found in these papers.

THE PROBLEM AND METHODS OF INVESTIGATION 67

and Loeb and Wasteneys have demonstrated that oxygen consump-
tion is greatly decreased in animals by cyanides, and it has also
been shown experimentally that the cyanides inhibit oxidations
and the action of oxidizing enzymes in various cases outside the
organism. To the hypothesis that the cyanides inhibit oxidations
in the organism the objection has been made that they affect, not
only aerobic or oxybiotic, but anaerobic animals as well, although
in the latter, oxidations requiring atmospheric oxygen do not occur.
In answer to this, it has been pointed out that even in anaerobic
forms oxidations occur, the oxygen being derived from substances
in the body instead of from the atmosphere.

The cyanides and other substances containing the cyanogen
radical, CN, are in general extremely powerful poisons, but their
action resembles in certain respects that of the substances known
as narcotics or anesthetics.

The characteristic physiological effect of all these substances is
a decrease or complete loss of irritability, which, however, is com-
pletely reversible up to a certain limit and so may be followed by
complete recovery. But the narcotics are like the cyanides poisons,
and if they act in sufficiently high concentration or for a sufficiently
long time they bring about changes of some sort which are not
reversible and which lead to death by retardation and final cessa-
tion of metabolism. Scientific investigation has thus far chiefly
concerned itself with the narcotic, i.e., the reversible, rather than
with the poisonous, irreversible, effects of these substances. Many
theories of narcosis‘ have been advanced, and most of them are
still in the field. Brief mention must be made of the more impor-
tant among these theories.

Verworn and his school have long maintained that narcotics
decrease the oxidation processes and the respiratory activity of the
protoplasm, and Verworn has recently suggested that the narcotics,
either by adsorption or by loose chemical combination, render the

1 The following references include some of the more important literature bearing
upon the different theories of narcosis: Alexander and Cserna, ’13; Bernard, ’75;
Dubois, ’94; Héber, ’10; Kisch, ’13; R. S. Lillie, ’12a, ’12b, ’13a, ’13b, ’14; Loeb
and Wasteneys, ’13@, ’13b; A. P. Mathews, ’1ro, ’13; H. Meyer, ’99, ’o01; Overton,

’o1; J. Traube, ’o4a, ’o4b, ’08, ’10, ’11, 713, etc.; Verworn, ’03, ’12, ’13; Warburg,
’toa, ’10b, ’10¢, 114,110,120, ’12b, 13, "14a, ’14b, ’14c; Winterstein, ’02, ’05, 13, 14.

68 SENESCENCE AND REJUVENESCENCE

oxygen carriers of the cell incapable of activating the molecular
oxygen, and that the cell consequently asphyxiates. A.P. Mathews
and some others have maintained that the action of narcotics
upon the oxidations is direct and chemical, and Mathews has re-
cently suggested that the residual valences of narcotic substances
are responsible for their action. In this connection it may be noted
that the temperature coefficient of the susceptibility of Planaria
to potassium cyanide and alcohol is of the same order of magnitude
as the usual temperature coefficient of chemical reactions (Child,
’13a). This fact indicates that the susceptibility increases in the
same ratio as the rate of chemical reaction and therefore suggests
that the cyanide and alcohol act directly upon the metabolic reac-
tions or some of them. But this relation between the temperature
coefficients of susceptibility and the rate of chemical reaction can-
not be made the basis of positive conclusions because it is possibly
nothing more than a coincidence, or it may result from a complex
of factors which we cannot analyze.

Within the last few years various investigators have recorded
results at variance with the Verworn theory of narcosis. Warburg
found that certain narcotics produced narcosis without decreasing
the oxygen consumption of the organism. Later Loeb and Waste-
neys reported very similar results. They found that in some forms
of narcosis the decrease in oxygen consumption was very slight,
while in others it was much greater. With the cyanides particu-
larly, narcosis occurs only when oxygen consumption is greatly
reduced, while in alcohol narcosis the decrease in oxygen consump-
tion may be very slight. Oxygen consumption is decreased in
all cases, however, if sufficiently high concentrations of the nar-
cotic are used. Kisch has concluded from certain experiments
on protozoa that while narcosis does decrease certain oxidations it
does not affect all. Winterstein has also found that in alcohol
narcosis of the spinal cord of the frog a slight increase rather than
a decrease in oxygen consumption may occur even when irritability
is completely lost; there is, however, no increase in oxygen con-
sumption with stimulation.

Assuming that these results are correct and not due to unrecog-
nized technical or other sources of error, we are forced to conclude

THE PROBLEM AND METHODS OF INVESTIGATION 69

with these authors that decrease in oxidation is an incident or a
result of narcosis which may or may not occur, and that the funda-
mental feature must be sought in some other change. As regards
some of these experiments, however, certain possible sources of
error exist and further investigation may alter the results. At
present it is difficult to conceive how narcosis can occur without
decrease in oxidation.

Arguing from the observed parallelism between the fat solu-
bility of various substances and their narcotic power, Meyer and
Overton advanced the theory that the cell membrane consisted
in at least a considerable part of lipoid or fatty substances and
that the action of the narcotics was determined by their solubility
in these substances. This theory has undergone development and
modification at the hands of later investigators, and the question
as to the nature of the narcotic action of the substances which
enter the cell by dissolving in the lipoids of the membrane has
received various answers. Some have held that the lipoids of the
membrane were responsible only for the entrance of the narcotics,
which once inside the cell acted chemically or otherwise. Others
believe that narcosis is the result of the changes in the lipoids of
the membrane produced by the narcotic substances. Warburg
considers the physical condition of the lipoids to be of great impor-
tance in connection with narcosis. According to Hober, narcosis
occurs when the narcotics have collected to a certain molecular
concentration in the cell lipoids, because the narcotics then inhibit
a change in colloid aggregate condition of the lipoids which is
characteristic of excitation. R. S. Lillie finds that narcotics de-
crease the permeability of the cell membrane or its ability to
undergo increase in permeability, and so decrease or inhibit the
increase in permeability which he believes to be the essential
feature of stimulation.

Some forty years ago Claude Bernard suggested that narcotics
brought about a partial reversible coagulation of the protoplasm
of the nerve cell. Later Dubois advanced the hypothesis that the
narcotics bring about loss of water from the protoplasm and so
decrease metabolic activity. Recently J. Traube has concluded
on the basis of extensive experimentation that the narcotic effect

70 SENESCENCE AND REJUVENESCENCE

is due to changes in the colloid substratum. According to Traube
the narcotics act by decreasing surface tension and so increasing
the degree of aggregation of the cell colloids, and decrease in oxida-
tion or in metabolism in general results from this change in aggre-
gate condition. Other factors may play a part in certain cases,
but Traube has shown that a relation exists in many cases between
the decrease in the surface tension of water by narcotic substances
and their narcotic power, and that narcotic concentrations. of
many different substances are isocapillary, i.e., decrease surface
tension by the same amount. Warburg has shown that a close
interrelation exists between the oxidations in the cell and the funda-
mental structure and that, at least in many cases, the narcotics de-
crease oxidation. He concludes, in essential agreement with
Traube, that the narcotics act by altering surface tension and so
produce capillary changes, particularly in the lipoids.

The lipoid theory of Meyer and Overton and their followers
and Traube’s surface tension theory differ from Verworn’s asphyxi-
ation theory in that they regard the decrease in metabolic activity
in narcosis as resulting from or associated with the changes in the
colloid substratum of the cell. The unsatisfactory character of
purely or pre-eminently chemical theories of the organism has
been pointed out in chap. i, and it seems probable that in narcosis
as well as in other changes in chemical activity in the organism,
the substratum and the changes which occur in it must be taken
into account. It seems not improbable, moreover, that narcosis
is not always produced in exactly the same way. Irritability, as
Winterstein suggests, probably depends upon the maintenance of
a complex dynamic equilibrium of some sort, and this equilibrium
may be destroyed with a resulting loss of irritability, by changes of
various kinds in the cell. It is even conceivable that in some cases
the change may concern primarily or chiefly the substratum, and
in other cases the chemical reactions, or certain of them, and we
must admit the further possibility that both the substratal and the
chemical changes may differ with different narcotic substances
and yet produce much the same general result as regards irrita-
bility. Various observations show that very considerable differ-
ences do exist in different forms of narcosis. It was noted above

THE PROBLEM AND METHODS OF INVESTIGATION 71.

that the decrease in oxygen consumption may apparently differ
widely in different narcoses, and Alexander and Cserna have found
that not only is this true, but that the decrease in carbon-dioxide
production is not parallel to the decrease in oxidation in different
brain narcoses. In short, it is possible that the changes in the cell
which bring about narcosis may differ in character with different
narcotics and perhaps with different cellular conditions. Perhaps,
as so often in the history of biological theory, all the theories of
narcosis are more or less correct.

But, however the narcotic substances act upon the cell, there
can be no doubt that within a given species or organism a general
relation exists between metabolic condition and susceptibility to a
given narcotic. Differences in metabolic condition do not exist
independently of differences in condition of the colloid substratum,
and whether the narcotic affects primarily the substratum or cer-
tain of the chemical reactions, the susceptibility of the organism
or part to its action must differ as the conditions which determine
or are associated with metabolic activity differ.

Narcosis is only one stage in the action of the narcotic sub-
stances. When they are present in sufficiently high concentration
or act for a sufficiently long time, they bring about changes which
are not reversible and which finally end in death by making the
continuation of metabolism impossible. The wide range of varia-
tion observed in some cases between narcotic and killing concen-
trations, both with different narcotics and with the same narcotic
at different stages of development (Vernon, ’13), indicates that
the reversible changes involved in pure narcosis are different in
some way from those which result in death. With the killing con-
centrations the relation between susceptibility and metabolic con-
dition is more distinct and uniform than with the lower, purely
narcotic concentrations, where incidental factors may sometimes
mask or reverse the fundamental relation (see pp. 75-76). With
the cyanides, however, where narcotic and killing concentrations
do not differ very greatly, this relation appears more distinctly
and uniformly than with any other agents thus far used.

It cannot of course be maintained that the susceptibility to
cyanides or other narcotics of an organism or part at a given moment

72 SENESCENCE AND REJUVENESCENCE

is an exact measure of its total metabolism at that moment. If the
cyanides or other narcotics act directly on the oxidation processes,
a general relation between susceptibility and oxidation must exist,
but while the oxidations are fundamental metabolic reactions, and
serve in a general way as a measure of metabolic activity, a con-
siderable range of variation in the different reactions which go to
make up the the metabolic complex may undoubtedly exist. If, on
the other hand, these substances act on the substratum and affect
the metabolic reactions only or primarily through the substratal
changes, susceptibility must be related to the general average of
metabolic activity, but certain reactions may be more affected than
others in the early stages of action, though sooner or later the
metabolic process as a whole is retarded or inhibited.

In concentrations of the cyanides or other narcotics, which not
only narcotize but gradually kill, a decrease in metabolism, as
measured by oxygen consumption, by carbon-dioxide production,
by functional activity, or by other means, occurs in all cases, and
metabolism finally ceases. In concentrations in which death
occurs at times varying from a few minutes to a few hours and when
complicating factors are absent, the susceptibility varies directly
with the general metabolic rate. Conditions which increase meta-
bolic activity increase susceptibility, and vice versa. This method
of determining susceptibility I have called the direct susceptibility
method (Child, ’13@).

The capacity of organisms to acclimate themselves to, or acquire
a tolerance to, narcotics has long been recognized: this capacity is
well illustrated by the high degree of tolerance for alcohol, cocaine,
etc., developed in the human organism. In concentrations of nar-
cotics which are sufficiently low to permit partial, but not complete,
acclimation, we find that the relation between susceptibility and
metabolic rate undergoes reversal. In such concentrations the
individual or part with the higher metabolic rate becomes more
readily and more completely acclimated and therefore lives longer
than the individual or part with the lower metabolic rate which is
unable to acclimate itself and so dies earlier. This relation between
metabolic rate and capacity for acclimation is to be expected, for
the occurrence of acclimation evidently depends on conditions in

THE PROBLEM AND METHODS OF INVESTIGATION 73

the organism which are associated with metabolic activity. Thus
the metabolic condition of different individuals or parts may also be
compared by means of this indirect or acclimation method.

These differences in susceptibility to narcotics, particularly
those determined directly with relatively high concentrations,
afford, when properly controlled, a very delicate method for com-
paring general metabolic rates in different individuals and parts,
at least in many of the lower animals. In a recent paper (Child,
’13a) the technique of the method for flatworms and similar forms,
its different modifications and its limitations have been considered
at length. As regards the relation between susceptibility or resist-
ance to cyanide and rate of metabolism, it was shown in that
paper that susceptibility is altered by motor activity, that the
temperature coefficient of susceptibility is of the same order of
magnitude as that of most chemical reactions, and that differences
in carbon-dioxide production correspond to differences in suscepti-
bility.

The estimations of carbon-dioxide production were made by Dr.
S. Tashiro with the ‘‘biometer” devised and recently described by
him (Tashiro, 7136). The sensitiveness and great value of this
apparatus are shown by the fact that Tashiro has been able to
demonstrate the production of carbon dioxide in the resting nerve,
its increase by stimulation, and its decrease by narcotics, and has
also shown that living seeds resemble the nerve in most respects as
regards irritability (Tashiro, ’13a). In the comparison between the
results of the susceptibility method and the carbon-dioxide produc-
tion the flatworm Planaria dorotocephala (see Fig. 6, p. 93) was
used in most cases. The susceptibility method shows that the rate
of metabolism is higher in young than in old animals, in starved
than in fed, and in animals stimulated to movement than in resting
animals. In distilled water the rate of metabolism as measured by
the susceptibility method is higher and in 5 per cent sea-water lower
than in tap-water. In pieces isolated by cutting, the rate of metab-
olism is higher in long anterior pieces than in posterior pieces of
the same length (cf. Child, ’145). In each of these cases the animal
or piece which possessed the higher rate of metabolism according
to the susceptibility method produced more carbon dioxide than

74 SENESCENCE AND REJUVENESCENCE

the other. The complete agreement between the two methods
indicates very clearly that both are concerned in one way or another
with fundamental metabolic reactions and that both afford a very
delicate means of comparing in a general way the rates of these
reactions.

It is evident that accuracy in the use of susceptibility as a
method of investigation depends to a considerable extent upon
the exactness with which it is possible to determine the quantitative
effect of the cyanide or other agent used upon the organism. In
the lower invertebrates, particularly the protozoa, coelenterates,
and flatworms, which have formed the material for most of my
experiments, and in the early stages of development of many other
animals where hard skeletal structures are absent and supporting
tissues do not possess a high degree of firmness and coherence, or
are entirely absent, death is followed in a short time, often at once,
by more or less complete disintegration. The body loses its form,
swells, breaks down into a shapeless mass, and may finally dis-
appear completely, except for a slight turbidity in the water, which
results from the minute particles in suspension. In such cases,
however, movement may continue to some extent, particularly in the
cyanides, until a short time before disintegration begins, or in some
forms up to the very instant of disintegration. In these forms then
it is possible to determine with considerable exactness the time when
death occurs and so to compare the length of life of different indi-
viduals under certain specific conditions, e.g., a certain concen-
tration of cyanide, alcohol, etc., or under low temperature or lack
of oxygen. In many of my experiments changes of this kind have
been taken as the criterion of death, but essentially the same results
are obtained with the lower animals if the times of complete cessa-
tion of movement in response to stimulation are determined instead
of the times of disintegration.

Where such disintegration does not occur, or is retarded by the
physical consistency of the organism or part concerned, it is often
possible to determine the occurrence of death in small animals under
the microscope by other changes in appearance, such as an increase
in opacity, a change in color, etc. Moreover, all these methods of
determining the death point can be checked and the time of death

THE PROBLEM AND METHODS OF INVESTIGATION 75

determined in cases where such methods are not available by
determining the limits of recovery, i.e., at stated intervals a certain
number of the organisms are removed from the narcotic solution to
water: the length of time in the narcotic at which recovery ceases
to occur is at least approximately the survival time.

With the flatworms and other simple naked forms the suscepti-
bility method can usually be employed independently of differences
in size, for in such cases the death changes at the surface of the body
may be used as a basis for comparison. Moreover, in such elon-
gated flattened forms as the flatworms, surface increases almost
as rapidly as volume. But in forms where the permeable surfaces
are limited to certain regions of the body or are internal, as in air-
breathing forms, or where the body is covered by an exoskeleton,
the certain elimination of the factor of size often presents a difficult
problem.

While most of my determinations of susceptibility have been
made upon the lower invertebrates, some experiments with the
higher invertebrates and the lower vertebrates have demonstrated
that the relation between susceptibility to cyanide and general
metabolic rate is the same in these as in the lower forms. But at
least as regards the vertebrates this is not true for all narcotics.
Vernon (’13) has found, for example, that the susceptibility of tad-
poles to some narcotics increases and to others decreases with ad-
vancing age, and suggests that these differences are due to changes
in the constitution of the cell lipoids. This is probably not the only
factor concerned: differences in the lipoid solubility of the different
narcotics and differences in the amount as well as the constitution
of lipoids in the nervous system and still other factors are probably
also involved, but further investigation is necessary before the sub-
ject is cleared up. In the lower invertebrates I have as yet found
no indication of such differences in the action of different narcotics
as Vernon describes. With some narcotics the age changes in sus-
ceptibility are greater than with others, but in all cases thus far
the changes during a given developmental period, as determined by
different narcotics, proceed in the same direction. It seems prob-
able that the differences in the direction of change in susceptibility
observed by Vernon result, at least in part, from differences in the

76 SENESCENCE AND REJUVENESCENCE

relation between the narcotics and the cell lipoids. In the verte-
brates the accumulation and differentiation of lipoids, particularly
in the nervous system, is very much greater than in the lower inver-
tebrates, and it is probable that with some narcotics which are
highly fat soluble, the fundamental relation between susceptibility
and general metabolic condition is completely masked, or even
reversed, by their higher concentration in the cells of the nervous
system with a given external concentration, and consequently by
their greater narcotic effect on these cells. In the lower animals
and in early stages of development the action of narcotics is general,
but with the advance in differentiation the susceptibility of the
nervous system as compared with other organs increases very
greatly. In general it appears that the differences in susceptibility
to all narcotics are much more nearly alike in the lower forms and
the early stages of all, while in the later stages of the higher forms
those substances which are highly water soluble act in much the
same way as in the lower forms, but the action of the highly fat-
soluble narcotics is modified because of the increasing development
and differentiation of lipoids in the nervous system, and very
probably other modifications also occur. Nevertheless, and in
spite of these complicating factors which appear in certain cases,
differences in susceptibility to various agents can, with proper
precautions and checks, be used to a certain extent as a means of
comparing general metabolic condition, even in the vertebrates.
The use of the cyanides seems to be freer from complicating fac-
tors than that of other agents.

Undoubtedly, however, the chief value of the susceptibility
method lies in its applicability to small simple organisms and to
different regions of a single, intact, not too highly differentiated
individual. By means of it we are able to gain some idea of differ-
ences in metabolic rate in many cases to which other methods are
not applicable.

Thus far susceptibility to narcotics, cyanides, and other sub-
stances in its relation to metabolism has received but little atten-
tion. Lyon (’o2, ’o4) and A. P. Mathews (’06) have used
susceptibility to cyanides and to various other substances and con-
ditions as a method for showing differences in rate of metabolism

THE PROBLEM AND METHODS OF INVESTIGATION 77

in the cleavage stages of eggs, and Loebt and others have made use
of the cyanides to decrease or inhibit the oxidation processes in
eggs, and Drzewina and Bohn (’13) have observed parallel differ-
ences in susceptibility to cyanides and lack of oxygen along the lon-
gitudinal body-axis of certain flatworms. Some other incidental
observations also exist, but the general significance of differences
in susceptibility has been either ignored or not recognized.

THE DIRECT METHOD

By this method the resistance or susceptibility is determined
directly by concentrations of cyanide or other agents which kill
the animals within a few hours. For a particular species a con-
centration must be determined which kills without acclimation,
but which does not kill so rapidly that the differences in suscepti-
bility do not appear clearly. For Planaria dorotocephala (see p. 93)
and other related species a concentration of one one-thousandth
gram-molecular solution (0.001 mol., 65 milligrams per liter,
0.0065 per cent) of potassium cyanide has been found most satis-
factory at temperatures about 20° C. and for most purposes. This
kills the animals in from two to twelve hours according to their con-
dition. But a range of concentrations from 0.0002 mol. up to
o©.005 mol., or even higher, may be used, except where the meta-
bolic rate is very high, as in young animals, without altering any-
thing but the time factor. Essentially the same results are obtained
from 4 per cent alcohol or from 2 per cent ether as from 0.001 mol.
potassium cyanide.

Since the death and disintegration of different parts of the body
usually follow a regular sequence (Child, ’13b), it is possible to
determine the time, not merely of disintegration of the whole ani-
mal, but of the various regions of the body. The body of Planaria
consists of two or more zooids (see p. 123) of which only the anterior
one is morphologically developed. In this anterior zooid death and
disintegration usually begin at the head-region and proceed pos-
teriorly, and the lateral margins of the body usually die and disin-
tegrate before the median region. The most satisfactory method

t Loeb, ’og, ’10; Loeb and Lewis, ’02; Loeb and Wasteneys, ’10; and various
other papers.

98 SENESCENCE AND REJUVENESCENCE

of recording the course of death and disintegration has proved to
be that of examining the lots of animals at stated intervals, e.g.,
every half-hour, and recording the condition of each individual.
In order to accomplish this most readily five stages of disintegra-
tion have been more or less arbitrarily distinguished as follows:

Stage I. Intact, not showing any appreciable disintegration.
Such animals or pieces are always alive and show movement.

Stage II. In whole animals from the first appearance of disin-
tegration, which is practically always in the head-region, to the
first appearance of disintegration of the lateral margins of the body.
In pieces, from the beginning of disintegration at one or both ends
to the first appearance of disintegration on the lateral margins.
Considerable motor activity may still be present.

Stage III. In both whole animals and pieces from the appear-
ance of disintegration on the lateral margins until it has extended
over the whole length of the margins. Movement may still occur
in the parts least affected.

Stage IV. From the end of Stage III to the time when the sur-
face of the body in the median regions disintegrates. Motor
activity ceases.

Stage V. Disintegration has extended to all parts of the sur-
face and the progress of death over the body is completed. The
remaining parts representing the internal organs gradually swell
and break up, but the process is not followed beyond the completion
of surface changes.

Attention must be called to the fact that these stages represent
primarily the progress of the surface changes over the body from
one region to another rather than the progress of disintegration
through the internal organs. In these and other naked animals
‘differences in size of the animal do not affect the progress of the
surface changes, while they may be an important factor in the rate
of penetration of the reagent and consequently in the disintegra-
tion of the internal organs. But since the surface changes in any
region are practically coincident with the death of that region, it is
not necessary to follow the internal changes, and in naked-bodied
animals the method becomes for all practical purposes independent
of size.

THE PROBLEM AND METHODS OF INVESTIGATION 79

There is no difficulty in distinguishing between these five stages
with sufficient exactness for all purposes. Where the differences
in rate of metabolism between two animals or lots are great, they
are clearly shown by the times of the beginning and completion of
disintegration in each lot, but by following the different stages of
the process it is possible to distinguish slight differences. As re-
gards length of time, the different stages are not strictly comparable
in all cases; in large animals, for example, Stage III extends over
a somewhat longer time than the other stages, because the progress
of disintegration along the margins in the posterior direction
requires a longer time than in small animals and pieces where the
length of the margins is much less.

In comparing susceptibilities determined at different times
with different solutions, great care is necessary, for slight differ-
ences in alkalinity of the water alter the susceptibility very con-
siderably, and susceptibility also varies with the temperature. In
order to avoid these and other complications, whenever possible
susceptibilities to be compared should be determined at the same
time, with the same solution, and under the same conditions of
temperature and light, etc.

Table I will serve as an example of the method of recording the
observations and of the results obtained. In this table, the first

TABLE I
Stages of Disintegration
Length of Time Lots
in KCN
I II III IV Vv
OnBOd. s dewed dic { IT 6 3 rT
2 Io
TYOO\s staat ots cag Zt 2 3 4 I
2 9 I
DBO kes dens Z 2 3 5
3 iL :
2. 0Onciwouglicod sn { I I 9
2 3 7
BIO t, vant TAsitbilas hs a To) letqueesrns oleae vaaceey ene aeons | peas made 10
{ 2 8 2
BisOON Rave ednacte weet 2 Io
2s Oe 2 7 3
4 OO fae a erase oad axe 2 I 6 m3
4 BO. cern een ccnne 2 5 5
500k sas wagmee weds 2 3 7
5. 80n avd awies yee ea Be | Te atlanta lleaeimeeatats | vine ean emehen eat Io

80 SENESCENCE AND REJUVENESCENCE

vertical column gives in hours and minutes the length of time in
cyanide at each examination; the second gives the serial number
of each lot, and the five columns headed by Roman numerals under
“Stages” give the number of animals of each lot in each stage of
disintegration at each examination. In this case Lot 1 consists
of ten young worms, four to five millimeters in length, and Lot 2

Stages and
their values

ac
oT

II

Iot

207

40 ttt
Hourso % I 1% 2 23 3 33 4 43 5 5%

Fic. 3.—Planaria dorotocephala: susceptibility curves of young (ab) and old
(cd) animals in KCN 0.001 mol. Graphic presentation of the data of Table I. The
vertical intervals represent the arbitrary numerical values of the average disintegra-
tion stages, the horizontal intervals half-hour periods.

of ten old worms fifteen to sixteen millimeters in length, both from
the same stock.

The table shows that in the young worms of Lot 1 disintegration
begins earlier and proceeds more rapidly than in the old worms of
Lot 2. The young worms have all reached Stage V after two and
one-half hours in cyanide, while none of the old worms have reached
this stage at this time and all of them reach it only after five and

THE PROBLEM AND METHODS OF INVESTIGATION 81

one-half hours. Essentially the same differences appear in 4 per
cent alcohol, in 2 per cent ether, and in solutions of various other
depressing agents.

These data may be presented more clearly and briefly in graphic
form, as in Fig. 3, which is a graphic presentation of Table I. In
Fig. 3 the curve ad is the death curve or susceptibility curve of the
ten young worms of Lot 1, the curve cd the susceptibility curve
of the ten old worms of Lot 2.1. Each curve is a descending curve:
the distance of its starting-point (a, c, Fig. 3) to the right of the
vertical line, the axis of ordinates, indicates the length of time
between placing the animals in cyanide and the beginning of death
and disintegration; its slope indicates the average rate of disinte-
gration; the distance of its lower end (0, d, Fig. 3) from the axis
of ordinates indicates the length of time between placing the animals

t The transformation of the tabulated data into graphic form is accomplished
by giving a numerical value to each stage of disintegration and determining the average
stage of disintegration in any lot at any given time by multiplying the number of worms
in each stage at that time by the value of that stage, adding the products for all stages,
and dividing by ten. By marking off vertical intervals from above downward, cor-
responding to the numerical values assigned to the different stages, as in Fig. 3, the
average stage of disintegration can be plotted at once by counting downward from
the zero point the number of spaces equal to its numerical value, or, in other words,
the ordinate of the susceptibility curve for any average stage of disintegration is equal
to 40 minus the value of that stage.

The determination of the average stages of disintegration and of the disintegra-
tion ordinates for the time 1.30 in Table I will serve to illustrate the method of pro-
cedure. The values assigned to the different stages are: Stage I, 0; Stage II, 10;
Stage III, 20; Stage IV, 30; Stage V, 4o.

Condition of Lot 1: 2animalsin Stage III: 2X20= 40

3 « «“ « IV: 3X30= 90 Average

Stage of
5 “ “ “ V: 5 X40= 200 Disinte-
— gration
330+ 10=33
Condition of Lot 2: 8 “ aren I: 8X o= o
2 ai II: 2X10= 20
20+10= 2

Ordinate for Lot 1 at 13 hours =40—33= 7

Ordinate “ “2% “ “ =y4o— 2=38

The horizontal distances of the points of the curve from the zero point at the left
(abscissae) in Fig. 3 represent lengths of time in the cyanide, half-hour intervals,
the intervals at which the condition of the animals was recorded being indicated on
the axis of abscissae.

82 SENESCENCE AND REJUVENESCENCE

in cyanide and the death of the last part of the body in the animals
of each lot. Thus the differences in susceptibility of two or more lots
of worms are evident at a glance, for the farther to the right the
curve lies, the less the susceptibility, and vice versa. In Fig. 3, for
example, the susceptibility of the young worms, as indicated by
the curve ab, is very much greater than that of the old worms, as
indicated by the curve cd.

The susceptibility curves in the following chapters are all drawn
in the same way as those in Fig. 3 and from data similar to those in
Table I. In general this method .is more convenient than the
indirect method described below, and the results are less likely to
be affected by complicating factors.

THE INDIRECT METHOD

. By this method the susceptibility or physiological resistance to
the depressing agent is determined indirectly, through the ability
of the animals to become acclimated to a given concentration. In
general, but with certain exceptions, the ability of an animal to
acclimate to the cyanides or other depressing agents varies with the
rate of metabolism, that is, animals with the higher rate live longer
than those with a lower rate. In experiments by this method a
concentration of the agent used is determined which does not kill
the animals directly, but allows more or less acclimation. The
concentration to be used depends to some extent upon the condition
of the animals to be tested. For those with a high rate of metab-
olism higher concentrations are necessary than for those with a
low rate. With different temperatures also different concentrations
must be used. For Planaria dorotocephala at temperatures near
20° C., potassium cyanide, 0.00002-0.00004 mol. (0. 00013—-0.00026
per cent) serves in most cases and 1-13 per cent alcohol or o. 2—
o.3 per cent ether gives essentially the same results. The details
of technique and certain complicating and limiting factors have
been considered elsewhere (Child, ’11, ’13@, 14a).

The results of such experiments are best presented in graphic
form. Fig. 4 shows the different ability of old and young indi-
viduals of Planaria dorotocephala to acclimate to 13 per cent alco-
hol. Each small interval represents 2 per cent of the total number

THE PROBLEM AND METHODS OF INVESTIGATION 83

of worms in each lot compared, and each horizontal interval repre-
sents one day. Each point of the curve represents the percentages
of worms intact at a given time during the experiment. Each
curve is plotted from fifty worms and from examinations two days
apart. The curve ad shows the survival time of old, large indi-
viduals, the curve ac, that of fifty younger individuals of medium
size.

It will be noted that the relation between survival time and rate
of metabolism is the opposite of that observed by the direct method.

tT
ims

a

C

U;

Fic. 4.—Planaria dorotocephala: death curves of young and old animalsin 1.5 per
cent alcohol; ad, curve of fifty old worms; ac, curve of fifty young worms.

Here the younger animals with the higher rate live much longer
than the older with the lower rate. It is also evident that the rela-
tion between surface and volume in animals of different size plays
no part in the result, for the smaller animals live longer than the
larger. The results obtained with cyanide and other depressing
agents, and even with low temperatures, are essentially the same.
The difference in the ability of the animals to become acclimated
to low concentrations of depressing agents is apparent, not merely
in the length of life, but in the motor activity. The primary effect
of the depressing agent is greater upon the young than upon the

84 SENESCENCE AND REJUVENESCENCE

old animals, but the young animals recover more rapidly and more
completely under the depressing conditions, and within a few days
are very evidently more active than the old.

The relation between the capacity for acclimation and rate of
metabolism can be demonstrated very clearly by combining the
effect of depressing agents with that of different temperatures.
Animals in low concentration of cyanide or alcohol are less capable
of acclimation and die earlier at lower than at higher temperatures.
Fig. 5 shows the results in an experiment of this sort. The curves

i

E
tT
ty

a

I I I

77
03

Fic. 5.—Planaria dorotocephala: death curves of full-grown animals in 1.5
per cent alcohol at 8°-10° C. (ab) and at 20° C. (ac).

are plotted in the same way as in Fig. 4. The curve ad is the
death curve of forty animals in 13 per cent alcohol at a temperature
of 8°-10° C., the curve ac that of forty animals of the same size and
from the same stock in 13 per cent alcohol at 20° C. The greater
resistance of the animals at the higher temperature is clearly
apparent.

But that the rate of metabolism is not the only factor involved
in acclimation to depressing agents is evident from the comparison
of starved with well-fed animals. In experiments to be described
in following chapters it will be shown that in animals undergoing

THE PROBLEM AND METHODS OF INVESTIGATION 85

reduction from starvation the rate of metabolism gradually rises,
so that a starved animal, reduced to, let us say, one-half its size at
the beginning of the experiment, has a much higher rate of metab-
olism than well-fed animals of its original size and about the same
rate as well-fed animals of its reduced size. But the reduced animal
has to a large extent lost its ability to become acclimated to depress-
ing agents and conditions, and in spite of its high rate of metabolism
is more susceptible to low concentrations of cyanide, alcohol, etc.,
and also to low temperatures, than well-fed animals of the same size
as itself, and shows about the same susceptibility as well-fed animals
of its original size, although these possess a much lower rate of
metabolism. In other words, the animal which is using its own
structural substance as a source of energy is much less able to
acclimate itself to depressing conditions than an animal with the
same rate of metabolic reaction but with abundant nutritive ma-
terial. Consequently, it is impossible to determine the differences
in rate of metabolism between well-fed and starved animals by the
indirect method.

In some cases also, where the differences of size between animals
compared are very great, the smaller animals die of starvation
before the larger animals undergo sufficient reduction to reach the
death point, but this occurs only where the differences are extreme.

In general the indirect method is of value as a means of confirm-
ing the results of the direct method, and it can be applied to certain
forms where the direct method may be complicated by the relation
between surface and volume. The concentration to be used for
either method must of course be determined for each species.

OTHER METHODS

There are other physiological differences between young and
old organisms besides the rate of metabolism. In many cases
marked differences in motor activity exist between young and old

tSince I was unaware of this relation between the capacity for acclimation and
the nutritive condition at the time of my earlier experiments on rejuvenescence by
starvation, the use of the indirect method in those experiments led to incorrect con-
clusions concerning the changes in rate during starvation (Child, ’11, pp. 547-55),
but correction has been made in a later paper (Child, ’14@). The reader is also
referred to chapter vii below.

86 SENESCENCE AND REJUVENESCENCE

animals, and the capacity of an individual for growth and develop-
ment must be regarded as to some extent a criterion of its youth or
age. If we can induce an animal to pass through an indefinite
number of agamic generations, each of which shows the same vigor
and the same cycle of growth and development, we must conclude,
either that senescence does not occur in such cases, or else that
there is a periodic rejuvenescence associated in some way with the
reproductive process or other processes, and we may use the sus-
ceptibility methods to determine which of these two alternatives
is correct. In at least many organisms, probably in all, if the
nutritive and other conditions are controlled with sufficient care,
the percentage increment of growth decreases with advancing
age and serves as a more or less exact indication of physiological
condition, though subject to periodic or irregular variation. In
those forms which attain or approach a more or less definite limit
of size, size itself under the normal or usual conditions of existence
may serve as a criterion of age, since the size of the organism indi-
cates approximately its position in the life cycle.

The morphological characters, whether those of the cells or of
the organism as a whole, may serve as an indication of the youth or
age of the individual, but it must be remembered that senescence
and rejuvenescence are primarily physiological rather than morpho-
logical changes, and that morphological characters are available
as criteria only so far as we have learned by experience that cer-
tain of them are characteristic of organisms which we can distin-
guish by other means as physiologically young or old. In man and
the higher animals the morphological differences between youth and
age are clearly evident, but for many of the lower forms this is not
the case, although sufficiently minute anatomical or histological
investigation would probably disclose some characteristic differ-
ences. If these various criteria of youth and age are all valid, we
should find that, so far as they can be applied to any particular case,
they lead to essentially the same conclusion as regards that case.
As a matter of fact, they are very generally in agreement, but
there are various cases in which one or another of these criteria
leads to conclusions different from the others. Some of these
cases will be considered in later chapters.

THE PROBLEM AND METHODS OF INVESTIGATION 87

We are accustomed, and experience justifies the custom, to
measure age in man and the higher vertebrates by the time elapsed
since birth. We say that the individual is a certain number of
years old, and from the age in years we can reach fairly definite
conclusions as to physiological condition, i.e., physiological age.
In many of the lower forms, however, senescence does not neces-
sarily proceed at an approximately definite rate. In such organisms
the time elapsed since the beginning of development does not afford
any measure of the physiological age attained, for, as the following
chapters will show, the organism has not necessarily continued to
grow old during all of that time. Thus it is possible that among
members of the same brood, beginning development at the same
time, some may attain a much greater physiological age in a given
length of time than others. In short, we cannot measure age in
all organisms in terms of time.

And, finally, we may attempt to modify the processes of senes-
cence and rejuvenescence and so to gain further insight into their
nature. The influence of external conditions and of quantity
and quality of nutrition may be determined. We may expect to
find that factors which influence the fundamental metabolic pro-
cesses or the structural substratum will affect the course or char-
acter of senescence and rejuvenescence in one way or another if
their action continues for a sufficiently long time. In many of
the lower forms reproduction may be induced experimentally by
the isolation of pieces of the body, which undergo a reorganization
into complete new individuals. These experimental reproductions,
wherever they can be induced to occur, affect the course of senes-
cence and as a matter of fact bring about a greater or less degree
of rejuvenescence. The problem is then accessible to analytic
investigation in the lower forms, and the results of such investiga-
tion afford a firm foundation for the interpretation of the phe-
nomena of senescence and rejuvenescence in the higher organisms,
where they are less accessible to experimental methods.

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1906. ‘“‘A Note on the Susceptibility of Segmenting Arbacia and As-
terias Eggs to Cyanides,” Biol. Bull., XI.
tg1o. ‘The Action of Ether on Anaerobic Animal Tissue,” Jour. of
Pharm. and Exp. Therap., II.
1913. ‘The Nature of Irritability and the Action of Anesthetics,”
Science, XX XVII (Proc. Am. Chem. Soc.).

go SENESCENCE AND REJUVENESCENCE

Matuews, A. P., and WALKER, S.
1go9. ‘‘The Action of Cyanides and Nitriles on the Spontaneous Oxida-
tion of Cystein,” Jour. of Biol. Chem., VI.
Mavpas, E.
1888. ‘‘Recherches expérimentales sur la multiplication des infusories
ciliés,” Arch. de zool. exp., (2), VI.
1889. ‘‘La rajeunissement karyogamique chez les ciliés,” Arch. de zool.
exp., (2), VII.
Mever, H.
1899. ‘‘Zur Theorie der Alkoholnarkose: Erste Mitteilung. Welche
Eigenschaft der Andsthetica bedingt ihre narkotische Wirkung ?”
Arch. f. exp. Pathol. u. Pharm., XLII.
tgor. ‘‘Zur Theorie, etc.: Dritte Mitteilung. Einfluss wechselnder
Temperatur auf Wirkungstairke und Teilungscoefficient der Nar-
cotica,” Arch. f. exp. Pathol. u. Pharm., XLVI.
Minor, C. S.
1908. The Problem of Age, Growth and Death. New York.

OvERTON, E.
tgo1. Studien tiber die Narkose. Jena.

Ricwarps, A. N., and WALLACE, G. B.
1908. ‘The Influence of Potassium Cyanide upon Proteid Metabolism,”
Jour. of Biol. Chem., IV.
ScHULTZ, E.
1904. ‘Uber Reduktionen: I. Uber Hungererscheinungen bei Planaria
lactea,’”’ Arch. f. Entwickelungsmech., XVIII.
1908. ‘Uber umkehrbare Entwicklungsprozesse und ihre Bedeutung fiir
eine Theorie der Vererbung,” Vorir. und Aufs. ti. Entwickelungs-
mech., IV.
TASHIRO, S. |
1913a. ‘‘Carbon Dioxide Production from Nerve Fibers When Resting
and When Stimulated; A Contribution to the Chemical Basis
of Irritability,” Am. Jour. of Physiol., XXXII.
19130. “A New Method and Apparatus for the Estimation of Exceedingly
Minute Quantities of Carbon Dioxide,” Am. Jour. of Physiol.,
XXXII.
TRAUBE, J.
1go4a. “Theorie der Osmose und Narkose,”’ Arch. f. d. ges. Physiol., CV.
1904). “Der Oberflachendruck und seine Bedeutung im Organismus,”’
Arch. f. d. ges. Physiol., CV.
1908. ‘‘Die osmotische Kraft,” Arch. f. d. ges. Physiol., CX XIII.
1910. “Die Theorie des Haftdruckes (Oberflachendrucks) und ihre Bedeu-
tung fiir die Physiologie,” Arch. f. d. ges. Physiol., CXXXII.
1g11. ‘Die Theorie des Haftdruckes (Oberflachendrucks), V,’’ Arch.
f. d. ges. Physiol., CXL.
1913. ‘‘Theorie der Narkose,” Arch. f. d. ges. Physiol., CLIII.

THE PROBLEM AND METHODS OF INVESTIGATION oI

VERNON, H. M.

1906.
Igo9.

IgIo.

1913.

VERWoRN, M

1903.
IgI2.
1913.

WARBURG, O

IgIod.

tg10b.

Igtoc.
IgIia.
rg11b.

1912d.
19120.

1913.

IQI4a.

1914.

IgI4c.

“The Conditions of Tissue Respiration,” Jour. of Physiol., XXXV.
“The Conditions of Tissue Respiration. Part III. The Action
of Poison,” Jour. of Physiol., XXXIX.

“The Respiration of the Tortoise Heart in Relation to Functional
Activity,” Jour. of Physiol., XL.

“The Changes in the Reactions of Growing Organisms to Nar-
cotics,” Jour. of Physiol., XLVII.

Die Biogenhypothese. Jena.
Narkose. Jena.
Irritability. New Haven, Conn.

“Uber die Oxydationen in lebenden Zellen nach Versuchen am
Seeigelei,” Zeitschr. f. physiol. Chem., LXVI.

“Uber Beeinfliissung der Oxydationen in lebenden Zellen nach
Versuchen an roten Blutkérperchen,” Zeitschr. f. physiol. Chem.,
LXIX.

“Uber Beeinfliissung der Sauerstoffatmung,” Zeitschr. f. physiol.
Chem., LXX.

“Uber Beeinfliissung, etc.: II. Mitteilung. Eine Beziehung zur
Constitution,” Zeitschr. f. physiol. Chem., LUXXI.
“Untersuchungen tiber die Oxydationsprozesse in Zellen,”’ Miin-
chener med. Wochenschr., LVII.

“Untersuchungen, etc., II,” Miinchener med. Wochenschr., LVIII.
“Uber Beziehungen zwischen Zellstruktur und biochemischen
Reaktionen,” Arch. f. d. ges. Physiol., CXLV.

“Uber die Wirkung der Struktur auf chemische Vorginge in
Zellen.” Jena.

“Uber Verbrennung der Oxalsaure an Blutkohle und Hemmung
dieser Reaktion durch indifferente Narkotika,” Arch. f. d. ges.
Physiol., CLIV.

“Uber die Empfindlichkeit der Sauerstoffatmung gegeniiber in-
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“‘Beitrige zur Physiologie der Zelle, insbesondere iiber die Oxyda-
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WINTERSTEIN, H.

Ig02.
1905.
IgI3.

1914.

“Zur Kenntnis der Narkose,” Zeztschr. f. allgem. Physiol., 1.
“Warmelahmung und Narkose,” Zeiischr. f. allgem. Physiol., V.
“Beitraége zur Kenntnis der Narkose: I. Mitteilung. Kritische
Ubersicht iiber die Beziehungen zwischen Narkose und Sauer-
stoffatmung,”’ Biochem. Zeitschr., LI.

“Beitrage, etc.: Il. Mitteilung. Der Einfluss der Narkose auf
den Gaswechsel des Froschriickenmarks,” Biochem. Zeitschr., LXI.

CHAPTER IV

AGE DIFFERENCES IN SUSCEPTIBILITY IN THE LOWER
ANIMALS

THE EXPERIMENTAL MATERIAL

Three species of fresh-water planarians, Planaria dorotocephala,
P. maculata, and P. velata, have constituted the chief material for
the more extended investigations. P. dorotocephala is found in
great abundance in various parts of the United States, chiefly in
springs and the streams issuing from them. In nature the animals
usually attain a length of twenty to twenty-five millimeters, but
in the laboratory with abundant food may reach double that
length.

The body, like that of most turbellaria, is dorso-ventrally
flattened; the body-wall consists of a one-layered ciliated ectoderm
beneath which lie longitudinal and transverse muscle layers and
in the spaces between the internal organs a parenchymal tissue.
A pigment layer beneath the dorsal ectoderm gives the dorsal sur-
face a deep-brown color, the ventral surface being much less deeply
pigmented. The chief features of the internal anatomy are indi-
cated in Fig. 6. The central nervous system consists of a pair of
cephalic ganglia beneath the eyes and two longitudinal cords (ss)
which give off branches and are connected by commissures. The
chief sense-organs are the eyes, consisting of pigment cups con-
taining sensory cells and the lateral pointed cephalic lobes, which
are organs of chemical sense. The margins of the head and body
are also sensitive tactile organs.

The mouth (m) lies ventrally in the middle of the body and opens
into a pharyngeal pouch containing a tubular pharynx (ph). At
its anterior end the pharynx opens into the alimentary tract which
consists of three main branches (a/) and many secondary branches.
A diffuse branching excretory system is also present, but not shown
in the figure. Under the usual conditions the animals do not
become sexually mature, and sexual organs if present at all do
not develop beyond very early stages.

g2

AGE DIFFERENCES IN SUSCEPTIBILITY 93

The general plan of internal structure of
other related species is much the same, but
they differ in shape and general appearance.
Planaria maculata (Fig. 7) does not attain as
large a size as P. dorotocephala and is less
active. The head differs in shape from that
of P. dorotocephala and the pigment is dis-
tributed in large spots. P. velata (Fig. 8) is
more slender, somewhat less flattened, and
without the pointed cephalic lobes. The
younger worms are almost black, but become
light gray with advancing age.

Various other flatworms, protozoa, the
fresh-water hydra, and several marine
hydroids have been used in comparative ex-
periments.

AGE DIFFERENCES IN SUSCEPTIBILITY IN
Planaria maculata

Animals of this species kept in the labora-
tory and fed become sexually mature and
deposit egg capsules containing fertilized
eggs, and from these capsules the young
worms emerge in about four weeks at
ordinary temperatures. When first hatched
the young worms possess the form of the
adult, but are only about two millimeters in
length, while in my stock the old, sexually
mature worms, which were laying eggs, were
about twelve millimeters long.

Fig. 9 shows the susceptibility curves (see
pp. 80-82) of young and old animals of
this species to potassium cyanide, 0.001 mol.
The curve abd gives the susceptibility for ten
newly hatched worms, the curve cd, that
for ten full-grown sexually mature worms
about twelve millimeters in length. The

At Mende FF

wee

Fic. 6.—Planaria
dorotocephala: m, mouth;
ph, pharynx; al, alimen-
tary tract; ms, nervous
system.

04 SENESCENCE AND REJUVENESCENCE

susceptibility of the newly hatched worms is much greater than
that of the full-grown animals, disintegration of the former being

GQ 6

Fics. 7, 8.—Planaria maculata
and P. velata.

far advanced before it begins in
the latter. Since susceptibility meas-
ured by the higher concentrations of
the direct method varies with rate
of metabolism, the young animals
must have a much higher rate than
the old.

But the method enables us to dis-
tinguish age differences in rate of
metabolism which are very much less
than these. In Fig. 10 the curve ad
shows the susceptibility of ten worms
hatched within the twenty-four hours
preceding the beginning of the experi-
ment, and the curve cd the suscepti-
bility of ten animals four days after
hatching and without food. Here
the difference in size between the
animals of the two lots is much
less than in the preceding case, the
younger worms being two millimeters,
the older three and one-half milli-
meters long. The figure shows that
the susceptibility of the newly
hatched animals is consider-
ably greater, i.e., their rate of metab-
olism is higher than that of the
animals four days after hatching.
Since the differences in susceptibility
as shown in Fig. 1o are considerable

for four days’ time, it is evident that the rate of metabolism must
decrease rapidly after hatching.

The young worms are capable of movement before they emerge
from the egg capsules, and by opening the capsules with fine needles
it is possible to obtain young worms of various stages before hatch-

AGE DIFFERENCES IN SUSCEPTIBILITY 95

ing. A comparison of the resistance to cyanide of unhatched
worms capable of movement with that of worms just hatched
shows, as in Fig. 10, that the younger worms have the higher rate
of metabolism, although in this case also the difference in age meas-
ured by time is no more than a few days.

But it is only during these earlier stages of the life cycle that
the rate of metabolism changes appreciably during such short
intervals of time.

The rate of metab- Stages} g C
olism decreases most
rapidly during the II

earlier stages, and as
development ad-
vances the decrease
in rate for a given iit
time interval becomes
always less. In ani-
mals eight or nine

millimeters in length, a
for example, the
differences in rate of
metabolism for an in- vi

terval of two or three
weeks, under ordinary 6 d
conditions of nutri- yours

tion and temperature Aes

: P 2 Fic. 9.—Susceptibility of Planaria maculata to
and in many cases KCN o.cor mol.: ab, recently hatched worms; cd,
for a much longer full-grown, sexually mature worms.

interval, are no

greater than the differences shown in Fig. ro for an interval of four
days immediately after hatching. In still older animals the
decrease in rate of metabolism under constant conditions is even
slower.

_In Fig. 11 the susceptibilities of two lots of large old worms are
compared. The curve ad is from ten worms twelve millimeters in
length, and cd from ten worms sixteen to eighteen millimeters in
length. These worms were collected from their natural habitat

1

Se

ae

z 1 1
Iq 2a 3a 4

96 SENESCENCE AND REJUVENESCENCE

at this size and it is impossible to say whether the larger worms are
older in point of time than the smaller. They have, however,
attained a stage of growth and development which under anything
approaching natural conditions could be reached by the smaller
worms only after at least some weeks.

The larger, physiologically older worms begin to disintegrate
two hours later and also complete their disintegration one and one-

half hours later than the smaller ones.
SHES Tee In other words, their survival time is
about one-fifth greater than that of
the smaller worms. But in Fig. 10
above, the survival time of worms
four days after hatching is almost
one-half greater than that of worms
newly hatched, that is, the difference
in rate of metabolism between the
two lots of Fig. 10, which are only
four days apart, is much greater than
that between the two lots of Fig. 11,
which represent physiological condi-
tions several weeks apart in terms of
Vv time. Clearly the rate of metabolism
decreases very much more slowly in
6 \d the larger, older worms than in the
Hours + 1 2t 3g stages immediately following hatch-
Fic. 10.—Susceptibility of Pla- ing. A comparison of Figs. ro and
naria maculata to KCN 0.00r qq also shows, as does Fig. 9, the
mols abs worms’ hatched within great difference in susceptibility be-
24 hours; cd, worms four days
after hatching. tween very young and full-grown
animals.

These results are in complete agreement with the observations
of Minot (’o8) and others on the rate of growth in mammals and
birds. The rate of growth as measured by the percentage incre-
ment is highest in the youngest animals and decreases with advan-
cingage. As Minot says, “the period of youth is the period of most
rapid decline.” And now we find this to be true, not only for the
rate of growth in the higher animals, but for the rate of metabolism

ane

II

IV

AGE DIFFERENCES IN SUSCEPTIBILITY 97

in such simple forms as the planarian worms. But as will appear
more clearly in following chapters, time is not a correct measure
of physiological age in these lower forms. The animal which has
lived longer is not necessarily the older: the older animal is the one
which has undergone more growth and development, but the
amount of growth and development is dependent upon nutrition,
temperature, and other external conditions. It is possible to

Stages ] a

II

I

Hours I 2 3 4 5 6 7
Fic. 11.—Susceptibility of Planaria maculata to KCN 0.001 mol.: ab, worms
12 mm. in length; cd, worms 16-18 mm. in length.

measure the physiological age of these animals in terms of time
only when the conditions of existence are controlled.

Fig. 12 will serve to illustrate this point. In this figure the
curve ab shows the susceptibility of ten worms nine millimeters
long from a stock raised in the laboratory from eggs and only about
ten weeks “‘old,”’ while the curve cd is plotted from worms ten milli-
meters long, but which had lived at least a year. The temperature
was somewhat higher in this series than in those preceding, and the
survival times are therefore shorter than they would be for animals
of this age at the temperature of the other series.

98 SENESCENCE AND REJUVENESCENCE

The worms which are so much “older” in point of time show
only a slightly greater resistance, i.e., a slightly lower rate of metab-
olism than the worms of the “younger’’ lot. As a matter of fact,
the worms of the curve cb had been considerably older physiologi-
cally at an earlier period than they were at the time when the
comparison was made and had been undergoing rejuvenescence
in consequence of reduction. We cannot measure the age of such
organisms in terms of
time unless we know
that they have been
growing old without
interruption, and even
then the rate of senes-
cence may vary with
conditions.

On the other hand,
size, or, more strictly,
length—for in the later
stages the growth is
largely a growth in
length—is under the
usual conditions and
within certain limits, a
oy —a fairly good criterion of
Hours I 2 3 4 physiological age.

Fic. 12.—Susceptibility of Planaria maculata Barring individual size
to KCN 0.001 mol.: ab, worms 9 mm. in length differences, which are

and ten weeks after hatching; cb, worms 1o mm. in :
length and at least one year after hatching. slight, the length of the
animal is an index of

the amount of growth and development which has occurred, and
we find in general, as the preceding figures show, that the longer
animal has a lower rate of metabolism than the shorter. But it
does not follow that individuals of the same length always possess
the same rate of metabolism. A given size may be attained either
by growth from a smaller or reduction from a larger size, and the
physiological condition of the animal is not the same in the two
cases. But in a single stock, where all individuals have been under

Stages +

I

Til

IV

AGE DIFFERENCES IN SUSCEPTIBILITY 99

essentially the same conditions for a considerable period and where
the animals are not undergoing fission, the length of the worm is a
real criterion of its physiological condition, the rate of metabolism
being lower in the longer than in the shorter worms.

Results obtained by the direct method, such as those presented
above, can be confirmed by the indirect or acclimation method,
‘which was described on pp. 82-85. Except where the differences of
size are extreme, the animals which have the higher rate of metab-
olism and die earlier in the concentrations of the direct method
live longer than those with the lower rate in the low concentrations
used for the acclimation method. In other words, the animals
which are larger and therefore physiologically older become less
readily and less completely acclimated to the depressing reagent,
and so die earlier than the younger animals. Since the results
obtained by this method in the present case merely confirm the
results of the direct method, it is unnecessary to consider them in
detail.

AGE DIFFERENCES IN SUSCEPTIBILITY IN Planaria dorotocephala

In a stock of Planaria dorotocephala collected from the natural
habitat of this species, animals are found ranging in length from four
or five millimeters up to twenty millimeters or more. Since there
is reason to believe that sexual reproduction does not occur, or at
most occurs very rarely in this species under natural conditions in
the localities which have come under my observation, it is certain
that at least most of the animals collected have arisen by fission
(see pp. 125, 384-86). But, ignoring for the present the question of
their origin, we should naturally regard the smaller worms in such
a stock as the younger and the larger as the older, and we find as a
matter of fact that the same differences in susceptibility exist be-
tween the larger and the smaller worms as in P. maculata. This
difference is shown in Fig. 3 and in Fig. 13. Fig. 13 gives the
susceptibility curves of four lots of ten worms each from a stock
which had been in the laboratory only one day. Curve ab shows
the susceptibility of worms five millimeters in length, curve ac of
worms seven millimeters, curve ad of worms ten to twelve milli-
meters, and curve ef of worms eighteen to twenty millimeters in

100 SENESCENCE AND REJUVENESCENCE

length. The survival times are considerably longer than those in
Fig. 3 because of lower alkalinity of the water used.

A marked difference in the susceptibility of the worms of differ-
ent size appears in the figure. The smallest worms (curve ab)
begin to die and disintegrate earlier and disintegrate more rapidly
than the others, and the susceptibility in the other lots decreases
as the size increases. In short, the larger worms possess a lower

Stages { a @

II

IV

6

Hours 20 3k 4B St EES

Fic. 13.—Susceptibility of Planaria dorotocephala to KCN 0.001 mol.: ab,
worms 5 mm. in length; ac, worms 7 mm. in length; ad, worms 10-12 mm. in length;
ef, worms 18-20 mm. in length.
rate of metabolism than the smaller, and in general the rate of
metabolism decreases with increasing size.

Hundreds of animals of this species have been compared in
this way, with cyanide, alcohol, ether, etc., as reagents, and the
result has been in all cases essentially the same. Tested by the
acclimation method, the smaller worms show a greater capacity
to acclimate to the reagent, i.e., a higher rate of metabolism, than
the larger, so that the results of the two methods check and confirm
each other. Moreover, the smaller animals grow more rapidly
than the larger under like conditions and are more active.

AGE DIFFERENCES IN SUSCEPTIBILITY IOL

The only possible conclusion is that in this species individuals
resulting from the asexual process of fission show age differences
similar in character to those in the sexually produced individuals
of Planaria maculata. In both cases the rate of metabolism is
highest in the young worms and decreases with advancing age.
Later chapters will confirm this conclusion (see chaps. v, vii).

AGE DIFFERENCES IN SUSCEPTIBILITY IN OTHER FORMS

In order to determine whether age differences in susceptibility
are of general occurrence and of the same sort, the susceptibility
of young and old individuals of a considerable number of species
from different groups has been compared by direct method. The
general results of these investigations are briefly stated without
the data of experiment.

The age differences in susceptibility have been determined for
various other species of flatworms. In Dendrocoelum lacteum,
Phagocata gracilis, and certain unnamed species of the Mesostomidae,
all of which reproduce only sexually, the susceptibility by the direct
method of the young animals to the cyanides is much greater than
that of the old. In Planaria velata, the old worms break up into
fragments which encyst and undergo reconstitution into new indi-
viduals in the cysts and later emerge as young worms capable of
repeating the life cycle. In this species also the susceptibility, as
determined by the direct method, is greatest in the young worms
after they emerge from the cysts, and decreases from this stage on
until the next fragmentation (Child, ’13).

Differences in susceptibility which are undoubtedly connected
with physiological age have been found in certain protozoa (see
pp. 141-42). Among the coelenterates the fresh-water hydra
and two species of hydroids, Pennaria tiarella (see Fig. 50, p. 148)
and Corymorpha palma, have been tested. In the two hydroids
the sexually produced young at any stage after attaining the form
of the adult show a much greater susceptibility than the full-grown
mature animals. In hydra, sexually produced young have not as
yet been obtained, but the young animals asexually produced show
a higher susceptibility than the parent. In the ctenophore, Mnemi-
opsis leidyi, the susceptibility decreases with advancing physiological

102 SENESCENCE AND REJUVENESCENCE

age, ie., as growth and development proceed. Here the earliest
stages tested were young of about five millimeters in diameter.
Their susceptibility is greater than that of later stages and very
much greater than that of full-grown animals. In the course of
investigations not yet published on several species of oligochete
annelids, Miss Hyman has found that the young animals show a
greater susceptibility to cyanide than the old. The young in these
cases arose by the asexual process of fission and not from fertilized
eggs. Various species of entcmostracean crustacea which have
been examined show in every case a greater susceptibility in the
young than in the old animals, but it is possible that differences in
size may be a factor in the result in these forms. In the larvae cf
amphibia the susceptibility is greater in newly hatched animals
than in later stages.

CONCLUSION

The uniform results obtained from widely different groups show
very clearly that age differences in susceptibility to cyanides and
other narcotics are of general occurrence. Moreover, in all cases
the young animals, at least beyond a certain stage, show the
highest susceptibility, and susceptibility decreases with advancing
development. In other words, the rate of metabolism is highest
in the young animals and decreases with advancing age. This
conclusion is in full agreement with what we know of the physio-
logical aspects of senescence in the higher animals, and it forces
us to the further conclusion that a decrease in rate of metabolism is
at least very generally associated with growth and differentiation.

REFERENCES

CuILp, C. M.
1913. ‘‘The Asexual Cycle in Planaria velata in Relation to Senescence
and Rejuvenescence,” Biol. Bull., XXV.
Minot, C. S.
1908. The Problem of Age, Growth and Death. New York.

CHAPTER V

THE RECONSTITUTION OF ISOLATED PIECES IN RELATION TO
REJUVENESCENCE IN PLANARIA AND OTHER FORMS

THE RECONSTITUTION OF PIECES IN Planaria

In consequence of the ability of isolated pieces cut from the body
to develop into complete individuals, the various species of Planaria
have served to a very large extent as material for the study of
“‘form-regulation,” “regeneration,” “‘restitution,”’ as the changes
which occur in such pieces have been variously called. The mor-
phological and histological features of the reconstitution of such
pieces into new wholes have been repeatedly discussed by various
authors and for various species. Since the essential features of
the process do not differ widely in the different species, a brief
description of-reconstitution as it occurs in P. dorotocephala will
serve the present purpose. The reconstitution of such a piece as
a in Fig. 14 is shown in Figs. 15-17. The cut surfaces of the piecc
contract after its isolation, and in the course of two or three days
outgrowths of new embryonic tissue appear on these surfaces,
these outgrowths being readily distinguishable from other parts of
the piece by the absence of the dark-brown pigment characteristic
of the species. In Fig. 15 and following figures these outgrowths
of new tissue are marked off from other parts by lines which indicate
the boundaries between new and old tissue. During the next two
or three days the anterior outgrowth develops into a head with
eyes, cephalic lobes and, as the section shows, a new cephalic
ganglion, and the posterior outgrowth develops into a posterior
end (Fig. 16). At about the same time the new pharynx becomes
visible, near the posterior end of the old tissue of the piece, and the
intestinal branches present in the piece begin the changes which
end in the formation of an alimentary tract like that of a whole
animal. The developing animal also elongates and decreases in
width, the postpharyngeal region grows at the expense of the pre-
pharyngeal, and finally an individual results (Fig. 17) which is in
all respects, so far as can be determined, a whole animal of small

103

104 SENESCENCE AND REJUVENESCENCE

a

aa
l

|

16

7
Fics. 14-17.—Reconstitution of
pieces of Planaria dorotocephala: Fig.
14, body-outline indicating levels of

section; Figs. 15-17, three stages in
the reconstitution of an isolated piece.

b
c
4

i

size. Various details of the pro-
cess differ according to the size of
the piece, the level of the body
from which it is taken, the physio-
logical condition of the animal,
and the environmental conditions,
and a limit of size exists which
also varies with all these factors;
pieces below this limit of size do
not reproduce complete normal
animals. The influence of these
various factors is evident chiefly
in the character of the head,
which may range from the normal
through a series of teratological
forms with a headless condition
as the extreme term of the series
(Child, ’11b, ’11c; see also Figs.
20-23, pp. r11-12). In other
species of planarians the process
of reconstitution is in general
much the same, but with differ-
ences in details and in the relation
to the various factors mentioned
above.

The process of reconstitution
in these cases differs somewhat
from the replacement of a missing
part in higher animals. The
isolated piece of Planaria does not
replace the missing parts in their
original condition and size, but
develops merely a new head and
posterior end and then undergoes
an extensive reorganization into
a new individual of small size,
the size being dependent upon the

THE RECONSTITUTION OF ISOLATED PIECES 105

size of the isolated piece. In the course of the process some parts
of the piece atrophy and disappear, new parts arise and differen-
tiate, and a large amount of cell division and growth occur. The
piece does not, in many cases cannot, feed until the development of
the new individual has reached a certain stage, consequently the
energy for the changes which occur must be derived from the
nutritive reserves and the tissues of the piece itself. In this con-
nection it may be noted that the volume of the new animal is al-
ways considerably less than that of the piece from which it arose;
in other words, the piece undergoes a considerable amount of reduc-
tion in producing a new individual.

The development of the new animal in this process of recon-
stitution is not fundamentally different from embryonic develop-
ment (Child, ’12a, ’13)—it merely occurs under rather different
conditions; nor is it essentially different from the process of agamic
reproduction in nature; it is, in short, an experimental reproduction.
Moreover, the new animal thus produced resembles a young ani-
mal in its morphological features and is capable, when fed, of growth
and development, in fact, of going through all stages of the life
history beyond that which it apparently represents. All these
facts raise the question whether such an animal is or may be younger
physiologically as well as morphologically than the animal from
which the piece was taken. This question is considered in the
following section.

CHANGES IN SUSCEPTIBILITY DURING THE RECONSTITUTION
OF PIECES

An extensive investigation of the changes during reconstitution
in the susceptibility of isolated pieces to cyanide has been made by
the direct susceptibility method. It should be borne in mind that
changes in susceptibility as indicated by this method indicate
change in the same direction of rate of metabolism. The results
of these experiments are given here only in general terms. The
complete data have appeared elsewhere (Child, ’142).

The first change follows immediately upon the act of isolation.
The susceptibility of the piece immediately after isolation is greater,
ie., its rate of metabolism is higher, than that of the same region

106 SENESCENCE AND REJUVENESCENCE

of the body in uninjured animals which are as nearly as possible
in the same physiological condition as that from which the piece
was taken.

This is of course to be expected, for the operation of cutting
the piece out of the body undoubtedly stimulates it and so increases
its rate of metabolism, and the presence of the wounds at the two
ends of the piece undoubtedly serves to continue this stimulation.
It is an interesting fact that short pieces show a greater increase
in rate of metabolism than long, as the result of section. This
again is only to be expected, for the nearer the cut is to a given
region of the body, the more directly the nervous structures inner-
vating that region are affected by it. When the piece includes a
half or a third of the body, the stimulation following section, as
indicated by an increase in rate in the piece as a whole, is slight,
but the degree of stimulation increases as the length of the piece
decreases, and in short pieces, including one-eighth or less of the
body-length, the increase in rate is great.

But this increase in rate following section is only temporary,
as we should expect, if it is due to the stimulation resulting from
section. The rate of metabolism in the isolated piece, as measured
by its susceptibility to cyanide, decreases during the first few hours
after section. In long pieces, including a half or a third of the
body-length, the rate falls to about the same level as that in the
corresponding region of the parent body, or somewhat lower. But
in shorter pieces the rate does not fall as low, and in very short
pieces it may remain considerably higher than in the same region
of the uninjured animal, probably because in such cases the wound
stimulus involves the whole piece to a greater or less extent. The
decrease in metabolic rate following the increase after isolation is
evidently due to the gradual recovery from the condition of excita-
tion following the act of section.

But this condition, like the initial conditisn of stimulation, is
only temporary in cases where the piece 1mdergoes reconstitution.
Within three or four days after section the processes of reconstitu-
tion are well under way, and they are accompanied by an increase
in susceptibility, i.e., an increase in rate of metabolism in the pieces.
This continues as reconstitution goes on, and when the develop-

THE RECONSTITUTION OF ISOLATED PIECES 107

ment of the new animal from the piece is completed, the suscepti-
bility is greater than that in the corresponding region of the parent
animal. This means that during reconstitution the rate of metab-
olism increases until it is higher than before section. This increase
in rate is not the result of a stimulation which soon disappears, but
is connected with the process of reconstitution and is relatively
permanent. The rate after reconstitution is the rate characteristic
of a physiologically young animal, and it undergoes a gradual
decrease as the animal grows and becomés physiologically older.
Here also size is a factor in the result: the smaller the piece which
undergoes reconstitution into a new whole, the greater the increase
in rate of reaction during reconstitution. This increase in meta-
bolic activity during reconstitution was first discovered by means
of the acclimation method with alcohol as a reagent (Child, ’11).
In these earlier experiments a marked increase in rate was found
in small pieces, but in very large pieces a decrease in rate apparently
occurred. As a matter of fact, the rate does not decrease in large
pieces during reconstitution, but increases slightly. My error on
this point was due to failure to keep the normal animals under the
same conditions as the experimental pieces. In the case of the
large pieces the effect of the conditions more than compensated the
slight increase in rate due to reconstitution, but in the small pieces,
where the increase was much greater, it appeared in spite of the
external conditions.

More recent and extended investigation by the direct method
with cyanide as reagent has demonstrated beyond a doubt that
reconstitution is accompanied by an increase in rate, the amount
of increase varying with the size of the piece, the amount of reconsti-
tutional change, and various other factors.

The partial record of one series of experiments will serve to
show both the increase in susceptibility, i.e., of rate of metabolism
resulting from reconstitution, and the relation between the amount
of increase and the size of the piece. In this experiment large,
physiologically old worms eighteen to twenty millimeters in length
constituted the material. From a part of these worms pieces in-
cluding the region ac in Fig. 18, from another part pieces including
the region ab, i.e., just half the length of the preceding lot, were

108 SENESCENCE AND REJUVENESCENCE

OO

Fic. 18.—Body-outline
of Planaria dorotocephala,
indicating levels of section.

cut. These two lots of pieces were allowed
to develop into new animals. A third part
of the stock consisting of uninjured worms
was kept under the same conditions as a
control and since the pieces do not feed
during the process of reconstitution, this
third lot was not fed. During the recon-
stitution of the pieces several comparative
tests were made of their susceptibility, and
of that of the uninjured animals, to
cyanide. The results of one of these tests
made sixteen days after the pieces were
cut from the parent bodies is given in
Fig. 19. Both the pieces and the whole
animals had been without food during this
time, but the effects of sixteen days’
starvation are not very great as regards
susceptibility. During these sixteen days
the pieces had become fully developed
animals, the longer being seven to eight
millimeters, the shorter, five millimeters in
length. In Fig. 19 the curve ad shows the
susceptibility of ten animals developed
from the shorter pieces, the curve cd the
susceptibility of ten animals from the
longer pieces, and the curve ef the suscepti-
bility of uninjured animals the same size
as those from which the pieces were taken.
It is evident at once from the figure that
the susceptibility of the pieces which have
undergone reconstitution to whole animals
is very considerably greater than that of
the uninjured animals like those from
which these pieces came, and that further
the susceptibility of the animals which

develop from the shorter pieces is greater than that of those from
the longer. The results of all other similar tests of susceptibility

THE RECONSTITUTION OF ISOLATED PIECES 109

have been essentially the same. When the pieces are very large
and include a considerable portion of the body, the increase in
susceptibility is slight or inappreciable, but with decrease in size of
piece increase in susceptibility becomes greater, provided the pieces
are not so small that they fail to undergo complete reconstitution.

Recalling the age differences in susceptibility shown in the
preceding chapter to exist, it is evident that the animals resulting
from the reconstitution of pieces are, at least as regards their

Stages + ace

II

III

Hours 2 3 4 5 6 7 8
Fic. 19.—Susceptibility of Planaria dorotocephala to KCN 0.001 mol.: ab, short
pieces; cd, long pieces; ef, uninjured worms like those from which pieces were taken.

susceptibility, younger than the animals from which the pieces were
taken. Apparently the process of reconstitution brings about in
some way a greater or less degree of rejuvenescence as regards the
susceptibility to cyanide, i.e., the rate of metabolism. The smaller
the piece, the greater the amount of reorganization in the forma-
tion of a whole animal and the greater the degree of rejuvenescence.

In this connection it is of interest to note that the new tissue
formed at the cut ends of the piece is for a considerable time after
its formation distinctly more susceptible to cyanide, i.e., younger

IIo SENESCENCE AND REJUVENESCENCE

physiologically, than the old tissues of the rest of the piece. As
the new tissue differentiates, however, this difference in suscepti-
bility between it and the old parts gradually disappears, for the
new tissue gradually grows old and its rate of metabolism decreases,
while the old tissue gradually undergoes reconstitutional changes
which involve the atrophy and disappearance of some parts and the
formation of others by cell division and growth, and besides this
the tissues of the piece, particularly the old tissues with their lower
rate of metabolism, are being used up as a source of nutrition for
the developing organism. In other words, the new embryonic
tissue formed at the cut surfaces gradually becomes old after its
formation, while other parts of the piece gradually become young
by reduction and reorganization, until a dynamic equilibrium is
established in the rate of metabolism in the different parts, after
which the animal, if fed, undergoes senescence as a whole.

With various other organisms which show a high capacity for
reconstitution similar results have been obtained. In various other
species of flatworms, so far as tested, in Hydra and in the hydroid
Corymorpha, the animals resulting from the reconstitution of
pieces show a higher rate of metabolism than the animals from which
the pieces were taken. Miss Hyman has found that this is also
true for animals developed from pieces of Lumbriculus and other
fresh-water oligochete annelids.

Animals produced in this way are also younger in other respects
than those from which the pieces came. They grow more rapidly
and are capable of repeating the developmental history from the
stage which they represent onward. There can be no doubt that
the process of reconstitution brings about in some way a greater
or less degree of rejuvenescence in these relatively simple animals,
and that the degree of rejuvenescence is in general proportional to
the degree of reorganization in the process of reconstitution of the
piece into a whole.

THE INCREASE IN SUSCEPTIBILITY IN RELATION TO THE DEGREE
OF RECONSTITUTION

The reconstitutional capacity of pieces of Planaria dorotocephala,
as of other species, is limited. Pieces below a certain size limit,

THE RECONSTITUTION OF ISOLATED PIECES III

which varies with the condition of the animal, with the level of the
body from which the piece is taken, and with various external
factors which influence the rate of metabolism, do not produce
complete normal animals, although they may undergo a greater
or less degree of reconstitution and approach more or less closely
‘to the normal form. Such pieces show all gradations between the
normal animal at one extreme and a completely headless form at
the other (Child, ’11d, ’11c, ’12b). It has been found convenient
to distinguish in this graded series of forms five different types, as
follows:

Normal.—The head is like that of animals found in nature with
two completely separated eyes and cephalic lobes at lateral margins

(Fig. 17).

pe oO, De we IN

7; we oe ~ a%

Fic. 20.—Various degrees of teratophthalmia in Planaria dorotocephala

Teratophthalmic.—The head is of the usual form, but the eye
spots show differences in size, asymmetry in position, approach to
the median line, or various degrees of fusion. Some of the eye
forms are shown in Fig. 20. In all teratophthalmic animals the
cephalic ganglia show various degrees of fusion or asymmetry, the
condition of the eyes being to a considerable extent indicative of
that of the ganglia.

Teratomor phic.—Here the preocular region of the head fails to
attain its full size or does not appear at all. Consequently the
cephalic lobes arise on the anterior margin of the head as in
Fig. 21 A, or in extreme cases are fused together in the median line
at the front of the head (Fig. 21 B).

112 SENESCENCE AND REJUVENESCENCE

Anophthalmic.—The anterior outgrowth of new tissue is vari-
able in form and without eyes, but contains a small, single, gangli-
onic mass, i.e., it is a rudimentary head (Figs. 22 A, 22 B).

Headless.—The anterior outgrowth merely fills in the contracted
cut surface and does not extend beyond the contours of the margin;
the posterior outgrowth, however, is usually even longer than in
other pieces, but its differentiation proceeds very slowly and is
never completed as long as it is attached to the headless piece
(Fig. 23).

The difference between the extremes of this series, the normal
and headless forms, in the degree of reorganization is very great,

2i

22

A iv) B

Fics. 21-23.—Different degrees of reconstitution in Planaria dorotocephala:
Fig. 21 A, B, teratomorphic forms; Fig. 22 A, B, anophthalmic forms; Fig. 23,
headless form.

particularly in pieces from the postoral region (eg., a, Fig. 24). In
the development of a normal animal the anterior half or more of
such a piece undergoes extensive changes in giving rise to a pharyn-
geal and prepharyngeal region, and outgrowths of new tissue appear
at both ends. In the piece from this region which remains headless
no prepharyngeal or pharyngeal region arises, and changes are
limited to the longer outgrowth at the posterior end and the smaller
amount of new tissue at the anterior end.

In the teratophthalmic, teratomorphic, and anophthalmic forms
the degree of reconstitutional change ranges from a little less than
in the normal animal to somewhat more than in the headless form.
Moreover the degree of reconstitution decreases somewhat as the

THE RECONSTITUTION OF ISOLATED PIECES II3

character of the head departs from normal.
In pieces of the same length and from the
same region the size of the head and the
length of the pharyngeal and prepharyn-
geal region are less in teratophthalmic and
teratomorphic than in normal animals and
less in anophthalmic than in teratomorphic
or teratophthalmic forms. Between the
teratophthalmic and teratomorphic forms
the differences in this respect are not very
great except when opposite extremes of the
two types are compared.

That the production of a normal or
nearly normal animal from a piece requires
more energy than the production of a head-
less form is indicated by the fact that a
much greater amount of reduction occurs
in the former than in the latter case.
Moreover, in a given lot of pieces it is
possible by means of external conditions
such as temperature, low concentrations of
narcotics, etc., whose effect is primarily
quantitative rather than qualitative, to
determine experimentally within wide
limits which of the five forms shall be pro-
duced (Child, ’116, ’12b). Experiments of
this kind have demonstrated that all four
forms from the teratophthalmic to the
headless are what might be called sub-
normal, i.e., they are due to various degrees

. of retardation or inhibition of the dynamic
processes (Child, ’11, ’14a, ’14b). And,
finally, after their development is com-
pleted, the normal head shows in general
a higher susceptibility than the teratoph-

00

Fic. 24.—Body-outline
of Planaria dorotocephala,
indicating levels of section.

thalmic and teratomorphic, and these a higher susceptibility than

the anophthalmic.

114 SENESCENCE AND REJUVENESCENCE

It is evident, then, from all points of view, that these different
forms represent different degrees of reconstitution. If the degree
of rejuvenescence, as indicated by the increase in susceptibility,
is associated with the degree of reconstitution, then these different
forms, when produced under comparable conditions, should show
the highest susceptibility in the normal, the lowest in the headless
animals, with intermediate conditions in the intermediate forms.
The following experiment shows to what extent this is the case.

The stock for the experiment consisted of a hundred or more
pieces like a in Fig. 24, cut from animals of equal size and similar
physiological condition and allowed to undergo reconstitution
under uniform external conditions. Even under such conditions
pieces of this size and from this region may produce anything from
normal to headless forms, although the great majority are headless
or anophthalmic.

Eleven days after section reconstitution was practically com-
plete, and the susceptibilities of lots of ten each of the different
forms and at the same time of a lot of ten intact worms like those
from which the pieces had been taken were determined. The
control animals had been kept under the same conditions as the
pieces, and, like them, without food during the eleven days of the
experiment, and the difference in susceptibility between the pieces
and these whole animals should show how much rejuvenescence
had occurred in connection with reconstitution.

The results appear in the susceptibility curves of Fig. 25. The
curve of the whole animal is drawn in an unbroken line, that of the
normal animals developed from pieces in short dashes, that of
the teratophthalmic forms in long dashes, that of the anoph-
thalmic forms in alternate long and short dashes, and that of head-
less forms in dots. The susceptibility is highest in the normal
animals developed from pieces, slightly lower in the teratophthalmic
forms, considerably lower in the anophthalmic forms, and again
still lower in the headless forms. In all except the headless forms
the susceptibility is higher than in the whole animals, ie., it has
increased during reconstitution.

The susceptibility curve of the headless pieces shows an inter-
esting relation to that of the whole animals. In earlier stages the

THE RECONSTITUTION OF ISOLATED PIECES II5

susceptibility of the headless forms falls below that of the whole
animals, but later rises considerably above it. This is simply
an expression of the fact that there is no part of the headless piece
which has as high a rate of metabolism as the head-region of the
whole animal, but that the rate in the headless piece is considerably
higher than that of the regions of lowest rate in the whole animal.
It is also evident from Fig. 25 that the difference between normal

Stages 1

II

III

Hours I 2 3. 4 5 6 7
Fic. 25.—Susceptibility of Planaria dorotocephala to KCN 0.001 mol. after
different degrees of reconstitution: unbroken line, uninjured animals like those from
which pieces were taken; short dashes, normal forms after reconstitution; long
dashes, teratophthalmic forms; alternate long and short dashes, anophthalmic forms;
dots, headless forms.

and teratophthalmic forms is slight and much less than that between
teratophthalmic and anophthalmic forms.

These curves are a graphic presentation in dynamic terms of
the degree of rejuvenescence in its relation to the degree of recon-
stitution. Similar tests of the susceptibility of the different
reconstitutional forms have been made repeatedly with pieces of
different size and from different regions of the body and always
with essentially the same result.

116 SENESCENCE AND REJUVENESCENCE

THE SUSCEPTIBILITY OF ANIMALS RESULTING FROM EXPERIMENTAL
REPRODUCTION AND SEXUALLY PRODUCED ANIMALS

The belief that the germ cell is the source of youth and that the
old organism cannot become young has been so widely current

OR)

Fic. 26.—Body-
outline of Planaria
maculata, indicating
levels of section.

among biologists that it is of some interest to
determine whether the physiological condition
of the animal resulting from reconstitution
approaches that of the sexually produced young
animal. Planaria dorotocephala is not available
for such experiments, since it does not repro-
duce sexually under ordinary conditions, con-
sequently another species, P. maculata, has been —
used in which the young produced from eggs
can readily be obtained.

In experiments of this kind pieces were cut
from old, sexually mature animals and allowed
to undergo reconstitution; after reconstitution
their susceptibility was compared with that of
sexually produced young of the same size. In
the particular experiment of which the results
are given in Fig. 27 below, two lots of pieces
(a and 6, Fig. 26) were cut from old, sexually
mature worms twelve millimeters in length.
These pieces were left for ten days under uni-
form conditions, at the end of which time they
had become normal animals five to six milli-
meters long. They were then fed, and two days
later their susceptibility was compared both
with that of old, sexually mature worms like
those from which the pieces were taken and also
with that of young, growing worms five to six
millimeters long, which had been hatched from
eggs in the laboratory.

Fig. 27 shows the susceptibilities to KCN
o.oo1 mol. of ten old, sexually mature worms

(cd), ten young, growing worms hatched from eggs (ab, long
dashes), ten animals developed from the a-pieces (ab, short

THE RECONSTITUTION OF ISOLATED PIECES 117

dashes), and ten animals developed from the d-pieces (ad, unbroken

line). The figure shows that the susceptibility of animals resulting

from the reconstitution of pieces is practically the same as that of

the young, growing, sexually produced animals of the same size

and much greater than that of the old, sexually mature animals.

In other words, the animals resulting from experimental repro-

duction possess about the

same rate of metabolism as_ Stages +

sexually produced growing

animals of the same size, and II

a much higher rate than the

animals from which the pieces

were taken. The process of

reconstitution has made the III

experimentally produced ani-

mals as young as the sexually

produced animals of the same

size. Iv
It is of interest, however,

to note that the b-pieces from _

the posterior end of the ani-

mal (Fig. 26) show a some- Vv

what greater susceptibility

than the a-pieces from the

anterior body region. This Ae
y 8 Fic. 27.—Susceptibility of Planaria macu-

difference in susceptibility lata to KCN 0.001 mol.: ad, long dashes,
corresponds to a real differ- sexually produced young; ab, short dashes
ence in the process of recon- 2nd unbroken line, animals resulting from

‘ - P : reconstitution of pieces; cd, animals like
stitution in pieces from these those from which the pieces were taken.
two regions. In the recon-
stitution of the b-pieces there is less outgrowth of new tissue
and more reorganization of the old than in the a-pieces, so that
the old tissue becomes somewhat younger in the former than
in the latter; consequently, as the new tissue becomes older and
the old tissue younger, they finally attain the same physiological
age at a stage somewhat younger in the b-pieces than in the a-
pieces. Slight differences of this kind are characteristic of pieces

Hours I 2 3 4

118 SENESCENCE AND REJUVENESCENCE

from different body levels and are correlated with differences in
the process of reconstitution.

If pieces smaller than these are taken, the increase in suscepti-
bility is greater and the animals attain the condition of still younger
sexually produced forms. Evidently these experimental repro-
ductions, while they do not carry the organism back to the
beginning of development, do carry it back to the physiological
condition characteristic of the sexually produced, growing animal
of the same size. Experimental reproduction is apparently in this
species just as efficient a means of producing physiologically young
animals as sexual reproduction.

REPEATED RECONSTITUTION

It has been shown in preceding sections that the animals
produced by reconstitution are physiologically younger than the °
animals from which the pieces are taken, and moreover that they
are about as young as sexually produced animals of the same size.
If this is the case, it should be possible to breed animals indefinitely
by means of this process of experimental reproduction. On the
other hand, the animal rejuvenated by reconstitution may differ in
some way from the sexually produced animal, but so slightly that
the difference does not become apparent in a single generation,
but requires several or. many generations of breeding by experi-
mental reproduction to become distinguishable. Thus far two
attempts at reconstitutional breeding have been made, both of
which were terminated by accident, but one of them continued
long enough to throw at least some light on the question.

The breeding stock for these experiments was obtained as
follows: Large individuals of the same size, which had been kept
under uniform conditions, were selected, and from each of these
a piece of a certain size and from a certain region of the body was
taken. These pieces were allowed to undergo reconstitution and
after this was completed were fed until they attained approxi-
mately the original size. Then from each a piece, including the
same region of the body, was taken; these were again allowed to
develop, were fed, andsoon. In one of these breeding experiments
the piece used in each generation was the anterior fifth of the body,

THE RECONSTITUTION OF ISOLATED PIECES 11g

including the old head. In such pieces the old head remains from
one generation to another and new tissue appears only at the
posterior end; consequently the amount of reorganization is less
than in pieces which form a new head or in pieces from the posterior
region of the body. Moreover, the head-region is less capable of
reorganization than other parts of the body. If a progressive
senescence occurs from generation to generation in spite of recon-
stitution in each generation, it should become more distinct or
appear earlier in such pieces than in those where the reconstitu-
tional changes are more extensive.

In the course of a year and a half the animals passed through
thirteen experimental generations without any indications of
senescence or depression of any sort. During the growth of the
thirteenth generation, however, most of the stock was killed by
high temperature and the remaining animals never regained good
condition, but died in the course of the next few generations. The
worms that remained alive in each generation grew more or less
normally, and the breeding was continued with these. In the six-
teenth generation only eight worms remained alive, and in order to
determine whether more extensive reconstitutional change would
bring the animals back to their original condition, the old heads
were removed and each animal was cut into several pieces. Some of
these pieces produced complete animals, but deaths continued to
occur among these, and some of the pieces died without reconstitu-
tion. The living animals were again cut into pieces after growth,
and this was repeated to the nineteenth generation in which the
last of the stock died without recovery.

In another stock pieces from the middle region of the body were
used for each generation. In the fifth generation this stock was
subjected to high temperature at the same time as the preceding,
and most of the animals died. Those that remained alive gradually
died during the following generations, until in the tenth genera-
tion all were dead.

The results of these two breeding experiments are of value only
as far as they go. The first does show, however, that the animals
can be bred by experimental reproduction without loss of vigor
for at least thirteen generations, even when the old head is

120 SENESCENCE AND REJUVENESCENCE

continuously present. The first stock was subjected to high
temperature in the thirteenth generation, the second in the fifth
generation, but in both the result was the same, in that most of
the stock was killed and the survivors failed to recover after several
months. There can be little doubt that the high temperature
rather than the physiological condition of the animals was respon-
sible in one way or another for the death of both stocks.

As a matter of fact, however, the question which these experi-
ments attempted to answer is answered by reproduction in nature
in Planaria dorotocephala and P. velata. It will be shown in the
following chapter that the process of agamic reproduction in these
forms is not essentially different in any way from the process
of reconstitution of pieces, and this is the only method of reproduc-
tion which has been observed in these two species under natural
conditions.

The results obtained by another method of experiment are of
interest in this connection. This is essentially breeding by experi-
mental reproduction without food. Pieces from large, old animals
are allowed to undergo reconstitution; then, without feeding, pieces
are taken from these animals, and so on. Here of course each
generation is smaller than the preceding, and the experiment is
finally brought to an end by the advancing starvation of the animals
and the failure of the minute pieces to undergo reconstitution. But
susceptibility tests show that the susceptibility increases with such
reconstitutions, and in Planaria maculata, where sexually produced
animals are available for comparison, the animals after a few genera-
tions of reconstitution without food show a susceptibility equal to
that of animals just hatched from the egg capsule. Their rate of
metabolism has increased in consequence of the successive recon-
stitutions and the absence of food until it equals that of very
young sexually produced animals. If fed after such a series of
reconstitutions, they grow and are indistinguishable from the
animals hatched from eggs.

In short, by successive reconstitutions alternating with feeding
and growth, the animals may be brought back to essentially the
same stage in the age cycle in each successive generation, and by
successive reconstitutions without feeding and growth they may be

THE RECONSTITUTION OF ISOLATED PIECES 121

made progressively younger physiologically in each successive
generation, until further reconstitution becomes impossible.

REFERENCES

Cuitp, C. M.

Iglia.
Ig11b.

IQIIc.

1913.

1914a.

1914).

“A Study of Senescence and Rejuvenescence Based on Experi-
ments with Planarians,” Arch. f. Entwickelungsmech., XXXI.
“Experimental Control of Morphogenesis in the Regulation of
Planaria,” Biol. Bull., XX. ;

“Studies on the Dynamics of Morphogenesis and Inheritance in
Experimental Reproduction: I, The Axial Gradient in Planaria
dorotocephala as a Limiting Factor in Regulation,” Jour. of Exp.
Zool., X.

. “The Process of Reproduction in Organisms,” Biol. Bull., XXIII.
. “Studies on the Dynamics, etc.: IV, Certain Dynamic Factors in

the Regulatory Morphogenesis of Planaria dorotocephala in Rela-
tion to the Axial Gradient,” Jour. of Exp. Zool., XIII.

“Certain Dynamic Factors in Experimental Reproduction and
Their Significance for the Problems of Reproduction and Develop-
ment,” Arch. f. Entwickelungsmech., XXXV.

“Studies on the Dynamics, etc.: VII, The Stimulation of Pieces
by Section in Planaria dorotocephala,”’ Jour. of Exp. Zool., XVI.
“Studies on the Dynamics, etc.: VIII, Dynamic Factors in Head-
Determination in Planaria,’”’ Jour. of Exp. Zool., XVII.

CHAPTER VI

THE RELATION BETWEEN AGAMIC REPRODUCTION AND RE-
JUVENESCENCE IN THE LOWER ANIMALS

THE PROCESS OF AGAMIC REPRODUCTION IN Planaria dorotocephala
AND RELATED FORMS

Planaria dorotocephala, like many other species of flatworms,
undergoes from time to time a process of agamic or asexual repro-
duction, which consists in the separation by fission of the posterior
third or fourth of the body from the rest and its development into
anew animal. The posterior region which separates is not morpho-
logically distinguishable in any way from adjoining regions of the
body, yet the separation occurs at a more or less definite level of
the body.

In the course of an extended study of experimental reproduc-
tion in Planaria I have found that the posterior body region in all
except very young animals, while not morphologically distinguish-
able as a new individual, is nevertheless clearly marked off physio-
logically from the region anterior to it. Along the main axis of
the planarian body a gradient in the rate of metabolism exists
(Child, ’12, ’13a), the rate being highest in the head-region and
decreasing posteriorly to the region where separation occurs in
fission: here a sudden rise in rate occurs, and posterior to this
point another gradient similar to that in the anterior region. That
is, the posterior region of the body, which is separated from the
rest by the act of fission, possesses an axial gradient in rate of metab-
olism similar to that of the anterior region. In long worms, two,
three, or even more of these metabolic gradients may appear, one
posterior to the other. These metabolic gradients in the body of
Planaria appear, not only in the susceptibility of different regions,
but also in the differences in the capacity for reconstitution of
pieces from different levels (Child, ’11), ’11¢).

The existence of these metabolic gradients in the posterior
region of Planaria indicates, as chap. ix will show more clearly,

122

AGAMIC REPRODUCTION AND REJUVENESCENCE

that this region has undergone
the first step in the process of
individuation. Each one of the
gradients is the dynamic expres-
sion of this individuation. In
fact, the body of Planaria, after
a certain stage of development,
is physiologically a chain of two
or more zooids, i.e., of individ-
uals organically connected. In
young animals four or five milli-
meters long only two zooids are
distinguishable, the longer,
anterior zooid making up the
greater part of the body and
bearing the head, and the
shorter, posterior zooid indi-
cated only dynamically by a
second metabolic gradient in the
posterior region. The boundary
between the two zooids in these
small animals is indicated by
the dotted line across the body
in Fig. 28. As the animal be-
comes longer, other zooids arise
in the posterior region by fur-
ther physiological division of
the original posterior zooid, and
when it has reached a length of

Fics. 28-30.—Development of zooids
in Planaria dorotocephala: Fig. 28, a
young animal with two zooids, r and 2;
Fig. 29, a half-grown animal in which
the original posterior zooid has divided
into zooids 2.1. and 2.2., and 2.2. has
undergone further division; Fig. 30, a
full-grown animal in which still further
zooids have appeared.

28

a&

~

SS

123

TJ.

7.2,

2.1.1.

2.1.2.

2.2.+

124 SENESCENCE AND REJUVENESCENCE

ten or twelve millimeters the posterior region is more or less clearly
marked off by metabolic gradients into two or more zooids
(Fig. 29), and the extreme posterior end appears to be a growing
tip in which new zooids are arising. In nature, separation at the

00

Fic. 31.—Planaria
dorotocephala in process
of division.

boundary between the first and second zooids
very commonly occurs at about this stage,
but if the animals are prevented from divid-
ing, which may be accomplished in various
ways, they may grow to a length of twenty-
five to thirty millimeters and the posterior
region may consist of four to five zooids and
a growing tip (Fig. 30).

The dynamic demarkation of these pos-
terior zooids results, as has been shown else-
where,’ from a physiological isolation of the
regions concerned in forming the dominant
head-region of the animal. The consequence
of this physiological isolation is the beginning
of a new individuation in the isolated region,
in essentially the same manner as in the
physically isolated piece which begins to
undergo reconstitution, and for the same
reason. But the physiological isolation of
the posterior region of the planarian body is
less complete than in the piece isolated by
section; consequently the development of
new individuation beyond a very early stage,
which is only dynamically distinguishable, is
inhibited. In Planaria maculata and various
other species of Planaria new zooids arise in
the same way and exist dynamically as axial
gradients, but their morphological develop-

ment is similarly inhibited until after their physical separation
from more anterior regions.

The act of fission in these animals results from an independent
motor reaction of posterior and anterior zooids. If the animal is

tChild, ’10, ’11a, ’11¢; see also chap. ix.

AGAMIC REPRODUCTION AND REJUVENESCENCE = 125

slightly stimulated when creeping about, or in some cases without
any stimulation from external sources being apparent, the posterior
region suddenly attaches itself tightly to the underlying surface
by its margins, using the ventral surface as a sucking disk, while
the anterior zooid continues to creep, and when it feels the resist-
ance to forward movement it exerts itself violently to pull away.
The consequence of this lack of co-ordination between the two
regions is that the body just anterior to the attached region be-
comes more and more stretched and finally ruptures, and the
posterior region is left behind. Fig. 31 shows an animal in the act
of fission. The anterior zooid bearing the head is endeavoring to
move forward, and the posterior zooid has attached itself firmly
to the surface on which the animal was creeping. In many cases
the posterior region of the first zooid becomes stretched into a long,
slender band, and even then, particularly in large old animals
where the tissues seem to be tougher and rupture less readily, the
anterior zooid often apparently becomes exhausted and ceases to
exert itself, or else the posterior zooid is torn from its attachment
to the substratum or releases itself before the connecting parts are
ruptured. Such failures of fission are very common in the larger,
older animals. Fission can also be prevented by keeping the ani-
mals on surfaces to which they cannot attach themselves firmly,
e.g., in vaseline-lined dishes.

After separation the smaller posterior piece undergoes reconsti-
tution into a new animal of small size in exactly the same manner
as do pieces cut from the body, and the anterior zooid develops a
new posterior end in which one or more new zooids may arise. In
Planaria dorotocephala this is the only form of reproduction which
has been observed in nature during a period of observation covering
some ten years, but in the laboratory, animals which have been
prevented from undergoing fission have become sexually mature
in a few cases.

THE OCCURRENCE OF REJUVENESCENCE IN AGAMIC REPRODUCTION
IN Planaria dorotocephala AND P. maculata

Since a greater or less degree of rejuvenescence occurs in the
reconstitution of pieces of Planaria (see chap. v) and since the

126 SENESCENCE AND REJUVENESCENCE

00 00

32
33

Fics. 32-34.—Reconstitution after fission in
Planaria dorotocephala: Fig. 32, animal before
fission; ff, fission-plane, @, anterior, b, posterior
zooid; Fig. 33, reconstitution of posterior zooid;
Fig. 34, reconstitution of anteriorzooid.

natural process of agamic
reproduction resembles so
closely the process of
reconstitution the occur-
rence of some degree of
rejuvenescence is to be
expected in agamic repro-
duction.

It has already been
shown in Fig. 3 (p. 80)
and in Fig. 13 (p. 100) that
individuals of P. doroto-
cephala of small size and
young in appearance, but
which supposedly arose
agamically, are physiologi-
cally much younger as re-
gards their susceptibility
than the large, apparently
old animals. But in order
to obtain conclusive evi-
dence upon this point it is
necessary to compare ani-
mals which are known to
have arisen by fission
under controlled con-
ditions with animals like
those in which the fission
occurred.

This comparison has
been made repeatedly and
the result confirms expec-
tation. The small animal
which develops from the
separated posterior region
of the parent animal is
physiologically much

AGAMIC REPRODUCTION AND REJUVENESCENCE 127

younger than the latter. Since the results of these experiments
are in all respects essentially identical with those obtained with
pieces artificially isolated by section, it is unnecessary to present
them in detailed form.

In the process of fission the separated posterior zooid undergoes
much more extensive reorganization than the anterior zooid. In
an animal of medium size fission usually occurs at about the level
indicated by the line f in Fig. 32. The posterior piece b (Fig. 32)
is much smaller than the anterior a, and it develops a new head and
a new pharynx, and extensive changes in the alimentary tract
occur in the formation of the prepharyngeal region. Moreover,
it cannot take food until the new mouth and pharynx have reached
a certain stage of development, consequently the energy for develop-
ment is derived from its own tissues and it undergoes more or
less reduction during the process. In Fig. 33 the animal developed
from the posterior fission-piece is drawn to the same scale as Fig. 32.
This animal is physiologically much younger than the parent from
which it came. Its susceptibility is much higher and it is capable
of more rapid growth than the original animal.

In the anterior fission-piece (a, Fig. 32), on the other hand, the
original head and the mouth and pharynx persist, the only out-
growth of new tissue formed is at the posterior end, and the only
other change in form is the growth of the postpharyngeal at the
expense of the prepharyngeal region, in consequence of which the
pharynx seems to migrate forward (Fig. 34). When food is present,
this piece may feed and increase in size during the whole process
of reconstitution, but even when it is not fed, the degree of reduction
during reconstitution is slight, because the developing regions have
a relatively large mass to draw upon as a source of energy. The
relation which was shown in the preceding chapter to exist between
the size of the piece, the amount of reconstitutional change, and the
amount of increase in susceptibility would lead us to expect that
the increase in susceptibility resulting from the reconstitutional
changes in the anterior fission-piece would be much less than in the
posterior piece, and this is in fact the case.

The increase in susceptibility in the posterior piece is the same
as that in artificially isolated pieces of the same size. In Planaria

128 SENESCENCE AND REJUVENESCENCE

maculata the animals developed from these pieces are about as
young physiologically as sexually produced animals of the same
size. In P. dorotocephala, where sexually produced animals are
not available for comparison, the degree of increase in suscepti-
bility over that of the parent animals is about the same as in P.
maculata. Since these results are so completely in agreement,
both with expectation and with the results obtained from arti-
ficially isolated pieces, experimental records are unnecessary.

Stages + ac

II

Ill

IV

ON

Hours 2 3 4 5 6 7 8

Fic. 35.—Susceptibility of Planaria dorotocephala to KCN 0.001 mol.: ab,
anterior fission-pieces after reconstitution; cd, entire animals before fission.

With respect to the anterior fission-piece, however, it is a matter
of some interest to demonstrate that the reconstitutional changes
occurring in the posterior region of so large a piece as this do alter
the physiological condition of the whole piece, including even the
head-region. For this reason the record of one susceptibility test
of these anterior pieces is given in Fig. 35. For this experiment
worms ten to twelve millimeters in length were induced to undergo
fission and the anterior fission-pieces were kept without food for
twelve days. Another lot of worms of the same size and in the

AGAMIC REPRODUCTION AND REJUVENESCENCE 129

same physiological condition, but undivided, was kept without
food during the same period as a control. In Fig. 35, curve ab
shows the susceptibility of the anterior fission-pieces, curve cd
that of ten of the undivided animals, also without food. At this
time the animals had attained the stage of development shown in
Fig. 34.

The susceptibility of the fission-pieces is distinctly greater
than that of the undivided animals, and as a matter of fact the
differences are greater than the curves show. At the points in the
curve where the two lots appear to be in the same or nearly the
same stage of disintegration, examination of the pieces showed
that even though the two lots might fall within the same one of
the five arbitrarily distinguished stages, the fission-pieces were
always more advanced in that stage. The fission-pieces are evi-
dently younger physiologically than whole worms, and this is true,
not only for the posterior region where the reconstitutional changes
are localized, but for the whole body, including the head. Un-
doubtedly the anterior regions have served to some slight extent
as a source of energy for the developmental changes in the posterior
region.

Similar results have been obtained repeatedly in other similar
experiments. If the anterior fission-pieces are fed during recon-
stitution and their susceptibility compared with that of whole
animals fed at the same time, the increase in susceptibility is found
to be less marked or inappreciable. In such cases the food taken,
rather than the tissues, provides the energy for the development
of the new posterior end. Similarly the larger the animal when
division occurs, the less the increase in susceptibility. In the very
large, heavily fed animals, in which the anterior fission-piece may
be fifteen millimeters or more in length, there is usually no appre-
ciable increase in susceptibility in this piece after fission. Here
the amount of reconstitutional change is so slight in relation to
- the size, and the amount of nutritive reserve is so great, that the
body as a whole is not appreciably affected by the development
of the posterior end.

The relation between agamic reproduction and susceptibility
is the same in Planaria dorotocephala and in P. maculata. In both

130 SENESCENCE AND REJUVENESCENCE

species the posterior fission-piece undergoes a considerable increase;
the anterior, except when very large or heavily fed, exhibits a
slight increase in susceptibility. In other words, agamic repro-
duction brings about a greater or less degree of rejuvenescence.

AGAMIC REPRODUCTION AND REJUVENESCENCE IN Planaria velata

Planaria velata (Fig. 8), a flatworm found very commonly in
temporary pools and ditches as well as sometimes in permanent
bodies of water, is another species in which only agamic or asexual
reproduction has been observed during some thirteen years. The

‘asexual cycle of this species and its relation to senescence and re-
juvenescence have been considered at length elsewhere (Child,
’13b, ’14), and only the more important points need be reviewed here.

Agamic reproduction in this species is a process of fragmenta-
tion which occurs only at the end of the growth period. The
animals appear early in spring, chiefly in temporary pools and
ditches in which dead leaves have accumulated. When they first
appear they are only two or three millimeters in length, very active,
and to all appearances young in every respect. They grow rapidly
and become deeply pigmented, but the rate of growth gradually
decreases, and at the end of three or four weeks, when they have
attained a length of about fifteen millimeters, they cease to feed,
become lighter in color, their motor activity undergoes a distinct
and progressive decrease, and the pharynx undergoes complete
disintegration. Within a few days after these changes fragmenta-
tion begins at the posterior end of the body. The process of
fragmentation resembles in certain respects the process of fission
in P. dorotocephala, described in the first section of this chapter.
As in that species, the act of separation is accomplished by attach-
ment of the posterior end to the substratum while the animal is
creeping, with the result that a small piece tears off and is left behind.
But in P. velata the process may be repeated frequently in the course
of a few hours and the fragments vary widely in size. In P. velata,
as in P. dorotocephala, fragmentation is undoubtedly the result of
physiological isolation and independent motor reaction of the
posterior end of the body, but, instead of occurring periodically
during the life of the animal, it does not occur until senescence is

AGAMIC REPRODUCTION AND REJUVENESCENCE = 131

far advanced and the rate of metabolism is very low. Posterior
zooids are not distinctly marked off dynamically, as in P. doroto-
cephala, but the portions which separate are merely small bits of
the body at the posterior end which, as the animal becomes pro-
gressively weaker, finally cease to be controlled and co-ordinated
with other parts by the dominant head-region, and so, sooner or
later, react independently and are torn off. In some cases the
animal may leave a trail of such fragments behind it as it creeps
slowly along. The stimulation resulting from the rupture of the
tissues leads to the secretion of slime on the surface of the separated
pieces, and this slime hardens and forms a cyst within which the
pieces gradually undergo reconstitution to whole animals of small
size which sooner or later emerge.

Fragmentation may continue until only the head and a short
piece of the body two or three millimeters in length remain, or it
may be confined to the posterior third or half of the body. After
fragmentation is completed, the anterior piece, whether large or
small, may encyst, or it may remain more or less active and grad-
ually undergo reduction in size in consequence of starvation.
Finally, after considerable reduction has occurred, it develops a
new pharynx and mouth and a new posterior end, and begins to
feed and grow again. Cases of this sort will be considered in
chap. vii.

The encysted fragments do not withstand complete desiccation,
but the bottoms of the ditches and pools in which they live retain
sufficient moisture to keep them alive. In the autumn the ditches
do not usually fill again before cold weather, although they may do
so, in which case the worms may emerge from the cysts at that
time, but their growth is soon stopped by low temperature. Com-
monly, however, they appear only in spring, as soon as the ditches
thaw out. This cycle is repeated year after year, and thus far
neither sexually mature animals nor animals with any part of the
sexual ducts or copulatory organs have ever been found, though
ovaries and testes in early stages of development may sometimes
be present.

In the laboratory the animals may pass through the whole life
cycle in two or three months, for the encysted fragments when

132 SENESCENCE AND REJUVENESCENCE

kept in water often emerge as young worms within two or three
weeks after encystment. There is therefore no difficulty in ob-
taining small animals which are known to have developed from
encysted pieces for comparison with the larger animals at various
stages of the life cycle.

Fig. 36 shows the susceptibility of ten animals about two milli-
meters in length newly emerged from cysts (curve ab) compared
with that of ten full-grown animals raised from cysts in the labora-

x

Stages f¢ 4 &

II

It

b a

Hours I 2 3 4 5 6 7

Fic. 36.—Susceptibility of Planaria velata to KCN 0.001 mol.: ab, animals
newly emerged from cysts; cd, full-grown animals.

tory (curve cd). The susceptibility of the small, newly emerged
animals is very much greater than that of the full-grown animals.
In other words, the newly emerged worms are young as regards
rate of metabolism, as they appear to be in every other respect, and
the full-grown animals which are about to undergo fragmentation
are old. In this species, asin P. dorotocephala, agamic reproduction
is simply a separation and reconstitution of pieces, and rejuvenes-
cence is associated with the reconstitutional changes in the piece.

AGAMIC REPRODUCTION AND REJUVENESCENCE 133

Since the pieces are usually very small, the reorganization is ex-
tensive and the degree of rejuvenescence is very much greater than
in the larger pieces separated in agamic reproduction in P. doroto-
cephala and P. maculata. In cases where large instead of small
fragments are formed the animals which develop from them are of
‘course longer than those from the small fragments, the reconsti-
tutional changes are less extensive, and the degree of rejuvenescence
is less than in the small fragments.

Apparently the degree of rejuvenescence is essentially the same
in successive generations, for this method of reproduction is ade-
quate for the maintenance of the species without visible decrease
in vigor or advance in senescence, at least for a considerable number
of generations. In the laboratory a stock of these worms has been
bred asexually over three years and has passed through fifteen
generations without any apparent progressive change in the
physiological condition of the animals in successive generations.
In each generation the rate of metabolism decreases and the process
of senescence ends in fragmentation and encystment, and young
animals emerge from the cysts and repeat the life cycle.

This case is of particular interest because the process of senes-
cence, as it occurs under the usual conditions of existence, does not
end in death but leads directly to reproduction and rejuvenescence.
The occurrence of fragmentation in these animals is very clearly
associated with the decrease in rate of metabolism which is the
characteristic dynamic feature of senescence (Child, ’130). As
the animal grows old its decreasing rate of metabolism makes im-
possible the maintenance of physiological individuality. Physio-
logical isolation of parts (see chap. ix) occurs and is followed by
physical isolation, and the isolated parts of the old individual
undergo reconstitution into new, young individuals. Senescence
itself is the physiological factor inducing reproduction and _ re-
juvenescence. .

AGAMIC REPRODUCTION AND REJUVENESCENCE IN Stenostomum
AND CERTAIN ANNELIDS

In certain flatworms, among which is the genus Stenostomum,
the morphological development of the new zooids reaches an

134 SENESCENCE AND REJUVENESCENCE

advanced stage before they separate from the parent body. In
such forms the body consists visibly of a chain of zooids in various

r ame
T1. LI.
a 1.1.2.
2. 1.1.2.
1.2. ce.
37 Rae os
2.
1.2.2.
2.1.
2.1.1.
38
2.2. —
2.1.2.
2.2.

Fics. 37-40.—Progress of agamic reproduction in Steno-
stomum: the sequence in the formation of new zooids is indi-
cated by the numerals.

40

stages of development. The development of such a chain of
zooids in Stenostomum is shown in Figs. 37-40. In Fig. 37 only
the zooids 1 and 2 are present; in Fig. 38 zooid 1 has divided into

AGAMIC REPRODUCTION AND REJUVENESCENCE 135

1.1. and 1.2., but zooid 2 has not yet divided. In Fig. 39 zooid
1.1. has divided again into 1.1.1. and 1.1.2., zooid 1.2. has not
yet divided, and zooid 2. has divided into 2.1. and 2.2. In Fig. 39
still further divisions have occurred, and the relations of the differ-
ent zooids are indicated by the numbers designating each. Here
morphological development of each zooid is almost completed
before separation occurs. The first separation takes place at the
most advanced fission-plane and as other zooids reach a correspond-
ing stage other separations occur, but meanwhile new zooids have
begun to develop. Thus the breaking up of the old chains and the
formation of new go hand in hand.

Such processes of agamic reproduction do not differ essentially
in any way from the process of reconstitution of pieces isolated by
section in the same species. In both cases a certain region of the
body gradually transforms itself into a whole animal. In both
cases certain parts atrophy and disappear, cell division and localized
growth occur, and new parts develop. In Stenostomum, however,
the new zooid receives food during its development, for the ali-
mentary tract common to the whole chain passes through it; con-
sequently it is not dependent upon its own tissues for the energy
necessary for its development as is a physically isolated piece, and
therefore it does not undergo the reduction in size characteristic
of such pieces. In fact it usually increases in size during develop-
ment.

In Stenostomum as in Planaria the susceptibility method
demonstrates the existence of a longitudinal axial gradient in rate
of metabolism. Before agamic reproduction begins this gradient
extends the length of the individual, but as new zooids arise the
anterior region of each shows a higher rate of metabolism than the
region immediately anterior to it, and each zooid develops its own
axial gradient like that of the original animal. In the earlier stages
of zooid development the susceptibility of the new zooid is less,
i.e., its rate of metabolism is lower, than that of the fully developed
zooid which heads the chain, but as development proceeds the sus-
ceptibility increases, until at the time of separation, or soon after,
it is higher than that of the anterior zooid. Separation of the
zooids at an earlier stage of development than that at which it

136 SENESCENCE AND REJUVENESCENCE

naturally occurs may be induced by strong stimulation, and in such
cases development and the increase in susceptibility are usually
somewhat accelerated.

From these facts we must conclude that in Stenostomum as in
Planaria the reconstitution of a given region of the body into a
new individual is accompanied by some degree of physiological
rejuvenescence. Without doubt the age differences in suscepti-
bility between the developing young zooids and the fully developed,
relatively, old anterior zooid of the chain are obscured to some extent
by the much greater motor activity of the latter, but the fact that
sooner or later the young zooids become more susceptible than this
older zooid indicates that rejuvenescence does occur.

In various species of aquatic oligochete annelids agamic repro-
duction occurs in much the same manner as in Stenostomum. In
the course of investigations as yet unpublished Miss Hyman has
found that these animals, like the flatworms, undergo a greater or
less degree of physiological rejuvenescence in connection with
agamic reproduction.

THE RELATION BETWEEN AGAMIC REPRODUCTION AND REJUVENES-
CENCE IN PROTOZOA

The question whether the protozoa undergo senescence or not is
of considerable interest at present. The generally accepted view
based on the researches of Maupas (’88, ’89) that conjugation in
the ciliate infusoria terminates an invariable process of race senes-
cence and brings about rejuvenescence requires some modification
in the light of recent researches. Woodruff has bred a race of
Paramecium through nearly five thousand generations without
conjugation and without loss of vigor.t This number of gen-
erations is so large that we are justified in maintaining that
for the race of Paramecium used, and under the conditions of
experiment, conjugation is not an essential feature of the life
cycle. On the other hand, various investigators? have shown

1 Woodruff, ’08, ’o9, ’11a, ’13a, ’13b, ’14; Woodruff and Erdmann, ’14. In
these and other papers the author records the progress of the agamic breeding.

? Among these may be mentioned Calkins, ’o2¢, ’02b,’04; Enriques, ’03, ’07,
708; Woodruff (see note 1); Jennings, ’10, ’13; Baitsell, ’12, ’14; Zweibaum, ’12;
Calkins and Gregory, 713.

AGAMIC REPRODUCTION AND REJUVENESCENCE 137

during the last few years that the occurrence of conjugation
is dependent, at least in a large measure, upon external factors.
Woodruff has experimentally induced conjugation in members of
his culture which has been agamically bred through thousands of
generations. Jennings concludes from extended experimentation
that conjugation does not bring about rejuvenescence, but merely
increases variability, while Calkins and Gregory believe that reju-
venescence does occur, at least in some cases.

If conjugation is not a necessary feature of the life cycle, or if
it fails to accomplish rejuvenescence, two alternative conclusions
present themselves: either these animals do not necessarily undergo
senescence or else rejuvenescence is accomplished in some other
way than by conjugation. The relation found to exist between
agamic reproduction and rejuvenescence in the flatworms suggests
at once the possibility that a similar relation may exist in the
protozoa.

Since the protozoa are unicellular animals, agamic reproduction
is essentially a process of cell division, but since it is also true that
at least many protozoa possess a more or less complex morphological
structure, agamic reproduction, as in multicellular forms, resembles
the process of reconstitution in that it involves various morpho-
logical changes, consisting in the dedifferentiation and disappear-
ance of certain structures and the formation and development of
others. In Paramecium, for example, agamic reproduction does
not consist merely in nuclear and cytoplasmic division, but exten-
sive reorganization also occurs. In Figs. 41-43 the most important
changes are diagrammatically represented. Fig. 41 shows the
animal before division, the oral groove, og, the pharynx, p, and the
two vacuoles, v, being indicated in the figure, as well as the meganu-
cleus, mg, and the micronucleus, mc. The first indications of
division are cytoplasmic, not nuclear, and consist in the formation
of a new contractile vacuole in what is to become the anterior region
of each individual, the two vacuoles of the parent individual becom-
ing the posterior vacuoles in the daughter animals and new vacuoles,
yy’, appearing in the anterior region of each. The mouth and
pharynx and the posterior portion of the oral groove undergo more
or less change and become parts of the posterior daughter animal,

138 SENESCENCE AND REJUVENESCENCE

while in the anterior daughter animal a new mouth and pharynx
and probably a new oral groove arise (Fig. 42), while both mega-
nucleus and micronucleus’ undergo division (Fig. 42), the process
in the former being apparently a direct or amitotic division, while
in the latter it resembles the process of mitosis in certain respects.
Before these divisions are completed a transverse constriction
appears at about the middle of the parent body (Fig. 42), and this

41

Fics. 41-43.—Three stages in the division of Paramecium: mc, micronucleus;
mg, meganucleus; og, oral groove; ~, pharynx; v, vacuoles of original individual;
v’, new vacuoles.

deepens (Fig. 43), until finally separation of the two daughter
individuals occurs at this level. Before division occurs the cyto-
plasmic reorganization has reached an advanced stage (Fig. 42),
but the development of the oral groove and the attainment of the
characteristic proportions are not completed until after separation.

In Stentor coeruleus the process of agamic reproduction differs
in certain respects from that in Paramecium. In Stentor the first
visible stages in division are cytoplasmic, as in Paramecium, and

In the caudatum group of Paramecium only one micronucleus is present, while

in the aurelia group there are two. See Jennings and Hargitt (’10), Woodruff (11d),
for the characteristics of these groups or species of Paramecium.

AGAMIC REPRODUCTION AND REJUVENESCENCE = 139

consist in the appearance of a new vacuole near the middle of the
body and the development of a band of peristomial cilia (Fig. 44),

mgt mg.

mg.

41

Fics. 44-47.—Four stages of division in Stentor: the margin of both old and new
peristomes is indicated by a heavy line; the separation of the new vacuole, v’, from the
old, v, and the changes in shape of the meganucleus, mg, are also indicated. After
Johnson, ’93.

140 SENESCENCE AND REJUVENESCENCE

which at first extends almost longitudinally. After these changes
have occurred the elongated moniliform meganucleus, mg, under-
goes concentration to a spherical form, as in Fig. 45, and the new
peristomial band of cilia gradually assumes a curved outline. Then
a transverse constriction appears in the meganucleus, which defines
two approximately equal halves, and this is followed by elongation of
the meganucleus (mg, Fig. 46), but separation of the two halves does
not occur until later. As regards the micronuclei, of which there
are usually a large number in Stentor (Johnson, ’93), it is not known
whether all or only a part of them divide in each fission. The new
peristomial band of cilia changes its position, becoming more nearly
transverse and semicircular in outline (Fig. 46), and a mouth
begins to develop at its posterior end. This change in shape is
accomplished by a lateral outgrowth on one side of the body near
the middle which represents the anterior end and the peristome of
the posterior daughter individual. Just anterior to this develop-
ing peristome the level at which separation will occur is now indi-
cated by a constriction, as in Fig. 46. Other changes, indicated in
Figs. 46 and 47, consist in the further development of the new per-
istome and its continued approach to the transverse position, the
deepening of the constriction between the two individuals, and the
breaking up of the meganucleus into the characteristic segments,
beginning at the two ends. Still later the meganucleus separates at
the level of the cytoplasmic constriction, which continues to become
deeper, until the anterior member of the pair is attached to the
peristome of the posterior member only by a slender peduncle.
This finally separates and the process of fission is completed. As
regards the essential features of the process of fission, other species
of ciliates resemble Paramecium and Stentor, but the details of recon-
stitution differ for each species.

The process of fission in these forms has been described at some
length because it is evident that it is a much more complex process
than ordinary cell division in the metazoa. So far as the cyto-
plasmic structures are concerned it is manifestly a process of recon-
stitution resembling that which occurs in agamic reproduction in
nature and in isolated pieces in the flatworms and many other
metazoa. Moreover, the process differs in the two forms. In

AGAMIC REPRODUCTION AND REJUVENESCENCE I4I

Paramecium, the original mouth becomes, with more or less reorgani-
zation, the mouth of the posterior daughter individual and a new
mouth arises in the anterior individual, while in Stentor the original
mouth and peristome remain as a part of the anterior individual
and the new peristome is that of the posterior individual. And,
finally, extensive developmental changes occur in the cytoplasm
before any visible nuclear changes. Evidently the process is more
than ordinary cell division. It is in fact an agamic reproduction
comparable to this form of reproduction in the multicellular forms,
and as such it exhibits characteristic features for each species and
involves much more extensive reconstitutional changes than cell
division.

The data presented in chap. v and in the preceding sections of
the present chapter demonstrate that in at least many of the meta-
zoa a relation exists between reconstitution and rejuvenescence.
That being the case, the extensive reconstitutional changes involved
in fission in the ciliates make it at least probable that fission brings
about a greater or less degree of rejuvenescence. With this idea
in mind, the attempt has been made to determine whether appre-
ciable changes in susceptibility occur in connection with fission in
the ciliates. The forms tested thus far are Paramecium, Stentor
coeruleus, a small form of Colpidium, and Urocentrum turbo, and the
results are essentially the same for all. The tests were made upon
actively dividing cultures reared from sterile infusions inoculated
with a few individuals. The rearing of pure line cultures was not
attempted, because definite results were obtained without this
procedure.

In the early stages of fission no appreciable increase in suscepti-
bility to cyanide has been observed. If any exists, it is not suffi-
ciently great to appear clearly in comparison with individual
differences in susceptibility. In pure line cultures some increase
in susceptibility in the earlier stages of fission might perhaps be
demonstrated. In the later stages of fission, however, when the
two daughter individuals are approaching separation and the recon-
stitutional changes are advanced, the susceptibility is distinctly
greater than in the single animals of approximately the same size
as the two members of the pair together. The possibility that the

142 SENESCENCE AND REJUVENESCENCE

dividing pairs and the single animals belong to different races which
differ in susceptibility cannot of course be excluded in individual
cases except in pure line cultures, but the uniformity of the results
obtained with large numbers of individuals and in repeated tests
render this possibility negligible.

But the susceptibility is highest after fission is completed. In
all cases the smaller individuals are in general very clearly more
susceptible than the larger. This difference is not a matter of
size or of the relation between surface and volume, for the cilia and
the whole body-surface show it. The cilia and ectoplasm of the
larger animals are in general much less susceptible to a given con-
centration of cyanide than those of the smaller animals. As death
and disintegration proceed in a lot consisting of hundreds or thou-
sands of individuals, it soon becomes very evident that the smaller
animals are dying earlier than the larger. In a culture of Colpidium,
for example, where division was proceeding very rapidly, animals
below a certain size were more than twice as numerous as those
above this size, but after deaths began to occur in cyanide, the
smaller animals became less than half as numerous as the larger,
and still later only about one small to five large was found alive.
Similar results were obtained with the other species. In a Stentor
culture where divisions were occurring only in the animals of
medium size or above, the susceptibility of the animals below
medium size was much greater than that of the larger animals.
Some of the smaller animals in these cultures may conceivably
have belonged to small races possessing a greater susceptibility at
all stages than the large, but as the culture was increasing rapidly
in numbers, most of them were certainly the products of recent
fission.

These data are in complete agreement with those obtained
from the study of the flatworms and indicate very clearly that an
increase in rate of metabolism is associated with the process of
fission in the ciliate infusoria and that the rate of metabolism is
highest soon after fission. In other words, after fission the
animals are physiologically younger than before fission, and in
the interval between two fissions they undergo some degree of
senescence.

AGAMIC REPRODUCTION AND REJUVENESCENCE 143

These changes, however, are apparently not the only factors
concerned in preventing progressive race senescence. In a recent
paper Woodruff and Erdmann (’14) have described periodic changes
of another sort which they call ‘“endomixis”’ and which they believe
to be the essential factors in preventing race senescence. These
changes consist in the gradual fragmentation, degeneration, and
disappearance of the meganucleus, at least two divisions of the
micronuclei, degeneration of some of the micronuclei thus produced,
and the formation of new meganuclei from others. This process
of endomixis resembles the nuclear changes in conjugation, except
that the third micronuclear division of conjugation which gives
rise to the migratory and stationary micronuclei apparently does not
occur here, and there is no union of micronuclei at any time. Wood-
ruff and Erdmann point out that endomixis is in certain respects
similar to parthenogenesis, but not directly comparable with the
usual forms of it. The occurrence of rhythms of growth and rate
of division in protozoan cultures has been recognized by Calkins,
Woodruff, and various other investigators. Periods of more rapid
and less rapid growth and division alternate more or less regularly
in the history of cultures. Woodruff and Erdmann find that the
process of endomixis which extends over some nine cell generations
is coincident with the period of lowest rate of growth and division
in the rhythms, that at the climax of the process division is greatly
delayed, and that with the beginning of differentiation of the new
meganuclei recovery is rapid. They conclude that a causal rela-
tion exists between the reorganization process and the rhythms.

This process of endomixis occurs in different races of Paramecium
aurelia and in P. caudatum also, and probably in other ciliate
infusoria. Many of the observations of earlier authors on degenera-
tive changes and abnormal nuclear conditions undoubtedly concern
stages of endomixis.

While further investigation is necessary to determine how gen-
erally this process occurs and to what extent its occurrence may be
experimentally controlled, it is evident that the rhythms and the
process of endomixis represent a senescence-rejuvenescence period,
and we must inquire what factors are primarily or chiefly concerned
in this periodicity. I believe that we must look to the meganucleus

144 SENESCENCE AND REJUVENESCENCE

for the answer to this inquiry. The meganucleus of the infusoria
is apparently a specialized vegetative organ of the cell not found in
the same form in other cells, although Goldschmidt (’o5) has
attempted to show that all animal cells are physiologically if not
morphologically binucleate and that a distinction between vegeta-
tive or somatic and reproductive nuclear substance must be made.
Whether or not we accept this view, the meganucleus is evidently
a specialized organ, and all the facts indicate that it plays an impor-
tant réle in the metabolic activity of the cell. In the process of
division it apparently undergoes no great degree of reorganization,
but is merely separated into two parts and continues to grow. If
the successive divisions of the meganucleus do not balance the
progressive changes between divisions, it will necessarily undergo
progressive senescence, and if no other method of rejuvenescence
occurs, death from old age must finally result.

This, I believe, is what actually occurs. The period from the
low point of one rhythm to the low point of the next represents the
length of life of the meganucleus under the existing conditions.
As the meganucleus undergoes senescence after its differentiation
as a meganucleus, the rate of growth and division decreases, sooner
or later the meganucleus begins to degenerate, and a physiological
relation of some sort undoubtedly exists between these changes
and the micronuclear divisions which occur. In other words, the
process of endomixis is apparently the periodic replacement of a
part which has grown old by a new, young part and is therefore
analogous in certain respects to the replacement of differentiated
old cells by young in the multicellular organism. Like such cells,
the meganucleus apparently does not undergo rejuvenescence but
dies of old age and is replaced by a new one.

Further investigation will probably show that the length of
time between two successive endomixes may, like many other
senescence periods, be altered and controlled experimentally to a
greater or less extent. It is in fact possible that under certain con-
ditions the degree of rejuvenescence occurring in the ordinary
divisions may be sufficient to maintain the race without progressive
senescence of the meganucleus and so without endomixis, although
it may be that the rejuvenescence in division is rather cyto-

AGAMIC REPRODUCTION AND REJUVENESCENCE 145

plasmic than nuclear. That the age cycle of certain flatworms may
be altered to a very considerable extent by experimental nutritive
and other conditions will be shown in chap. vii. Moreover, the
different behavior of different races as regards conjugation’ suggests
that internal as well as external factors will be found to play a part
in determining the periodicity.

But whatever the differences resulting from race or environ-
mental conditions, the occurrence in the ciliates of some degree of
senescence in each generation and some degree of rejuvenescence
in each agamic reproduction and the occurrence of progressive
senescence in the meganucleus ending in its death and replacement
by a new, young organ demonstrate that these unicellular animals
are not fundamentally different from multicellular forms. They
are not, as Weismann (’82) believed, immortal because they do not
grow old, but simply as other organisms are, because they repro-
duce and undergo reconstitution during reproduction and because
old organs die and are replaced by young.

AGAMIC REPRODUCTION AND REJUVENESCENCE IN COELENTERATES

Among the coelenterates only the fresh-water hydra and one
species of the colonial hydroids have been tested by the suscepti-
bility method. In hydra agamic reproduction is a process of
budding. In Aydra fusca the bud arises near the junction of the
thicker body with the more slender stalk, and in its earlier stages is
merely a rounded outgrowth including both ectodermal and ento-
dermal layers of the body-wall (Fig. 48). Cell division and growth
occur rapidly in it, it elongates, and in the course of a few days
tentacles and a mouth begin to develop at its distal end (Fig. 49).
Meanwhile the region of attachment to the parent body gradually
undergoes constriction, until finally the new, small animal separates
from the parent, falls to the bottom, attaches itself, and begins
to lead an active life. In this process a portion of the body-wall of
the parent has undergone reconstitution into a new, independent
individual.

A comparison of the susceptibility to cyanide of small animals
newly developed in this way with the larger parent shows that the

1 Jennings, ’10, ’13; Calkins and Gregory, ’13.

146 SENESCENCE AND REJUVENESCENCE

newly developed individuals are distinctly more susceptible than
the parents, i.e., they are physiologically younger. In the earlier
stages of the bud, however, while it is still attached to the parent
body and before it has developed the capacity for motor activity,
its susceptibility is not appreciably different from that of adjoining
regions of the parent body, or it may be even less susceptible than
these regions.

The fact that the increased susceptibility appears only after
the asexually produced individual is separated from the parent

48 49

Fics. 48, 49.—Two stages in the development of a bud in Hydra

seems at first glance not to agree fully with the data and conclusions
from other forms, but this disagreement is only apparent, and re-
sults from the complication of the results by the factors of motor
activity and food. Motor activity of an individual, or even of a
region of the body in hydra, increases very considerably the sus-
ceptibility of that individual or region to cyanide. It is very
generally the case that the animals which show the greater motor
activity after being placed in cyanide die and disintegrate earlier
than the less active, and it has often been observed that marked

AGAMIC REPRODUCTION AND REJUVENESCENCE 147

contraction in cyanide of a particular body region is followed by
the death and disintegration of that region before other parts.
Evidently motor activity, although slow, increases the rate of
metabolism in hydra to a very marked degree. This is perhaps to
be expected from the fact that the motor mechanism in this organ-
ism is not highly developed, but is merely a part of the ectoderm
cell. Motor activity undoubtedly involves the whole cell and at
least all the cells of the ectoderm in the region where it occurs. To
all appearances it is a very laborious process, and even after the
strongest stimulation it is relatively slow and inefficient. In short,
the observations made by the susceptibility method indicate that
the increased metabolism associated with motor activity is relatively
very great.

The bud in the early stages of development exhibits very little
motor activity, and movement does not attain its maximum until
separation from the parent takes place. The result of this differ-
ence in motor activity between bud and parent is that, even though
growth and development are proceeding more rapidly in the bud
than in the parent, the rate of metabolism is not greater in the
bud where motor activity is slight than in the parent where it is
much greater. But as soon as the bud becomes independent,
its motor activity is comparable with, perhaps even greater
than, that of the parent, and then its susceptibility to cyanide
is distinctly greater, i.e., its rate of metabolism is higher than
that of the parent.

Moreover, the young bud while still attached to the parent
grows at the expense of food ingested by the parent body, rather
than at the expense of its own tissues. It does not undergo reduc-
tion, but grows during its reconstitution from a part of the parent
body into a new individual. Since rejuvenescence is undoubtedly
associated with reduction, as the following chapter will show, the
bud, which receives food and grows rapidly throughout its devel-
opment, does not become as young physiologically at any stage as
if its development occurred at the expense of its own tissues.

In the marine hydroid Pennaria tiarella, agamic buds are pro-
duced as in hydra but remain permanently in connection with the
parent stem or branch, so that a branching tree-like colony with the

148 SENESCENCE AND REJUVENESCENCE

zooids or hydranths at the tips of the branches results. Fig. 50
shows a portion of such a Pennaria colony. In this species the new

50 52

Fics. 50-52.—Pennaria tiarella: Fig. 50, part of a colony, including a large,
old hydranth, #, bearing a medusa bud, m, a younger hydranth, h’, and a hydranth
bud, 4”; Figs. 51, 52, developmental stages of hydranth.

hydranth bud arises laterally a short distance below the terminal
hydranth of a stem or branch (Fig. 50, #’”). It is an outgrowth

AGAMIC REPRODUCTION AND REJUVENESCENCE 149

including both layers of the body-wall, as in hydra, and in its earlier
stages is rounded in form and inclosed in the chitinous perisarc
which covers the stem. As development proceeds, it emerges from
the perisarc, undergoes elongation, and the tentacles begin to appear,
as indicated in Fig. 51. A later stage of development is shown in
Fig. 52, a fully developed hydranth in Fig. 50, h’, and an old
hydranth bearing a medusa bud, m, in Fig. 50, h. The agamic
production of hydranths in this form is then a reconstitution of a
portion of the stem into a new hydranth.

As regards the susceptibility of the different stages, both motor
activity, as in hydra, and the presence of the chitinous perisarc
contribute to obscure the changes in susceptibility associated with
the reconstitution of stem into hydranth. The susceptibility of
the early stages of hydranth development, such as h” in Fig. 50,
cannot be compared directly with that of stages like Figs. 51 and
52, because these early stages are inclosed like the stem in the
chitinous perisarc, while in the later stages the hydranth is naked.
Neither are these early stages directly comparable with such stages
as Fig. 50, # or h’, for in the former motor activity is absent, while
in the latter it is fully developed. It is possible, however, to com-
pare the susceptibility of such a stage as Fig. 50, kh”, with that of
adjoining regions of the stem, for both are inclosed in perisarc, and
a comparison of this sort shows that the early bud is in general
distinctly more susceptible, i.e., it possesses a higher rate of metab-
olism and is physiologically younger than the stem adjoining it.
But in this case, as in hydra, the increase in rate connected with
the formation of a new individual is less than it would be if the
region were physiologically isolated and underwent development
at the expense of its own tissues rather than of nutritive material.
As it is, the bud has abundant food and grows during development,
while the isolated piece undergoes reduction.

In the later stages of development the perisarc no longer enters
as a factor, but differences in motor activity still exist between
different stages. At the stage shown in Fig. 51 motor activity is
absent or inappreciable, but the susceptibility of this stage is
nevertheless usually somewhat greater than that of an old hydranth,
like h in Fig. 50, and less than that of a younger hydranth, like

150 SENESCENCE AND REJUVENESCENCE

h’ in Fig. 50. At the stage of Fig. 52 motor activity is present to
some extent, though much less than in still later stages. This
stage is distinctly more susceptible than such hydranths as / in
Fig. 50. Here, where motor activity has begun to appear, even
though it is still slight, the difference in physiological condition
between morphologically young and old hydranths becomes dis-
tinctly evident. From this stage on the susceptibility decreases
as development proceeds, but it does not attain a constant level
even after the morphological form of the hydranth is fully devel-
oped. On a stem like that shown in Fig. 50, for example, the
hydranth h’, which is younger in point of time than the terminal
hydranth /, shows in general a higher susceptibility, i.e., is physio-
logically younger than the latter. In spite then of the presence
of the perisarc in certain stages and the differences in motor activity
in other stages, the differences in susceptibility indicate that a
certain degree of rejuvenescence is associated with the agamic
reproduction of hydranths in Pennaria. It is still a question,
however, to what extent new parts which arise by budding in
hydroids are formed by dedifferentiation and redifferentiation of
old cells and to what extent by the interstitial cells which are small
cells lying in groups between the other cells of the body-wall and
which are commonly regarded as embryonic reserve cells. From
this point of view the apparent rejuvenescence which occurs in
connection with budding might be regarded as simply a replace-
ment of the older differentiated cells by the younger, undiffer-
entiated. Doubtless the interstitial cells are less highly specialized
than various other cells and so react more readily to the change
in conditions, but the very fact that they were inactive before and
became active in the development of the bud indicates a change in
their physiological condition in the direction of a higher rate of
metabolism. Moreover, there is every indication that at least
many of the specialized cells of the body-wall do take part in bud-
formation and actually undergo more or less dedifferentiation.

In addition to the asexual production of hydranths, Pennaria also
gives rise asexually to medusa buds, which do not usually, however,
develop into free-swimming medusae but remain attached to the
parent body. These appear on the body of the hydranth im-

AGAMIC REPRODUCTION AND REJUVENESCENCE I51

mediately distal to the circle of proximal tentacles (m, Fig. 50).
Three stages of development of the medusa bud drawn to the
same scale are shown in Figs. 53-55. In the early stages the
medusa bud is always more susceptible to cyanide than the adjoin-
ing regions of the hydranth from which it arose, and its suscepti-
bility decreases as development proceeds, the large, fully developed
bud being much less susceptible than the adjoining regions of the
parent hydranth. These differences in susceptibility are not
dependent upon differences in size, for they concern primarily
the surface of the body. Differences in motor activity may be
concerned in the difference in susceptibility between the fully
developed medusa bud and the hydranth, but the greater suscep-
tibility of the bud in early stages as compared with the hydranth
cannot be accounted for in this way, for motor activity is present

FIGs. 53-55.—Pennaria tiarella: three stages in the development of a medusa bud

in the hydranth but not in the medusa bud. Evidently the
medusa bud in early stages is physiologically younger than the
region of the hydranth from which it arises.

But the susceptibility of young medusa buds is in general
distinctly less than that of young hydranths of the stage of Figs.
51 and 52, after emergence from the perisarc. That is, the young
medusa bud is not as young as the young hydranth. The medusa
bud arises from a more highly specialized region of the colony than
the hydranth bud and develops into a more highly specialized
zooid or individual. Apparently the reconstitution of a portion
of the hydranth body into a medusa bud does not carry the region
concerned back to so early a physiological stage as that attained
in the reconstitution of a region of the stem into a young hydranth.
This difference in physiological condition between hydranth bud
and medusa bud is probably the dynamic basis, or at least the

152 SENESCENCE AND REJUVENESCENCE

dynamic correlate, of the difference in morphological development.
In this connection it is also of interest to note that in Pennaria
medusa buds appear only upon hydranths which are physiologically
relatively old, while the hydranth buds usually arise on the physi-
ologically younger regions of thestem. In other species of hydroids,
where the growth form is different, the physiological relations may
also prove to be more or less widely different, although medusa buds
in general arise in connection with a fully developed hydranth, or
a highly specialized reproductive zooid or from an apparently
specialized region of the stem just proximal to a hydranth, while
hydranth buds arise from less highly specialized regions. It is
probable that where such complicating factors as presence of the
perisarc or differences in motor activity do not obscure the differ-
ences in susceptibility associated with physiological age, similar
differences between the different forms of agamic reproduction
will be found in other species.

To sum up, the susceptibility method indicates not only that a
considerable degree of rejuvenescence is associated with agamic
reproduction in Pennaria but also that different stages of rejuvenes-
cence are represented in the different forms of agamic reproduction
in this species. In the more specialized reproductive process the
young stages are apparently somewhat older physiologically than
in the less specialized process.

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“On So-called Conjugating and Non-conjugating Races of Para-
mecium,” Jour. of Exp. Zool., XVI.

Wooprurr, L. L., and ErRpMANN, RHODA.

1914.

‘“A Normal Periodic Reorganization Process without Cell Fusion
in Paramecium,” Jour. of Exp. Zool., XVII.

ZWEIBAUM, J. (ENRIQUES et ZWEIBAUM).

IQI2.

“La conjugaison et la différenciation sexuelle chez les Infusories:
V, Les conditions nécessaires et suffisantes pour la conjugaison du
Paramoecium caudatum,” Arch. f. Protistenkunde, XXVI.

CHAPTER VII

THE ROLE OF NUTRITION IN SENESCENCE AND REJUVENES-
CENCE IN PLANARIA

REDUCTION BY STARVATION IN Planaria

The various species of Planaria are capable of living for months
without food from external sources. During such periods of
starvation, however, they undergo reduction in size, many cells
degenerate, and some organs may completely disappear. Various
investigators, among them F. R. Lillie, ’00; Schultz, ’04; Stoppen-
brink, ’05, have considered one phase or another of this process of
reduction, and Lillie and Schultz particularly have called attention
to the fact that in its proportions and chief morphological charac-
teristics the animal reduced by starvation resembles the young
animal and have pointed out that the changes which occur during
reduction indicate that the process of development is reversible.
In an earlier chapter (p. 57) I have suggested that it is preferable
to use the term “‘regressibility”’ rather than reversibility for such
changes, since the occurrence of reduction or dedifferentiation in an
organism does not necessarily imply a reversal of the reactions con-
cerned in progressive development. Only from the morphological
viewpoint are we justified in speaking of a reversal of development.

The reduction in size of Planaria during starvation is unques-
tionably due to the re-entrance of its structural material into
metabolism as a source of energy. Schultz finds that reduction
in Planaria is due to the disappearance of whole cells and organs
rather than to decrease in size of the cells in general. This is un-
doubtedly true to a large extent, but my own unpublished observa-
tions indicate that some decrease in size does occur in at least many
cells in the starving planarian, and other authors who have investi-
gated the cellular changes in animals during starvation have reached
similar conclusions.

The following references constitute a partial bibliography of the subject:

Kasanzeff, ’o1, and Wallengren, ’o2, found marked reduction in the size of Paramecium
during hunger. Citron, ’o2, observed decrease in size of ectoderm cells in a coelenterate

155

156 SENESCENCE AND REJUVENESCENCE

In the course of observations on Planaria dorotocephala I have
found that the lower limit of reduction differs rather widely accord-
ing to the original size of the animal. Animals of twenty-five
millimeters in length before starvation begin to die when they are
reduced to a length of five or six millimeters, while animals which
are six or seven millimeters in length before starvation may undergo
reduction to a length of one or two millimeters before death.
As I have suggested elsewhere, death in these cases is probably not
due to lack of available material, for pieces isolated from starving
animals are capable of reconstitution to whole animals and may then
undergo reduction to a much smaller size before death. Death,
at least in the larger animals reduced by starvation, is probably due
to altered correlative conditions resulting from changes in the
axial gradient in rate of metabolism (Child, ’14, p. 443).

In consequence of their ability to undergo extreme reduction
before death occurs from starvation the planarians would consti-
tute valuable material for the study of physiological and particu-
larly of metabolic changes connected with inanition if it were not
for their small size. But now with the Tashiro biometer and with
the susceptibility method we are able to obtain some light on at
least certain features of the metabolism in these starving animals.
Some of the data bearing upon this problem are presented in the
following section.

CHANGES IN SUSCEPTIBILITY DURING STARVATION IN
Planaria dorotocephala AND P. velata

Since the animals reduced by starvation resemble young animals
morphologically, the question whether they are young physio-
logically at once suggests itself. If the reduced animals are fed,
growth begins again, and the animals are not only indistinguishable
from young, growing animals in appearance and behavior, but are
able to go through the life history again from the stage at which
feeding began. Moreover, the reduced animals are very active

during starvation. In the higher animals decrease in size of gland cells, muscle cells,
and nerve cells during starvation has been recorded by various authors, among
whom are Heumann, ’s50; Rindfleisch, 68; Morpurgo, ’88, ’89; Downerowitsch, ’92;
Statkewitsch, ’94; Lukjanow, ’97; Morgulis, ’rr.

NUTRITION IN SENESCENCE AND REJUVENESCENCE 157

and highly irritable, reacting strongly and rapidly to various kinds
of stimuli. Slight movements of the water or a slight jarring of
the aquarium, to which well-fed, old worms do not respond at all,
will bring them into active movement, and when wounded or when
the body is cut in two they react much more strongly than old
worms. In all these respects they resemble young rather than old
animals. In fact, their general behavior indicates very clearly
that they have become physiologically young during the course of
reduction. But with the aid of the susceptibility method it is
possible to obtain more positive knowledge upon this point.

The comparative susceptibility of starving animals may be
determined in two ways: when temperature and other external
conditions are controlled, the susceptibilities of a uniform stock at
different stages of starvation may be directly compared with each
other. This method of procedure will show directly whether the
susceptibility increases, decreases, or remains constant during
starvation. On the other hand, the susceptibility of animals at
any stage of starvation may be compared with that of fed animals
of the same size or of animals of the original size and condition of
the stock before starvation. In this way also changes in suscepti-
bility may be determined. Records of experiments of both sorts
are given below.

In Table II the decrease in length and increase in susceptibility,
determined at intervals of about two weeks during three months of

TABLE II
5 . . Survival Time of Ten
Length of Starvation Length of Animals in i - “ “
Period in Days Millimeters pees oe Mean, Survival ‘Time
Odie Fie senaea dade 15-18 6530™ gboo™ 7h45m
DP Asay os bore alga eaten seen 15-17 64oo™7hoo™ 6b30™
BOs anwar np esame in Raat 10-12 shoo™6b30™ 545”
WG Sosa reigsas a eatanils's Amber g-I0 4boo™-sboo™ 4530™
OO: nisseveuaeuee ees 7-8 2hoo™ 4hoo™ 3hoo™
ee 5 2boo™-3h30™ gh45m
QD hee ena. b Sibeatirage ate Sle 3.5-4 1h39™2h39m 2hoom

starvation, are recorded. The first two columns of the table are
self-explanatory; in the third column the times given are the times
of complete disintegration of the first and last of the worms of each

158 SENESCENCE AND REJUVENESCENCE

lot of ten worms, i.e., this column gives the extremes of the survival
times and the fourth column the means. The table shows at a
glance that the susceptibility of the animals increases very greatly
during the course of starvation, the mean survival time decreasing
from seven hours and forty-five minutes in the large, well-fed
animals at the beginning of the starvation period to two hours in
the reduced animals after ninety-one days of starvation.

The changes in susceptibility have been determined in the same
way for several other starvation stocks, some made up from larger
animals than these, others from smaller, and still others from ani-
mals of the same size. Different stocks were kept during starva-
tion under various conditions of temperature, light, aeration, and
change of water, but in all essentially the same result was obtained,
viz., a great and, except for slight irregularities in a few cases which
were evidently due to incidental uncontrolled factors, a continuous
increase in susceptibility during starvation.

According to the second method of procedure mentioned above,
the susceptibility of the starved animals may be compared directly
with that of fed animals. The records of two tests of this sort
are presented.

In the first of these several hundred worms fifteen to eighteen
millimeters long were selected from freshly collected material as a
starvation stock. After eighty-one days of starvation the animals
were reduced to a length of seven to eight millimeters, and the
susceptibility of ten of the reduced worms is shown in the curve cd
of Fig. 56. For comparison the susceptibility curves of ten ani-
mals of the same size and condition as the members of the starva-
tion stock before reduction (ef, Fig. 56) and of ten well-fed, young
animals of the same size as the animals reduced by starvation (ad,
Fig. 56) are given. The young, fed animals are most, the old,
fed animals the least, susceptible, but the susceptibility of the
animals reduced by starvation is much nearer that of the young
animals than that of the old and therefore must have undergone
marked increase during reduction.

In another case the starvation stock was composed of animals
twenty to twenty-four millimeters long, and the determination of
susceptibilities recorded in Fig. 57 was made after ninety days of

NUTRITION IN SENESCENCE AND REJUVENESCENCE 159

complete starvation in filtered water. The curve ad, drawn as an
unbroken line in Fig. 57, is the susceptibility curve of ten starved
animals which have undergone reduction to a length of seven to
eight millimeters. The second curve ab, drawn as a broken line,
shows the susceptibility of ten newly collected, young, growing
animals of the same size as the reduced worms. A part of the
original stock was fed, while the others were starved, and the curve

Stages + aceoe

II

Il

——— + + “+

Hours I 2 3 4 5 6 7

Fic. 56.—Susceptibility of Planaria dorotocephala to KCN 0.001 mol. in relation
to nutritive condition and age: ab, susceptibility of well-fed, growing animals 7-8
mm. in length; cd, susceptibility of animals reduced by starvation from 15-18 mm
to 7-8 mm.; ef, susceptibility of well-fed animals 15-18 mm. in length.

cd shows the susceptibility of these animals. During the three
months of feeding these worms have of course grown somewhat
older, but in full-grown animals like these the change in three
months is slight. But the susceptibility of the starving animals
has increased until it is about the same as that of young, growing
animals of the same size.

Determinations of susceptibility by the direct method with
cyanide, alcohol, and ether as reagent have been made on several

160 SENESCENCE AND REJUVENESCENCE

hundred individuals of Planaria dorotocephala in various stages of
starvation, and in all cases the susceptibility has been found to
increase during starvation. In P. velata also the susceptibility to
cyanide has been found to increase during starvation. This
species does not undergo reduction in size as rapidly as P. doroto-
cephala, but the effect of starvation is essentially the same in both.
If the susceptibility of these animals is in any degree a measure of

Stages i a Cc

sagt

Hours I 2 3 4 5 6 v4 8 9 10 Ir

Fic. 57.—Susceptibility of Planaria dorotocephala to KCN 0.001 mol. in relation
to nutritive condition and age: ab, dashes, well-fed, growing animals; ab, unbroken
line, animals reduced by starvation from 20-24 mm. to 7-8 mm.; cd, animals from the
same stock and of the same size at the beginning of the experiment as the starved
animals, but which have been fed while others were starving.

physiological age, the starving animals certainly undergo rejuvenes-
cence, the degree of rejuvenescence varying with the degree of
starvation and reduction.

THE PRODUCTION OF CARBON DIOXIDE BY STARVED ANIMALS

The invention of the Tashiro biometer (Tashiro, ’13) has made
possible a direct estimation and comparison of carbon-dioxide

NUTRITION IN SENESCENCE AND REJUVENESCENCE 161

production in different individuals and pieces or tissues of small
animals. The agreement between the results obtained with this
apparatus and those of the susceptibility method has already been
mentioned (pp. 73, 74).

A number of estimations of carbon-dioxide production in starved,
reduced animals, as compared with well-fed, growing animals of
the same size, have been made with the aid of this apparatus.
The worms used for the estimation of carbon-dioxide production
were taken from a starvation stock after ninety-four days of star-
vation. The animals were twenty to twenty-four millimeters
long at the beginning of the starvation period, and after ninety-
four days without food had undergone reduction to a length of
seven millimeters. In each estimation the carbon-dioxide pro-
duction of one of these starved animals was compared with that
of a young, well-fed animal of the same size.

Two estimations were made with normal uninjured animals and
in both cases the carbon-dioxide production of the starved animal
in a given length of time was slightly greater than that of the fed
animal. But since the animals moved about to some extent, and
since the apparatus is so sensitive that differences in carbon-
dioxide production resulting from differences in motor activity
might be a serious source of error, it was thought desirable to elimi-
nate movement as far as possible. This was accomplished by re-
moving the heads of the two animals to be compared and making
the estimation after they had become quiet. These headless
animals remained quiet in the chambers of the biometer, but gave
essentially the same result as those with heads. In the two esti-
mations made with such animals the carbon-dioxide production of
the starved animal was practically the same as that of the fed
animal. In other words, the rate of production of carbon dioxide
in the starved, reduced animal is practically equal to that in the
young, growing animal of the same size, and this rate is much
higher per unit of body weight than that in large, old animals. The
results obtained by the direct susceptibility method are thus fully

1 These estimates were made at my request by Dr. Tashiro before the biometer
was available for general use, and I take this opportunity of acknowledging my obliga-
tion to him, both for conducting the experiments and for permitting me to use the
results.

162 SENESCENCE AND REJUVENESCENCE

confirmed by the estimations of carbon-dioxide production. In
rate of carbon-dioxide production the starved, reduced animals
resemble young rather than old animals, such as they were before
starvation.

THE RATE OF DECREASE IN SIZE DURING STARVATION

When the animals are kept entirely without food the rate of
decrease in size shows in general an increase, at least during the
later stages of starvation. Thus far only incidental observations
have been made concerning this point, the approximate lengths of
lots of animals being noted as they were removed from time to
time for determination of the susceptibility. But even in these
measurements the differences in rate of decrease in size appear,
though with some irregularities, and in most cases the increase in
rate in the later stages of starvation is evident without measure-
ment. Table III, for which the data are given in Table II (p. 157),
gives the average length of the animals in a starvation stock at
monthly intervals, and Table IV gives similar information, but

TABLE III
Length of Starvation | Length of Animals gic hoeerae of
Period in Days in Millimeters an
P67 S8) eiiileco wae’
lo = 12 30
7 - 8 31
3-5- 4 51
TABLE IV

Percentage of

Length of Starvation Length of Animals *
Period in Days in Millimeters ae
Guy cvecioas coxa 6=7 skew eee ema aigie
cy ee ee ee 4-5 30
Ons Pets adres 2>2:..5 50

from a stock of animals of smaller size before starvation. In
Table III the average decrease in length during the first month is
about 30 per cent, during the second about the same, and during

NUTRITION IN SENESCENCE AND REJUVENESCENCE 163

the third about 50 per cent. Similarly, in the much smaller worms
of Table IV the average decrease in length during the first month
is 30 per cent, and during the second, 50 per cent. In these cases
the measurements for each month were made on different lots of
worms from the same stock. Doubtless a continuous series of
measurements of the same individuals would bring out the differ-
ences in rate of decrease still more clearly. When the animals are
not kept entirely without food the rate of reduction does not in-
crease, but may even decrease in later stages, for the smaller the
animals, the more completely does a small amount of food retard
or inhibit reduction. This increase in rate of reduction during
starvation confirms the observations on susceptibility and on
carbon-dioxide production, for it indicates that the rate of meta-
bolic processes increases as reduction proceeds.

In this connection the study by Mayer (’14) of loss of weight
in a jelly-fish, Cassiopea, is of interest. From his data Mayer con-
cludes that the relative loss of weight for each day or other period
is in general the same throughout the course of starvation. More-
over, the nitrogen-content and water-content of the body do not
show any change in relation to starvation. At first glance it
appears that the course of starvation in this medusa differs from
that in Planaria. While the metabolic condition of the animals
during starvation has not been determined, the constancy in the
percentage of loss of weight indicates that the metabolic rate does
not increase as starvation and reduction proceed. As a matter of
fact, however, Mayer’s data, and particularly the curves of loss
of weight, show that in most cases the loss of weight in uninjured |
animals during the first two or three weeks of starvation is slightly
less than the calculated loss according to the formula which Mayer
has adopted, while during the later period of starvation the observed
loss of weight equals or in many cases exceeds the calculated loss.
In mutilated animals, which are undergoing regeneration as well
as starvation, the observed loss of weight during the earlier stages
of starvation is in most cases more rapid than the calculated loss,
but the two coincide more nearly in later stages.

It is probable then that Mayer’s law of loss of weight is only an
approximation based on averages, and that some slight increase

164 SENESCENCE AND REJUVENESCENCE

in the percentage of loss in a given time interval does occur in unin-
jured animals. In regenerating animals, on the other hand, the
loss is more rapid in earlier stages because of the use of body sub-
stance in the formation of new parts as well as for function. As
regeneration proceeds, the growth of the new parts becomes less
rapid and requires less material, and the loss of weight becomes
slightly less rapid. If these suggestions are correct, starvation in
Cassiopea follows essentially the same course as in Planaria and
is accompanied by increase in metabolic rate and some degree of
rejuvenescence. For the study of this aspect of starvation, how-
ever; the medusa is a particularly unfavorable form because the
volume of cellular substance is exceedingly small, as compared
with the volume of gelatinous material which, according to Mayer,
constitutes the chief source of nutrition during starvation, and since
this is extra-cellular, its disappearance does not alter the cellular
condition. For the same reason changes in chemical constitution
and water-content of the protoplasm, so far as they occur, are
inappreciable, though in an animal with so little differentiation as
the medusa the changes are probably not very great. There is
also the possibility that, as Piitter believes, substances in solution
in the water serve as a source of nutrition to some extent. If this
is the case, the influence of such substances on the rate of loss of
weight must be greater in the later stages of starvation when the
animal is smaller and the absolute loss less than in the earlier
stages, and will therefore contribute to mask the increasing rate of
loss in these stages. Taking all these facts into account, it appears
highly probable that the changes in the cellular substance of the
medusae are very similar to, though probably less extensive than,
those in Planaria. Mayer notes that the cells decrease in size,
their boundaries become indistinct, and some cells die. Determina-
tions of the changes in susceptibility of the cellular portions of the
body of the medusa during starvation would be of interest.

THE CAPACITY OF STARVED ANIMALS FOR ACCLIMATION

In general the ability of planarians to become acclimated to
depressing agents or conditions varies with the rate of metabolism.
Young animals, for example, become much more readily and more

NUTRITION IN SENESCENCE AND REJUVENESCENCE 165

completely acclimated to cyanide or alcohol, low temperature,
etc., than old, and acclimation occurs more readily at higher than
at lower temperatures (Child, ’11). In the low concentrations of
reagents used in the acclimation susceptibility method (pp. 82-84),
starved animals show very little capacity for acclimation as
compared with well-fed animals of the same size; in most cases even
less than large, old animals. In my earlier studies of suscepti-
bility only this acclimation method was used, and since in general
the capacity for acclimation had been found to vary with the rate
of metabolism, the very slight capacity of starved animals for
acclimation was regarded as indicating that their rate of metab-
olism was low. But the results obtained in later investigation
by the direct susceptibility method which have been briefly pre-
sented above, and the confirmation of these by the estimations of
carbon-dioxide production, force us to the conclusion that the
rate of metabolism increases during starvation. This being the
case, the decrease in capacity for acclimation in starved animals
cannot be due to a low rate of metabolism, but must be associated
with the nutritive condition in some way independent of meta-
bolic rate (Child, ’14). When feeding is begun after a long period
of starvation, the capacity for acclimation rises almost at once
(Child, ’r1) and continues to increase as feeding continues and
growth replaces reduction.

Since the nature of the process of acclimation is at present
unknown, this relation between nutritive condition and capacity
for acclimation cannot at present be analyzed, but must simply
be recorded as a fact. But whether acclimation results primarily
from a change in the metabolic substratum, or in the character
and relation of the metabolic reactions, the fact that the individual
with a supply of nutritive material from external sources has a
greater capacity for acclimation than the starving animal which
is undergoing reduction is at least suggestive, as indicating the
greater possibility of change under changed external conditions
in the well-fed animal.

Whatever may be the nature of the relation between nutrition
and capacity for acclimation, the facts demonstrate that, although
the starved, reduced animals are practically identical with young,

166 SENESCENCE AND REJUVENESCENCE

growing animals of the same size as regards rate of metabolism,
they differ widely from these in their capacity for acclimation. This
difference raises the question whether capacity for acclimation is
a fundamental or only an incidental feature of the age cycle. If
it is a fundamental feature, then the reduced animals have under-
gone rejuvenescence only in certain respects and have actually
become older physiologically in certain other respects. If, on the
other hand, it is merely incidental, then the reduced animals have
undergone what is essentially rejuvenescence and merely require
food in order to make them identical with young, growing individuals.
The latter alternative seems to be the correct one. If the decrease
in capacity for acclimation during starvation is regarded as a
process of senescence, it becomes necessary to admit that an animal
which is old in this respect may become young within a few hours
whenitisfed. The susceptibility as measured by the direct method
and the rate of carbon-dioxide production are certainly much more
‘adequate criteria of physiological age and condition than the
capacity for acclimation. In other words, reduction by starva-
tion is essentially a process of rejuvenescence in these animals,
and the difference between them and young, growing animals as
regards capacity for acclimation is an incidental rather than a
fundamental difference.

When the animal reduced by starvation is again fed, its physio-
logical condition very soon becomes indistinguishable from that of
growing animals of about the same size. In the advanced stages
of reduction the susceptibility of the reduced animal is almost always
somewhat greater than that of fed animals of the same size, and the
effect of renewed feeding is a decrease in susceptibility to about
the same level as that of the fed animal. The capacity for accli-
mation, as already noted, increases even after a single feeding,
but in advanced stages of reduction by starvation several feedings
are usually necessary, i.e., the animal must attain a well-fed con-
dition before the capacity for acclimation is equal to that of grow-
ing animals. The effect of a single feeding may appear within an
hour or two, but lasts at most only a few days, the animal rapidly
returning to the completely starved condition. But if other feed-
ings follow at sufficiently short intervals, growth soon begins, and

NUTRITION IN SENESCENCE AND REJUVENESCENCE 167

both susceptibility and capacity for acclimation undergo a gradual
decrease as the animal once more becomes physiologically older.
After at most a few feedings, then, the reduced animal is indistin-
guishable from the young animal in nature, and, as regards sus-
ceptibility, carbon-dioxide production, and capacity for acclimation,
is capable of undergoing senescence again. That a real rejuvenes-
cence has occurred during starvation cannot be doubted.

PARTIAL STARVATION IN RELATION TO SENESCENCE

The asexual life history of Planaria velata was described in
chap. vi and it was pointed out that in this species the decrease in
rate of metabolism characteristic of the period of growth, differen-
tiation, and senescence apparently leads automatically to fragmen-
tation of the body and so to the reconstitution from the fragments of
small, physiologically young animals, which repeat the life history.

If this process of fragmentation is associated with senescence
and if starvation and reduction bring about rejuvenescence, it
should be possible, not only to prevent the occurrence of fragmen-
tation, but to keep the animals indefinitely at a certain age by
giving them a quantity of food just sufficient to prevent reduction
but not sufficient to permit growth. This experiment has been
performed with a stock of these animals. During almost three
years they have been fed at intervals varying from two or three
days to two or three weeks, the feeding being regulated according
to the condition of the animals. If growth occurred, the intervals
between feedings were increased, and if the animals decreased in
size they were fed with greater frequency. If some animals showed
more growth or reduction than others, they were isolated and the
feedings regulated as required until all were again of approximately
the same size. During the early stages of the experiment growth
was twice allowed to proceed too far, and a few of the larger worms
of the stock underwent some fragmentation.

During the three years of the experiment the animals have been
kept at lengths varying from four to seven millimeters. In all
this time no fragmentation has occurred except in the two cases
mentioned above, when growth was allowed to go too far. The
animals are still in good condition and show the activity of young

168 SENESCENCE AND REJUVENESCENCE

animals. Susceptibility determinations have not been made, since
the stock is not large and is gradually depleted by occasional acci-
dental losses in changing water. However, there is every reason to
believe that the animals are as young physiologically as their size
would lead one to suspect, and they have shown no indications of
the changes in color, cessation of feeding, and decrease in motor
activity characteristic of old worms.

While the animals of this insufficiently fed stock have remained
at essentially the same physiological age during almost three years,
another portion of the same original stock which emerged from
cysts in the laboratory at the same time, but which has been fed
often enough to permit rapid growth, has passed through thirteen
asexual generations. A comparison of these two stocks leaves no
doubt as to the effect of partial starvation in inhibiting senescence
and the changes accompanying it. In these animals the length
of life or of the developmental period is not measured by time, but
by rapidity of growth. With abundant food this species may pass
through its whole life history, from the stage of emergence from a
cyst to fragmentation and encystment, in three or four weeks, but
when growth is prevented by loss of food, it may continue active
and young for at least three years, as the foregoing experiment has
demonstrated, and doubtless for a much longer period. It is of
course possible that continuation of the experiment during a suffi-
ciently long time might show that a slow process of senescence was
occurring in spite of the absence of growth. Only such continua-
tion can determine whether this will be the case or not. But the
fact remains that senescence can be retarded or inhibited for a
length of time, which, compared with the length of the active life
in nature, is very long—in the present case about thirty-six times
as long, and eighteen times as long as the average length of a genera-
tion in the laboratory.

Similar experiments with Planaria dorotocephala have been
carried sufficiently far to show that this species also can be kept
in approximately the same physiological condition for some months.
As long as the animals do not receive food enough to permit growth,
there are no indications of senescence, but when growth occurs the
susceptibility begins to decrease.

NUTRITION IN SENESCENCE AND REJUVENESCENCE 169

In these experiments with partial feeding the susceptibility
does not of course remain the same at all times. Each feeding is
followed by a distinct decrease in susceptibility, and later, as the
animals begin to starve, the susceptibility increases again. Thus
the life of such animals actually consists of alternating periods of
senescence and rejuvenescence. But if the intervals between
feedings are sufficient, the changes in the two opposite directions
balance each other and the mean physiological condition remains
the same.

THE CHARACTER OF NUTRITION IN RELATION TO THE AGE CYCLE

Up to the present time the problem of the relation between the
character of nutrition and the life cycle has received comparatively
little attention, although it is evident from the results already
obtained that an interesting and important field of investigation
isopenhere. In the attempt to find a suitable food for the breeding
of Planaria velata in the laboratory it was soon observed that the
size attained before the animals ceased to feed, the character of
fragmentation, and even its occurrence and the physiological con-
dition of the small animals which develop from the encysted frag-
ments, were all dependent to some extent upon the character of
nutrition. In these experiments the food did not in all cases con-
sist of single tissues or organs, so that it is not possible to correlate
the effects produced with the characteristics of particular tissues
and still less with particular chemical constitution. There is no
doubt, however, that this species constitutes favorable material
for nutrition experiments of this kind, such, for example, as Guder-
natsch (’12, ’r4) and Romeis (’13, ’14) have carried out on the tad-
pole, using various tissues and organs, including thyroid, thymus,
adrenals, etc., as nutritive material.

Only certain important points in the feeding experiments on
P. velata need be mentioned here. When the animals are fed beef
liver the life cycle approaches more closely to that of animals in
nature than with any other food thus far used, but cessation of
feeding and fragmentation occur at a smaller size than in nature.
The liver-fed animals also differ from animals in nature in not
losing their pigment before fragmentation and in encysting rather

170 SENESCENCE AND REJUVENESCENCE

frequently without fragmentation. The encysted fragments from
liver-fed animals give rise to physiologically young animals which
are able to repeat the life cycle, and asexual breeding may be con-
tinued with liver as food through at least many generations.

Animals fed with earthworm have a rather different life history.
They attain a larger size before fragmentation and, when kept at a
low temperature, they continue to grow until very much larger
than any individuals ever seen in nature, and finally die, apparently
of old age, usually without fragmentation and always without
sexual reproduction. At higher temperatures they cease to feed
at a certain stage, and some give rise to two or a few fragments
which are usually larger than under natural conditions. Some
animals encyst whole without fragmentation, and some do not
encyst at all.

The further history of these different groups is of interest. The
encysted fragments give rise to physiologically young worms. The
animals which encyst without fragmentation remain in the cysts
until they have used up their reserves and more or less of their own
tissues, and then emerge as smaller, physiologically younger animals
also capable of repeating the life cycle. But the history of the
animals which do not encyst shows the most interesting features.
The normal form of a full-grown, well-fed animal is shown in Fig 8
(p. 94). At the time these animals cease to feed, the pharynx
disintegrates and no new pharynx develops in its place. In the
course of a few days the posterior end of the body becomes inactive
and assumes a rounded form, as in Fig. 58, being dragged about
by the rest of the body as if it were a dead mass or a foreign sub-
stance. During the next few days this change in form and behav-
ior extends farther anteriorly, so that the rounded mass becomes
larger and the active portion of the body smaller (Fig. 59). At
this stage this process may cease in some individuals, but in others
it continues still farther, as in Fig. 60, until only a short anterior
portion with the head remains active. In this condition the small,
active anterior region is scarcely able to drag the large inert mass
about, although it makes violent attempts to do so.

In some cases the rounded mass disintegrates at this stage and
is lost, and the anterior region slowly undergoes reconstitution to a

NUTRITION IN SENESCENCE AND REJUVENESCENCE 171

whole animal of small size by development of a new posterior end
and a pharynx (Fig. 65), and is once more ready to feed and repeat

O® @® (OY

(OMY)
! 60
61
69
58
(cho)
62 63 oe Oe 65

Fics. 58-65.—Planaria velata: a life cycle without reproduction: Figs. 58-61,
the changes of advanced age; Figs. 62-65, the period of rejuvenescence.

the life history. But in other cases the change in form continues
until nothing but the head remains active, as in Fig. 61, and then

172 SENESCENCE AND REJUVENESCENCE

disintegration begins and the whole animal, including the head,
dies. In the rounded mass the internal structure gradually dis-
appears with extensive necrosis and disintegration of cells, until
little more than a sack remains containing some living tissue and a
large amount of granular substance resulting from the cell disinte-
gration. In other words, this mass represents to a large extent a
process of involution and death of cells and tissue.

In those individuals in which this process of involution ceases
at the stage of Fig. 59 or Fig. 60, the mass usually does not undergo
complete disintegration, but remains attached to the body and is
gradually resorbed, the process extending over a month or two.
During this time the mass evidently serves as a source of nutrition
for the active region and is in some sense analogous to the yolk
sac of many embryos. In such individuals the anterior region
remains continuously active and the involution mass gradually
becomes smaller (Figs. 62 and 63), until completely resorbed and
only a longer or shorter anterior region considerably reduced in
size remains. In cases where the resorption of the posterior mass
begins at a stage like that of Fig. 59, the portion of the body remain-
ing after complete resorption may include the anterior half, but
where resorption does not begin until involution is more advanced,
as in Fig. 60, the portion remaining after resorption may be only
the anterior fourth (Fig. 64).

After resorption of the posterior mass is completed, the remain-
ing portion slowly undergoes reconstitution, developing a new
posterior end and a new pharynx and mouth (Fig. 65), and thus
finally attaining the same condition as in those cases where the
involution mass disintegrates and is lost without resorption. At
this stage the small animal is physiologically young, as its high
susceptibility indicates, and is again ready to take food and grow
and repeat the life cycle.

In this remarkable process of senescence and death of a part of
the body and rejuvenescence of the remainder, no reproductive
process is involved except the reconstitution of the anterior region
into a new whole. That portion of the body which under natural
conditions undergoes fragmentation and encystment, the fragments
undergoing reconstitution to new animals, is in these cases appar-

NUTRITION IN SENESCENCE AND REJUVENESCENCE 173

ently too far advanced in senescence to recover, and undergoes
complete death and disintegration or gradual degeneration and
resorption. That it serves as a source of nutrition for the portion
which remains active is indicated by the fact that the reduction
in size of this portion is much less rapid than in starving normal
animals. Nevertheless, it is evident that the supply of food
in the involution mass is not adequate to prevent the occurrence of
reduction sooner or later, and since the animal during resorption
of the posterior region is without pharynx or mouth, it cannot take
food in the usual way; consequently as the source of supply in the
involution mass gradually fails, the anterior region gradually
starves and undergoes reduction. But when a certain stage of
reduction is reached, the new posterior end and pharynx develop
at the expense of other regions, and the process of rejuvenescence
is completed. In these cases, then, senescence leads to death in
certain parts of the body while other parts remain alive and undergo
rejuvenescence by starvation, reduction, and reconstitution.

The question of the conditions concerned in the localization of
death in the posterior region of the body requires some considera-
tion. The facts indicate that fragmentation is usually inhibited
by certain internal conditions and that, as the rate of metabolism
decreases during senescence, the lower limit for the continued
existence of differentiated structure is finally reached and passed
in the posterior region, and the processes of involution or disinte-
gration begin. The earthworm diet has been repeatedly used with
animals of different stocks and the results are always essentially
the same. Continued feeding in successive generations of the same
stock has not thus far brought about any further changes, and the
animals which do not die show no indications of progressive senes-
cence in successive generations.

Another diet used consists of the bodies of fresh-water mussels.
The portions used for food are chiefly the reproductive organs and
the digestive gland, and the animals apparently eat chiefly the
reproductive cells.

In the first generation the effect of this diet is to decrease the
frequency of fragmentation. In most animals the involution of
the posterior region occurs, as in Figs. 58-61, but very commonly

174 SENESCENCE AND REJUVENESCENCE

this process ends with the death of the whole animal and no resorp-
tion or rejuvenescence occurs. In some animals, however, the
involution mass disintegrates and is lost at the stage of Fig. 60,
and the anterior portion develops a new pharynx and posterior end.
With the mussel diet a few very small fragments arise from some
individuals.

The animals which undergo partial involution and disintegration
followed by reconstitution feed a few times on mussel, but cease
to grow at about half the size of the preceding generation, and most
of them undergo involution and die. Some encyst entire and others
produce one or two fragments and then encyst, but in all cases thus
far the encysted animals or pieces die in the cysts and no third
generation appears, i.e., that portion of the second generation which
arises from the non-encysting members of the first generation dies
without giving rise to a third generation.

As regards the encysted fragments from the first generation,
about half die in the cysts, the others emerge as small worms;
these feed a few times on mussel, grow slowly to about half the size
of the first generation, and undergo involution or in a few cases
fragmentation, as in the preceding generation. Most of these
worms die at this time, either as the result of involution or in the
cysts, but a very few emerge from cysts as a third generation.
These scarcely react to food at all, show almost no growth, and soon
undergo involution and die with or without fragmentation, or
die in the cysts. In no case has a single animal of the fourth gener-
ation been obtained from stocks fed on mussel, and very few live
to the third generation.

These stocks show every indication of a progressive senescence
in successive generations. It is of interest to note that a few of the
animals from encysted fragments reach the third generation, while
the animals developed from the pieces surviving partial involution
or encystment without fragmentation all die in the second genera-
tion. The encysted fragments are smaller than the others and
undergo more extensive reorganization, and consequently a some-
what greater degree of rejuvenescence in the process of reconstitu-
tion to whole animals. But the animals after emergence from cysts
or reconstitution following partial involution are not as young

NUTRITION IN SENESCENCE AND REJUVENESCENCE 175

physiologically as those kept on other diets. Their susceptibility
is distinctly lower than that of animals at the same stage in nature
or in stocks kept on a diet of liver or earthworm. Their motor
activity is also less than that of these animals and their rate of
growth is slow. There can be no doubt that these animals undergo
much less rejuvenescence in the reproductive and reconstitutional
processes than do those on the other diets, and it is evident that the
degree of rejuvenescence is progressively less in each successive
generation.

These experiments with different diets have been described at
some length because they demonstrate that the course of the life
cycle may be very greatly altered by the character of nutrition.
The effect of the mussel diet is to a certain degree inherited and
cumulative from one generation to another and in this respect
differs from that of the other diets. The chief value of these
experiments lies in their suggestiveness as indicating what
’ may be accomplished with diets carefully limited to particular
kinds of cells or tissues or to substances of particular chemical
constitution.

REFERENCES

CuHILp, C. M.
tgtr. ‘‘A Study of Senescence and Rejuvenescence Based on Experiments
with Planarians,” Arch. f. Entwickelungsmech., XXXI.
1914. “Starvation, Rejuvenescence and Acclimation in Planaria doro-
tocephala,” Arch. f. Entwickelungsmech., XX XVIII.

Citron, E.
1902. “Beitrége zur Kenntnis von Syncoryne sarsii,” Arch. f. Naturge-
schichte, Jog. LXVIII.

DOWNEROWITSCH.
1892. ‘On the Changes in the Spinal Cord during Complete Starvation”
(Russian), Bolnitschnaja Gaseta Botkina, 1892.

GUDERNATSCH, J. F. :
1912. ‘‘Feeding Experiments on Tadpoles: I, The Influence of Specific
Organs Given as Food on Growth and Differentiation,” Arch.
f. Entwickelungsmech., XXXV.
1914. ‘(Feeding Experiments on Tadpoles: II, A Further Contribution
to the Knowledge of Organs of Internal Secretion,” Am. Jour. of
Anat., XV.

176 SENESCENCE AND REJUVENESCENCE

HEUMANN, G.
1850. Mikroskopische Untersuchungen an hungernden und verhungerten
Tauben. Giessen. (Referat aus Canstatt’s Jahresberichte ii. d.
Fortschritte d. ges. Med., I, 1851.)

KASANZEFF, W.
1go1. LExperimentelle Untersuchungen iiber “Paramecium caudatum.”
Dissertation. Ziirich.

Lititz, F. R.
tgoo. ‘Some Notes on Regeneration and Regulation in Planarians,”
Am. Nat., XXXIV.

LuxKjJANow, S.
1897. “L’Inanition du noyau cellulaire,” Rev. Scient., 1897.

Maver, A. G.
1914. ‘“‘The Law Governing the Loss of Weight in Starving Cassiopea,”’
extract from Carnegie Instit. Publ. 183.

Morcvtis, S.
tg11. ‘Studies of Inanition in Its Bearing upon the Problem of Growth,”
Arch. f. Entwickelungsmech., XXXII.

Morpvrco, B.
1888. ‘Sull processo fisiologico di neoformazione cellulare durante la
inanizione acuta dell’ organismo,” Arch. Sci. Med., XII.
1889. ‘“‘Sur la Nature des atrophies par inanition chez eg animaux 4 sang
chaud,” Arch. Ital. de Biol., XII.
RINDFLEISCH.
1868. Lehrbuch der pathologischen Gewebe. Bd. III.

Romets, B.
1913. ‘‘Der Einfluss verschiedenartiger Ernihrung auf die Regeneration
bei Kaulquappen (Rana esculenta),” I, Arch. f. Entwickelungs-
mech., XXXVI.

1914. ‘‘Experimentelle Untersuchungen iiber die Wirkung innersekreto-
rischer Organe: II, Der Einfuss von Thyreoidea- und Thymusfut-
terung auf das Wachstum, die Entwicklung und die Regeneration,”
Arch. f. Entwickelungsmech., XL, XLI.

Scuuttz, E.
1904. “Uber Reduktionen: I, Uber Hungererscheinungen bei Planaria
lactea,” Arch. f. Eniwickelungsmech., XVIII.
STATKEWITSCH, P.
1894. “Uber Veranderungen des Muskel- und Driisengewebes, sowie

des Herzganglien beim Hungern,” Arch. f. exp. Pathol. u. Pharm.,
XXXII.

NUTRITION IN SENESCENCE AND REJUVENESCENCE 177

STOPPENBRINK, F.
1905. “Der Einfluss herabegesetzter Ernahrung auf den histologischen
Bau der Siisswassertricladen,’’ Zeitschr. f. wiss. Zool., LX XIX.
TASHIRO, S.
1913. “‘A New Method and Apparatus for the Estimation of Exceedingly
Minute Quantities of Carbon Dioxide,” Am. Jour. of Physiol.,
XXXII.
WALLENGREN, H.
1g02. “‘Inanitionserscheinungen der Zelle. Untersuchungen an Proto-
zoen,” Zeitschr. f. allgem. Physiol., I.

CHAPTER VIII

SENESCENCE AND REJUVENESCENCE IN THE LIGHT OF THE
PRECEDING EXPERIMENTS

REVIEW AND ANALYSIS OF THE EXPERIMENTAL DATA

In addition to the differences in size, structure, and behavior
which constitute more or less definite criteria of age in the lower
organisms, characteristic differences in rate of metabolism have
been shown to exist, the rate being highest in the youngest animals
and decreasing with advancing age. These age differences in rate
of metabolism are sufficiently well marked, as compared with such
individual and incidental differences as occur under ordinary con-
ditions, to make possible their use as criteria of physiological age,
and so to compare the physiological ages of different individuals.

In this way it has been shown that, in general, physiological
senescence accompanies the productive and progressive processes,
i.e., growth, specialization, morphogenesis, and differentiation, and
that physiological rejuvenescence is a feature of reduction and of
processes associated with the reconstitution and agamic develop-
ment in nature of new individuals from parts of a pre-existing
individual.

There can, I think, be little question that among the experiments
described the reduction experiments are most significant. Here
the possible complications connected with reproduction and recon-
stitution are absent, and only loss of substance with the changes
conditioned by it occurs. The association, on the one hand, of
physiological rejuvenescence with reduction, and, on the other,
of senescence with growth and differentiation, not only demon-
strates that rejuvenescence is not necessarily associated with
reproduction, but also constitutes a positive experimental foun-
dation for a physiological conception of the age changes. It is
evident that in the organism in which differentiation has begun
and is progressing the addition of substance brings about in some
way a decrease in metabolic rate and so a decrease in the capacity
for further growth and development, while the removal of substance

178

CONCLUSIONS FROM EXPERIMENTS 179

by starvation increases the rate of metabolism and so the capacity
for growth and development. From an advanced physiological
age it is possible to bring the animals back practically to the begin-
ning of post-embryonic life by forcing them to use up and eliminate
the substance which they have accumulated during post-embryonic
growth and development. Here no reproductive process, asexual
or sexual, is involved, but, to return to the analogy between the
organism and the flowing stream, the metabolic current is forced
to erode its channel instead of depositing material along its course.

These experiments leave no basis for the contention that the
organism or the cell cannot become young after it has once
undergone senescence, and that the only source of youth is an
undifferentiated germ plasm. The planarian reduced by starva-
tion consists entirely or almost entirely of cells which formed
functional differentiated parts of the original, physiologically and
morphologically old animal, but after renewed feeding it is younger
in every respect and in all parts of the body, so far as can be deter-
mined, than before starvation, and is again capable of growth and
senescence. In short, these experiments demonstrate that the
differentiated somatic cells can return to a physiological condition
which at least approaches that of embryonic or undifferentiated
cells, and there is no reason for believing that a hypothetical
parcel of germ plasm in the nucleus of these cells is in any way
responsible for this regression. ‘The results of these physiological
experiments are in complete agreement with the conclusions reached
by E. Schultz (04, ’08), on the basis of morphological data.

The few experiments on the influence of the kind of nutrition
upon the course of the life cycle indicate clearly that the course and
results of senescence may differ widely with the character of the
food. The experiments do not throw any light on the question of
the factors concerned in the differences produced, but with more
complete control of the kind of nutrition more definite results on
this point will doubtless be possible. Even these experiments
show, however, that the age cycle in these lower animals is by no
means independent of nutritional factors. Perhaps the most
important point is that with certain foods a progressive senescence
from generation to generation occurs, while with other foods

180 SENESCENCE AND REJUVENESCENCE

senescence and rejuvenescence apparently balance each other in
each cycle. Evidently certain physiological characteristics of the
organism, which are associated either with its metabolic processes
or with its structural substratum, or more probably with both,
are dependent upon the character of its nutrition, to such an extent
at least as to modify the age cycle very essentially.

In the light of the starvation experiments the occurrence of
rejuvenescence in connection with the reconstitution of pieces and
with agamic reproduction in nature is not difficult to understand.
In the reconstitution of pieces some cells undergo dedifferentiation
to a greater or less extent and take part in the development of new
structures, or the new parts arise from cells which have remained
relatively young and less specialized than others; some cells may
undergo degeneration and disappear completely, and, except where
the isolated piece takes food, the energy for the various changes is
derived from reserves and from the tissues themselves which
undergo more or less reduction.

The degeneration of differentiated cells does not contribute
directly to the rejuvenescence of the piece, but if cells undergo
dedifferentiation or if the new structures arise from cells which
have retained a more or less ‘‘embryonic”’ condition, the result is
of course a younger organism. And if in addition any appreciable
amount of reduction occurs, rejuvenescence, particularly in the
old parts which constitute the chief source of nutritive supply in
such cases, proceeds still farther.

We have seen that the degree of rejuvenescence varies with the
size of the piece and with the degree of reconstitution, i.e., the
degree of approach to wholeness in the piece. The reason for these
relations is clear. Provided reconstitution occurs, the smaller
the piece the greater the loss of old structure and the devel-
opment of new, and the greater the reduction of the whole piece
in furnishing energy for the process. Moreover, the greater the
degree of reconstitution, the greater the reorganization, and the
greater the supply of nutritive material required from the piece.

Thus in the piece undergoing reconstitution a new metabolic
equilibrium is attained. The parts formed anew are young and

_ have a higher rate of metabolism than the others, but they become

CONCLUSIONS FROM EXPERIMENTS 181

older and their rate decreases as they grow and differentiate. At
the same time, the remaining parts of the piece are drawn upon
as a source of energy for the growth of the new parts, and in con-
sequence they undergo reduction and their rate of metabolism
rises: in fact, they become younger. Sooner or later a condition is
attained in which the young, new parts can no longer grow at the
expense of the old parts because the rate of metabolism in the former
is declining while that in the latter is increasing. When this stage
is attained reconstitutional changes can proceed no farther. If
the animal is fed at this stage it grows essentially like any other
animal, and if not fed it undergoes reduction like any other starved
animal. At the time equilibrium is attained the rate of metabolism
in general will vary with the size of the piece and the degree of
reconstitution. The smaller the piece and the greater the amount
of reconstitutional change, the higher the rate at which this equi-
librium is reached, and so the younger the animal becomes during
reconstitution.

As already noted, the cases of agamic reproduction examined
in chap. vi do not differ fundamentally from the experimental
reproductions or reconstitutions following the physical isolation
of pieces, and we should expect that if rejuvenescence occurs in
the one case it would in the other. Whether a piece develops into
a new whole as the result of artificial isolation by section or other
means, or of physiological isolation by conditions arising in the
organism in nature, the result is essentially the same. In one
respect, however, there is a difference of degree: in many cases of
budding, fission, etc., the new developing individual remains in
organic continuity with the parent until its development is ad-
vanced or completed and so is supplied with nutritive material.
In such cases, as for example, in hydra, the new individual, instead
of undergoing reduction, grows throughout its development, and
the degree of rejuvenescence is much less marked than in those
cases where the tissues of the developing piece or region are the
source of energy. Here the dedifferentiation of cells, or the sub-
stitution of less differentiated younger cells for those previously
existing, are the chief factors in rejuvenescence, although appar-
ently some degree of metabolic equilibration does occur in the old

182 SENESCENCE AND REJUVENESCENCE

parts, ie., these parts become somewhat younger, even though
nutrition is present.

The results of the experiments together with the results of
observation in nature constitute an adequate foundation for the
conclusion that a greater or less degree of rejuvenescence must be
associated with agamic reproduction. As we have seen in the case |
of Pennaria (pp. 148-51), it may be less in the more specialized
than in the less specialized types of reproduction and it must
differ in degree with various other conditions, but wherever recon-
stitutional or reductional changes are involved we must expect
to find some degree of rejuvenescence.

The persistence of the embryonic condition in the growing tip
and meristematic tissues of the higher plants and in the growing
regions of many of the lower animals shows, however, that under
certain conditions growth may continue over long periods of time
without any very great degree of, and in many cases perhaps
without any, senescence. So far as we know, the long-continued
persistence of the embryonic condition in rapidly growing tissues
is always associated with a high frequency of cell or nuclear division,
and the experiments on the infusoria (see pp. 137-42) indicate
that at least in these forms some degree of rejuvenescence occurs
in connection with cell division. There is every reason to believe
that in nuclear and cell division in general, as in other forms of
reproduction, some degree of change in the direction of rejuvenes-
cence occurs. Whether this balances the changes which occur
between successive cell divisions depends upon the frequency of
division, the rate of growth, and various other conditions. Where
a balance is attained or approached, differentiation and senescence
do not occur, or proceed slowly; otherwise they proceed more or
less rapidly, according to conditions.

The only possible conclusion in view of all the facts seems to be
that senescence is associated with the productive and progressive
phases, and rejuvenescence with the reductive and regressive
phases, of the life cycle.

THE NATURE OF SENESCENCE AND REJUVENESCENCE

The theories of senescence that have been advanced fall mainly
into two groups. Those of the one group regard the phenomena

CONCLUSIONS FROM EXPERIMENTS 183

of senescence as in some sense secondary or incidental, and not as
a necessary and inevitable consequence or a part of the cycle of
development. According to such theories senescence is due to
incomplete excretion of toxic products of metabolism of one kind
or another, or to a wearing out of certain organs for one reason or
another, to evolutionary adaptation, or to some other incidental
factor. The theories of the other group regard senescence as a
result of the same processes which determine growth, differentia-
tion, and what we call development in general. These theories
attempt to find the conditions and processes which determine
senescence in the conditions and processes which underlie develop-
ment. From this point of view senescence is a feature of develop-
ment. The experimental data presented in the preceding chapters
leave little room for doubt that both senescence and rejuvenescence
are necessary and inevitable features of the life cycle. Certainly
the worn-out organs of old animals cannot be repaired by an
extended period of starvation, nor is the elimination of toxic meta-
bolic products likely to be assisted by the structural degeneration
of parts which occurs in various cases of reconstitution. Senescence
and development are simply two aspects of the same complex
dynamic activities.

Since our knowledge of the metabolic reactions, on the one hand,
and of the colloid substratum of the organism, on the other, is not
very far advanced, we cannot at present determine the exact nature
of the relation between growth, differentiation, and senescence, and
reduction, dedifferentiation, and rejuvenescence. Nevertheless we
can point with considerable confidence to certain features of growth
and development as affording a basis for the changes of the age
cycle.

It was pointed out in Part I thdt during development the
general metabolic substratum of the organism, the unspecialized
or embryonic cell, undergoes a progressive change in the direction
of greater physiological stability in consequence of changes in the
substratum and additions to it in the course of growth and differ-
entiation. The general result of these changes is a decrease in the
metabolic activity of each unit of weight or volume of the organism
because the proportion of the relatively stable constituents in the
substratum increases.

184 SENESCENCE AND REJUVENESCENCE

Such changes are most conspicuous in those cells which become
loaded with non-protoplasmic inclosures, such as granules or
droplets, or in which the cytoplasm is largely transformed into the
inactive substance of skeletal or supporting tissues, but it is evident
that similar changes occur to a greater or less extent in all cells
during differentiation. Development must then be accompanied
by a progressive decrease in the rate of metabolism per unit of
weight or volume of the substance of the organism.

But other factors are probably more or less generally concerned
in bringing about the decrease in metabolic rate which occurs
during development. It is a familiar fact that emulsoid colloid
sols and gels outside the organism undergo changes in aggregate
condition with time. The degree of aggregation increases, the
water-content decreases, and shrinkage occurs. To what extent
such changes occur in the colloids of the living organism is a ques-
tion, but that there is more or less change of this sort in the more
stable portions of the colloid substratum is highly probable, and in
any case the continued accumulation of colloids in the cell as a
product of metabolism probably brings about an increase in con-
centration and of aggregation in the colloid. The rate of chemical
reaction in a colloid substratum is more or less intimately associated
with the condition of the colloid and very generally decreases with
increasing aggregation. The increasing density and aggregation of
the colloid substratum may lead, then, to an actual decrease in the
rate of chemical reactions. Moreover, the increase in density and
thickness and the decrease in the permeability of membranes may
retard the exchange through them. The retardation of enzyme
activity by accumulation of the products may also play a part in
decreasing metabolic rate, though it is probable that such decreases
in metabolic activity are usually less permanent than the age
changes and are associated with other shorter periods in the life
of the organism. Various other factors, as yet unrecognized,
may also be concerned, but it is evident in any case that the decrease
in rate of metabolism is a part of development itself and not an
accidental or incidental feature of life. The decrease in metabolic
rate during development is in fact a necessary and inevitable
consequence of the association of the chemical reactions which

CONCLUSIONS FROM EXPERIMENTS 185

constitute metabolism with a colloid substratum produced by the
reactions.

The development of metabolic mechanisms, such as the striated
muscles, which are capable when stimulated of a very high rate of
metabolism, is in no sense an exception to or a contradiction of the
general law that a decrease in rate of metabolism is associated with
development. In the early stages of development correlative
functional stimulation of the cells of the organism certainly occurs
only to a very slight degree, so far as it occurs at all, and cannot be
compared to the degree of functional stimulation which occurs
in later stages after development of the stimulating mechanism—
in the case of striated muscle, the nervous system. This being the
case, we must compare the rate of metabolism in the unstimulated
or very slightly stimulated differentiated cell—not the rate of the
cell under strong stimulation—with the rate of the embryonic cell,
if we are to attain a correct conception of the difference. Bearing
this point in mind, it is easy to see how great the difference in
rate is. In the case of striated muscle, for example, the rate of
metabolism in the earlier stages of development is sufficiently
high to bring about the morphogenesis of the muscle without the
accelerating influence of nerve impulses, but later the muscle
atrophies unless its rate is frequently accelerated by nervous
stimulation.

From this point of view senescence in its dynamic aspect con-
sists in a decrease in the rate of metabolism determined by the
changes in the substratum during development, and, in its morpho-
logical aspect, in the changes themselves. The idea that senescence
is in one way or another simply an aspect or result of development
itself has been more or less clearly expressed by various authors,
and various features of the developmental process have been re-
garded as the essential factors," but discussion of the different
theories is postponed to a later chapter.

Attention has already been called to the fact that growth may
give place to reduction and progressive development to regressive.

« Among more recent writers who have advanced this view in one form or another
are the following: Cholodkowsky, ’82; Enriques, ’07, ’o9; Jickeli, ’02; Kassowitz,
’99; Minot, ’o8, ’13, and several papers of earlier date; Miihlmann, ’oo, ’10.

186 SENESCENCE AND REJUVENESCENCE

In reduction, substance previously accumulated in the cell is
broken down as a source of energy and eliminated or serves for new
syntheses, and the cell undergoes regression toward the embryonic
condition. Such a change means the removal to a greater or less
extent of the conditions which have brought about a decrease in
rate of metabolism, the proportion of less stable to more stable
substance increases, the aggregation of the substratum decreases,
and the rate of metabolism increases. These changes constitute
rejuvenescence. Dynamically rejuvenescence consists in increase
in rate of metabolism and morphologically in the changes in the
substratum which permit increase in rate.

If this definition of rejuvenescence is correct, it follows that
there is no necessary relation between rejuvenescence and gametic
or any other kind of reproduction. The changes in the substratum
may result from reduction connected with starvation, or from some
change in the character of metabolism which brings about the
removal of certain substances previously accumulated, as well as
from the reductional and reconstitutional changes connected with
the reproduction of cells, parts of a complex organism, or new
whole organisms. And earlier chapters have demonstrated that
not only agamic reproduction in nature and experimental reproduc-
tion, but also reduction by starvation may bring about rejuvenes-
cence to such an extent that the animals thus produced are as
young physiologically as sexually produced animals in the same
morphological stage. And, finally, as will appear in chaps. xiii-xv,
the facts indicate that in the cycle of gametic reproduction the
period of gamete formation is a period of senescence and that of
early embryonic development a period of rejuvenescence.

As regards the conception of the nature of senescence, this
theory does not differ fundamentally from others which have been
advanced at various times, but in its emphasis upon the occurrence
and significance of rejuvenescence it departs from commonly
accepted views. The idea that life proceeds only in one direction
from youth to age and death must be abandoned. Rejuvenescence
is as essential a feature of life as senescence. Senescence often
leads inevitably and automatically through reproduction or reduc-
tion and dedifferentiation to rejuvenescence.

CONCLUSIONS FROM EXPERIMENTS 187

PERIODICITY IN ORGANISMS IN RELATION TO THE AGE CYCLE

Before leaving the question of the nature of senescence and
rejuvenescence it is necessary to call attention to their relation to
other periodic or cyclical changes in the organisms. According
to the conception developed here, there is nothing unique in the
processes of senescence and rejuvenescence; they are, on the con-
trary, of the same general character as many other changes in rate
of metabolism in the organism, the chief difference being that the
factors concerned in the age changes are the more stable and less
rapidly changing features of the substratum, while other shorter
cycles may result from changes in less stable features. In fact,
it is not possible to make any sharp distinction between the age
changes and many other periodicities. The differences are differ-
ences of degree rather than of kind. Recognition of this fact is
important, because senescence has often been regarded as a rather
mysterious process, quite different from anything else in the life
cycle, but the experimental evidence points to a very different
conclusion.

The more or less regularly periodic or cyclical changes are among
the most conspicuous and characteristic features of living organisms.
They range in the individual from momentary, evanescent changes,
such as occur in stimulation and the return to the original condition
which follows, to the changes of the age cycle which often coincide
with the whole life of the individual. Some of these periodic changes
are of course directly determined by external conditions, such as
temperature, light, etc., while, as regards others, internal factors
are more important. Any extended consideration of these various
periodicities is quite beyond the present purpose, but the fact that
many of them seem to be more or less similar in character to the
age cycle, except as regards the time factor, demands some sort of
interpretation. According to the physico-chemical conception of
the organism, many different periodic changes in rate of metabolism
are possible, for different conditions in the substratum which accel-
erate or retard the rate of metabolism may arise and disappear with
very different rapidity, and the variety of more or less definitely
periodic phenomena in life is in full agreement with theoretical
possibility.

188 SENESCENCE AND REJUVENESCENCE

A simple case in point is the accumulation of carbon dioxide
which decreases the rate of metabolism in a very short time, while
recovery occurs as rapidly when it is eliminated. According to
the theory of stimulation by R. S. Lillie (’oga, ’o9b), the concen-
tration of carbon dioxide in the cell is the chief factor in decreasing
the rate of reaction after stimulation. Lillie suggests that in the
absence of excitation the plasma membrane of cells is impermeable
or only slightly permeable to carbon dioxide, consequently the car-
bon dioxide resulting from metabolism accumulates in the cell
and decreases the rate of metabolism. A stimulus is any external
factor which increases the permeability of the membrane to carbon
dioxide and so permits its escape from the cell and consequently
brings about an increase in rate of metabolism, which is followed by
a decrease in rate as the temporary increase in permeability of the
membrane disappears.

Fatigue, i.e., the decrease in rate of metabolism which follows
continued stimulation, is generally believed to be due to the accu-
mulation of toxic products of metabolism (see p. 297). During rest
these products are eliminated and recovery occurs. Various meta-
bolic intoxications are probably very similar in character, although
in many of these cases the toxic substances are the products of metab-
olism of micro-organisms and not of the affected organism itself.
The decreased metabolic activity which occurs after feeding in
many animals is undoubtedly due to accumulation of some sub-
stance or substances which decrease the rate of reaction. As the
accumulated substance disappears, activity increases until feeding
again takes place.

In these and many other cases the changes in metabolism are
readily and rapidly reversible, because the substances or conditions
which determine them are readily eliminated or are themselves
reversible. Moreover, except where the activity of the cell is
largely accumulatory or secretory, these changes are not ordinarily
accompanied by any very marked morphological changes. When
extreme or long continued, however, stimulation may bring about
very considerable structural changes, even in cells where functional
activity is largely dynamic rather than structural, such, for example,
as the nerve cells, in which the morphology of function has been

CONCLUSIONS FROM EXPERIMENTS 189

described by various authors. As might be expected, such
changes, if they do not proceed beyond a certain limit, are reversible,
and recovery occurs rapidly.

In cells where function is accompanied by extensive accumula-
tion and discharge of substances, such, for example, as the gland
cells, storage cells, etc., the cycles of activity and morphological
change are essentially age cycles, that is to say, the period of loading
of the cell is a period of decreasing metabolic activity, of “senes-
cence,” and the period of discharge one of increasing activity, of
‘‘rejuvenescence,” which makes possible a repetition of the cycle.
In such cells the structural changes are often very marked. In the
pancreas, for example, the cell which is loaded with the granules
which give rise to the secretion presents a very different appearance
from the cell after continued stimulation and discharge.

Figs. 66-68 show different stages in the cyclical changes of the
pancreas cells of the toad. Fig. 66 shows the loaded cells ready to
secrete when stimulated. The whole outer portion of the cell,
ie., the part next to the duct, is filled with large granules, and
cytoplasm appears only near the base about the nucleus. This
condition is analogous to that of advanced differentiation in which
the cytoplasm has been largely transformed into substances which
are inactive or less active. In this loaded condition the pancreas
cell is only very slightly active metabolically, and its activity is
probably due in large measure to the fact that it does secrete
slightly, and so the substance of the granules is being changed and
eliminated to some extent, more or less continuously.

But when stimulated to secretion, the oxygen consumption of
the cell increases greatly (Barcroft, ’o8), the granules rapidly
disappear, and the cytoplasmic zone extends from the base of the
cells out toward the periphery. Fig. 67 shows four cells in various
stages of discharge and Fig. 68, cells after long-continued stimula-
tion. In this condition the cell is again capable of a high rate of
metabolic activity; if nutrition is present the process of loading
occurs once more, and the cell approaches quiescence.

«See, for example, Dolley, ’13, ’14; Hodge, ’92, 94; Lugaro, ’95; Mann, 95;
Pick, ’98; Pugnat, ’o1; Valenza, ’96. Further references concerning periodic and
other functional changes in structure will be found in these papers.

Igo SENESCENCE AND REJUVENESCENCE

This cycle of changes, which may occur within a few hours and
which may be repeated in a single cell, is, I believe, not funda-
mentally different from the age cycle in organisms. All the essen-
tial features of both senescence and rejuvenescence up to a certain

Fics. 66, 67.—Pancreas cells of toad: Fig. 66, fully loaded and almost quiescent;
Fig. 67, partially discharged after stimulation. From preparations loaned by R. R.
Bensley.

point are present. The cell probably does not return to the em-
bryonic condition at any point in the cycle, but it certainly does
undergo changes similar in character to those of the age cycle,
though their period is short. At the same time the gland cell
may be undergoing senescence in the stricter sense, that is, more

CONCLUSIONS FROM EXPERIMENTS IgI

stable components of the protoplasm may be accumulating or
undergoing changes which are not, or not wholly, compensated
by the functional cycle.

Other gland cells undergo very similar periodic changes in
structure, the whole peripheral region being discharged bodily in
some cases and the cell regenerating from a small basal portion.
Many other cells in the organism not regarded as gland cells pass
through somewhat similar cycles. Various cells, for example,
accumulate reserves, such as starch in plants and fat in animals
and various other substances. As the loading of such cells pro-

Fic. 68.—Pancreas cells of toad almost completely discharged after prolonged
stimulation. From preparations loaned by R. R. Bensley.

ceeds, they approach quiescence, but when conditions change so
that the previously accumulated substances are removed, they may
undergo a rejuvenescence. Although we have at present little
positive knowledge along this line, it seems probable that various
periodic changes in organisms or parts are of this general character.
Quiescent periods following periods of abundant nutrition and
accumulation of substance occur in the protozoa and other lower
animals as well as in many plants, particularly in parts specialized
as storage organs, such as bulbs, tubers, etc. It is a familiar fact
that in certain tropical species of trees the loss of leaves, followed
by a quiescent period, occurs at different times on different branches

192 SENESCENCE AND REJUVENESCENCE

of the same tree. In such cases the periodicity may perhaps be
associated with the alternate accumulation and removal of sub-
stance. It is also possible that periods which appear superficially
to be seasonal may be at least often of this character. Schimper
believed that an internally determined periodicity might occur
independently of climatic and other conditions. Klebs, however,
denies the existence of such periodicity, yet at the same time he
regards the accumulation of organic substances, which as products
of enzyme activity inhibit or retard further activity, as a factor in
bringing about quiescent periods. If such substances are produced
more rapidly than they are used, they must accumulate, and it seems
probable that, at least sometimes, an internally determined perio-
dicity may result.

The view that the formation of the gametes or sex cells is essen-
tially a process of differentiation and senescence and the early
stages of embryonic development a process of rejuvenescence has
already been mentioned and will be discussed more fully in later
chapters. The cycle of changes in the egg is somewhat similar to
that in the gland cell, with the difference that in the egg the yolk
becomes a source of energy and substance for growth.

If the point of view advanced here is correct, then the age cycle
in the strictest sense is merely one of many periodicities or cycles
in organisms, some longer, some shorter, which result from the rela-
tions existing between the chemical reactions of metabolism and
the substratum in which they occur. The distinction between an
age cycle and other cycles is but little more than a matter of con-
venience or custom. The changes which fall into the category of
what we are accustomed to call age changes are merely those in
which the more stable and less rapidly changing features of the
organism are involved. Various other cycles of different length
differ mainly in that less stable and more rapidly changing condi-
tions in the substratum are concerned. Whether we call one cycle
an age cycle and another something else is of little importance, except
as regards convenience. From the cycle of fatigue and recovery
at one extreme, to the cycle of senescence and rejuvenescence
in the stricter sense at the other, there are many intermedi-

See, for example, Schimper, ’98, pp. 260-81; Klebs, ’11; Volkens, ’12; Simon, ’14.

CONCLUSIONS FROM EXPERIMENTS 193

atecycles. In some of these the products of metabolism accumulate
only temporarily, and the period may cover only a few moments or
a few hours, while in others the fundamental features of organic
structure are concerned, and the period coincides with the life cycle.

SENESCENCE AND REJUVENESCENCE IN EVOLUTION

It is pertinent, at this time, at least to raise the question whether
the point of view and the conclusions reached from the study of
individuals have any value beyond the individual life cycle. Is
there any indication of the progressive senescence of species or
groups, and, if such senescence occurs, does it always lead to death,
i.e., extinction, or is rejuvenescence possible? On the other hand, is
continued existence of a species without senescence possible ?

Any answers to these questions must at the present time be little
more than guesses. It is possible, however, that the metabolic
substratum of the species may undergo very gradual progressive
changes of the same general character as those concerned in indi-
vidual senescence, but which are not entirely eliminated or com-
pensated during the periods of individual rejuvenescence, and it is
conceivable that under altered conditions regression might occur as
in individual rejuvenescence. It is also possible that the union of
two gametes from different lines of descent in gametic reproduction
may be an important factor in retarding or accelerating such
changes, if they occur.

The records of paleontology are so fragmentary and our igno-
rance of the factors involved in the extinction or persistence of
species is so great that positive answers to these questions cannot be
looked for in that direction. Certainly many species have become
extinct in the course of geological time, but whether their extinction
has in any case been the result of a senescence we cannot deter-
mine. Decreasing numbers or decreasing size preceding extinction
may be due entirely to external conditions. But certain forms, such
for example as Limulus, the horseshoe crab, and the brachiopod
Lingula, have persisted practically unchanged from exceedingly
remote geological periods. Have such species not undergone senes-
cence, or has a rejuvenescence occurred somewhere, or perhaps
periodically, in the course of their descent ?

194 SENESCENCE AND REJUVENESCENCE

That a process similar to senescence has occurred in the evolu-
tion of the higher organisms from the lower is suggested by various
lines of evidence. The protoplasmic substratum of the higher forms
is certainly more stable and undergoes structural alteration less
readily and less extensively than in the lower. The higher forms
undergo a greater degree of differentiation during development
than the lower, and in the higher animals the capacity for agamic
and experimental reproduction is absent and growth is limited.
Moreover, the metabolic activity for each unit of weight is prob-
ably less under similar conditions of temperature, oxygen supply,
nutrition, etc., in the higher than in the lower forms, even in early
stages of development. In short, there are various resemblances
between the course of evolution and that of individual development,
and the latter is a period of senescence. And as in the individual
altered conditions may bring about rejuvenescence, so in the course
of evolution the occurrence of rejuvenescence is conceivable. Ifa
secular senescence of protoplasm has constituted a factor in evolu-
tion, the protoplasm of the higher forms must have undergone this
change more rapidly than that of those which remained as lower
forms. Moreover, such a senescence might proceed more or less
independently of the environment, though the course and rate of
the change would doubtless be influenced by environmental con-
ditions. In other words, protoplasmic senescence, if it plays any
part in evolution, is to some extent an internal factor, and evolution
itself is in some degree a progressive change from less to more
stable equilibrium, rather than in the opposite direction.

The purpose of the present section is to suggest possibilities,
rather than to develop theories. Since there is continuity of pro-
toplasmic substance from generation to generation, there niay be
internally determined progressive change in that substance similar
in some degree to the change during individual life (see pp. 464-65).

REFERENCES
Barcrort, J.
1908. ‘‘Zur Lehre vom Blutgaswechsel in den verschiedenen Organen,”
Ergebn. d. Physiol., VII.
CHOLopKowsky, N.
1882. “Tod und Unsterblichkeit in der Tierwelt,” Zool. Anzeiger, V.

CONCLUSIONS FROM EXPERIMENTS 195

ConkLI, E. G.
1912. ‘Cell Size and Nuclear Size,” Jour. of Exp. Zool., XII.
1913. ‘‘The Size of Organisms and of Their Constituent Parts in Rela-
tion to Longevity, Senescence and Rejuvenescence,” Pop. Sci.
Monthly, August, 1913.
Dottey, D. H.
1913. “The Morphology of Functional Activity in the Ganglion Cells
of the Crayfish, Cambarus virilis,”’ Arch. f. Zellforsch., IX.
1914. ‘On a Law of Species Identity of the Nucleus-Plasma Norm for
Nerve Cell Bodies of Corresponding Type,” Jour. of Comp.
Neurol., XXIV.
ENRIQUES, P.
1907. ‘“‘Lamorte,” Riv. di Sci., Ann. I.
1gog. ‘‘Wachstum und seine analytische Darstellung,” Biol. Centralbl.,
XXIX.
Hopeg, C. F.
1892. “A Microscopical Study of Changes Due to Functional Activity
in Nerve Cells,” Jour. of Morphol., VII.
1894. “‘A Microscopical Study of the Nerve Cell during Electrical
Stimulation,” Jour. of Morphol., IX.

JIckeELI, C. F.
1902. Die Unvollkommenheit des Stoffwechsels, etc. Berlin.

Kassowirz, M.
1899. Allgemeine Biologie. Wien.

Kegs, G.
tgt1. ‘Uber die Rhythmik in der Entwicklung der Pflanzen,” Sitzungs-
ber. d. Heidelberger Akad. d. Wiss.: Math. naturwiss. Kl.

Li1E, R. S.
tgoga. ‘On the Connection between Changes of Permeability and
Stimulation and on the Significance of Changes in Permeability to
Carbon Dioxide,” Am. Jour. of Physiol., XXIV.
1999b. ‘The General Biological Significance of Changes in the Permea-
bility of the Surface Layer or Plasma Membrane of Living Cells,”
Biol. Bull., XVII.

Lucaro, E.
1895. “Sur les modifications des cellules nerveuses dans les divers états
fonctionnels,” Arch. Ital. de Biol., XXIV.
Many, G.
1895. ‘Histological Change Induced in Sympathetic, Motor and Sensory
Nerve Cells by Functional Activity,” Jour. of Anat. and Physiol.,
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Minor, C. S.
1908. The Problem of Age, Growth and Death. New York.
1913. Moderne Probleme der Biologie. Jena.
Mituimann, M.
1900. Uber die Ursache des Alters. Wiesbaden.
tgto. ‘Das Altern und der physiologische Tod,’ Sammlung anat. u.
physiol. Vortr., H. XI.

Pick, F.

1898. ‘Uber morphologische Differenzen zwischen ruhenden und

erregten Ganglienzellen,”’ Deutsche med. Wochenschr., XXII.
Puenat, C. A.
tgo1. ‘‘Modifications histologiques des cellules nerveuses dans la fa-
tigue,” Jour. de Physiol. et de Pathol. gén., III.
Scuimper, A. F. W.
1898. Pflanzen-Geographie auf physiologischer Grundlage. Jena.
ScHULTZ, E.

1904. “Uber Reduktionen: I, Uber Hungererscheinungen bei Planaria
lactea,’”’ Arch. f. Entwickelungsmech., XVIII.

1908. ‘Uber umkehrbare Entwickelungsprozesse und ihre Bedeutung
fiir eine Theorie der Vererbung,”’ Vortr. und Aufs. ii. Entwicke-
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Sruon, S. V.
t914. ‘Studien iiber die Periodicitét der Lebensprozesse der in dauernd

feuchten Tropengebieten heimischen Baume,” Jahrbiicher f. wiss.
Bot., LIV.
VALENZA, G. B.
1896. “I cambiamenti microscopici della cellula nervosa nell’ attivita
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VOLKENS, G.
1912. Laubfall und Lauberneuerung in den Tropen. Berlin.

PART III

INDIVIDUATION AND REPRODUCTION IN RELATION TO THE
AGE CYCLE

CHAPTER Ix

INDIVIDUATION AND REPRODUCTION IN ORGANISMS
THE PROBLEM

Living organisms exist as more or less definite individuals. An
individual may be provisionally defined as a more or less complex
entity which acts to some extent as a unit or whole. Such a defi-
nition emphasizes the unity of the individual, but affords no clue
to the integrating factor or factors, i.e., to that which makes a
unity, a whole out of the complex.

Two very conspicuous characteristics of the organic individual,
particularly in its more highly developed forms, are its orderly
behavior and the definiteness of form and structure which is one
feature of this behavior. Nowhere do these characteristics appear
more clearly than in the remarkable sequence of events which con-
stitutes what we call the development, the ontogeny of the indi-
vidual. In the simpler organisms the morphological definiteness
is often less conspicuous, both the structure and the behavior being
more susceptible of modification by external factors, but the modi-
fications are themselves definite and orderly and are manifestly
not a direct and specific effect of the external factors which are
acting, but rather a reaction of an individual of some sort to an
external change.

In short, although we may attempt to ignore or deny it, as
various biologists have done, the fact remains that an ordering,
controlling principle of some sort exists in the organic individual.
The existence of such a principle does not, however, as has so often
been asserted, distinguish the living from the non-living inorganic
individual. In an electrical or a magnetic field or in a planetary
system, for example, we have individuations of a definite, orderly
character, though it is evident that such individuations are not
very similar to living organisms. The crystal also is an indi-
viduation of a highly orderly and definite character, and the at-
tempt has often been made to find some fundamental similarity
between living organisms and crystals, but without any great

199

200 SENESCENCE AND REJUVENESCENCE

success. The crystal is fundamentally a physical individuation
among molecules of like chemical constitution, although in certain
cases some heterogeneity of composition occurs. In the organism,
as the facts show, individuation is evidently associated with
chemical activity, and widely different substances may enter into
the constitution of the individual. The mere existence of axes in
both the organism and the crystal, which is one of the grounds for
comparison, is no criterion of essential similarity, for axes may be
the expression of very different conditions in different cases. No
adequate evidence for the identity or similarity of the axes of the
organism and those of the crystal has ever been presented, and
there is much evidence to show that they are very widely
different.

Apparently two distinct types of individuation exist in the
organic world. In the one, which may be called the centered or
radiate type, the parts are arranged and their behavior is integrated
with reference to a central region; in the other, which we may call
the axiate type, with reference to one or more axes. The radiate type
of individuation appears most clearly in the simple cell and in the
radiate structures which arise within it in connection with division,
while the axiate type is found both in cells and in organisms. More-
over, the two types of individuation often appear in combination:
in the starfish, for example, the body as a whole possesses an oral
aboral axis in the direction between the two surfaces, and the arms
are axiate structures with longitudinal and transverse axes, but
they are arranged radially about a central region. Most unicellular
organisms and most cells which form parts of multicellular organ-
isms show indications of a more or less definite and permanent axis
or axes superimposed upon the centered activities of the cell. In
the organism, as contrasted with the cell, the axiate type of indi-
viduation is predominant, and the axiate organization becomes
increasingly definite, conspicuous, and permanent as individuation
advances. In fact, the very general occurrence of an axiation of
some sort, or of physiological polarity as it is commonly called, is
the foundation of the belief widely current among zodlogists that
polarity is a fundamental characteristic of protoplasm. While
most cells undoubtedly do possess at least temporary polarity,

INDIVIDUATION AND REPRODUCTION 201

there are many facts which indicate that their polarity is not
self-determined, but is either acquired during the course of their
existence as a reaction to external conditions, or is merely the
polarity of the parent cell persisting in the products of division.
Moreover, there are various activities in the cell which are mani-
festly not axiate but radiate, and, finally, no one has been able to
discover the slightest indication of polarity in the fundamental
physical structure or optical properties of protoplasm.

But the fact remains that most organisms possess one or more
axes. the axes of polarity and symmetry, so called, and that these
axes are manifestly of fundamental importance in individuation.
The degree of physiological coherence and unity in the individual
is associated with the definiteness and fixity of its axes, and develop-
ment always proceeds in a definite and orderly way with reference
to whatever axes may exist. Evidently the axes of the organism
are not simply geometrical fictions, but rather the expression of
some fundamental factor in the axiate type of individuation, a
iactor which influences the rate and character of the metabolic
reactions and so plays an essential part in both morphogenesis and
functional activity.

In the more complex organisms a polarity and symmetry of the
whole organism often exist at the same time with a multitude of
polarities and symmetries of various parts, organs, and cells
which do not coincide with the general axes, but make all possible
angles with them and may be widely variable. This fact makes it
evident at once that the axiation of the organism as a whole is not
simply the general expression of the axiation of its parts. Many
different polarities and symmetries coexist and persist independ-
ently of each other, and yet the whole course of development is
an orderly process with a definite result.

These characteristics of organic individuals are not satisfactorily
accounted for by the current theories of the organism. Whether
we regard the organism from the viewpoint of the corpuscular
theories as an aggregation of distinct, self-perpetuating entities.
or as a chemical or physico-chemical system, we cannot escape the
necessity of accounting in some way for its definite and orderly
behavior and for the very evident relation in axiate forms between

202 SENESCENCE AND REJUVENESCENCE

this behavior and the axes of polarity and symmetry. Here lies
the problem of organic individuation.

From time to time parts of the individual give rise to new indi-
viduals, in which either the original axiation may persist or a new
axiation arise. This is reproduction. In the case of gametic or
sexual reproduction the process is further complicated by the union
of two nuclei, usually the nuclei of two highly specialized cells, pre-
ceding the development of the new individual. The problem of
how and why these new individuals arise is the problem of repro-
duction. And, finally, it is at once evident that the problems of
senescence and rejuvenescence are closely associated with these
problems of individuation and reproduction.

During some fifteen years’ study of reproductive processes in
the lower animals under experimental conditions I have been
brought face to face with these problems and have attempted to
gain some insight into the nature of the factors concerned in indi-
viduation and reproduction. In the remainder of the present
chapter the theory of individuation and reproduction which has
grown out of this investigation is outlined, and some of the more
important experimental evidence upon which it is based is briefly

stated.
THE AXIAL GRADIENT

By means of the susceptibility method described in chap. iii,
controlled in certain cases by estimations of carbon-dioxide pro-
duction by means of the Tashiro biometer (Tashiro, ’130), it has
been possible to demonstrate the existence of a distinct gradient
in rate of metabolic reactions along the chief or so-called polar
axis of axiate animals, so far as they have been investigated. In
its simple, primary form this axial gradient consists in a more or
less uniform decrease in rate of metabolism from the apical or
anterior region along the main axis. The point of importance is
that the apical region, or the head-region in cases where a head is
formed, is primarily the region of highest rate of metabolism and
that in general regions nearer to it have a higher rate than regions
farther away. In some animals, as for example in Planaria, this
gradient persists throughout life in the single individual, except

t Child, ’12, ’13a, ’13b, ’14a, ’14b, ’14¢.

INDIVIDUATION AND REPRODUCTION 203

for some temporary changes during growth, but when new zooids
arise in the posterior region of the body (see pp. 122-25) each
zooid develops its own axial gradient. In other cases, such as the
segmented worms, where the body increases in length for a time or
indefinitely by the addition of new segments arising from a growing
region just in front of the posterior end, the gradient appears in its
simple form during the early stages of development, but undergoes
some secondary changes in the posterior regions of the body as the
new segments are formed.

Up to the present time axial gradients have been found in all
forms examined, which include among unicellular forms some ten
species of ciliate infusoria, and among multicellular forms hydra
and several species of hydroids and sea anemones, eight species of —
turbellaria, the developmental stages of the sea-urchin and starfish
and of the polychete annelids Nereis and Chaetopterus, several
species of oligochete annelids examined by Miss Hyman, the
developmental stages of two species of fishes, and the cleavage and
early larval stages of salamanders and frogs. The variety of forms
examined with positive results leaves no doubt that the axial
metabolic gradient occurs at least very widely among axiate
animals.

Where definite axes of symmetry exist there are indications that
metabolic gradients are also present along these axes, and these
gradients show a definite and constant relation to the course of
development with reference to these axes.

These metabolic gradients are of course merely the expression
of a general condition and may undergo more or less variation in
steepness, i.e., in the amount of change in rate of metabolism from
level to level, or may even disappear temporarily, or in later life
permanently. But the fact that in each species gradients exist
which are characteristic and constant within certain limits, at
least during the earlier stages of development, is of the greatest
significance.

In addition to these results, obtained chiefly by means of the
susceptibility method, there are many other data of observation
and experiment which point unmistakably to the existence of
axial metabolic gradients as a characteristic feature of axiate

204 SENESCENCE AND REJUVENESCENCE

organisms in both plants and animals. At present, however, it
is possible to call attention only very briefly to some of these. It
is, for example, a well-known fact that in those plants which possess
a definite physiological and morphological axis or axes the apical
region of the axis is the region of highest rate of metabolism, and a
more or less definite downward gradient in rate exists along the
axis, at least for a certain distance from the apical region. This
gradient appears in the rate of growth at various levels of the axis,
in the precedence in development of the lateral buds near the apical
end when the chief growing tip has been removed, and in many
other features of plant life, but the question of its significance has
received little attention.

As regards animals, the so-called law of antero-posterior devel-
opment indicates the existence of a metabolic gradient along the
main axis of the organism during embryonic development. This
“law” is merely the statement of the observed fact of embryology
that in general the first parts to become morphologically visible
are the apical or anterior regions, and these are followed in sequence
by successively more posterior or basal parts. In other words, that
region of the egg or early embryo which has the highest rate of
metabolism gives rise to the apical or head-region, which, in conse-
quence of the higher rate, becomes differentiated in advance of other
parts, and these follow in sequence along the axis. This fact of
embryology is familiar to every zodlogist, and its significance as the
expression of a gradient in dynamic activity along the axis cannot
be doubted, although, so far as I am aware, no one has called atten-
tion to it.

Moreover, other facts of animal embryology indicate very
clearly the existence of symmetry gradients. In the bilaterally
symmetrical invertebrates, with ventral nerve cord, including most
worms and the arthropods, and particularly in those forms where
the egg contains much yolk so that the embryo is more or less spread
out upon it, the ventral and median regions of the embryo at any
given level of the body develop more or less in advance of the dorsal
and lateral regions. In such forms the regions which give rise to
ventral and median parts must have a higher rate of metabolism
than those which give rise to dorsal and lateral parts.

INDIVIDUATION AND ‘REPRODUCTION

Fig. 69, a longitudinal
section near the median
plane of the embryo of a
turbellarian worm, Plagio-
stomum girardi, shows very
clearly both the antero-
posterior and the ventro-
dorsal gradients. At this
stage only the head and
ventral region of the ani-
mal are represented by cell
masses, the regions where
the more dorsal structures
will later develop con-
sisting chiefly of yolk.
Moreover, the anterior re-
gion is more advanced in
development than any
other part. Fig. 70 is the
embryo of the earthworm.
In the anterior region the
body has attained its final
form, but posteriorly the
segmentation is more and
more limited to the ventral
region, the dorsal region
being little more than a
yolk sac, and in the ex-
treme posterior region seg-
ments have not yet become
visible. In the arthropods
the relations are in general
similar. The embryology
of other invertebrate
groups indicates more or
less clearly the existence
of symmetry gradients, but

205

Fics. 69, 70.—Axial developmental gradients
in embryonic stages of invertebrates: Fig. 69,
a somewhat oblique, longitudinal (sagittal)
section of the embryo of a turbellarian worm,
Plagiostomum girardi; the cephalic ganglia and
eye—at the left—are advanced in development,
as is also the pharynx, but farther posteriorly
fewer cells are present; the ventral (lower)
region is also much farther advanced than the
dorsal (from Bresslau, ’o4); Fig. 70, advanced
embryo of the earthworm Lumbricus agricola:
development is more advanced anteriorly and
ventrally than posteriorly and dorsally (from
Kowalewsky, ’71).

206 SENESCENCE AND REJUVENESCENCE

the axes of symmetry differ in different groups, and it is impossible
to consider the various details here.

In the vertebrates the developmental gradients of the longi-
tudinal and transverse axes like those of most bilaterally symmet-
rical invertebrates, show a decrease in rate from the anterior region
posteriorly and from the median region laterally, but the gradient
along the dorso-ventral axis is the reverse of that in the inverte-
brates, the dorsal region preceding instead of the ventral. Fig. 71

Fics. 71, 72.—Axial developmental gradients in the fish embryo: in Fig. 71 the
embryo consists chiefly of the median dorsal region, in which the nervous system, us, is
developing; in Fig. 72 development has proceeded laterally and ventrally, the somites
s, the notochord xc, and the alimentary canal ac being present. From H. V. Wil-
son, ’89.

represents a transverse section of a fish embryo at an early stage of
development. At this stage the embryo consists chiefly of the
embryonic nervous system (ns), the other parts being represented
by only a few cells. Ventral to the embryo is a very large mass of
yolk, not shown in the figure. Here the median dorsal region pre-
cedes lateral and ventral regions in morphogenesis. Fig. 72 shows
a later stage in which morphogenesis has advanced both laterally
and ventrally from the median dorsal region. The development

INDIVIDUATION AND REPRODUCTION 207

of the chick is essentially similar. Fig. 73 is from a transverse
section of a very early stage in which cells from what will later
become the median dorsal region are separating from the outer
ectodermal layer to form the mesoderm. Somewhat later the
central nervous system arises by an infolding of the ectoderm,
beginning at the anterior end and proceeding posteriorly in this
same region. In Fig. 74, a more advanced stage, the embryonic
nervous system is already present in the form of the neural tube,
and it is evident that morphogenesis is proceeding both laterally
and ventrally from the median dorsal region. The developmental
gradient along the longitudinal axis is also indicated by Figs. 73
and 74, for both are from the same embryo, the latter from a more
anterior, the former from a more posterior, level of the body. The
more posterior level has only attained the stage of Fig. 73, while
the more anterior level has passed far beyond this stage.

Particular parts and organs of the individual very often possess
an axis or axes of their own and without any uniform relation to the
axis of the body as a whole. Although but little attention has been
paid to this point, there are many facts which indicate that meta-
bolic gradients exist along these axes, at least in the earlier stages
of development.

In many animals the chief axial gradient along the longitudinal
axis and often also the symmetry gradients persist throughout life
or disappear only in advanced stages of development. In fact,
as will appear below, the continued existence of the individual in
the lower organisms is dependent upon the persistence of the
gradients. In higher forms where agamic reproduction from pieces
of the body does not occur it is possible that in the adult the gradi-
ents may be altered or eliminated without altering the individuation
to any marked degree.

The axial gradients arise in various ways which cannot be con-
sidered in detail here, but the different lines of evidence indicate that
in the final analysis they result from the differential action of ‘factors
external to the protoplasm, cell, or cell mass concerned. We see
gradients arising in nature in this way, and it is possible to produce
them experimentally by these means. In many cases of the recon-
stitution of pieces into new individuals the stimulation of the

SENESCENCE AND REJUVENESCENCE

208

or8 SNe SOS ¥ eee z =
eer a SSS Sag COL 6, 7 “PGS. bg =,
Ss Dg a FG LZ Baas sre ang ®Wyeo “oe 8 TF gig S® wry,
SRB y, oA Per a + PSE SOP ae W. 22 oy Neen Be Oh je le
RGSS Fowl g POMS atte © TATA Gari SP SGHIr Garis
No eee get eats IESE nT aH

From embryological prep-

Fics. 73, 74.—Axial developmental gradients in the chick embryo: Fig. 73,

showing the formation of the mesoderm, is from the posterior region of the same
embryo as Fig. 74, from a more anterior region, in which morphogenesis has extended

both laterally and ventrally from the mid-dorsal region.

arations of the University of Chicago.

INDIVIDUATION AND REPRODUCTION 209

region adjoining the wound determines the origin and direction of
a new gradient and so the axis of a new individual. In many
cases also the origin and direction of the new gradient may be
controlled and determined experimentally in other ways. Undoubt-
edly, after it is once established a gradient may often persist from
one individual to another through the process of reproduction,
but there are no adequate grounds for believing that such gradients
are fundamental properties of protoplasm, although, on the other
hand, it is probable that no cell or cell mass can exist for any
great length of time in any natural environment without acquir-
ing, at least temporarily, one or more gradients, because external
conditions at different points of its surface can never remain uni-
form. In general it may be said that the axial gradients of an
organism are either the parental gradients persisting in the organ-
ism, as in many cases of fission, or that they are produced de novo
by conditions which determine different rates of metabolism in
different parts of the cell or cell mass at some stage of its existence.

The essential feature in the establishment of a gradient in meta-
bolic rate in living protoplasm is the establishment of the region
of highest rate. If such a region is established in an undiffer-
entiated cell or cell mass, a more or less definite gradient in rate,
extending to a greater or less distance from this region, arises
because the changes in the primary region spread or are trans-
mitted, but with a decrement in intensity or energy, so that at a
greater or less distance they become inappreciable. In this way
the region of highest rate becomes the chief factor in determining
the rate of other regions, and since the rate thus determined is
higher in regions nearer to it and lower in those farther away, a
gradient in rate results. In its simplest form, then, the gradient
may arise merely from the spreading or transmission of metabolic
changes from the region of highest rate.

If metabolic gradients are characteristic features of the axes in
living organisms, the question at once arises whether the axis in
its simplest terms is anything more than such a gradient. In other
words, are not physiological and morphological polarity and
symmetry primarily the expression of gradients in rate of metab-
olism? At present it can only be said in answer to this question

210 SENESCENCE AND REJUVENESCENCE

that there is much evidence in favor of this view and none which
seriously conflicts with it. But whatever their relation to polarity
and symmetry, the metabolic gradients are fundamental factors
in individuation, as the following sections will show.

DOMINANCE AND SUBORDINATION OF PARTS IN RELATION TO THE
AXIAL GRADIENTS

The process of experimental reproduction in the lower animals,
that is, the development of new individuals or parts of individuals
from pieces cut from the bodies of other individuals, affords an
insight into the problem of individuation which cannot be obtained
in any other way. In many of these cases of experimental repro-
duction a new individuation takes place under such conditions that
it is possible to learn something of the manner in which it occurs.
A few of the more important points which have been established
are briefly considered here.

Apical regions or heads may arise and develop in complete
independence of any other part of the body, but other levels along
the main axis can arise only in connection with an apical or head
region, or in its absence with some region representing a more
apical or anterior level. A few examples will make the point clear.

Tn its simple, unbranched form the hydroid Tubularia consists
of the parts indicated in Fig. 75, at the apical end the hydranth
with its two sets of tentacles and the reproductive organs between
them, below this a long stem, and in contact with the substratum
a stolon. Isolated pieces of the stem more than two or three
millimeters in length produce a hydranth at the distal end and a
second hydranth may arise later at the proximal end (Fig. 76), this
second hydranth being the result of a reproductive process similar
to that occurring in this species in nature (see p. 220). But when
the pieces are below a certain length, which varies with different
regions of the body and different animals and also with different
external conditions, they give rise to hydranths or apical regions of
hydranths at one or both ends with more or less complete absence
of other parts. In the longer pieces of this sort a short stem may
be formed (Figs. 77, 78), in slightly shorter pieces single or double,
or more properly biaxial hydranths both complete ‘in all respects
(Figs. 79, 80), or a biaxial structure like Fig. 81 with one complete

INDIVIDUATION AND REPRODUCTION 211

hydranth and another consisting of only the more apical portions
(Fig. 81). In still shorter pieces the proboscis with the sex organs,

short tentacles, and mouth
may appear in single or
biaxial form without any
vestiges of other parts (Figs.
82, 83). And, finally, very
short pieces give rise only to
single biaxial apical portions
of the proboscis with mouth
and short tentacles (Figs.
84, 85).

Whether the short pieces
produce single or biaxial
structures, it is at once evi-
dent that the more apical
regions of the tubularian
body, i.e., the hydranth, or
the apical regions of the
hydranth, can develop from
any piece of the stem quite
independently of the presence
of any other part of the body.
The conditions necessary for
the development of these
parts are present in each
piece, and the absence of
the stem or even the basal
portion of the hydranth
makes no essential difference
inthe result. The occurrence
of the biaxial structures is as
a matter of fact an inci-
dental result of the shortness
of the pieces. In such pieces
the rate of metabolism at

76

a

>

Fics. 75, 76.—Tubularia: Fig. 75, a single
individual; Fig. 76, reconstitution in a long
piece of stem.

the two ends is often practically the same because they repre-
sent only a very small fraction of the whole axial gradient.

212 SENESCENCE AND REJUVENESCENCE

Ps

Ah
a
719
y\/
80
| | 85
84

Fics. 77-85.—Different results of reconstitution in short pieces of the stem of
Tubularia, showing that the formation of the apical region is independent of other
parts.

INDIVIDUATION AND REPRODUCTION 213

Consequently the two ends react with equal rapidity, and begin
development at the same time, and neither becomes dominant
over the other.

Short pieces of this character have never been known to
undergo transformation into stolons or stems without hydranths.
A stolon or a stem develops only in connection with a hydranth, or
with a piece of stem or stolon, and as an outgrowth from it. In
other hydroids and in coelenterates in general, as far as they have
been examined, the same relations obtain. The apical region can
arise independently of other parts, but stems and stolons arise
only in connection with other parts and more specifically with
parts which represent physiological regions nearer the apical end,
rather than with those to which they give rise.

In the flatworms we find similar relations of parts. Short
pieces from the body of Planaria, for example, may develop into
single or biaxial heads without any other part of the body. The
head of Planaria when separated from the body by a cut at the
level a in Fig. 86 may develop a head on its cut surface, as in Fig.
87; and short pieces from other regions, such as the piece bc in
Fig. 86, may give rise to single heads like Figs. 88 and 89, or some-
times to biaxial heads with a short anterior body region between
them, like Fig. 90. Evidently development of a head from a piece
is possible, even in the complete absence of other parts (Child, ’11d).

In Planaria, as in Tubularia, posterior regions do not arise
independently of other parts, but always in connection with regions
which are more anterior. Any piece of the planarian body is ca-
pable of giving rise to all parts posterior to its own level, whether a
head is present or not (Fig. 91), but no piece is capable of producing
any part characteristic of more anterior levels than itself, unless a
head begins to form first. This point is illustrated by Figs. 91
and 92. These pieces represent the region bd in Fig. 86. When such
pieces remain headless, as in Fig. 91, no changes occur at the anterior
end except the slight growth of new tissue, the piece does not give
rise to a new pharynx, nor does the more anterior region undergo
transformation into a prepharyngeal region. At the posterior end,
however, a large outgrowth occurs which slowly attains the

t See Child, ’o7a, b, c, 11a, pp. 101-19.

214 SENESCENCE AND REJUVENESCENCE

a aa

6
c
d s

~emn,

é

Fics. 86-93.—Reconstitution in short pieces of Planaria dorotocephala: Fig. 86,
body-outline, indicating levels of section; Figs. 87-89, biaxial and single heads formed
independently of other parts; 90, biaxial form with partial body; Fig. 91, headless
piece without reconstitutional changes in the anterior region; Fig. 92, anophthalmic
form in which anterior region has undergone reconstitution into the anterior and
middle body-region of a whole worm; Fig. 93, biaxial tails.

INDIVIDUATION AND REPRODUCTION 215

characteristic structure of a posterior end. Under certain conditions
short pieces give rise to biaxial posterior ends, asin Fig. 93. Morgan
(’04) has also described biaxial posterior ends from Planaria sim-
plicissima. But when such pieces give rise to a head, even though
it is of the rudimentary, anophthalmic type of Fig. 92, a new pharynx
and mouth arise and the anterior region becomes structurally and
functionally a prepharyngeal region, as the change in the intestinal
branches in Fig. g2 indicates. In some way all the changes in the
piece which concern the development of parts anterior to its own
level are dependent upon the presence of a head, or, more correctly,
of a head-forming region.

It has also been shown (Child, ’13a, ’140, ’14c) that the develop-
ment of a head on a piece of the planarian body is not the replace-
ment of a missing part under the influence of other parts of the
piece, but that head formation takes place, if it takes place at all,
in spite of the remainder of the piece. The more vigorous the
other regions of the piece, i.e., the higher their rate of metabolism,
the less likely is the piece to give rise to a new head, and vice versa.
On the other hand, the higher the rate in a piece, the more likely it
is to produce a posterior end. In short, the development of a new
individual from such pieces of Planaria is essentially the same pro-
cess as the development of an individual from the egg. It begins
with the formation of a head, and the head-region in some way
determines the reconstitution of certain parts of the piece into
more anterior parts, while other parts persist with more or less
change in size and proportion as corresponding parts of the new
animal. In the absence of a head-region any level of the body
controls and determines the development of all more posterior
levels. Much evidence, largely as yet unpublished, indicates that
similar relations exist in other forms where the development of whole
animals from headless pieces occurs.

These facts force us to the conclusion that in such experimental
reproductions there is a relation of dominance and subordination
of parts. The apical or head-region develops independently of
other parts but controls or dominates their development, and in
general any level of the body dominates more posterior or basal
levels and is dominated by more anterior or apical levels.

216 SENESCENCE AND REJUVENESCENCE

It is a well-known fact that a similar relation of dominance and
subordination exists in plants, the apical region or growing tip of
an axis being the dominant or controlling region of that axis. The
“Jaw” of antero-posterior development in animals suggests that
the relations are at least primarily the same in embryonic develop-
ment as in experimental reproduction. The cases of apparent
mutual independence of different regions or parts of the embryo
represent beyond question a secondary condition, so far as the
independence shall prove to be real.

As regards the longitudinal axis of the organism, then, the
region of highest rate of metabolism dominates other regions in the
earlier stages of development, and in general any region of higher
rate dominates regions of lower rate. The developmental gradients
along the axes of symmetry mentioned above (pp. 204-7) suggest
the existence of a dominance and subordination along these axes also.

The remarkable parallelism between the relations of dominance
and subordination and the relations of metabolic rate along the
axis suggests that dominance and subordination may depend pri-
marily on rate of metabolism. As regards the plants, it is evident
that dominance depends on metabolic activity, for the effect on
other parts of decreasing or inhibiting the metabolism of the grow-
ing tip without killing it, for example, by inclosure in plaster or in
an atmosphere of hydrogen, is the same as that of killing it, or
removing it completely. In other words, the reproduction or
development of other growing tips which was previously inhibited
now proceeds. McCallum (’o5) has demonstrated very clearly
that this relation of dominance and subordination in plants is not
dependent upon nutrition, water-content, or other more or less
incidental and widely varying conditions, but that it is a physio-
logical correlation of some sort apparently dependent upon funda-
mental factors in the plant constitution. As regards animals also,
there are many facts, some of which will be considered below, which
indicate clearly that dominance and subordination of parts in the
individual are primarily dependent upon rate of metabolism, al-
though with the development of a highly irritable conducting sys-
tem between dominant and subordinate parts, such as the nervous
system, it is conceivable that other factors may play a part.

INDIVIDUATION AND REPRODUCTION 217

THE NATURE AND LIMITS OF DOMINANCE

As regards the nature of the influence of the dominant region
upon other parts, the physico-chemical theory of the organism
affords two alternatives. Physiological correlation in the organism,
the influence of one part upon another, so far as it is not directly
mechanical, is accomplished in two ways: by the production and
transportation of substances, commonly known as chemical corre-
lation, and by the transmission through the protoplasm in general,
or along specialized conducting paths, of excitations which have
often been regarded as electrical in nature, but which now appear
to be associated with chemical changes (Tashiro, 13a). If chemical
correlation is the basis of the influence of the dominant region on
other parts, then we must suppose that metabolism in the dominant
region gives rise to certain chemical substances which are trans-
ported in some way through the body, but are gradually used up or
transformed so that their effects cease at a certain distance from
the region of origin. We may assume, further, that different sub-
stances are transported at different rates or are completely used up
at different distances from the point of origin. On the other hand,
the dominance and subordination of parts may conceivably be
accomplished by transmitted impulses. On the basis of this
alternative the metabolic activity of the dominant region must
produce certain changes or excitations which are transmitted
through the protoplasm, but which decrease in energy or effective-
ness as they are transmitted, so that finally a limit is reached beyond
which they are ineffective.

Many facts favor the second alternative. In the first place,
chemical substances may be transported to any distance in the
fluids of an organism, and it is difficult to see how any definite and
characteristic limit of effectiveness of such substances could exist,
unless we could assume that they were diffusing through a homoge-
neous medium or being transported at a definite rate and under-
going destruction also at a definite rate during transportation.
But it is certain that neither of these possibilities is realized in all
organisms in which a limit of effectiveness of dominance appears,
and it is a fact that the existence of a decrement and a limit of
effectiveness in transmission has been observed in many cases

218 SENESCENCE AND REJUVENESCENCE

among both plants and animals, and for excitations transmitted
through the general protoplasm, as well as those transmitted
through muscle and nerve.t In some of the lower animals the
gradual fading out, with increasing distance from the point of
origin, of the muscular contractions following a slight local stimu-
lation, affords a visible demonstration of the decrease in effective-
ness with transmission, and the relation between the distance from
the point of stimulation at which the contraction ceases to occur
and the strength of stimulation indicates further that the more
intense excitation is transmitted to a greater distance than the less
intense. And, finally, there can be no doubt that impulses may be
transmitted to greater distances over specialized conducting paths,
of which nerves are the most highly developed form, than through
the general protoplasm, and apparently some nerves conduct with
less decrement per unit of distance than others.

Certain physiologists maintain that the medullated nerves of
vertebrates conduct impulses without any decrement. If this is
true, an impulse might be transmitted in such a nerve to an in-
finite distance from its point of origin. There are, however, certain
facts which indicate that even in these nerves a decrement does
occur in the course of transmission, although it is often so slight as
to be inappreciable under ordinary conditions in the relatively short
pieces of nerves usually available for experiment. In the first place,
the electrical change, the negative variation accompanying the
passage of a nerve impulse, has been shown to undergo decrease
with increasing distance from the point of stimulation, and the
effectiveness of the impulse in producing muscular contraction
decreases in the same way. Moreover, various investigators have
recorded the existence of a decrement in the intensity of the impulse
in partially anaesthetized nerves, and there is no reason to believe
that the partial anaesthesia alters the fundamental nature of the
nerve as conductor: in all probability it merely makes the nerve a
less efficient conductor, so that the decrement becomes apparent

«For general consideration of the whole subject of conduction see Fitting, ’o7,
for plants, especially pp. 91-93 and 122-24; Biedermann, ’o3, especially pp. 204-8;
and Verworn, ’13, chap. vi. for animals. See also Boruttau, ’o1; Ducceschi, ’or;
A. Fischer, ’11; Kretzschmar, ’o4; Lodholz, ’12.

INDIVIDUATION AND REPRODUCTION 219

within a shorter distance than in the normal nerve. It is impos-
sible to consider the literature of this much-discussed problem here,
but it may be said that there is considerable evidence which indi-
cates that a decrease in energy or effectiveness occurs in the course
of transmission, even in the most highly developed nerve fibers,
while, up to the present time, no one has actually demonstrated
that conduction without decrement over any considerable distance
occurs. It appears, then, that transmitted excitations in organisms
do in general show a more or less rapid decrement and conse-
quently a limit of effectiveness at a greater or less distance from the
point of origin. In other words, such excitations gradually die
out like a wave or an electric impulse, but the more intense the
excitations or the better the conducting path, the greater the dis-
tance between point of origin and limit of effectiveness. From our
knowledge of conduction of excitations in non-living substances,
this is what we should expect in conduction in living substance.

If the dominance of one region over another in the organism
depends upon such transmitted excitations, there must be a spatial
limit to such dominance. And since the excitations which proceed
from the dominant region must result from metabolic changes
occurring there, we should expect to find them varying in intensity
with the rate of metabolism in the dominant part. Moreover, the
more intense the excitation and the better the conductor through
which the excitation is transmitted, the greater its effective range,
i.e., the distance to which it can travel before becoming ineffective.
Consequently the spatial limit of dominance must vary with the
rate of metabolism in the dominant part and the efficiency of the
conducting path between that and other parts. In the plants and
lower animals and in early stages of embryonic development of all
forms the efficiency of conduction is low and dominance is in general
effective over rather limited distances. In the later stages of
development of those forms which possess a nervous system the
efficiency of conduction increases very greatly as the nerves
develop, and the spatial limit of dominance likewise increases very
greatly.

In the plants and lower animals the limit of dominance is indi-
cated very clearly by the size of the individual or part concerned,

220 SENESCENCE AND REJUVENESCENCE

and growth beyond this size results in the formation of a new indi-
vidual or individuals from some part of the old, that is, in some form
of reproduction. The repetitive development in
series of parts, such as node and internode, in
the stem of the plant, of segments in segmented
animals, and many other cases, are examples of
similar relations between parts. The organic
individual in fact exhibits a more or less definite
sequence of events in space as well as in time,
and it is impossible to doubt that a physiological
spatial factor of some sort is concerned. This
problem has been considered at some length in
an earlier paper (Child, ’11a), and only brief
mention of some of the important points is
possible here.

In the simpler cases of reproduction the
spatial factor in dominance is clearly evident in
the position of the part concerned in reproduc-
tion with respect to the original dominant region.
In Tubularia (Fig. 75, p. 211), for example, the
stem and stolon increase in length, and when
a certain length, varying with conditions which
affect rate of metabolism, is attained, the tip of
the stolon turns upward away from the sub-
stratum and gives rise to a hydranth, as in Fig.
94. This hydranth and its stem grow in turn;
a stolon arises from the base, and when a cer-
tain length
of stem plus
stolon is
reached, the
process of
reproduc-
tion is then
repeated.
Evidently the stolon tip gives rise to a hydranth only when it has
attained a certain distance from the original hydranth. The

Fic. 94.—The primary form of agamic reproduction in Tubularia

INDIVIDUATION AND REPRODUCTION 221

formation of a hydranth at the basal end of pieces of the stem of
Tubularia under experimental conditions (Fig. 76, p. 211) is simply
the same reproductive process which occurs in nature, except that
under the experimental conditions it occurs in a shorter length of
stem because the rate of metabolism is lower. In Planaria and
other flatworms which undergo fission the body attains a certain
length and then the posterior region becomes a new zooid, as de-
scribed in chap. vi. The length which the individual attains
can be widely varied and controlled by experimental conditions
which affect the rate of metabolism (Child, ’r1c).

Fic. 95.—Reproduction of new plants from runners in the strawberry. From
Seubert, ’66.

In plants similar relations are of very general occurrence. In
the strawberry plant, for example (see Fig. 95), the runner attains
a certain length before the growing tip gives rise to a new plant,
but by cutting off or inhibiting the metabolism of the growing tip
of the parent plant the development of a new plant at the tip of
the runner can be induced at any time. These few cases will serve
to call to mind many others among both plants and animals in
which a spatial factor and a limit of effectiveness of the dominance
of the apical’ or head-region is evident.

Within the limits of the individual organism the same factor
appears in the length and position of various parts, and it has been

222 SENESCENCE AND REJUVENESCENCE

shown elsewhere (Child, 116) that in Planaria the spatial relations
of parts can be altered experimentally by altering the rate of
metabolism in the dominant head-region. For example, a piece of
Planaria including any considerable portion of the postpharyngeal
region such as be, Fig. 86 (p. 214), when allowed to undergo recon-
stitution in water at room temperature, forms an animal which in

100

Fics. 96-100.—Reconstitution of similar pieces of Planaria dorotocephala under
different conditions, to show different positions of pharynx and lengths of prepharyn-
geal region: Fig. 96, reconstitution in well-aerated water at 20° C.; Figs. 97-09,
different degrees of reconstitution in weak solutions of narcotics; Fig. roo, reconsti-
tution in well-aerated water at 28° C.

its earlier stages is like Fig. 96. The new pharynx and mouth
appear anterior to the middle of the piece at a certain characteristic
distance from the head, and in the region between the pharynx
and head the characteristic structure of the prepharyngeal region
develops. But if such pieces undergo reconstitution in weak solu-
tions of alcohol, ether, chloretone, or other anaesthetics, or under

INDIVIDUATION AND REPRODUCTION 223

other conditions which decrease the rate of metabolism, the head is
smaller and develops more slowly, the pharynx appears much nearer
the head, and the new prepharyngeal region is correspondingly
shorter (Figs. 97, 98). In extreme cases the head may be terato-
morphic (Fig. 99), or even anophthalmic (see pp. 111-12), and
no reconstitution occurs posterior to it. In similar pieces, under
conditions which increase the rate of metabolism, such as high
temperature, the prepharyngeal region is longer and the pharynx
appears farther from the head (Fig. 100). Evidently the distance
from the anterior end at which certain conditions arise in the piece
under its influence varies with the rate of metabolism in the domi-
nant anterior region. When the rate is very low the anterior region
does not bring about any visible change in regions posterior to itself,
and the higher the rate the greater the distance at which particular
changes occur.

In the higher animals, such as the vertebrates, as well as in the
higher invertebrates, the size of the adult individual is limited by
other factors than the limit of dominance, so that such animals
never attain anything like what might be called the physiological
maximum of size. The chief limiting factor in these cases is
apparently the higher degree of differentiation of the cells which
results in the retardation and sooner or later in the almost complete
or complete cessation of growth. Only in those forms in which
agamic reproduction occurs can we be certain that the individual
attains the physiological maximum, i.e., the size determined by the
limit of dominance. In the adult stages of the higher animals
dominance may extend to almost indefinite distances, but individual
size is limited by differentiation and lack of capacity for indefinite
or long-continued growth. Even in these forms, however, the size
of parts and their repetitive reproduction during development may
be determined by the limits of dominance in the early stages.

When we consider all these facts and many others, some of which
have been mentioned elsewhere’ but cannot be discussed here, we
are forced to conclude that a relation of dominance and subordi-
nation of parts in the organism really exists, that it is effective
only within a certain spatial limit, varying with conditions in the

t Child, ’11a, ’11b, ’11¢, ’13@, ’14b, ’14c.

224 SENESCENCE AND REJUVENESCENCE

organism, and that it seems to depend primarily upon impulses or
changes of some sort transmitted from the dominant region, rather
than upon the transportation of chemical substances. Chemical
substances arising in the course of metabolism are undoubtedly
important factors in determining the constitution and character of
particular organs and parts, but it is difficult to understand how
they can account for the definite and orderly spatial characteristics
of living things. Hormones, internal secretions, and other chemi-
cal substances unquestionably play a very essential réle in physio-
logical correlation, particularly in the higher animals where
different organs are highly differentiated, but for the production of
such different specific substances different organs are necessary.
At present we are concerned with the question of the primary
origin of these organs, with the appearance and localization of
differences which make possible the production of different specific
substances in different parts of the individual, and it is evident
that these primary specializations and differentiations, their locali-
zation and orderly and definite spatial arrangement, cannot be
accounted for by the action or interaction of such substances.
According to the conception developed above, the dominance of
a region depends primarily upon its rate of metabolism as compared
with that of other regions within the range of its influence. Where
the region of high rate is the primary factor in maintaining the
gradient, as it undoubtedly is in the lower organisms and in the
early stages of development of many higher forms, it is of course
the chief factor in determining the metabolic rate in other regions
and so maintains its original dominance. But in more highly
differentiated forms, or in later developmental stages, where rela-
tively permanent structural differentiations have arisen along the
course of the gradient, so that it has become structurally fixed,
the region of highest rate still remains dominant because it gives
rise to more powerful impulses than do other regions and conse-
quently influences them more than they doit. Lastly, in the higher
animals, where, in all except early embryonic stages, transmission
through nerves is the chief factor in physiological integration (see
Sherrington, ’06), the original gradient in metabolic rate may
persist chiefly, or perhaps in some cases only, in the efferent con-

INDIVIDUATION AND REPRODUCTION 225

ducting paths of the nervous system, while in other parts of the
body the metabolic rate has been altered by various factors.

At present there seems to be no good reason for believing that
the changes or impulses transmitted from the dominant region
affect the metabolic processes in regions which they reach in any
other than a quantitative way. The dominant region is not to be
conceived as giving rise to a variety of different kinds of impulses
which produce different, specific, formative effects, but rather
merely as a region of high metabolic rate, from which changes con-
nected with its metabolic activity spread or are transmitted to
other regions and increase their metabolic activity. Since these
transmitted changes decrease in energy or effectiveness with trans-
mission, they must determine a higher rate in the regions nearer
the dominant region than in those farther away. In this way the
determination of a high rate of metabolism in one region may result
in the establishment of a metabolic gradient in one or more direc-
tions from that region. Each point along an axis is then character-
ized by a more or less definite rate of metabolism, and if more than
one axis is present each point in the organism has a rate determined
by its position in each of the axial gradients.

From this point of view the axiate individual, whether it is a
whole organism or a part, when reduced to its simplest terms con-
sists of one or more gradients in rate of metabolism in a cell or cell
mass of specific constitution. Of course this condition represents
only the first step in individuation. Whether every individual
organism in every generation has its beginning in a condition as
simple as this can be determined only by extensive investigation.
Certainly other factors, such as difference of conditions at the sur-
face and in the interior, the presence of reserve substance such as
yolk in certain cells, etc., play a part sooner or later in many cases.
But that the simplest axiate individuals among organisms consist
essentially of metabolic gradients in a specific protoplasm is a
conclusion supported by a large body of evidence. The axes of
the organism or its parts are, according to this view, in their simplest
terms nothing but such gradients, and the structure of the apical
region or head of the organism represents merely the develop-
mental result of a high rate of metabolism and independence of

226 SENESCENCE AND REJUVENESCENCE

other parts. With a sufficiently high rate of metabolism and when
not subordinated to other parts, any part of the simpler organisms
is capable of developing into an apical region or head.

The objection may be raised that even if such a metabolic
gradient is established, there is nothing to maintain it with the
necessary degree of constancy to produce definite results. As a
matter of fact, regional differences in metabolism do maintain
themselves to a remarkable degree and may even be accentuated.
Certain muscles frequently or strongly stimulated become capable
of greater activity, and little-used parts gradually lose their
capacity for activity. There is good reason to believe that within
certain limits an increase in rate of metabolism in a protoplasmic
substratum changes the condition of the substratum so that a still
higher rate is possible, and vice versa. The analogy between the
organism and the stream referred to in chap. i is perhaps of service
here. An increase in rate of flow of the stream alters the channel
so that a still higher rate is possible, and a decrease in rate of flow
produces conditions which bring about further decrease. Moreover,
the region of high rate of metabolism in the organism once estab-
lished is more susceptible because of its high rate to the action of
external conditions: in animals, particularly in motile forms, this
region becomes the seat of the special sense-organs and is therefore
the most important part of the body as regards relations between
the organism and the external world. These conditions result from
the original high metabolic rate of the region, but they also con-
tribute toward maintenance of a relatively high rate of metabolism.

And, finally, the question whether purely quantitative differences
along an axis are sufficient to account for the morphological differ-
ences which arise along that axis is one which can be answered only
after the most extended and painstaking investigation. At present
we know that morphological characters can be altered very widely
by conditions whose effect upon the organism is primarily quanti-
tative. The different types of anterior end in pieces of Planaria
(see pp. 111-12) are cases in point. The very general belief that
qualitatively different substances or entities of some kind are
necessary as a basis for morphological development does not rest
upon direct or experimental evidence, but is an inference from the

INDIVIDUATION AND REPRODUCTION 227

morphological characters themselves. As a matter of fact we
know that even in relatively simple chemical reactions quantitative
differences may very often give rise to qualitatively different results.
And when we recognize the very great complexity of metabolism in
even the simplest organism, we cannot but admit that there must
be many possibilities in the metabolic complex for the origin of
qualitative differences in characters, organs, etc., from quantitative
differences in metabolism. Manifestly, quality and quantity in
organisms are not and cannot at present be clearly distinguished.
That qualitative differences in the chemical constitution and
metabolism of different organs exist is evident, but there is at
present no valid evidence that such differences cannot be reduced
to a quantitative basis.

DEGREES OF INDIVIDUATION

If the organic individual consists fundamentally of one or more
gradients in rate of metabolism with a relation of dominance and
subordination between regions of higher and those of lower rate, it
is at once apparent that the degree of integration of such an
individual into a physiological unit, the degree of physiological
coherence and of orderly behavior, must vary widely with various
factors of its constitution. Since it will often be necessary in follow-
ing chapters to call attention to differences in the degree of indi-
viduation, some of these factors must be briefly considered here.

The efficiency of conduction is a most important factor in
individuation. In the lower organisms and in the embryonic
stages of even the higher animals where the decrement in conduc-
tion is great, the degree of individuation is much lower than in
those forms or stages which possess a well-developed nervous sys-
tem, where the decrement is much less or almost inappreciable. In
the lower forms and in embryonic stages a higher metabolic rate is
necessary for permanent individuation; in other words, in order to
become or remain dominant, a given level must have a higher rate
of metabolism in relation to other levels than when a nervous system
is present.

Another factor in individuation is the physiological stability
of the structural substratum. The greater the stability of the

228 SENESCENCE AND REJUVENESCENCE

substratum, the greater the possibilities of specialization and differ-
entiation along the axis in relation to the gradient and therefore the
more intimate and complex the correlation between parts and the
higher the degree of unity in the whole. In the lower forms, where
structures once formed may disappear in a few hours or a few
days under altered physiological conditions, there is no possibility
of such minute and delicate interrelation and adjustment of parts
to each other as in the higher forms, where regressive changes are
much less extensive. In fact, the advance in development of the
nervous system itself from the lower to the higher forms is in part
dependent upon the increase in stability of the structural sub-
stratum.

The degree of individuation is dependent upon the rate of
metabolism. At any given stage of development the higher the
rate of metabolism, the higher the degree of individuation. But
we cannot properly compare earlier and later stages of development
in this way, for, although the rate of metabolism decreases during
development, the degree of individuation increases in most cases
up to the adult stage, because of the increasing efficiency of conduc-
tion and the specialization and interrelation of parts. It is only
after the adult stage is attained that the further decrease in meta-
bolic rate with advancing senescence determines a gradual decrease
in the degree of individuation, a physiological disintegration.

Many other incidental and external factors may alter the degree
of individuation in organisms. In general, depressing factors
decrease and stimulating factors, at least up to a certain limit,
increase it. The point of chief importance is, however, the possi-
bility of distinguishing different degrees of individuation and of
interpreting them to some extent, however incompletely, in physico-
chemical terms.

PHYSIOLOGICAL ISOLATION AND AGAMIC REPRODUCTION

If the axiate individual consists of a dominant and of sub-
ordinate parts, the structure, differentiation, and special function
of the subordinate parts are dependent, at least to a considerable
degree, upon their relation to the dominant part. Isolation of such
parts from the influence of the dominant part must result, if the

INDIVIDUATION AND REPRODUCTION 229

isolated parts are capable of reacting to the change, first, in a loss
of their characteristics as parts, and, secondly, if conditions permit,
in a new individuation which may bring about the development of
a complete new individual from the isolated part. In short the
isolation of a subordinate part from the influence of the dominant
part is a necessary condition for reproduction. In experiment
pieces are physically isolated from the body of the animal by section,
and in the lower simpler forms reproduction follows such isolation,
and the piece becomes a new whole, or at least undergoes changes in
that direction.

There are certain features of the simpler reproductive processes
in nature which suggest that in these cases, as in the experimental
reproduction of artificially isolated pieces, an isolation from the
influence of the dominant part is the essential condition for repro-
duction. In many forms, both plants and animals, growth beyond
a certain length or size, which is dependent upon rate of metabolism,
degree of differentiation, etc., results in the transformation of that
portion of the individual most distant from the dominant part into
a new individual. Thecase of Tubularia mentioned above (Fig. 94,
p. 220) is a good illustration, and in many plants similar vegetative
reproductions occur. It is impossible to doubt that in such cases
growth to a certain size brings the region in question into a condi-
tion where it is able to behave as if it were physically isolated,
like a piece cut from the body.

It is also a fact, however, that reproduction may occur in conse-
quence of the weakening or removal of the dominant part and with-
out any preceding increase in size of the individual. Such cases
are very common among the plants, where the removal or inhibition
of metabolism of the growing tip of the main axis or stem is fol-
lowed by development of a new axis from a lateral branch or bud.
Very commonly also the removal of all growing tips is followed by
the development of ‘‘adventitious”’ growing tips, which often arise
from differentiated cells by a process of dedifferentiation and growth.
Among the lower animals similar cases occur. Increase in size is
not then a necessary condition for reproduction. Decrease in rate
of metabolism or inhibition of metabolism in the dominant region
may bring about reproduction as readily as growth.

230 SENESCENCE AND REJUVENESCENCE

The analysis of the simple forms of agamic reproduction in
connection with the experimental reproductions in artificially iso-
lated pieces leaves no room for doubt that the formation of a new
individual from a part of a pre-existing individual results from the
removal of an inhibiting factor rather than from a positive stimu-
lation. According to the conception of the individual developed
above, a more or less complete physiological isolation of the region
or part concerned is a necessary condition for reproduction, or,
more specifically, this part must in some way escape from the con-
trol of the dominant region before it can lose its characteristics as
a part and so serve as the basis for a new individuation.”

In the simpler organisms, where isolated parts are capable of
reconstitution into new individuals, the effect of physiological
isolation of a part is essentially the same as that of physical isola-
tion by section, except that physiological isolation is a less violent
and injurious procedure. The isolated part undergoes dediffer-
entiation to a greater or less extent and begins a new development,
an agamic reproduction occurs. But in the higher forms, where
isolated parts are incapable of reconstitution, physiological isolation
may lead to death of the part isolated, or if nutrition is available
the part may continue to exist in its original form or to grow
and differentiate along the lines previously determined by its rela-
tions with other parts.

It is evident that the final size of the individual is determined by
the limit of dominance only in the lower, simpler organisms. It
was pointed out above that in the higher animals other factors—
such as the rapid differentiation and loss of capacity for growth and
division of cells and perhaps the increasing disproportion between
surface and volume—limit the individual to a size far below that
which the limit of dominance alone would determine. If, for ex-
ample, the size of man and mammals were limited only by the limit
of effective transmission of nerve impulses in fully developed nerve
fibers, they would certainly be very much larger than they are.
In early embryonic stages, however, the limit of dominance is

1 For experimental data see Child, ’07a, ’07b, ’10, ’11¢, and for a general considera-
tion of physiological isolation of parts, the ways in which it is brought about, and
its significance, see Child, ’11@.

INDIVIDUATION AND REPRODUCTION 231

undoubtedly a factor in determining the limits of the individual in
at least some mammals, for Patterson (’13) has shown that the
four embryos of the nine-banded armadillo are the result of agamic
reproduction, of a process of budding of the primarily single embryo,
and suggests that duplicate twins and double monsters may arise
in the same manner.

There can be no doubt that during the course of individual
development a greater or less degree of extension of dominance
occurs as the paths of transmission develop. In the early embry-
onic stages the influence of the dominant region extends only a
short distance, but, particularly in organisms where a nervous
system develops, transmission of impulses to greater distances
becomes possible as development proceeds. Consequently the
size of the individual may increase during development, in many
cases very greatly, without physiological isolation of any part and
so without agamic reproduction.

If the control of the dominant over the subordinate parts in the
individual is accomplished by means of transmitted impulses or
changes which show a decrement with transmission and a limit of
effectiveness, then physiological isolation of a part may be brought
about in four different ways (Child, ’r1a). First, physiological
isolation may result from increase in size to or beyond the limit of
dominance. Many of the phenomena of budding, fission, etc.,
which occur in consequence of growth, both in plants and in animals,
are examples.

Secondly, physiological isolation may result from a decrease
in the limit of dominance, which in turn is the consequence of a
decrease in rate of metabolism in the dominant part. It is a well-
known fact that many plants give rise to buds or other reproductive
bodies under conditions unfavorable to metabolic activity, and
while this form of reproduction has often been regarded teleo-
logically as in some sense an attempt of the plant to save its own
life, it is undoubtedly to be interpreted as the result of a decrease
in the limit of dominance. The formation of new buds in plants
in consequence of the removal or inhibition of metabolism of the
dominant region, the vegetative tip, are likewise reproductive
processes which belong to this category. In the lower animals also

232 SENESCENCE AND REJUVENESCENCE

many cases are known where conditions which decrease metabolism
bring about budding or fission. A comparison of these two methods
of physiological isolation makes it evident that the same result,
viz., the physiological isolation of parts and their development into
new individuals, may be attained by subjecting the organism to
conditions which act in very different ways, producing in the one
case an increase in rate of metabolism, growth, and increase in size,
in the other a decrease in rate of metabolism (Child, ’10). It is pos-
sible that both of these factors are concerned in many cases of bud-
ding and fission, that is, if an organism has attained a size at which
some part is approaching physiological isolation, a slight physiologi-
cal depression may bring about a sufficient isolation to initiate
dedifferentiation and reproduction.

Thirdly, physiological isolation of a part may conceivably result
from a decrease in the conductivity of the path over which the
correlative factors from the dominant region are transmitted.
In many organisms the conductivity of the paths apparently
increases as the morphological differentiation of conducting struc-
tures proceeds during development, so that in spite of a decrease in
rate of general metabolism the general physiological limits of the indi-
vidual are extended and physiological isolation of parts is delayed
or prevented. In many of the flowering plants, for example, new
growing tips arise and pass through the early stages of their devel-
opment at very short distances from each other and from the axial
growing tip (Fig. ror), but in later stages, when the conducting
structures are fully developed, the dominance of the growing tip
extends over a much greater distance. In the flatworms likewise
the length which the individual attains before formation of a new
zooid at the posterior end increases up to a certain point with
advancing development (Child, ’11c), while any considerable
changes in conductivity in the opposite direction may bring about
reproduction in many cases.

And, finally, it is possible that physiological isolation of a part
may result from the direct action of external factors upon it,
increasing its rate of metabolism, or otherwise altering it, so that it
is less receptive, or no longer subordinate to the correlative factors,
and so becomes independent in spite of them. In various plants

INDIVIDUATION AND REPRODUCTION 233

the development of buds can be induced, in spite of the presence and
activity of the chief growing tip, by subjecting the part concerned
to external conditions especially favorable for growth and develop-
ment. To what extent this process of physiological isolation occurs
in nature is as yet a question, though it probably occurs very fre-
quently.

Many cases of agamic reproduction have not as yet been ana-
lyzed from this point of view, but it appears probable that all are the
result of either physiological
or physical isolation. In
some cases, where the degree
of individuation is slight,
physical isolation is probably
the primary factor, that is,
some internal or external con-
dition operates to isolate a
part physically from other
parts and reproduction re-
sults. This may occur in va-
rious cases of spore formation
among the lower plants,
although even here it is prob-
able that physical isolation is
possible only because the
parts are normally but

slightly subordinated to a
dominant region. Fic. 1o1.—Longitudinal section of the
We <ss eonelide. then apical region of a seed plant: a, growing tip;

y aes _? 6, developing leaves; c, axillary buds. From
that the first step in agamic Strasburger, etc., ’03.

reproduction is the isolation

of a part from the correlative conditions in the individual which
determine its existence and persistence as a part. In at least
many cases this isolation is primarily physiological, rather than
physical. In consequence of this isolation the part undergoes
more or less dedifferentiation, a new individuation arises in it
in various ways, some of which have been analyzed in certain
cases (Child, ’14b, ’14¢), but which cannot be discussed here.

234 SENESCENCE AND REJUVENESCENCE

Such reproduction is possible only where the isolated part is capable
of reacting to the isolation by dedifferentiation and reconstitution.
According to this conception, agamic reproduction in organisms
results in one way or another from the physiological or physical iso-
lation of a subordinate part from the influence of the dominant part.
At first glance gametic or sexual reproduction appears to be a totally
different kind of reproduction, but, except for the occurrence of
fertilization, it is in reality very similar to the agamic process.
Before taking up the problem of sexual reproduction, however, it is
necessary to consider the relation between individuation, agamic
reproduction, and the age cycle.

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BRESSLAU, E.
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CuItp, C. M.

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CHAPTER X
THE AGE CYCLE IN PLANTS AND THE LOWER ANIMALS

Any consideration of the age cycle and particularly of rejuve-
nescence in plants would be incomplete without reference to a
remarkable book, Considerations on the Phenomenon of Rejuvenescence
in Nature, by the German botanist Alexander Braun, published in
1851. The book is remarkable, not only as a consideration of re-
juvenescence, but as one of the pre-Darwinian statements of a
theory of evolution. This work became known to me only after
I had attained definite conclusions on the basis of experiment, and
it has been a matter of very great interest to discover to how great
an extent Braun had anticipated in his views the results of experi-
ment. He regards reproduction in the broadest sense and pri-
marily cell reproduction as the basis of rejuvenescence, describes
and discusses dedifferentiation, and recognizes clearly the important
fact that the vegetative life of plants is in most cases a series of
reproductions. In fact, the conclusions reached in the present
chapter are in many respects essentially those of Braun, but modi-
fied and brought into relation with modern physiological conceptions
and with my own experimental results on the lower animals.

INDIVIDUATION AND AGAMIC REPRODUCTION IN THE
LIFE CYCLE OF PLANTS

According to the conception of individuation discussed in the
preceding chapter, every growing tip, together with the region
which it dominates, is in greater or less degree a plant individual.
All except the simplest plants therefore are in reality, as botanists
have repeatedly pointed out, asexual colonies consisting of a larger
or smaller number of individuals which are not completely isolated
from each other. In animal colonies such individuals are commonly
known as zooids, and for convenience the individuals in a plant
colony may be termed phytoids. In most plants there is evidently
also some degree of individuation of the colony as a whole, for new

t Betrachtungen tiber die Erscheinung der Verjiingung in der Natur.
237

238 SENESCENCE AND REJUVENESCENCE

buds arise in a definite sequence and space relation to each other,
and numerous experiments have demonstrated that the growing tip
of the main axis which is often itself a complex of young buds
dominates to a greater or less extent the whole stem. In the root
system somewhat similar relations exist between the growing region
of the main axis and the lateral branches. In such plants also
the relation between the spatial boundaries of the individual and
the development of conducting paths is clearly apparent. Various
facts indicate that in vascular plants transmission of stimuli takes
place more rapidly and to greater distances along the vascular
bundles than through other tissues (see Fitting, 07), and some
botanists have regarded the sieve vessels as the chief conducting
elements. In the apical growing region of the main axis, where the
tissues are embryonic and vascular bundles have not yet developed,
new buds, i.e., new phytoids, often arise at very short distances from
each other in spite of the high rate of metabolism in this region, while
farther down the stem, where the vascular bundles have differen-
tiated, the dominance of a growing tip may extend over much greater
distances and the dominance of the whole growing region at the
apical end of the main axis may extend over the whole length of
the stem.

The prothallia of the liverworts and ferns apparently are single
plant individuals, at least during their earlier stages, and some
throughout life, with a dominant growing region possessing the
highest rate of metabolism and a metabolic gradient along the
axis. But even these prothallia in many cases show agamic
reproduction after a certain stage is reached or under certain
conditions.

Many botanists regard the formation of new growing tips in the
vegetative life of the plant merely as growth, and reserve the
term ‘‘reproduction”’ for the specialized forms of reproduction,
such as the formation of spores, gemmae, and other reproductive
bodies, including the gametes. Actually, however, each new
growing tip represents a new individuation with the potentialities.
of a whole plant and fails to produce a whole plant only because
it is organically connected with other parts. Properly speaking,
then, the formation of new growing tips or buds is a reproductive.

AGE CYCLE IN PLANTS AND LOWER ANIMALS 239

process as truly as any other more specialized kinds of reproduction.
For convenience it may be distinguished from these as vegetative
reproduction.

Agamic reproduction is, then, a characteristic feature of the
vegetative life of plants. The degree of individuation is so low that
growth leads very readily to physiological isolation of parts and
new individuation, and, without doubt, also, conditions which
decrease the metabolic activity of the dominant region accomplish
the same result. Most of what is commonly called growth in plants
involves the formation of new phytoids. The new buds of each
season or active period in perennial plants are new individuals.

THE VEGETATIVE LIFE OF PLANTS IN RELATION TO SENESCENCE

It is important at the outset to distinguish clearly between the
occurrence of senescence in the plant as a whole and its occurrence
in single phytoids or parts. The vegetative propagation of plants
from cuttings, which in the case of some species—such, for example,
as the banana—has continued for hundreds of years, and the
capacity of the lower plants for indefinite vegetative growth under
proper nutritive conditions demonstrate clearly enough that the
life of the plant or some part of it may continue indefinitely without
any indication of aging. On the other hand, in many plants the
length of life under natural conditions is more or less definitely
limited, though the life period may range from a few hours to
centuries in different forms. In the higher plants, particularly
in the woody forms, certain of the cells cease sooner or later to
divide, undergo specialization, show all signs of aging, and sooner
or later die, while others apparently remain young indefinitely.
Must we then conclude that some plants and not others undergo
senescence? In all except the earlier stages of the life cycle the
old differentiated or dead cells usually constitute by far the larger
proportion of the plant mass, the young cells in which growth and
division occur being often but a minute fraction of the whole. Are
we then to conclude that some plants and not others, and some parts
of a plant and not others, undergo senescence and die of old age?

As regards metabolic condition, it is well known that plants
and plant organs in general show a higher rate of oxidation in

240 SENESCENCE AND REJUVENESCENCE

earlier stages of development, when they are physiologically
young, than in later stages. Under given external conditions
the rate of oxidation in buds, for example, is higher than in
fully developed stems and leaves, and in germinating seeds it is
higher than in later stages of development. Evidently in plants,
as in animals, a decrease in rate of oxidation, a real metabolic
senescence, occurs and is accompanied by a decreasing rate of
growth and by progressive differentiation to a greater or less ex-
tent... The case of the flower, which shows a very high rate of
respiration is considered in chap. xiv.

The metabolic changes of age proceed much more rapidly in
some parts of the plant than in others. The leaf and the stem
undergo differentiation and grow old, at least in large part, while
the growing tip and other meristematic tissues seem to remain
young indefinitely or to undergo senescence relatively slowly.

There can be no doubt that the behavior of the plant and its
parts in relation to senescence depends upon the relation between
individuation and reproduction. In general, the higher the degree
of individuation, or of physiological integration, the more definite
and continuous the process of senescence, because reproduction
is less frequent. In Part II it was shown for various animal species
that the reconstitution of a new individual from a part of a pre-
existing individual is associated with some degree of rejuvenescence.
Tn the case of the plant similar changes undoubtedly occur when the
part concerned in the reconstitution is a differentiated part, as it
often is, but the cells chiefly concerned in reproduction in the higher
plants are commonly regarded as undifferentiated or embryonic,
i.e., as physiologically young. In general the degree of rejuvenes-
cence associated with the reconstitution of a part into a new whole
depends upon the degree of individuation. In certain of the algae
and fungi the degree of individuation is so slight it is difficult to
determine whether the plant is anything more than a cell or an
aggregate of cells. In such plants as these the formation of a new
individual from any part of the old doubtless involves little
change beyond nuclear or cell division, and therefore but little

™For references to literature concerning respiration in plants see Pfeffer, ’97,
Pp. 523-31; Nicolas, 09. See also Nicolas, ’10.

AGE CYCLE IN PLANTS AND LOWER ANIMALS 241

dedifferentiation and rejuvenescence occur. In such cases, however,
the slight degree of individuation determines that reproduction shall
be almost continuous during vegetative existence; consequently
there is but little possibility of differentiation and senescence.
Under such conditions the plant as a whole may remain physiologi-
cally young for an indefinite period, simply because new individ-
uations from parts of pre-existing individuals occur very frequently.
Even in those algae and fungi which consist of a single multinucleate
cell, the localization and development of a new branch unquestion-
ably brings about some degree of reconstitutional change, for it
involves a local increase in the rate of growth. It is the continued
reorganization which keeps such plants from growing old under
such conditions.

In some of these lower plants certain parts, usually those which
bear the spores, become more highly individuated than the rest of
the plant and consequently undergo a greater degree of differen-
tiation and usually undergo a more or less continuous senescence
and die of old age, while the less highly individuated and so less
differentiated portions may continue to live and remain young
indefinitely. Many of the fungi, and particularly the mushrooms
and related forms, are cases in point. The mushroom itself is the
more highly individuated spore-bearing portion of a plant whose
vegetative form consists of thread-like branching hyphae, which
are merely strings of like cells attached end to end. The mush-
room passes through a definite course of development and differ-
entiation, attains maturity, ceases to grow, and finally dies,
but the vegetative hyphae may continue to grow indefinitely
without any perceptible progressive morphological or physiological
change.

The course of plant evolution from the lower to the higher forms
is characterized by an increasing differentiation in the vegetative
plant body and a more and more definite limitation of vegetative
reproduction, at least under the usual conditions, to certain parts
or tissues of the plant which remain undifferentiated and physio-
logically young for a long time or indefinitely, while the other parts
undergo differentiation, senescence, and, it may be, death. In
the mosses and ferns the regions which retain their youth and

242 SENESCENCE AND REJUVENESCENCE

embryonic character are more or less definitely localized as vege-
tative tips and certain other regions, but in these forms vegetative
reproduction often occurs from other more highly differentiated
parts of the plant as well as from these regions. In the seed plants,
however, these embryonic or meristematic tissues, as they are
called, are still more definitely localized, and in the highest forms
other regions of the plant body usually take but little part in
vegetative reproduction, at least as long as the meristematic
tissues are present and active.

The continued existence of this embryonic tissue in plants at
the same time that differentiation and senescence are occurring in
other parts raises at once the question why different parts of the
plant behave differently in these respects. While it is impossible
to give a complete answer to this question, certain facts indicate
very clearly the direction in which an answer is to be sought.

In the first place, cell division in the plant occurs chiefly in the
embryonic cells and the earlier generations of their descendants.
The susceptibility experiments on the infusoria recorded in Part II
(pp. 141-42) indicate that in those forms cell division is accompa-
nied by some degree of rejuvenescence and in all cases cell division
is a reproductive process, and as such involves more or less rejuve-
nescence. Cells which divide rapidly do not undergo any great
degree of differentiation, and cells which resume division after
udergoing differentiation first undergo a greater or less degree of
dedifferentiation. In short, continued nuclear and cell division
is undoubtedly an important factor in maintaining cells in the
embryonic condition and continued metabolism in the presence of
nutrition and without cell division is a factor in senescence. But
cell division alone is by no means always adequate to maintain cells
in the embryonic condition. In embryonic development many
cells apparently grow old in spite of division, and sooner or later
division becomes impossible or possible only under altered condi-
tions.

If frequent cell division is a factor in maintaining certain plant
tissues in the embryonic condition, we must inquire why cell
division is more frequent in certain regions than in others. This
question we are unable to answer at present, since our knowledge

AGE CYCLE IN PLANTS AND LOWER ANIMALS 243

of the conditions determining cell division and of the conditions
in different parts of the plant is very incomplete. As regards the
plant, we can only say that in certain regions progressive and
regressive changes balance each other more or less completely,
and consequently these regions remain undifferentiated and young
or undergo differentiation and senescence very slowly, while in
other regions progressive changes are more nearly or quite con-
tinuous. The fact that differentiated cells may become embryonic
or embryonic cells may differentiate when physiological conditions
change, shows that these differences in behavior depend, not upon
a fundamental difference in constitution of the cells, but upon the
conditions to which they are subjected in the regions of the plant.
The solution of the problem undoubtedly lies in the physiological
make-up of the plant individual as a whole and the character of
its metabolism.

But even in the so-called embryonic tissue of the higher plants
the cells are not absolutely alike. Some degree of individuation
exists, for the activities of this tissue are orderly, and a relation
of dominance and subordination exists in it. Many facts indicate
the existence of an axial gradient in rate of metabolism, the region
of the vegetative tip possessing the highest rate and dominating
other parts. Since this is the case, the formation of new vegetative
tips, i.e., of buds—a characteristic feature of the vegetative life
of most of the higher plants—must involve a change of some degree
and kind in the embryonic tissue. This change is probably pri-
marily an increase in rate of metabolism in the part concerned, but
such an increase in rate is essentially a rejuvenescence in some
degree. The changes involved in these vegetative reproductions
are undoubtedly slight in many cases, but nevertheless they
constitute a factor in the maintenance of the embryonic condition.
Each new bud formed from a part of a pre-existing plant individual
involves to some extent a reconstitutional process, even though it
may be merely an increase in rate and the establishment of a new
axial gradient. Vegetative reproduction is then another factor
concerned in retarding the progressive course of senescence and
differentiation in the plant tissues chiefly concerned. Observation
confirms this conclusion, for we find that the plants or the phytoids.

244 SENESCENCE AND REJUVENESCENCE

of a plant which show a low degree of individuation, and conse-
quently frequent vegetative reproduction, are capable of continu-
ing their vegetative activity for a long time or even indefinitely,
without indications of senescence of the meristematic tissues, while
the length of life is usually more or less definitely limited in plants
or phytoids with infrequent or no vegetative reproduction. In
various plants with subterranean stems, such as the flags and
rushes, for example, the stem shows repeated vegetative reproduc-
tion, giving rise to the aerial shoots, and its length of life is appar-
ently unlimited. The aerial shoots, however, show a much higher
degree of individuation with little or no vegetative reproduction,
and their length of life is short.

In spite of the occurrence of nuclear and cell division and
vegetative reproduction, however, the vegetative tips and other
meristematic tissues of many plants show indications of progres-
sive changes. The shoots produced from later buds may differ
in character from those of earlier origin, the later leaves often differ
in form and structure from the earlier and the rate of growth may
decrease until growth finally ceases (Diels, ’06; H. M. Benedict,
*z2,’15). The relations between vegetative growth and reproduction |
and the formation of tubers, bulbs, bulbilli, and other individuals or
parts which contain nutritive reserves also indicate the occurrence
of progressive changes, of a real life history, although Viéchting
(87, ’oo) and others have shown that the formation of reserve-
bearing structures, like other features of the life history, can be
controlled experimentally by retarding or accelerating the pro-
gressive development of the plant with the aid of external con-
ditions. There is much evidence in favor of the view that the
change from vegetative reproduction to flowering is connected with
advancing senescence and specialization of the meristematic tissues
of the plant (see chap. xiv).

The conclusion to which the various lines of evidence point is
that senescence is a characteristic feature of the vegetative life of
plants, but that it is not an uninterrupted, continuous process.
The low degree of individuation in plants determines a high fre-
quency of agamic reproduction, which brings about a greater or less
degree of rejuvenescence and so balances more or less completely

AGE CYCLE IN PLANTS AND LOWER ANIMALS 245

the progressive changes. Undoubtedly also the character of
metabolism determines a more rapid senescence with less
capacity for regression in some plants than in others, and the
work of Klebs and many other investigators on the effect of
nutritive and other external conditions indicates that these
also influence the rate of senescence and the character of
differentiation.

The process of differentiation of the plant cell is apparently not
fundamentally different from that of the animal cell. It consists
in the development of relatively stable structural features, the depo-
sition of relatively inactive substances in the cytoplasm or on its
surface, in many cases substances, such as starch, which may serve
as nutrition under other conditions. The accumulation of fluid in
vacuoles is also a very characteristic feature of differentiation in
plant cells. In general here, as in animals, the process of differen-
tiation involves a decrease in the proportion of the chemically
active “‘undifferentiated”’ protoplasm.

THE OCCURRENCE OF DEDIFFERENTIATION AND REJUVENESCENCE
IN PLANT CELLS

It was pointed out above that the formation of a new vegeta-
tive tip by the embryonic tissue of the plant must involve a new
individuation and some slight degree of physiological rejuvenes-
cence. But the occurrence of dedifferentiation, even among the
higher plants, is not limited to such changes as this. Cells which
have clearly lost their embryonic character and have undergone
more or less morphological as well as physiological change have
been repeatedly observed to undergo dedifferentiation and become
embryonic, both in appearance and in behavior. Experiment has
demonstrated again and again that among the lower plants every
cell, or almost every cell, of the plant body may be capable of giving
rise to a new individual with all the capacities of the individual
which develops from the egg. Among the liverworts and in many
of the ferns the cells of the prothallium very generally retain the
capacity to give rise to new individuals, either when physically
isolated by section, or when physiologically isolated by growth of
the prothallium, removal of the growing tip, or other conditions,

246 SENESCENCE AND REJUVENESCENCE

and this change in behavior in all cases undoubtedly involves a
greater or less degree of rejuvenescence.

Even in the seed plants new growing tips which are capable of
developing into new, complete plants and producing sex cells often
arise from cells which have undergone visible differentiation. In
Begonia, for example, the formation of so-called adventitious buds
from epithelial cells of the leaf has been observed, and in many
other plants new individuals develop from cells which are far from
being embryonic. The cells concerned in such cases lose their
differentiated character and return to the embryonic condition,
resume growth and division, and enter upon a new developmental
cycle. The formation of meristematic, or embryonic, tissue from
the parenchyma of the leaf petiole and from other differentiated
tissues has also often been noted. The transformation of inflores-
cence into vegetative shoots has been experimentally induced by
Klebs and others in various ‘plants, and its occurrence in nature
has been repeatedly observed. One case described by Winkler
(’o2) in a species of Chrysanthemum deserves brief mention. In the
disk flowers the style formed the stem and the stigma gave rise
to two leaves like normal upper leaves of the species. The
embryo sac developed and the pollen was capable of germination,
but the embryo died at an early stage. The corolla became green,
the vascular system increased and branched, and stomata appeared.
In this case the flower evidently underwent a partial transformation
into a vegetative structure, and this change must have involved
some considerable degree of dedifferentiation and rejuvenescence.

In fact, the occurrence of dedifferentiation among plants has
been demonstrated beyond question.’ Certainly in the plant, as
in the animal, senescence is associated with specialization and
differentiation of cells, and it is just as certain that dedifferentiation
is accompanied by rejuvenescence. Moreover, the increased activ-
ity in growth and division of the cells concerned, as well as their

1The following references will serve as an introduction to the extensive bibli-
ography of the subject: Brefeld, ’76, ’77; Burns and Heddon, ’06; von Faber, ’o8;
Goebel, ’08, pp. 141-65; Heim, ’96; Hildebrand, ’10; Jost, ’08, Vorlesung 26; Klebs,
’03, 06a, ’06b; Kéhler, ’07; Kreh, ’09; Magnus, ’06; Miehe, ’05; Noll, ’o3; Regel,

"76; Riehm, ’o05; Schostakewitsch, ’94; Tobler, ’o2, ’o04; Véchting, ’85; Winkler,
’02, 07.

AGE CYCLE IN PLANTS AND LOWER ANIMALS 247

ability to go through a new course of development and differentia-
tion, indicates very clearly that they have become physiologically
younger, and, though I know of no observations bearing directly
upon this point, no one can doubt that when a differentiated cell
dedifferentiates into a growing tip an increase in rate of respiration
and other metabolic processes occurs.

THE RELATION OF THE DIFFERENT FORMS OF AGAMIC REPRODUCTION
IN PLANTS TO THE AGE CYCLE

Most plants exhibit more than one form of agamic reproduction,
and in some species, e.g., certain mosses, several different forms
occur. But two forms of agamic reproduction are particularly
characteristic of nearly all plant species, one the vegetative form
of reproduction, often called vegetative growth, in which new vege-
tative individuals essentially similar to the old arise by the forma-
tion of buds, branches, etc.; the other the process of spore formation,
which usually occurs only in certain regions of the plant body and
after a period of vegetative growth. In some cases, as in the rusts,
four or five different kinds of spores are produced by a single species.
The spore is in general a cell which becomes isolated from the
plant body and sooner or later gives rise to a new individual. In
some cases this isolation is physiological, in others it is physical.
In the algae and fungi, which must be considered before turning to
the higher plants, the spores usually develop into individuals like
those from which they arose, and the spore may be either a resting
or a motile stage between two vegetative generations. Spore for-
mation in these plants is essentially a process of complete or partial
disintegration of existing individuals into cells, rather than the
addition of new individuals as the result of growth, as in vegetative
reproduction under the usual conditions. In the alga Ulothrix, for
example, any cell of the filamentous, unbranched plant body may
break up into zodspores (Figs. 102, 103); in the branching form
Vaucheria the terminal region of the branch separates as a multi-
nucleate zodspore (Fig. 104). Among the brown algae the spores
arise by separation into single small cells of the contents of special
organs, the sporangia (Fig. 105). In the fungus Saprolegnia (Fig.
106) the sporangium is the terminal region of the vegetative body,

248 SENESCENCE AND REJUVENESCENCE

while in Mucor (Fig. 107, A-C) the sporangium arises at the end of
a specialized stalk, the sporophore, which grows out of the nutri-
tive substratum into the air, and in Penicillium still another type of
sporophore appears (Fig. 108). In other forms still other methods
of spore formation occur with various degrees of specialization in
the spore-forming organs, but everywhere the process consists in a

3X)
KD

Fics. 102-105.—Formation of spores in various algae: Figs. 102, 103, Ulothrix;
Fig. 104, a stage in the development of the zodspore in Vaucheria; Fig. 105, a filament
of Ectocarpus bearing a sporangium and at the left a more highly magnified zodspore.
From Coulter, etc., ’10.

disintegration of the plant body or some part of it into independent
cells.

According to the conception of individuation presented in the
preceding chapter, return to the condition of the free-living, inde-
pendent cell must mean a decrease in the physiological coherence of
the plant individual, and it might be expected to result from con-
ditions which decrease the metabolism of the plant and so allow it,
or a part of it, to separate into its constituent units, the cell indi-

AGE CYCLE IN PLANTS AND LOWER ANIMALS 249

viduals. Various investigators, prominent among whom is Klebs,*
have investigated and analyzed the external conditions which
determine spore formation in the algae and fungi, and the results of
their work agree well with this idea.

Fics. 106-108.—Formation of spores in lower fungi: Fig. 106, a terminal cell of
Saprolegnia producing zoéspores; Fig. 107, A—C, three stages in the development of
the sporangium in Mucor; Fig. 108, branches of the sporophore of Penicillium, pro-
ducing series of conidia. From Coulter, etc., ’ro.

While these forms in nature usually go through a more or less
definite life history in which vegetative growth or growth with
reproduction of new vegetative phytoids occurs for a time, and is
followed by the formation of spores and in many cases still later

t See Klebs, ’93, ’96a, ’96b, ’98, ’99, ’004, ’oob, ’03, 04.

U7

250 SENESCENCE AND REJUVENESCENCE

by the formation of gametes, experiment has demonstrated that this
life history is by no means fixed in its course. In the fungus
Saprolegnia mixta, for example, which occurs on the bodies of dead
insects in water, Klebs (’o3, p. 41) has found that uninterrupted
vegetative growth may occur for an indefinite period in all good
nutritive solutions, provided they are kept fresh and do not under-
goalteration. On the other hand, a rapid and complete transforma-
tion of the vegetative form, the mycelium, into sporangia occurs
when a well-nourished mycelium is transferred from the nutritive
solution to pure water. Growth and vegetative reproduction,
together with continuous spore formation, occur in cultures nour-
ished on agar-albumin in flowing water. When mycelium grown
on gelatin-meat extract is transferred to water and allowed to
continue its growth on dead insects, growth and vegetative repro-
duction are followed, first, by formation of spores, and later by
gamete formation. In water containing fibrin or syntonin growth
and vegetative reproduction, formation of spores and of gametes
occur together on different parts of the plant. In a weak solution
of haemoglobin, growth and vegetative reproduction are followed by
formation of gametes and later by formation of spores.

Another example is the alga Vaucheria repens. According to
Klebs (’04, p. 497), the following conditions induce zodspore forma-
tion: decrease of the salt-content of the medium to a point near
the minimum by transference from more to less concentrated solu-
tions, or to water; increase of moisture by transference from air to
water; decrease of the oxygen content of the medium by trans-
ference from flowing to standing water; decrease of light intensity,
even to darkness; lowering of temperature to near the minimum;
increase of the salt-content to near the maximum.

Klebs believes that external conditions produce their effects on
organisms by acting upon a complex of internal conditions, and
he attempts to interpret his experimental results on this basis,
pointing out that many of the conditions which induce spore forma-
tion decrease or inhibit growth, i.e., vegetative reproduction. In
this way, as he believes, a higher concentration of organic substance
is attained in the plant, and this favors spore formation and a still
higher concentration, gametic reproduction. Apparently, for Klebs,

AGE CYCLE IN PLANTS AND LOWER ANIMALS 251

there is no question either of individuation or of possible age changes
involved, the reproductive changes being due primarily to the
action of the external conditions.

As a matter of fact, however, these data when considered in
their proper relations to individuation and the age cycle are readily
interpreted and are directly in line with what we know of other
forms. Spore formation is, at least in most cases, a more specialized
reproductive process than vegetative reproduction, and therefore
might be expected to occur in later stages of development than the
latter. Moreover, since spore formation usually consists in the dis-
integration into single, independent cells of a parent body or part
already formed rather than in the growth of a new individual or
part, we should expect it to occur when the rate of metabolism in
the plant is low as compared with the rate in vegetative growth and
reproduction. Such a low rate of metabolism may result, either
from aging of the individual or part, or from the action of external
conditions. If the conclusions reached from the study of the lower
animals are applicable to the algae and fungi, and the facts seem
to indicate that they are, the plant under certain conditions may
remain indefinitely in the vegetative condition, because the differ-
entiation and senescence in each individual is balanced by the
rejuvenescence occurring in each vegetative reproduction. Under
other conditions senescence may overbalance rejuvenescence, and
the plant individuals undergo progressive development and senes-
cence, their rate of metabolism undoubtedly decreases, and sooner
or later the disintegration of the plant or parts of it into spores
occurs. The results of Klebs’s experiments indicate that this con-
dition may be induced in the plant either by lowering the rate of
metabolism directly by low temperature, lack of oxygen, lack of
nutritive salts, etc., or by loading the cells with organic material.
While it is impossible from the data at hand to furnish a complete
demonstration, it appears highly probable that the effect of the
various conditions used by Klebs in his experiments in inducing
spore formation is either to bring about a natural senescence in the
plant by the accumulation of inactive substances or to decrease its
rate of metabolism so that a physiological condition like that
attained in natural senescence is brought about. In short, by

252 SENESCENCE AND REJUVENESCENCE

controlling the rate of vegetative reproduction, the rate of metab-
olism, or the accumulation of inactive material, it is possible
to determine whether the plant or the phytoid shall remain indefi-
nitely in the vegetative stage and physiologically young, or whether
it shall attain the physiological condition characteristic of an older
plant and produce spores. There are, however, certain cases which
apparently cannot be accounted for in this way: for example,
Klebs finds that when the alga Oedogonium is cultivated at a low
temperature a rise of a few degrees induces spore formation, but
when cultivated at a higher temperature a rise in temperature has
no such effect. As regards this case, it is probable that the degree
of individuation at the low temperature is so slight that when an
increase in metabolic activity occurs with a rise in temperature the
cells become independent before their activity is subordinated or
controlled by the increased degree of individuation.

To sum up, there is good reason to believe that algae and fungi
may undergo senescence and rejuvenescence like the lower animals,
and that the different forms of reproduction are characteristic of
different stages in the life cycle. But since reproduction and
consequently rejuvenescence are characteristic of younger as well
as older stages, it is possible to control and modify the course of
the life history in a great variety of ways. This possibility of con-
trol does not prove that these plants have no definite life cycle:
it indicates merely that progressive and regressive development
can be determined experimentally in the plant, as in the animal.

As regards the spores themselves, there can be no doubt that
extensive reconstitution and rejuvenescence occur in their forma-
tion. In the case of the motile zodspores characteristic of many
forms (Figs. 104, 105, 106), this is conspicuously the case, for the
zoéspore is a free-living, unicellular organism and bears little resem-
blance to the plant from which it arises. This new individuation
of the zodspore from the physiologically old vegetative stage
involves reconstitutional changes which result in a simpler and
more primitive kind of individual than the vegetative form. This
change must be associated in some way with the change from the
multicellular or multinucleate to the unicellular or uninucleate
condition. In the development of the vegetative form from the

AGE CYCLE IN PLANTS AND LOWER ANIMALS 253

spore, reconstitutional changes are again involved, at least in the
case of zodéspores, which show more or less morphological differen-
tiation, and here again some degree of rejuvenescence must occur.
Bearing all the facts in mind, it is not difficult to understand how
it is that, under proper conditions, spore formation may continue
through an indefinite number of generations without any appre-
ciable progressive senescence of the stock.

In the mosses, ferns, and seed plants where alternation of genera-
tions occurs, the fertilized egg gives rise to the asexual generation
or sporophyte which may show extensive and long-continued
vegetative reproduction, but sooner or later gives rise to spores.
The spore in turn gives rise to the sexual generation or gametophyte,
which also may show vegetative reproduction, but which finally
produces gametes; that is, sexual reproductive cells.

In the mosses and ferns spore formation is very evidently a
process belonging to the later stages of development of the sporo-
phyte and it is, as in the algae and fungi, a process of disintegration
of an individual or part into independent cells. In the fern, for
example, the spores are formed only when the frond has completed
or largely completed its growth. In the seed plants the gameto-
phyte generation is so reduced that spore formation is closely con-
nected with the formation of gametes, and there is much evidence
to be considered in later chapters which indicates that gamete for-
mation belongs to a more advanced stage of the life cycle than the
various agamic processes. In these plants, as in the algae and fungi,
spore formation is, then, in general a process belonging to more
advanced stages than vegetative reproduction.

Among algae and fungi there is apparently complete rejuvenes-
cence between the formation of the spore and the development of a
new plant from it, for it usually gives rise to a new plant like that
from which it arose, while in the plants with alternation of genera-
tions the spore gives rise to an individual of different character
from that which produced it. Evidently it has become different
in its developmental capacity from the egg. The simplest concep-
tion of this change is that the spore is in these forms a specialized
cell which does not entirely lose its specialization in reproduction.
In the seed plants, where the gametophytes do not lead an

254 SENESCENCE AND REJUVENESCENCE

independent vegetative life, but are usually so much reduced that
only a few cell divisions occur between the spore and the formation of
gametes, the specialization of this reproductive process is evident,
but in the mosses where the sporophyte is merely a sporogonium—
a spore case without an independent vegetative life—and the game-
tophyte is the vegetative form, it is not so clear. If, however, we
consider the whole cycle from the fertilized egg of one generation to
that of the next, it is at once evident that in the mosses the process
of spore formation comes relatively early in this cycle, in the ferns
at a more advanced stage, and in the seed plants at a still more
advanced stage. In this connection it is of considerable interest
to note that the amount of agamic reproduction in the gametophyte
varies according to the point in the life cycle at which the gameto-
phyte appears. In the mosses, where the sporophyte shows almost
no vegetative activity before spore formation, the gametophyte,
which is the moss plant, usually shows extensive, often indefinite,
vegetative reproduction, and in many cases various, more or less
specialized, forms of agamic reproduction occur. In the ferns where
the sporophyte—the fern plant—shows extensive vegetative growth
and reproduction there is usually but little and in many cases no
agamic reproduction in the prothallium which represents the
gametophyte. And, finally, in the seed plants, where the whole
vegetative life of the plant occurs in the sporophyte stage, the
gametophyte does not as a rule reproduce gametophytes asexually.
In other words, the earlier in the life cycle the gametophyte appears,
the less its specialization and the more conspicuous its vegetative
activity and reproduction.

All these facts indicate very clearly that a real life cycle with
progressive development and specialization exists in the plants,
but this life cycle is complicated by the occurrence of various forms
of agamic reproduction, and the regressive and reconstitutional
changes involved in the new individuations which occur in these
reproductions may balance the progressive changes and so retard
or prevent indefinitely the progressive advance of the plant in the
life cycle. And since external conditions influence individuation
and agamic reproduction, it is often possible to control experi-
mentally the developmental progress of the plant within very wide

AGE CYCLE IN PLANTS AND LOWER ANIMALS 255

limits. And, finally, there are certainly very clear indications that
a general decrease in rate of metabolism, doubtless interrupted by
greater or less increases in rate accompanying the various reproduc-
tions, occurs from the early vegetative stages to the stage of gamete
formation. There seems, in short, to be adequate ground for the
conclusion that the life cycle of the plant is not fundamentally
different from that of the animal and that senescence does occur
in the plant, not only in certain cells, organs, or tissues and in the
phytoids which make up most plants, but in the plant as a whole.
The slight degree of individuation in plants makes possible frequent
reproduction, so that senescence is not a continuous or nearly con-
tinuous process, as in the higher animals, but may be interrupted
repeatedly, or may even be compensated for an indefinite length
of time by periodic reproduction and rejuvenescence, such as has
been shown in Part II to occur in some of the lower animals.

INDIVIDUATION, AGAMIC REPRODUCTION, AND THE AGE CYCLE IN
THE LOWER ANIMALS

Experimental evidence on the relation between agamic repro-
duction and rejuvenescence in various animals was presented in
chap. vi, and only certain points of more general significance remain
to be considered. The occurrence of agamic reproduction in the
lower animals, as in the plants, is commonly either the result of
growth or decreased dominance, and often the same reproductive
process may be brought about in both ways. The variety of forms
of reproduction is less than in the plant, but in various protozoa
growth and division occur under the usual conditions, while under
others, apparently such as decrease metabolism, the body may
break up into small independent cells, which are usually known as
spores. Such fragmentations of the body may apparently result
either from a physiological senescence or from a decrease in meta-
bolic activity due to external conditions. Fragmentation often
occurs during encystment and is preceded or accompanied by
complete dedifferentiation of the original individual. These cases
in fact constitute some of the strongest evidence for the occurrence
of dedifferentiation in animals. Often, particularly in the sporozoa,
which are parasitic and show a very low degree of individuation,

256 SENESCENCE AND REJUVENESCENCE

fragmentation into spores follows the union of the gametes and
may probably be regarded as corresponding to the period of cleavage
and rejuvenescence in the embryonic development of multicellular
forms.

In many sponges new zooids arise as the result of growth, but
under depressing conditions and probably also in advanced senes-
cence, so far as it occurs, existing individuals may undergo more or
less extensive fragmentation into cell masses known as gemmules
which are capable of producing new sponge bodies. It was pointed
out in chap. vi that the medusa bud of the hydroids apparently
results from a decrease in dominance which is associated with a
decrease in rate of metabolism, while the hydroid bud usually
results from growth beyond the limits of individuation. In certain
of the bryozoa also budding occurs during growth and a partial
fragmentation into reproductive bodies, the statoblasts, under
depressing external conditions and apparently also in advanced
physiological age. On the other hand, in Tubdularia (p. 220), in
Planaria (pp. 122-25), and in various other animals the same form
of reproduction may result either from growth or from decrease
in dominance. The evidence presented in chap. vi justifies the
conclusion that the regressive and reconstitutional changes involved
in all these reproductive processes bring about a greater or less
degree of physiological rejuvenescence.

Reproduction, however, is not the only rejuvenating process in
the lower animals. Many forms undergo encystment or become
quiescent under conditions which do not permit active life and
become active again after a certain length of time, or when external
conditions permit. Usually there is at least some small amount of
metabolic activity during these quiescent periods, and a consider-
able degree of starvation and reduction may occur, as in the case
of Planaria velata (pp. 130-33), before resumption of active life.
The effectiveness of reduction as a rejuvenating factor in pla-
narians has been demonstrated in chap. vii, and it certainly plays
a similar réle in many other forms. Moreover, in some cases the
increase in number of individuals or the decrease in supply of
nutrition with the change of seasons or other environmental changes
determines more or less regularly recurring periods of starvation
during active life, and these also play a part in rejuvenescence.

AGE CYCLE IN PLANTS AND LOWER ANIMALS 257

And, lastly, the replacement of old by young cells in the body of
the animal also delays the senescence of the organism as a whole.
This process occurs more or less widely in all multicellular animals,
and in many of the lower forms it occurs to a very considerable
extent and more or less generally throughout the body. The old
cells or parts die and are either cast off or resorbed and replaced by
younger cells. In such cases senescence and even death are occur-
ring at all times, but the replacement may keep pace with the
aging and death of cells, so that the organism as a whole does not
grow old. Conditions in these forms are somewhat similar to those
in the higher plants discussed in an earlier section of this chapter,
where certain parts of the plant remain embryonic and give rise
more or less continuously or periodically to the various organs
which undergo senescence and death. In all cases of this sort cel-
lular reproduction is of course concerned and is unquestionably the
essential factor in the maintenance of an age equilibrium or retarda-
tion of senescence in the organism as a whole.

The occurrence in animals of morphological rejuvenescence, i.e.,
of dedifferentiation, has often been denied, but such denials are
based primarily rather on theoretical considerations than upon
observation. There can be no doubt that dedifferentiation occurs.
extensively among the lower animals. The dedifferentiation of
protozoan cells has already been mentioned, and concerning those
cases there is no room for doubt that the morphological differ-
entiation disappears and reappears in the same cell. E. Schultz
(’o8) and J. Nusbaum (’12) have brought together many cases of
dedifferentiation from the literature of the subject and have dis-
cussed their significance in a general way. It is impossible here to
do more than refer very briefly to a few of the well-established
instances of dedifferentiation. As regards the sponges, various
authors have described the occurrence of dedifferentiation of at
least some of the cells of the body under different conditions, such
as absence of lime salts, starvation, and dissociation of cells, and
there seems to be no doubt that extensive dedifferentiation may
occur in hydroids also. One of the most interesting cases in the

1 See, for example, on sponges: Bidder, ’95; Maas, ’06,’07,’10; Masterman, ’94;
K. Miller, ’11a, ’11b, ’11c; H. V. Wilson, ’t1a; on hydroids: Berninger, ’10; H. C.
Miller, ’13, 14; H. V. Wilson, ’11).

258 SENESCENCE AND REJUVENESCENCE

latter group is that described by H. C. Miiller, of the dedifferentia-
tion after isolation and mutilation of the parts which bear the
sexual organs—the so-called gonophores—of certain hydroids into
masses of embryonic cells which give rise to stolons and so may pro-
duce new vegetative, asexual colonies. Dedifferentiation occurs
in the reduction by starvation of planarians (E. Schultz, ’04). The
parenchymal cells of Planaria, which play the chief part in the
formation of new tissue in regeneration, are certainly to all appear-
ances differentiated cells and undergo dedifferentiation when they
begin their growth as new tissue. In the tapeworm Moniezia the
sex cells may arise by the dedifferentiation of parenchymal cells
(see pp. 331-32). The return of old, flat ectoderm cells to the
embryonic condition has been observed by Rémer (’o6) in the
regeneration of bryozoa. Krahelska (’13) has described the
dedifferentiation of the albumen gland in certain snails during
oviposition. In the remarkable reduction of the branchial region
in isolated pieces of the ascidian Clavellina, which represents a
return to the condition of a bud in an early stage of development,
extensive dedifferentiation of cells certainly occurs (Driesch, ’o2;
E. Schultz, ’07). Schaxel (’14), however, maintains that in this
case the differentiated cells are lost and the new parts arise from
undifferentiated cells which remain, but his assumption that the
cells which take part in the new development are undifferentiated
is not proved. In the regeneration of the lens of the eye in
amphibia the cells of the iris which give rise to the new lens very
evidently undergo dedifferentiation (G. Wolff, ’95; Fischel, ’oo).

Numerous other cases of more or less complete dedifferentia-
tion have been more or less closely observed and described and
doubtless many others still remain to be described in connection
with agamic reproduction, reconstitution, and even in the normal
life of organisms. The changes in gland cells during their cycle of
activity (pp. 189-91) and various other periodical changes also
belong in this category. But the morphological criterion of reju-
venescence is at best unsatisfactory, for it is merely a rather unre-
liable indicator of the physiological condition of the cells. As is
evident from the experimental study of the developmental stages
of many animals, cells may undergo considerable changes in the

AGE CYCLE IN PLANTS AND LOWER ANIMALS 259

direction of specialization without any characteristic morpho-
logical differentiation, and there is every reason to believe that
changes in the opposite direction, if not very great, do not neces-
sarily involve changes in the visible morphological features of the
cell. Since senescence and rejuvenescence are processes which
concern the dynamic activity of the cell, changes in this activity
must be the chief criterion for the occurrence of age changes,
although morphological changes, when they occur, may be of value
as indications of the changes in activity.

SENESCENCE AS A CONDITION OF REPRODUCTION AND
REJUVENESCENCE

Agamic reproduction of one kind or another unquestionably
occurs in the plants and lower animals in consequence of the decrease
or elimination of dominance, i.e., the physiological disintegration
of the individual may result in the reconstitution of new individuals.
Moreover, decrease or elimination of dominance may result from
decrease in rate of metabolism as well as from growth, and
finally a decrease in rate of metabolism occurs in senescence. It is
possible, therefore, that agamic reproduction with the accompa-
nying rejuvenescence may occur simply as the result of senescence.
The fragmentation of Planaria velata (pp. 130-33) is undoubtedly
a case of this sort, and it is probable that this relation between
senescence and reproduction is very general. In fact, the forma-
tion of spores in plants and in the protozoa, of gemmules in the
sponges and statoblasts in the bryozoa, and various other reproduc-
tive processes, which are not directly connected with growth, are
probably very often simply the result of senescence of the indi-
vidual concerned, although they may of course appear when the
rate of metabolism is lowered by external conditions. The forma-
tion or development of new buds in many perennial plants often
results from decrease in activity of the dominant growing tip, and
this decrease is probably very frequently due to senescence. The
formation of buds or the development of buds already formed on
the leaves of various plants may likewise result from senescence of
the leaf or plant. During the earlier stages of senescence disinte-
gration of the individual may be prevented by the development and

260 SENESCENCE AND REJUVENESCENCE

increasing conductivity of the paths of correlation, even though
increase in size occurs, but in the lower organisms where the degree
of dominance is slight and conduction paths do not attain any high
degree of development, the decrease in rate of metabolism in the
dominant region which occurs with advancing senescence may
sooner or later bring about.the physiological isolation of parts of
the individual, and reproduction and rejuvenescence result. Ex-—
tended experimental and analytic investigation is necessary to
determine how far a natural physiological senescence and how far
incidental or external factors are concerned in particular cases,
but it must be borne in mind that the possibility of inducing and
controlling these reproductions with the aid of external conditions
does not in any way prove that they may not also be induced or
controlled by internal conditions quite independently of the
environment.

Since this relation between senescence and reproduction unques-
tionably exists, it is evident that in the plants and lower animals
senescence must very frequently lead automatically to reproduction
and rejuvenescence in at least some parts of the previously existing
individual. In such cases senescence does not lead to death of the
whole, and often where the individual breaks up into separate cells
or fragments, death does not occur in any part. Instead of leading
inevitably to death, senescence in the lower organisms may itself
be a condition of reproduction and rejuvenescence and so of indefi-
nite continuation of life.

CONCLUSION

In the plants and lower animals the low degree of stability
of the protoplasmic substratum and the consequent low degree of
individuation make possible the frequent occurrence of agamic
reproduction. Since a greater or less degree of rejuvenescence is
associated with such reproduction, the process of individual senes-
cence may be more or less completely compensated in many cases
and the organism may appear not to grow old and may never reach
the death point. Often the decrease in metabolic rate with ad-
vancing senescence is the primary factor in bringing about physio-
logical isolation of parts, reproduction, and rejuvenescence, and in

AGE CYCLE IN PLANTS AND LOWER ANIMALS 261

such cases a certain degree of senescence is followed automatically
by reproduction and rejuvenescence. The agamic reproductions of
advanced age are often more highly specialized in character than
those of earlier periods of the life history.

Senescence may be retarded or compensated in many forms by
conditions which induce frequent agamic reproduction, while under
other conditions senescence may be accelerated and death may
occur. The relation between senescence and rejuvenescence de-
termines whether an organism undergoes progressive senescence
and passes through a definite life history or persists indefinitely in a
certain physiological condition, apparently without a definite life
cycle.

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CHAPTER XI
SENESCENCE IN THE HIGHER ANIMALS AND MAN

The problem of senescence in man and the higher animals has
very naturally claimed the attention of the anatomist, the physiolo-
gist, the investigator along medical lines, and the zodlogist, and for
the layman also it has always possessed a vital interest quite differ-
ent from that which attaches to many scientific problems. Man’s
interest in the problem of his own senescence, old age, and death
undoubtedly dates from the time when he first began to think and
ask himself questions concerning himself. From ancient times to
the present the problem has been discussed again and again, and
from the most various points of view. It has always been an
attractive field for speculation, but a large volume of scientific
data bearing upon one aspect or another of it has accumulated.
A considerable portion of the literature of the subject deals with
the problem from the point of view of the physician and medical
investigator rather than that of the general zodlogist or physiolo-
gist, and of course the data are very largely descriptive and
statistical, rather than experimental and analytic.

It is neither possible nor necessary at this time to attempt any
extended review and critique of the literature. My purpose is
merely to analyze and interpret the more important facts from the
point of view attained through study of the lower animals, and to
show how the age cycle in man and the higher animals, so far as it
differs from that in the lower organisms, is the necessary and inevi-
table result of the course of evolution.

INDIVIDUATION AND REPRODUCTION IN THE HIGHER FORMS IN
RELATION TO THE AGE CYCLE

The increase in the degree of individuation or physiological
integration of the individual, which is a conspicuous feature of
evolution, is evident in the higher animals and man in the increasing
co-ordination and interrelation of parts, both dynamically and
chemically, and in the greater structural and functional specializa-
tion and differentiation. The problem of the nature of this change

266

SENESCENCE IN HIGHER ANIMALS AND MAN 267

and the factors concerned in it is of course the problem of the evo-
lution of the individual, but only certain aspects of this problem
need consideration here.

The evolution of the individual is evidently closely associated
with an increasing functional and structural stability of protoplasm.
In the higher forms a cell or a group of cells, once started along a
certain course of development, reacts less readily than in the lower
organisms to altered conditions by regression and change in the
course of development. In the adult vertebrates the capacity for
regression is in most cases so narrowly limited that the cells of one
tissue are under any known conditions incapable of giving rise to
other tissues. In other words, the ability of the cells, so conspicu-
ous in the lower organisms, to react to altered conditions by a change
in activity which brings about the breakdown and elimination of
previously accumulated structural substance is very slight in the
higher animals. From this point of view evolution appears as a
change from less stable to more stable dynamic equilibrium, in the
course of which the morphogenetic and functional behavior of the
organism has become less directly dependent on external and more
dependent on internal conditions. This increase in structural and
functional stability results in a greater degree of continuity in
progressive development and so in a greater specialization of parts
and a greater differentiation of structural mechanisms with definite
functions, which in turn provide a basis for a more varied and
intimate correlation of parts and so for a wider range and greater
delicacy of functional adjustment.

Among these changes the most important for the integration of
the individual are the functional and structural evolution of the
nervous system. The high metabolic rate in the cells of the cen-
tral nervous system undoubtedly determines that the accumulation
and transformation of substance in the structural substratum
which bring about senescence occur less rapidly here than in other
tissues; because of its high rate of metabolic flow, the nerve cell
deposits structural sediment relatively slowly. This is particularly
true after the stage of specialized functional activity is attained,
for then stimulation through the sense-organs and other parts of
the body plays a very important part in maintaining the nerve

268 SENESCENCE AND REJUVENESCENCE

cell at a very high metabolic level. Consequently the degree of
dominance and of individuation may increase up to a certain point
as development proceeds. Moreover, the increasing differentiation
of the nerve fibers determines a more effective conduction of im-
pulses, and the increasing centralization of the nervous system and
complexity of nervous correlation results in a greatly increased
unity and co-ordination of the parts of the individual. It was
pointed out in chap. ix that the decrement in the conduction of
impulses in the nerves of the higher animals is scarcely appreciable
within the limits of the individual body. This means that in the
adult the limit of dominance, the physiological limit of individ-
uation, is far beyond the actual size attained by the individual.
Growth in these forms is limited by progressive differentiation, con-
sequently the final size of the individual remains far below the limit
of dominance in the differentiated nervous system, and the physio-
logical isolation of parts so frequent among the plants and lower
animals does not occur under ordinary conditions in the higher ani-
mals after the functional capacity of the nervous system has fully
developed.

For the occurrence of agamic reproduction in differentiated
organisms the physiological or physical isolation of a part and
capacity of the part to react to isolation by regression and recon-
stitution are necessary. These conditions are not present in the
later stages of development of the higher animals, but isolation of
parts does occur to a limited extent in early stages of development
before the cells have undergone appreciable differentiation and be-
fore the individual has attained the degree of integration character-
istic of later stages. Consequently agamic reproduction in these
forms is limited to these stages. In a few species polyembryony
occurs as a normal feature of development, the egg undergoing
separation during cleavage or later embryonic stages into two or
more individuals. In certain parasitic insects, for example, indi-
viduation is apparently almost entirely absent during early stages
and, instead of developing in an orderly way as a single embryo,
the eggs as they divide separate repeatedly into cells or cell groups,
each of which finally gives rise to an embryo (P. Marchal, ’o4;
Silvestri, ’06). In these cases a single egg may give rise to a large

SENESCENCE IN HIGHER ANIMALS AND MAN 269

number of individuals. In the nine-banded armadillo the embryo
begins development as a single embryo, but later undergoes recon-
stitution into four embryos by a process of budding (Patterson, ’13).
In other species of armadillo a similar process of embryonic repro-
duction undoubtedly occurs. The cases of duplicate twins and
various forms of double monsters are probably also cases of embry-
onic reproduction from a single egg (Wilder, ’o4), but it is not
certainly known at what stage the reproduction occurs.

In addition to the occasional occurrence of polyembryony the
process known as segmentation occurs as a characteristic feature
of development in all the higher animals, both invertebrates and
vertebrates. Segmentation, however, is rather a repeated indi-
viduation of parts from embryonic tissue than a reproduction from
differentiated cells, and does not therefore involve any considerable
regression and reconstitution. The segment-individuals which arise
in succession as morphogenesis proceeds posteriorly along the axis
(see Figs. 70, 197, 198) never complete development to whole
animals, but remain as segments subordinate to the dominating
head-region. Aside from these cases of polyembryony and repeti-
tive formation of segments, agamic reproduction plays no part in
the normal life history of the higher animals, and it is evident that
these reproductions, since they occur so early in development, can
have but little significance in bringing about rejuvenescence or
retarding the progressive course of senescence.

A most important consequence of the stability of structure and
the absence of agamic reproduction in these animals is the greater
continuity of progressive development and senescence. In the
lower forms progressive development may be interrupted repeat-
edly, or even periodically completely compensated, by agamic
reproduction of one kind or another with its accompanying rejuve-
nescence. Where such reproduction is absent the regressive changes
may occur to some extent in tissue regeneration, in the periodic
elimination of previously accumulated material in gland cells
(see pp. 189-91), or during starvation, and under certain other
conditions which bring about excessive structural breakdown, but
such changes are either narrowly localized and without appre-
ciable effect upon the body as a whole, or they are so slight that it

270 SENESCENCE AND REJUVENESCENCE

is a question whether they can properly be called rejuvenescence,
or else they bring about death before any great degree of rejuvenes-
cence occurs, so that in such animals life after the early embryonic
stages is practically a continuous progression and senescence. Such
a continuous progressive development and senescence without
counterbalancing regression and rejuvenescence must inevitably
and necessarily terminate sooner or later in death in consequence
of decrease in rate of metabolism. From this point of view, then,
the increasing continuity of senescence and the appearance of death
as a natural termination of development in the course of evolution
from the lower to the higher animals are to a large degree the con-
sequence of the increasing fixity or stability of the structural sub-
stratum of the organism which determines on the one hand the
increasing degree of individuation and on the other the limitation
of regression and reproduction.

But in the course of this life history which ends in death, sexual
differentiation appears, and at a certain stage of development the
individuals of each sex or the organs of each sex in a hermaphroditic
individual give rise to the gametes which are highly specialized,
sexually differentiated cells, the egg and the spermatozoon. These
cells are cast off from the body which produced them like other cells
which have completed their developmental history and grown old,
and in most cases they do not react to the isolation by regression,
rejuvenescence, and reconstitution of a new individual, but sooner
or later die, unless union between two gametes of opposite sexes,
that is, fertilization, occurs. This union, when it does occur, initi-
ates in some way the process of regression and rejuvenescence in
the resulting cell, the zygote, and the reconstitution of a new indi-
vidual, or what we call embryonic development, occurs. The
gametes are the only cells in the higher animals which undergo
complete rejuvenescence and so escape death. This conception
of gametic reproduction will be considered more at length in Part IV.

THE PROCESS OF SENESCENCE IN THE HIGHER FORMS

The process of senescence in man and the higher animals is not
widely different in its general features from the age changes which
occur in the lower forms when agamic reproduction is absent. The

SENESCENCE IN HIGHER ANIMALS AND MAN 271

rate of metabolism and the rate of growth decrease, the water-
content of the body likewise decreases, and the tissues become
denser. But the condition known as old age or senility accom-
panied by atrophy of tissues, which is well marked in man and has
also been observed in various mammals, is either less clearly defined
in the lower forms or else is not usually reached because advancing
senescence induces reproduction and rejuvenescence.

Because of the absence of agamic reproduction and the limited
capacity for regression and reduction in these forms, they consti-
tute much less favorable material than the lower forms for study
and analysis of age processes, and theories of senescence based only
or chiefly on data obtained from the higher forms have in most
cases but little general biological value. Much of the literature
of the subject belongs primarily to the medical field and throws
little light upon the general biological problem of senescence, but
various attempts have been made to formulate general theories of
senescence from the study of the higher animals and man alone."

In the following sections of this chapter the chief characteristics
of senescence in the higher forms are briefly considered and the
bearing of some of the recent experimental work upon the problem
is discussed.

THE RATE OF METABOLISM

Most authorities agree that the rate of metabolism in man and
mammals, so far as determined, undergoes in general a decrease
with advancing age.2- Rubner has attempted to show that in warm-
blooded animals the rate of metabolism per unit of surface of the

t The following references are selected from the more recent literature dealing
primarily with senescence and old age in man: Bilancioni, ’11, with bibliography;
Demange, ’86; Friedmann, ’02; Lorand, ’11, with bibliography; Metchnikoff, ’o3,
*t0; Ribbert, ’08; Rubner, ’08. Recent more general considerations of the problem
of senescence, but concerned chiefly with man and the higher animals, are Dastre, ’03;
Miihlmann, ’oo, ’10; Minot, ’08, 13.

2 The article by Magnus-Levy on “Metabolism in Old Age” with bibliography,
in the Anglo-American issue of von Noorden’s Metabolism and Practical Medicine
(1907), is a valuable general survey of our knowledge on the subject. See also Miihl-
mann, ’oo (p. 164). Among special papers dealing with the question of metabolic
changes in relation to age in man and mammals may be mentioned A. V. and A. M.
Hill, 13; von Hosslin, ’88,; K6vesi, 01; Magnus-Levy and Falk, ’99; Rubner, ’83,
’85, ’08, 09; Sonden and Tigerstedt, ’95; Speck, ’89.

272 SENESCENCE AND REJUVENESCENCE

body is constant irrespective of age. Table V (Rubner, ’85) gives
the rate of metabolism in man at different ages, measured in terms
of heat production in calories for periods of twenty-four hours,
and also the heat production per kilogram of body-weight and per
square meter of body-surface.

TABLE V
Weight of Persons in Experiment ee ee Calories per Body-Surface Calories per
in Kilograms Heat of Com- | Kilo in 24 Hrs. in Square Square Meter

bustion:of Feces Centimeters | of Body-Surface

Children 4.03........... 368 O1.3 3,013 1,221
De See hye mene 966 81.5 7,191 1,343
. Wrdwsoecaweeaes 1,213 73-9 7,681 1,579
& BBCi dyn wasnt ou 1,411 59.5 10,156 1,380
30. Onc oRanetn tes 1,784 577 12,122 1,472
# AOwA nen Sates 2 2,106 52.1 14,491 1,452
Man during medium labor 67 2,843 42.4 20,305 1,399

It is evident from this table that the heat production per square
meter of surface does show a considerable degree of constancy in
the individuals of different sizes and weights. In various other
papers Rubner has presented additional evidence for his view that
the rate of metabolism per unit of body-surface remains essentially
the same throughout life. According to Rubner then the rate of
metabolism is in some way regulated by the relative amount of
body-surface, i.e., the loss of heat determines the heat production,
and since the surface increases less rapidly than the volume or
weight of the body the rate of metabolism per unit of weight must
decrease, as the third column of Table V shows.

This view has not found general acceptance. Not only has the
method of measuring body-surface been criticized, but it has been
pointed out that during later life in man the rate of metabolism
and therefore of heat production certainly decreases progressively
while the body-surface remains practically unaltered. According
to Magnus-Levy the minimum metabolism in old age may be as
low as 20 per cent of the normal, and various authors have shown
that the daily metabolic exchange also decreases. Hill has recently
shown also that the ratio of heat production to body-surface is not
constant in rats of different size. In small individuals it is as high

SENESCENCE IN HIGHER ANIMALS AND MAN 273

as one hundred and forty calories; in medium-sized, ninety-nine
calories per square centimeter of body-surface. In other words,
the rate of metabolism is determined by age, rather than by surface.

According to the data compiled by Magnus-Levy from various
authors, the amount of proteid necessary to keep old persons in
health is less than that necessary in early life. After a certain
time old persons in general take less food than is necessary to
maintain their weight, and a gradual loss of weight occurs which
varies in rate and amount according to various conditions. More-
over, the whole course of the life history from youth to old age with
its decrease in bodily activity and in rate of growth, and its advan-
cing differentiation and accumulation of structural substance points
very clearly to a decreasing rate of metabolism per unit of weight.
It may also be noted that the process of chemical differentiation of
the brain of the white rat during growth indicates that the rate
of metabolism is decreasing during this period (W. and M. L.
Koch, ’13), and Dr. S. Tashiro kindly permits the statement from
unpublished data that in the horseshoe crab, Limulus polyphemus,
the production of carbon dioxide per unit of weight in the nervous
system decreases as the weight of the nervous system increases;
apparently, the larger and older the animal, the lower the rate of
carbon-dioxide production in the nervous system.

THE RATE OF GROWTH

The rate of growth also shows, in general, a decrease from early
stages of development onward; although in many cases periodic
or occasional increases in rate of greater or less magnitude occur.
The decrease in the rate of growth during development in man and
the higher vertebrates has been demonstrated beyond all question
from a great variety of data, and its significance for the problem of
senescence has been so ably presented by various authors’ that only
a brief consideration is necessary at this time. It must be remem-
bered that, as Minot (’91) pointed out, absolute increments of
weight, volume, length, or any other component of growth during
equal successive periods are not measures of the rate of growth, for

tSee particularly Donaldson, ’95, the chapters on growth; Minot, ’or, ’o8,
chap. iii, “The Rate of Growth”; Miihlmann, ’oo.

274 SENESCENCE AND REJUVENESCENCE

during each period the weight or other growth component of the
body increases. The rate of growth is measured by the propor-
tional or percentage increments in given periods, consequently the
rate of growth may remain constant or may even decrease, while
the absolute increments of growth become successively larger. In
fact, the latter possibility is realized during a large

ss oe ; part of the growth period in the higher vertebrates.
Many students of growth have failed entirely to
se | recognize the fact that the absolute increment is
= not a correct measure of the rate of growth, and
have therefore reached incorrect conclusions.
140 The curves presented in Figs. 109 and 110
show the percentage increments of weight in boys
120 and girls from the first to the twenty-third year."
The very great decrease in the annual percentage
Ss increment is at once apparent. During the first
Bol year after birth the percentage increment of weight
is 200 per cent in boys and 187 per cent in girls.
6ot During the second year it is only 22 per cent in
boys and 28 per cent in girls. From this time on
ad it decreases slowly with slight irregularities and
204

Years I2 3 4 5 6 7 8 g 1011 12 1314 15 16 17 18 1g 20 21 22 23

Fic. 109.—Curve showing the decrease in the rate of growth in boys from the
first to the twenty-third year: each vertical interval indicated on the axis of ordinates
represents 20 per cent increment in weight, each horizontal interval on the axis of
abscissae one year. Fom Miihlmann’s tables (Miihlmann, ’oo) calculated from
Quetelet’s data.

with a distinct but slight increase at the age of puberty, after which
it falls again. Various other data from different sources, including
statistics on the increment of body-length, monthly increments of
weight during the first year, decrease in weight during later life,
etc., all show that in man the rate of growth decreases, and that

« The curves are based on the percentage increments determined by Mihlmann
(’0o) from the statistics in Quetelet’s L’Anthropométrie (1835 and 1840).

SENESCENCE IN HIGHER ANIMALS AND MAN 275

as age advances growth sooner or later gives place to reduction.
Data from the population of England’ give essentially the same
results. Minot (’o08) also gives data and curves from his own
investigations of the growth of guinea-pigs, rabbits, and chicks
which likewise show that the rate of growth decreases very greatly,
particularly during the early part of postem-

Deas bryonic life. Figs. 111 and 112 are curves
180 | from Minot’s data showing the average daily
percentage increments in weight of male and
160 | female rabbits beginning three days after birth.
The abscissae represent number of days after
aise birth; the ordinates, percentages. Here again
samt it is evident that the rate of growth decreases
with a few interruptions, at first very rapidly
Gos t and later more slowly. According to Donaldson
(06) the curve of growth of the white rat is
80 J very similar to that of man, except that the
ro length of the growth-period is much shorter.
| If the decrease in the rate of growth is in any
#6 degree a measure of the rate of senescence—and
20 4
Years ‘Io2 3 4 5 6 7 8 9g Io1l 1213 1415 1617 18 19 20 21 22

Fic. 110—Curve showing the decrease in the rate of growth in girls from the
first to the twenty-third year: similar to Fig. 109. From Miihlmann’s tables (Miihl-
mann, ’oo), calculated from Quetelet’s data.

there can be little doubt that it is one of the features of senescence
—Minot is entirely correct in asserting that the rate of senescence
is highest in youth and lowest in advanced life.

In most vertebrates, as well as in many invertebrates, the final
size of the individual is subject to relatively slight variation, and
the amount of growth during development is within certain limits

t Figs. 38 and 39 and Tables II and III in Minot’s Age, Growth and Death give
these statistics in graphic and tabular form as revised by Donaldson from Robert’s
Manual of Anthropometry (1878).

276 SENESCENCE AND REJUVENESCENCE

a fixed quantity. Among the fishes, amphibia, and reptiles there
are, however, some forms in which growth apparently continues
during at least most of the life of the animal, although it is very
slow in later stages. Growth is apparently periodic rather than
continuous in all these cases, and its continuance throughout life
or up to a late stage is probably due to the fact that these animals
undergo partial rejuvenescence from time to

oe a time during periods of quiescence or star-
vation, a point which is discussed below
- (pp. 299-300). That the fundamental laws of
set growth are essentially the same throughout
is the organic world there is every reason to
12 believe. Everywhere apparently the rate of
II growth is high in the young organism, or in
30 the young cells and tissues of the organism,
4 and decreases as development proceeds and
. the rate of metabolism falls. With adequate
6 nutrition and under external conditions which
5 permit growth, the rate of growth appears to
4 be in a general way dependent upon the
:
Ir

Days 3818 2838 55 77% 106} 180 270

Fic. 111.—Curve showing the decrease in rate of growth in male rabbits from 3
to 270 days after birth: each vertical interval indicated on the axis of ordinates repre-
sents 1 per cent increment in weight and each horizontal interval on the axis of abscissae
the length of time between successive weighings; during the first 38 days after birth
weighings were made every 5 days, after that at increasingly longer intervals. From
Minot’s tables (Minot, ’08).

rate of metabolism. Discussion of the conception of growth as an
autocatalytic reaction which undergoes acceleration in rate to a
maximum is postponed to chap. xvi.

NUTRITION, GROWTH, AND SENESCENCE

The advance during the last ten years in our knowledge of the
chemical constitution of the proteid molecule, in which the work of

SENESCENCE IN HIGHER ANIMALS AND MAN 277

Kossel, E. Fischer, and Abderhalden and their students has played
a very important part, has opened up new fields of investigation.
It is now possible to attack the problem of nutrition and its rela-
tion to physiological condition, maintenance, development, and
growth, at least in the higher animals, with more exact and more
scientific methods than heretofore. Since we have become familiar

with the nature of the constituent substances

ee (Bausteine, i.e., building stones), the amino-
15 acids and certain other substances, which go to
14 make up the proteid molecule, and know more
73 or less exactly which of these substances are
oe present and in what proportions in various pro-
oi teids, we are able by feeding animals with
9 different proteins or with one or another of the
8 constituent substances to learn something of
7 the capacities of the animal for building up its
6 own specific proteid molecules and of the rela-
5 tions of each of the various nutritive substances
4
3
2
I | i

Days 3 8 19 28 38 55 80 1063 180 270

Fic. 112.—Curve showing the decrease in rate of growth in female rabbits from
3 to 270 days after birth: the intervals indicated are the same as in Fig. 111. From
Minot’s tables (Minot, ’08).

to its various activities. Many difficulties still exist in connection
with these investigations: the methods of isolating the various
substances in pure form for feeding are in many cases far from
satisfactory, and it is often difficult to devise a food from the
isolated substances which the animal will eat in quantities sufh-
cient to supply the necessary energy. Moreover, the complexity
of metabolism and the impossibility of following the various steps
within the organism are serious obstacles. Notwithstanding all
these difficulties there can be no doubt that this method of inves-
tigation will throw light on various features of life heretofore
obscure. Any extended discussion of the results already attained

278 SENESCENCE AND REJUVENESCENCE

in this field is quite beyond the present purpose, and I do not
regard myself as qualified to undertake it; but certain points which
bear more or less directly upon the problem of senescence demand
some consideration.

In extensive and carefully controlled feeding experiments with
white rats, Osborne and Mendel? have been able to show that cer-
tain proteins—gliadin from wheat and rye, hordein from barley—
are adequate for maintenance of weight and good nutritive condi-
tion, but not, or only to a slight degree, for growth under the usual
conditions. But after male and female animals had been fed during
some five months with gliadin as the only protein, they were mated,
and the female gave birth to four normal young which showed
normal growth as long as nourished on the milk of the mother, and
only later when placed on the gliadin diet showed retarded growth.
During gestation there must have been somewhere a synthesis
of the specific body-proteins in sufficient quantity to permit the
normal embryonic development and growth of the young. The
ability of the body to synthesize from a certain diet the substances
necessary for growth evidently differs under different physiological
conditions. McCollum has concluded on the basis of his experi-
ments that ‘‘the processes of replacing nitrogen degraded in cellular
metabolism are not of the same character as the processes of
growth,” and suggests further that cellular katabolism and repair
do not involve the destruction and reconstruction of an entire pro-
tein molecule. Growth, of course, so far as it involves increase
in amount of proteid substances, must involve the construction
of new molecules.

In an earlier chapter it was suggested that growth is funda-
mentally the accumulation of substances which cannot readily
leave the cell without change of constitution and which under the
usual conditions are not readily or rapidly changed so as to become
eliminable. If this conception is correct, the further possibility
suggests itself that tissue breakdown and repair, under ordinary
conditions, in the higher animals, may consist largely or wholly, on

tOsborne and Mendel, 11a, ’11b, ’12a, ’12b, ’12c, ’13, ’14; Mendel, ’14. See
also Hopkins, ’12; McCollum, ’11; Ruth Wheeler, ’13. Osborne and Mendel give
numerous references to the literature of the subject.

SENESCENCE IN HIGHER ANIMALS AND MAN 279

the one hand, of the separation and breakdown of certain constit-
uent chemical groups, which are less firmly attached to the mole-
cule or less stable than other parts which remain as a more stable
nucleus, and, on the other, of the replacement of the lost parts of
the molecule from nutritive substances. In actual protoplasmic
growth, however, the whole molecule, including the more as well
as the less stable portions, must be built up out of the Bausteine, or
in some other way. Consequently some proteins whose constituent
substances can supply the losses due to tissue breakdown may not
contain in sufficient quantity or not at all certain components
necessary for the building up of new molecules, but under excep-
tional conditions, as in the gestation period in Osborne and Mendel’s
rats, the organism may be able to synthesize these molecules in
other ways. The general relation between the rate of growth and
the rate of metabolism suggests that the synthesis of the more
stable molecules or molecular groups occurs more readily with a
high than with a low rate of metabolic reaction, and this suggestion
is also in accord with the fact that growth, morphogenesis, and
differentiation occur chiefly in the earlier stages of the life history.

The rats fed on gliadin with maintenance of weight but little or
no growth retain their capacity for growth for at least several
months and, when placed on a mixed diet, or one containing ade-
quate proteins, resume growth at the normal rate. But the experi-
ments do not as yet show whether they will retain indefinitely the
capacity for growth. Besides remaining young as regards growth
capacity, these animals also retain the general appearance of
growing animals of the same size. Apparently, progressive develop-
ment and with it senescence have been inhibited or greatly retarded.
Nevertheless, after long periods of such feeding the nervous system
shows the water-content characteristic of old animals and the pos-
sibility cannot be ignored that, even in the absence of growth,
progressive changes in the direction of greater stability of the
protoplasmic substratum may have occurred.

The results of experiments on mammals with a diet which is
adequate qualitatively, but sufficient in quantity only for main-
tenance and not for growth, are quite different from those of
Osborne and Mendel. Waters (’08, ’o9) found that underfed

280 SENESCENCE AND REJUVENESCENCE

cattle might remain for a long period at a constant body-weight
but at the same time undergo an increase in height and a decrease
in the amount of fat. Evidently the skeleton undergoes growth,
at least in length of bones, even under these conditions, and other
parts must grow to some extent and in certain dimensions in
accordance with the growth of the skeleton, but this growth is in
part at the expense of the reserves. After a certain length of time
this growth ceases.

Aron (’r1), working with growing dogs, succeeded in maintain-
ing a constant body-weight for a long time, in some cases nearly a
year, by limiting the quantity of food. He also found that the
animals increased in size, the skeleton underwent growth, and the
brain retained its weight or increased in weight, while the animals
became progessively thinner and their fat reserves and muscular
tissue suffered marked losses. If the food was not increased in
amount the animals finally died of starvation after three to five
months, with a slight loss of weight. But if the quantity of food
was somewhat increased they could still be maintained at a con-
stant weight and in a condition of extreme emaciation, but now no
further growth occurred. The results of later experiments on rats
(Aron, ’12, 713) are essentially similar and these experiments on
animals agree well with the observations of various earlier authors
on children.

Aron concludes from his experiments that the internal growth-
impulse exists primarily in the skeleton and that other parts merely
follow the growth of the skeleton as far as nutritive conditions
permit. This is probably true for mammals or for vertebrates as
regards growth in stature during later stages of development, but
it is certainly not true for the early stages of development of verte-
brates nor for many invertebrates where no skeleton is present.
It seems probable that in these animals growth of the more stable
substances of the body, in part at the expense of the less stable, has
occurred. The diet in these cases is merely quantitatively, not
qualitatively insufficient; it contains the constituents necessary
for the construction of the relatively stable structural substances,
but not in sufficient quantity for the growth of all parts. Under
these conditions it might be expected that growth or maintenance,

SENESCENCE IN HIGHER ANIMALS AND MAN 281

if it occurs anywhere, would be limited to the more stable tissues or
substances of the body, while the less stable would undergo more
or less reduction, for in the one case the losses from breakdown are
slight and are more than balanced, while in the other they are
greater and are not balanced and the products of breakdown of
the less stable tissues take part to a greater or less extent in the
upbuilding of the more stable. The organic structural substance
of the skeleton is scarcely to be regarded as living; it is rather of
the nature of a secretion, and after its formation it takes but little
part in metabolism, except when altered functional conditions
determine a change in bone structure. Consequently in underfed
animals there is little loss of skeletal substance, and every addition
counts for growth. Skeletal growth may therefore continue while
reduction is going on in various other organs, the products of
breakdown of the latter serving to build up the more stable sub-
stance of the former.

As regards the nervous system, conditions are somewhat
similar. The nervous system is certainly one of the most stable,
perhaps the most stable living tissue in the body. Its cells persist
throughout life, and dedifferentiation of nerve cells is not known to
occur in vertebrates. The losses of the nervous system during
starvation are relatively slight, and in underfed animals it main-
tains its weight or grows at the expense of the less stable tissue,
as the products of their breakdown are synthesized into more
stable forms in the nervous system, and so become more permanent
constituents of the structural substratum of the body. This
stability of the nervous system is not, however, like that of the
skeleton, the stability of a dead secretory substance, but is the
stability of a living protoplasm and is undoubtedly associated with
the high metabolic rate in the nervous system.

The result of return to a normal diet after a period of insufficient
nutrition apparently depends in part on the length of that period.
It has been clearly demonstrated that in man as well as in animals
the retarding effect upon growth of even a considerable period of
insufficient nutrition may be compensated later on a normal diet.
But it is also true that a sufficiently long period of underfeeding
may result in permanent “stunting,” the body apparently being

282 SENESCENCE AND REJUVENESCENCE

unable to recover its full capacity for growth. Stunting in man and
the mammals is undoubtedly due in large measure to subnormal
skeletal growth, and while the effect of long-continued underfeeding
on the physiological condition of the skeletal tissues is not known,
the facts suggest that the usual relation between senescence and
growth is altered. In other words, the cells which give rise to the
skeletal substance probably undergo some degree of senescence
during underfeeding without being able to produce as much skeletal
substance as under continuous good nutritive conditions, conse-
quently their rate of metabolism is lower and they are less capable
of producing skeletal substance after such a period than the cells
of an individual of the same size which has been continuously well
fed. The skeleton of the individual which has been subjected
to underfeeding for a sufficiently long time will therefore cease to
grow, even under good nutritive conditions, at a smaller size than
that of the continuously well-fed individual, and very probably
the same is true to a greater or less extent in other tissues. In the
underfed animal the proportion of more stable to less stable com-
ponents of the tissues must increase more rapidly than where nutri-
tion is sufficient for all requirements, for in the former case the less
stable components must break down to a larger extent than in the
latter. In the absence of sufficient food these substances must
serve to a larger extent as a source of energy or for the synthesis
of the more stable components than where sufficient nutritive sub-
stance is available. Consequently the substitution of more stable
for less stable substances in the tissues goes on during the period
of underfeeding, but with less than the usual amount of growth
because the less stable substances are present as structural com-
ponents in smaller proportion than under the usual conditions.
After a long period of underfeeding the tissues are physiologically
older and therefore less capable of growth, even when nutrition
is present in excess, than in the continuously well-fed animal of the
same size. According to this conception, senescence in the higher
animals and man may proceed to some extent even when little or
no growth occurs, because the body substance is gradually trans-
formed to a greater or less extent from more active to more stable
conditions.

SENESCENCE IN HIGHER ANIMALS AND MAN 283

CHANGES IN WATER-CONTENT AND CHEMICAL CONSTITUTION

From a certain stage of development on, the water-content of
the body undergoes in general a decrease with advancing age, as
many authors have shown. Davenport (’97) has found that in
the frog the percentage of water increases from 56 to 96 per cent
during the first two or three weeks after hatching, and then begins
to decrease. In the chick embryo and the human fetus the per-
centage of water decreases from an early stage. Aron (’13) has
compiled the data concerning the changes in water-content in man
and the higher animals.

The decrease in water-content is not uniform for the different
organs, nor is its progress in a given organ entirely uniform in all
cases. The extensive investigations of Donaldson and Hatai™ on
the water-content of the nervous system of the white rat show
that the percentage of water in this tissue changes very regularly
with advancing age. At birth it is about 88 per cent, at maturity
78 per cent, and it is altered only very slightly by nutritive con-
ditions and external factors. Donaldson states that it affords the
best index known of the age of these animals. It is probable that
further investigations on other mammals would give similar results
for the nervous system, but for various other tissues, e.g., the
muscles, the variation in water-content is much greater.

It is an undoubted fact that after a certain stage the body
becomes more and more solid as the structural substance accumu-
lates. The decreasing water-content is in fact probably to some
extent merely another aspect of the process of structural accumula-
tion in the cells, although it may be in part the result of changes in
the aggregate condition of the colloids, as Bechhold (’12) and others
have suggested.

It is impossible to consider at length the changes in chemical
constitution which occur with advancing age. Aron’s recent com-
pilation of the data on the biochemistry of growth (’13) affords a
good survey of our present knowledge on this question. In general
an increase in the percentage of proteid and of inorganic substances
occurs, and this increase is more rapid during the earlier years of

t Hatai, ’04; Donaldson, ’11a, ’11b; Donaldson and Hatai, ’11.

284 SENESCENCE AND REJUVENESCENCE

life than later. Certain organs also undergo characteristic changes
in constitution, but the relation between these changes and the age
cycle is in most cases not yet clear.

THE MORPHOLOGICAL CHANGES

If senescence is merely one aspect of progressive development
the morphology of senescence in man and the higher forms is simply,
as elsewhere, the morphology of progressive development. The
morphological changes in the cells consist in general of the appear-
ance of more or less definite structural substances, which differ in
form and character according to the direction of differentiation in
particular cells or organs. Morphological differentiation of the
cell involves either an accumulation in the cytoplasm of substances
different in appearance and constitution from the cytoplasmic sub-
stratum of the embryonic cell, or a replacement of the embryonic
substratum by such substances. This process of differentiation,
or cytomorphosis as Minot prefers to call it, very commonly involves
an increase in the volume of the cytoplasmic portions of the cell
as compared with the nucleus. In embryonic cells the nucleus is in
general, relatively to the cytoplasm, larger than in differentiated
cells. Minot has laid particular emphasis on this change in the
proportion of nucleus and cytoplasm as a fundamental feature of
progressive development and as the determining factor in the
decrease in metabolic rate which occurs in senescence. Such a
change undoubtedly does occur in at least many cells in the course
of differentiation, particularly in the higher animals, but it is by
no means universal, as Minot maintains. In certain of the lower
animals there is little if any difference between the embryo and

the adult in this respect, and the differentiation of plant cells is
~ very generally accompanied by vacuolization rather than by in-
crease of cytoplasm.

Figs. 113 and 114 show embryonic and differentiated cells from
the spinal cord of the chick. The cells in Fig. 113 are from the
neural tube soon after its formation, and in Fig. 114, drawn to
the same scale, nerve cells from the spinal cord after eleven days
of incubation, at which time some of the nerve cells have attained
practically their full size. Measurements of the volume of nuclei

SENESCENCE IN HIGHER ANIMALS AND MAN 285

and cell bodies indicate that there is comparatively little change
in proportion during the process of differentiation. Of course
such measurements are not exact, and, besides, the measurements of
the cytoplasm do not include the dendrites and the nerve fiber
arising from the cell: if the volume of these were added to the
cytoplasmic volume of the cell the total would undoubtedly show

Fics. 113, 114.—Cells from the nervous system of the chick embryo: Fig. 113,
embryonic cells from neural tube at 31 hours; Fig. 114, differentiated motor
cells from spinal cord at 11 days, drawn to the same scale. From embryological
preparations of the University of Chicago.

an increase in cytoplasmic volume during differentiation. But
how can the dendrites and the nerve fiber contribute to decrease the
rate of metabolism in the cell body, since they are merely slender
outgrowths from it? The cell body has unquestionably undergone
senescence during differentiation, but without any very great
change in the nucleo-cytoplasmic relation. A marked proportional

286 SENESCENCE AND REJUVENESCENCE

increase in the amount of cytoplasm does occur in many cases, but
it is an incidental rather than a fundamental feature of senescence.
The important change is not the change in amount, but the change
in the proportion of chemically active to inactive, or more active
to less active substance.

In the higher animals and man morphological differentiation
of the cells is much more conspicuous and varied than in the lower
forms, but the essential nature of the process is evidently the same
in all forms. Differentiation consists primarily, not in increase in
amount of cytoplasm, but in the accumulation of substances differ-
ent in some way from the embryonic cytoplasm and giving the cell
its characteristic structure. And it is unquestionably the increase
in these substances, not the increase in the amount of cytoplasm,
which determines the decrease in rate of metabolism and rate of
growth. The structural substances produced by different cells
differ in character in one way or another because in the course
of development different metabolic conditions arise in different
regions, and in the higher animals these conditions must be more
definite and fixed in character than in the lower organisms, because
the degree of individuation is higher, i.e., the correlation between
parts is more intimate and definite. These factors, together with
the limited regressibility in many parts, must also determine that
differentiation shall proceed farther than in the lower forms. The
structural differences in different cells are more permanent and more
conspicuous and in general involve the cell to a greater extent.

So far as they have turned their attention to the phenomena of
senescence the anatomists, histologists, and pathologists have
often failed to recognize what the study of the lower organisms
forces us to admit asa fact, viz., that senescence is merely one aspect
of development, and have confined their attention to, and based
their theories upon, the morphological changes which occur in later
life, and particularly in what we are accustomed to call old age.
One reason for this attitude among those investigators who have
been chiefly concerned with man lies in the fact that old age in
man and the higher vertebrates is associated with certain morpho-
logical changes in the cells which seem to be different in character
and direction from the developmental changes. These changes

SENESCENCE IN HIGHER ANIMALS AND MAN 287

are commonly known as senile atrophy.t They consist essentially
of a decrease in size, with more or less degeneration of cells. These
changes are often so extensive and so widely distributed that there
is considerable decrease in size and weight of the body as a whole.

The atrophy may involve to a greater or less extent most or all
of the more highly specialized organs of the body, liver, kidneys,
alimentary tract, lungs, muscular system, skeleton, and nervous
system. The arterial system always shows changes in the direc-
tion of decreased elasticity and contractility, and the hardening
of the walls known as arteriosclerosis is very commonly present,
although some authors maintain that it is not a characteristic
feature of old age. The heart often becomes hypertrophied in-
stead of atrophied, but this is believed by many to be a functional
reaction to the increased work of the heart in consequence of the
changes in the arterial system, rather than a feature of old age.
The connective tissue becomes stiffer and harder, but its less
highly specialized forms may increase and take the place of more
highly specialized organs or tissues which have undergone atrophy.
In connection with these changes of old age the deposition of fatty
substances, evidently products of metabolism, occurs in the cells
of muscles, liver, brain, and various other tissues.

The difference in appearance of the spinal ganglion cells of man
at birth and in a case of death from old age at ninety-two years are
shown in Figs. 115 and 116. In the first figure the young cells
have not yet attained their full size, but compared with them, the
cells on the left of the second figure are seen by the spaces about
them to be greatly shrunken and their cytoplasm contains numerous
fat granules stained black by the method of preparation. On the
right of Fig. 116 the débris of two cells which have undergone
degeneration is seen.

The atrophy of tissues in old age is manifestly associated with
the decrease in rate of metabolism. It is a well-known fact that a
decrease or cessation of functional activity in the specialized organs
after their development brings about atrophy quite independently

t For more recent discussions of senile atrophy see Bilancioni, ’11; Demange, ’86;
Metchnikoff, ’03,’10; Minot, ’o8, chap. ii; Miihlmann, ’oo,’10; Ribbert, ’o8; articles
in medical dictionaries, cyclopedias, etc.

288 SENESCENCE AND REJUVENESCENCE

of age. Under such conditions, or where the rate of metabolism
has fallen below a certain level in consequence of age, the break-
down and elimination of the substratum is not compensated by the
synthesis of new substance, consequently a decrease in size and
finally cell death occur. Atrophy in the higher animals differs
from reduction in the lower forms in that, while decrease in size
occurs, there is little or no dedifferentiation. The cell has appar-
ently become so highly differentiated that it has lost the capacity
for synthesizing a substratum adequate in quantity or constitution

POD

Fics. 115, 116.—Cells from the first cervical ganglion of man at different ages:
Fig. 115, from fetus killed by accident of birth; Fig. 116, from man dying of old age
at ninety-two years, showing on the left two cells shrunken and undergoing atrophy
and on the right the outlines of spaces formerly occupied by cells now degenerated.
After Hodge, ’94.

to carry on metabolism. Consequently the losses from degradation
and breakdown of the existing substratum are not compensated by
the synthesis of new substratal substance, and sooner or later the
fundamental mechanism of the cell is destroyed and degeneration
and death occur. The atrophy of old age in organs of such funda-
mental importance as the nervous system indicates that there is
some truth in the statement, so often made, that the later stages of
senescence are a “wearing out”’ of the physiological mechanism or
some essential part of it. Apparently the nerve cells or some of
them do ‘“‘wear out” because they are no longer able to synthesize

SENESCENCE IN HIGHER ANIMALS AND MAN 289

the substratum necessary for their continued function. But even
though the final stage of senescence, which terminates in death,
may be regarded as a wearing out and a breaking down of the
physiological mechanism at some point, it must not be forgotten
that this stage is merely the final stage of progressive development
and that the factors which determine it act from the beginning of
development on.

CONCLUSION

So far as the facts go, the process of senescence appears to be
essentially the same in the higher and lower organisms; the chief
difference is that with the absence of reproduction and the greater
degree of individuation and differentiation the later atrophic stages
of senescence are conspicuous and characteristic features of the
life history in the higher forms, while in the lower they either do
not appear or else occur in only a few cells at any given time. From
the lowest forms to man senescence is simply one aspect of the
developmental process, and we may expect to find it occurring
wherever the progressive changes are not balanced or overbalanced
by regression.

The apparent continuity and irregressibility of senescence in
man and the higher forms is responsible for the very general belief
that the process is irregressible everywhere, but the plants and lower
animals show us clearly enough that this is not the case. Viewed in
the light of what we have learned from the lower forms, senescence
in the higher animals and man is merely a less frequently inter-
rupted process of the same kind as that which occurs in all pro-
gressive stages of the life cycle in the plants and the lower animals.

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CHAPTER XII

REJUVENESCENCE AND DEATH IN THE HIGHER ANIMALS
AND MAN

REJUVENESCENCE IN THE LIFE HISTORY

While much has been written concerning senescence and death
in man and the higher animals, but little attention has been paid
to the question of the occurrence of rejuvenescence, and many
authorities still maintain that life is always a progressive process
and that rejuvenescence does not occur. It is of course true that
in the higher animals the progressive features of development are
predominant and that development ends in death, and many
studies of senescence have been based on these forms alone, without
consideration or knowledge of the lower organisms. But if we are
to reach a general conception of the age cycle in organisms, the wide
occurrence and significance of dedifferentiation and rejuvenescence
in the lower animals and the plants must at least raise the question
whether similar processes do not occur to some extent in higher
forms.

Even in man and the other mammals the different tissues do
not undergo senescence alike. Certain cells, such as the Malpighian
layer of the skin, continue to divide and replace the old dying or
dead cells of the epidermis, and remain relatively young in appear-
ance and behavior throughout the life and even after the death of
the individual. In various other tissues such replacement of old
differentiated, or dead cells by younger cells occurs more or less
extensively in normal life, and tissue regeneration, following injury
or loss of tissue cells, occurs to a greater or less extent in all tissues
except the nervous system.

The process of tissue regeneration, whether in normal life or as
a reaction to injury, undoubtedly retards the aging of the tissue
or organ concerned as a whole, but the question whether it involves
an actual dedifferentiation and rejuvenescence of the cells concerned
in the regeneration must be briefly considered. Minot (’o8, ’13)
has attempted to prove that dedifferentiation does not actually

293

204 SENESCENCE AND REJUVENESCENCE

occur in such cases and that the regeneration takes its origin from |
cells or parts of cells which have never undergone differentiation,
so that even in these cases development is progressive, not regres-
sive. His conclusions are based on the histological appearance,
not upon the behavior of the cells. One of the cases cited by him
as an example is the regeneration of striated muscle after injury.
He points out that the only portions of the muscle which take part
in the regeneration are the nuclei and the small accumulations of

Fics. 117-122.—Various stages of regeneration after wounding in striated muscle:
Fig. 117, injured muscle after three days, showing proliferation of nuclei and formation
of protoplasmic cells; Fig. 118, multinucleate masses resulting from proliferation;
Figs. 119, 120, ‘muscle buds” at ends of injured fibers; Fig. 121, regenerated fibers;
Fig. 122, giant cells, inclosing a piece of necrotic muscle fiber. From Ziegler, ’or.

granular undifferentiated cytoplasm, as he terms it, which surround
them. From these parts the new muscle cells arise by division of
the nuclei and growth of the granular cytoplasm (Fig. 117); these
cells form multinucleate masses either along the course (Fig. 118)
or at the injured end of the fibrillar substance (Fig. 119). From
the cytoplasm of these cells new fibrillar substance arises in con-
tinuity with the old (Figs. 120, 121). When these cells are not in
contact with living muscle substance, as at in Fig. 117, they form

REJUVENESCENCE AND DEATH 295

multinucleate “giant cells” (Fig. 122), and these do not give rise to
new fibrillar substance, but usually die sooner or later. Even if
Minot is correct in maintaining that the fibrillar substance has no
capacity for regeneration, it is of interest to note that the new
fibrillar substance seems to arise in continuity with the old, while
isolated cells apparently do not produce fibrillar substance.

The conclusion that there is no dedifferentiation involved in
such cases is, I believe, not warranted by the facts. The point of
importance is that during the earlier stages of their developmental
history the muscle cells produced granular cytoplasm and nuclear
substance and grew and divided, but later began to give rise to
fibrillar substance and the proportion of this substance to the
nuclei and granular “‘undifferentiated’’ cytoplasm increased enor-
mously. After injury, however, the activity of the muscle cells
changes, and they produce more granular cytoplasm and more
nuclear substance. In short, they have returned to a kind of
activity characteristic of early stages of embryonic development.
What is this if it is not dedifferentiation? The fact that the old
fibrillar substance degenerates instead of regenerating is quite
irrelevant. The question is not whether all parts of the cells are
capable of regeneration, but whether the cells can again resume a
kind of activity characteristic of an earlier stage of development,
and the process of regeneration of muscle and various other tissues
in man and the higher animals leaves no doubt that they possess
this capacity. Even in the outgrowth of new nerve fibers from the
central stump of a cut nerve there is a return to a process of growth
and development which is normally characteristic of an earlier
stage of development. Champy maintains that dedifferentiation
occurs in tissues cultivated outside the organism in nutritive
media—the method often termed explantation—and has described
at length the changes in cultures of kidney cells.t. Regression and
dedifferentiation certainly occur to a greater or less extent in most
tissues of man and the higher animals, but the apparent inability
of the cells of one tissue to give rise to other tissues indicates that,

tSee Champy, 713, ’14, and earlier papers which are included, together with
many other references bearing upon this question, in the bibliographic lists of these
papers.

296 SENESCENCE AND REJUVENESCENCE

at least under the usual conditions, regression does not bring the
cell back to a completely undifferentiated stage.

It is of course true that in some tissues, such as the skin, the
more highly differentiated cells show no capacity for dedifferentia-
tion, but die and are replaced by division and growth of cells which
remain throughout life in a more or less embryonic condition. In
such cases there is no evidence of regression and dedifferentiation,
but its absence in the one tissue does not justify the conclusion that
it is absent in another. Dedifferentiation and regression in tissue
cells are undoubtedly associated with rejuvenescence in the higher
as well as in the lower organisms, and tissue regeneration, whether
a feature of normal life or the result of injury, must bring about
some degree of rejuvenescence in the parts concerned.

After a period of hibernation, tissue regeneration is often very
extensive (Monti, ’05) and may involve tissues which usually show
but little regeneration. In such cases the large proportion of young
cells in the body must render the animal as a whole, though not
necessarily all parts of it, appreciably younger than before hiberna-
tion. In fact, the periodic cycle of activity and hibernation in
various forms is in many respects similar to an age cycle. It is
probable that the rejuvenescence begins during the hibernation
period when the animal is living upon its own substance, like the
starving planarian, and that this change leads sooner or later to
renewed division and growth of cells. At the same time, other
cells doubtless die and are later replaced by the younger cells.

Other periodic changes, particularly in the glandular tissues,
show the essential characteristics of an age cycle. In the pancreas
cell, for example (see pp. 189-191), the loading of the cell is both
morphologically and physiologically similar to senescence, and the
discharge to rejuvenescence. In such cases the changes occur in
individual cells without cell reproduction.

The cells of the nervous system in man and many animals are
believed to persist throughout life, and to possess no appreciable
capacity for regression and dedifferentiation beyond their ability
to regenerate the nerve fibers which arise from them. Doubtless
this belief is correct, so far as visible structural changes or measure-
able metabolic changes are concerned; but is there not reason to

REJUVENESCENCE AND DEATH 297

believe that the effect of a change in mental occupation or of a
vacation after long-continued mental labor in a particular field is
in some slight degree a rejuvenescence of the nerve cells? Many
facts indicate that a reasonable variety in mental occupation is a
factor in retarding mental senility. What we often call mental
fatigue may be something much less evanescent than fatigue in the
ordinary sense, but recovery may occur in time. Verworn (’o9,
Pp. 557) has drawn a distinction between fatigue, resulting from
accumulation of substances which retard metabolism, and exhaus-
tion, resulting from lack of oxygen or other substances necessary
for metabolism. Recently Dolley (’14) has maintained that both
of these changes may bring about senility in the nerve cell. Ex-
haustion, I believe, resembles senility as death from asphyxiation
resembles death from old age. In both exhaustion and senility the
rate of oxidation may be decreased, but the factors involved and
the condition of the organism in the two cases are very different.
Recovery from exhaustion is then not the same sort of change as
rejuvenescence except as it involves increase in rate of oxidation.
Fatigue and recovery constitute a cycle resembling much more
closely the age cycle.. As I have pointed out in chap. viii, it is im-
possible to draw the line sharply between age changes and various
other periodic or cyclical changes in the organism, and, although
the nervous system is without doubt a highly stable tissue, the very
definite physiologically regressive changes which occur in recovery
from mental fatigue or from long-continued mental activity of a
particular kind suggest that changes closely approaching rejuvenes-
cence occur. Even here development is not always and only pro-
gressive, as Minot and many others would have us believe, but is
made up of progressive and regressive changes with the balance
greatly in favor of the former.

The occurrence of rejuvenescence in connection with starvation
in planarians raises the question whether any changes in this direc-
tion are associated with starvation in the higher animals. The
metabolism of starvation in man and the higher vertebrates has
been extensively studied by many investigators,' and there is

« See the bibliographies in the the article by Weber, ‘“‘ Uber Hungerstoffwechsel,”’
Ergebnisse d. Physiol., 1, 1902, in the paper by Pembrey and Spriggs, ’o4, and in Bene-
dict’s studies of starvation metabolism in man (Benedict, ’o07, ’15).

298 SENESCENCE AND REJUVENESCENCE

general agreement that the rate of metabolism falls rapidly during
the early stages of starvation to a more or less constant level. In
the later stages of starvation the well-known premortal increase
in nitrogen elimination occurs, which most authors believe to be
due to increased breakdown of tissue substance after the reserves
of fat have largely disappeared. In Benedict’s latest study of
starvation-metabolism, covering a fasting period of thirty-one days
in the human subject, the oxygen consumption, carbon-dioxide pro-
duction, and heat production per kilo of body-weight show a slight
increase toward the end of the period, and other investigators men-
tion slight changes of the same sort, but whether these facts have
any significance in connection with rejuvenescence is not yet clear.
While considerable loss of weight occurs before death, in no case
is there a degree of reduction comparable to that observed in the
lower invertebrates. Apparently the higher animals are unable
for some reason to use their own tissues as a source of nutrition to
any such extent as the lower forms. Probably this inability is due
in large part to the relatively high physiological stability of the
tissue components, but other factors may also be concerned.

While there is no distinct indication of any rejuvenescence
during the starvation period, it has often been noted that the body-
weight after starvation becomes greater than before. Von Seeland
(’87) found this to be the case in fowls with periodic starvation. The
increase in weight was due primarily to increase in proteids and
not to deposition of fat. Noé (’oo) obtained similar results by
periodic starvation of rabbits and mice. In man also a starvation
period is often followed by an increase in vigor and body-weight,
and starvation, properly controlled, is believed by many to possess
a certain therapeutic significance.

The injurious effects of overnutrition in man are commonly
supposed to be due in large measure to the accumulation of fat or
to intoxications. The possibility must, however, be admitted that
overnutrition may actually increase the rate of senescence to some
slight extent by increasing the deposition in the cellular substratum,
not only of fat, but of other substances which aid in decreasing the
general rate of metabolism. Instances of longevity in man on a
low diet are not lacking, and much has been written during recent
years of the perils of overeating.

REJUVENESCENCE AND DEATH 299

In certain bacterial diseases, such for example as typhoid fever,
a very great decrease in body-weight may occur, and it is often
observed that the body-weight becomes greater and the person
apparently more vigorous after recovery than before the illness.
These various facts viewed in the light of the effects of starva-
tion and reduction in the lower invertebrates indicate that, even in
man, reduction by starvation or other means may bring about some
degree of rejuvenescence through the breakdown and elimination
of constituents of the cellular substratum. During reduction in
these cases the rejuvenescence is potential rather than actual, and
it becomes apparent only when recovery occurs. But rejuvenes-
cence by reduction is limited in the higher animals, for reduction
in these forms soon ends in death, so that there is at present no
immediate prospect of our being able to rejuvenate ourselves to
any great degree, or to retard senescence or delay death to any
great extent by any such means. Under certain conditions long-
continued or periodic starvation may bring about an appreciable
rejuvenescence, but it is not in any sense a cure-all for human ills.
There is not the slightest doubt that certain recent books and
articles on the therapeutic value of starvation, written by laymen
who have experimented on themselves, have done great harm to
many persons. Certainly no one who desires to subject himself to
experiment of this kind should do so without submitting first to a
thorough medical examination and to medical observation and
control during the experiment. Where weakness or organic disease
exists, such experiments may be only a means of aggravation and
so hasten, rather than delay, death. And even if such diseases as
typhoid fever do in some cases accomplish a slight degree of rejuve-
nescence, no one will be inclined to regard them as an unmixed good.
In too many cases they serve only to develop or aggravate
weaknesses or to prepare the way for other infections, and so to
shorten life rather than to prolong it.
. A recent study of the susceptibility to the cyanides and to lack
of oxygen of fishes during starvation, by Mr. M. M. Wells,’ seems
to indicate that, as regards the effect of starvation, the fishes

1 Mr. Wells, formerly an assistant in the Department of Zodlogy of the University
of Chicago, has not yet completed his investigations, but very kindly permits the
citation of certain of the results obtained.

300 SENESCENCE AND REJUVENESCENCE

occupy a position intermediate between the higher vertebrates
and the lower invertebrates, such as Planaria. Thus far Mr. Wells
has found that the susceptibility to cyanide and lack of oxygen
decreases early in starvation and remains more or less constant
during the first month or six weeks and then undergoes a rapid
increase and may become as high as that of well-fed growing indi-
viduals of much smaller size than the starved animals at the begin-
ning of the experiment. Apparently the rate of metabolism falls
early in starvation and remains relatively low for several weeks while
decrease in weight goes on, but after several weeks the rate begins to
rise and may reach that of animals which are physiologically much
younger than the starved animals were at the beginning. During
the first part of the period the starved fishes behave as regards rate
of metabolism like the warm-blooded animals, but later a rise in
rate occurs like that which the planarians show from the beginning.
Any attempt at interpretation of these results must at present,
however, be little more than a guess. The experiments suggest
that after removal or transformation of certain constituents of the
substratum the cells begin to burn themselves up at an increasingly
rapid rate as in Planaria, and so a much greater degree of rejuvenes-
cence occurs, at least in some tissues, than in the mammals.

It has long been known that frogs and salamanders may live
for long periods of time without food and may undergo a consider-
able degree of reduction during starvation. In his studies of the
effects of starvation on members of this group Morgulis (’11, ’13)
has found that protracted starvation has a distinctly rejuvenating
effect. After starvation the animals grow more rapidly, use a
larger percentage of the nutrition in growth, and attain larger size
than those continuously fed. Contrary to von Seeland (p. 298),
Morgulis finds that intermittent starvation has a stunting effect,
but suggests that in his experiments the animals did not com-
pletely recover between starvation periods.

In man and the higher vertebrates and probably also in the
higher invertebrates, such as the insects, individuation and differ-
entiation have progressed so far that after the earlier stages of
development any considerable degree of reduction or regression is
impossible under ordinary conditions without endangering in one

REJUVENESCENCE AND DEATH 301

way or another the continued existence of the whole mechanism.
But the facts indicate that even in such organisms some degree of
regression and rejuvenescence may occur.

LENGTH OF LIFE AND DEATH FROM OLD AGE

When the rate of metabolism becomes so low in consequence of
advancing senescence that the cell or organism can no longer
synthesize its metabolic substratum in sufficient amount to com-
pensate the losses, atrophy begins and must sooner or later end in
the destruction of the physiological mechanism, which is death.

In a complex organism like man, different cells and tissues grow
old at different rates, and death from old age of the organism as a
whole does not by any means imply the death of all its cells. Death
of cells apparently from old age occurs from early stages of develop-
ment throughout the whole life history, and we also know that
most of the cells of the body do not die when death of the individual
occurs. The individual dies when some tissue or organ which is
essential for its continued existence reaches the point of death,
and since the parts are incapable of dedifferentiation and a new
individuation, the other organs or cells die sooner or later because
of lack of nutrition or oxygen, or because of the accumulation of
toxic products of metabolism.

So-called physiological death in the higher animals is then due
to the breakdown of the physiological mechanism of the indi-
vidual at some essential point, and not to the simultaneous death
of all parts. As regards this fact different authorities are agreed,
but wide differences of opinion exist as regards the organ or organs
responsible for breakdown of the mechanism. Miihlmann (’oo,
’z0, ’14) and Ribbert (08) maintain that physiological death is
essentially a death of the brain; Lorand (’11), that the glands of
internal secretion are primarily responsible; and Demange (’86)
and Metchnikoff (’03, ’10) regard arteriosclerosis as the most
important factor in death.

Without attempting any extended discussion of these and other
views, it may be pointed out that the growth of the central nervous
system begins and is completed earlier, and that its development is
apparently more continuously progressive, with less rejuvenescence,

302 SENESCENCE AND REJUVENESCENCE

than that of other organs. Even in starvation the nervous system
shows little or no reduction. There is, therefore, some reason for
believing with Miihlmann and Ribbert that death from old age
uncomplicated by disease or incidental factors is primarily a death
of the nervous system, and both the histological characteristics of
the nerve cells and the physiological condition of the nervous system
in cases of extreme old age afford support to this view. Even in
invertebrates as low in the scale as annelids, Harms (12) has
observed that the first structural changes preceding natural death
occur in the cephalic portion of the central nervous system.

But death from old age alone without any complicating factors
is undoubtedly rare, and it is very difficult to determine in any
given case whether complicating factors are present or not; con-
sequently it is not possible to assert positively that natural death
is in all cases death of the brain or nervous system, although the
evidence points in that direction.

In various insects and in certain fish, e.g., the salmon, death
occurs almost at once after extrusion of the sexual products. In
such cases the factor immediately concerned in bringing about
death is probably exhaustion rather than old age, although the
organism is undoubtedly in an advanced stage of senescence when
sexual maturity is attained. In certain insects and some other
invertebrates which do not feed in the adult stage natural death
is probably a death from starvation.

The natural length of life of organisms must depend on a variety
of factors, such as specific constitution of protoplasm, rate of senes-
cence, continuity of progressive development, or in other words the
degree of rejuvenescence during the life history, functional activity,
perhaps the amount and in some forms probably also the character
of food. In general it represents the length of time from the
beginning of senescence in the early stages of development to the
stage where the rate of metabolism is so low that the physiological
mechanism disintegrates. Commonly the life of the organism is
very much longer than that of many of its constituent cells, but it
is probable that the extreme limit of life of the individual is deter-
mined by the length of life of its shortest-lived essential organ or
tissue, and this must be the organ or tissue which is least subject to

REJUVENESCENCE AND DEATH 303,

or capable of regression and rejuvenescence and whose develop-
ment is consequently most continuously progressive. In the higher
animals this organ is unquestionably the central nervous system.
This line of evidence, therefore, lends further support to the view
that natural death is a death of the nervous system.

In the warm-blooded vertebrates, where rejuvenescence plays
a minor part in the life history, the length of life in a particular
species is a more or less definite length of time, because the rate of
metabolism is largely independent of external conditions and the
rate of development and senescence is therefore determined largely
by internal factors which are more or less constant for the species.
In the cold-blooded animals, however, where rate of metabolism is
dependent on external temperature, senescence can unquestionably
be retarded, and so the length of life increased, by low temperature.
Moreover, in many of these animals long-continued starvation
and extensive reduction may occur with complete recovery, and
there is no doubt that under such conditions a greater or less degree
of rejuvenescence and consequently an increase in length of life
may occur in some cases. As regards the lower invertebrates, it
was shown in an earlier chapter that senescence may be retarded
or inhibited for a long time and probably indefinitely by the simple
means of underfeeding. This is of course not possible in the higher
animals, for their most stable tissues undergo senescence to some
extent even under these conditions.

Among the lower animals and the plants cell death occurs, as
in the higher forms, as the end of progressive development, and
death of the many-celled individual may occur if progression and
senescence are not balanced by regression and rejuvenescence.
Even in the unicellular forms reproduction by fission brings about
some degree of rejuvenescence, and it is probable that nuclear and
cell division in general accomplish the same result to some slight
degree. When cells lose the capacity to divide they differentiate,
grow old, and sooner or later die. In short, the only conclusion
warranted by the facts is that death is everywhere the final result
of progressive development, if the process goes far enough, but in
many organisms progressive development is interrupted by regres-
sive processes connected with repair, reproduction, lack of food, or

304 SENESCENCE AND REJUVENESCENCE

other conditions, and the death point is never attained by the indi-
vidual, although even in such forms death of cells, apparently from
old age, may be a characteristic feature.

The appearance of death in the course of evolution as the end
of the life history of the individual is to be regarded as a result of
the increasing physiological stability of the substratum of the
organism and the increasing degree of individuation which the
greater stability makes possible. These changes determine a
greater degree of continuity of progressive development and senes-
cence and so less frequent and less extensive regression, reproduc-
tion, and rejuvenescence.

As the evolution of the individual advances with its increasing
differentiation and more intimate correlation of parts, death as the
termination of the individual life history becomes more and more

inevitable.
SOME THEORIES OF LENGTH OF LIFE

Most authors who have discussed senescence have regarded
death as merely the final termination of the processes of senescence,
whatever their view concerning the nature of these. But certain
of the theories advanced which concern themselves particularly
with the problem of the length of life require special mention here.

Some thirty years ago Weismann (’82, ’84) first stated his view
that the cause of death lies in the limitation of capacity for cell
reproduction. In the unicellular organisms, according to Weis-
mann, this capacity is not limited, therefore the protozoa do not
die. In the multicellular organism, however, only the germ cells
retain the capacity for unlimited division; in the somatic cells the
number of possible cell divisions has been limited by the action of
natural selection, which determines in general that life shall not
continue long after the reproductive period is completed. In later
writings (’92, ’04) Weismann has elaborated this idea further, but
without essential change. The theory concerns itself with the
evolution of length of life and of death rather than with the problem
of the nature of the physiological processes involved. Death must
of course have occurred before the length of life could be subjected
to the action of selection. Weismann maintains, however, that
death is not a fundamental characteristic of life, but an adaptation

REJUVENESCENCE AND DEATH 305

which has arisen ‘‘because unlimited duration of the life of the
individual would be a senseless luxury.” In other words, death
appeared at some time as a chance variation which was inherited
and was of such value to the organic world that through the action
of natural selection it has become universal in multicellular organ-
isms. Death was possible in these forms because somatic and germ
cells were separated, while in the unicellular forms they are one and
the same cell.

The problems of death and length of life find no solution in these
speculations. The occurrence of death is simply assumed as the
foundation of the theory. But it is not true that all multicellular
forms necessarily die. As I have endeavored to show, many forms,
both plants and animals, may escape death by reproduction and
rejuvenescence in exactly the same way as do the protozoa. On
the other hand, there is every reason to believe that if the protozoa
live long enough without reproduction they too die of old age and
the germ cells of the multicellular forms also apparently undergo
senescence and die of old age if rejuvenescence is not initiated by
fertilization (see pp. 403-6). The evidence also indicates that
death occurs in general soon after the period of sexual reproduction
is over, not because of advantage to the species, but because sexual
maturity is a physiological feature of relatively advanced age. Pro-
gressive development, which ends in death, except where interrupted
by regression, is far advanced when sexual reproduction begins.
And, finally, it is rather remarkable that natural selection should
have succeeded so completely, as Weismann believes it has, in elimi-
nating the species in which death does not naturally occur.

A theory of length of life of a very different sort, based pri-
marily upon calorimetric investigations on various domestic mam-
mals and man, has been advanced by Rubner (’o08, 09). From the
available data Rubner has calculated the total energy requirement
in calories for a doubling of body-weight after birth and the require-
ment per kilogram of body-weight for the whole period of life after
growth is completed in a number of the domestic mammals and
man. The total calories required for the doubling of weight are
given in Table VI, and the total calories per kilogram of body-
weight for the period after completion of growth in Table VII.

306 SENESCENCE AND REJUVENESCENCE

The totals for all except man show a rather close agreement in
each table, and while Rubner admits that the data on which these
figures are based are not in all cases satisfactory, he concludes
from the figures that the amounts of energy required, first, for the
doubling of weight in growth and, secondly, for the maintenance of
each kilogram of body-weight during adult life, are the same in
all species in the tables except man. Man uses a much greater

TABLE VI
FOPSE ip og ssn gee teas 4,512 PIG eed eee oes 3,754
COW id ws bas Shaccts Saud 4,243 DOG sei sea gcitne eae 4,304
Sheep .ise cus eee 3,930 Ca ticmiecyie ens 4,554
IMEEM ) se auheet neat 4 28,864 Rabbit.......... 5,006
TABLE VII
Mate ncn ea Wend 725,770 DOB eo pains acis 163,900
Horse.......... 163,900 Gat segue eee 223,800
COWs sadsecdtars I41,090 Guinea-pig...... 265,500

amount of energy in both cases, i.e., a much smaller percentage of
the energy of food is concerned in growth and maintenance of body-
weight in man than in theothermammals. These results of his cal-
culations lead Rubner to suggest that the living substance can
undergo only a certain number of atomic rearrangements before
becoming exhausted and breaking down. According to this view,
life is terminated by the completion of a complex chemical
reaction.

While I do not regard myself as qualified to criticize the methods
of calculation, or the data on which these are based, though they
may be open to criticism at certain points, Rubner’s general conclu-
sion demands consideration on general biological grounds. Assum-
ing the validity of the data and methods of treatment, considerable
uniformity in energy requirement in the mammals is to be expected,
for they are closely related to each other, the rate of metabolism is
not widely different in different species, and progressive develop-
ment is not to any great extent interrupted by regression and
rejuvenescence. ‘The facts scarcely warrant us in going beyond the
conclusion that development is a similar process in all these mam-
malian species. If life is terminated, not by the completion of a

REJUVENESCENCE AND DEATH 307

complex reaction, as Rubner suggests, but by changes in the sub-
stratum which retard metabolism, the domesticated mammals might
certainly be expected to require somewhere near similar amounts
of energy to attain the death point.

Rubner fails entirely to take into account the fact that in all
the species under consideration the length of life of different cells
is very different. Some die after a life which is short compared
with the life of a whole organism, and are replaced by others, so
that in some tissues growth and development continue throughout
the life of the animal. Other cells apparently persist as long as the
animal lives, and it is probably these, e.g., the cells of the nervous
system, which are primarily responsible for natural death, as sug-
gested above. Rubner’s theory also does not admit the possibility
of rejuvenescence except in connection with fertilization, nor does
it show how the starting-point of the complex reaction is again
attained at the beginning of each generation. As regards the
exceptional position of man, Rubner believes that the human living
substance is different from that of other mammals and requires a
much larger amount of energy for a given amount of growth.
These data compare man with domesticated mammals; if it were
possible, it would be of considerable interest to determine whether
the energy requirements are the same in wild as in domesticated
animals. It seems probable that they would be higher in the wild
forms.

In a number of papers Loeb has discussed the nature of the
processes which bring about death in the mature egg when it is not
fertilized and has described certain methods by which its life can
be prolonged. In two papers, however (Loeb, ’o2, ’08), he has
dealt with the problems of death and length of life in a more general
way. The starfish egg, if not fertilized, dies, usually within a few
hours after maturation, but if it is prevented by lack of oxygen
from undergoing maturation its life may be prolonged for days.
From these facts Loeb concludes that natural death in these cases
is due to specific destructive processes which are set going by
maturation. These processes cannot be identical with the pro-
cesses underlying development, because they are inhibited or
delayed by the fertilization of the egg.

308 SENESCENCE AND REJUVENESCENCE

In the second paper he uses the temperature coefficient of the
length of life of sea-urchin eggs at high temperatures as a basis for
his conclusions. To determine the temperature coefficient of length
of life Loeb subjects lots of freshly fertilized eggs of sea-urchins to
different temperatures above that in which they normally develop,
and then, by removing portions of each lot at intervals to room
temperature and allowing them to develop, he finds the length of
time at the high temperature which is just necessary to prevent the
eggs from developing into normal swimming larvae. The ratio
of these times for different temperatures is the temperature coeffi-
cient. These experiments give a temperature coefficient of approxi-
mately 1,000 for 10° C., ie., it requires only about one-thousandth
as long at 30° as at 20° C. to injure the eggs so that they do not
produce normal larvae. The temperature coefficient of the length
of life of unfertilized eggs Loeb finds to be about the same.

The temperature coefficient of embryonic development in the
sea-urchins is 2.86 for 10° C., which means that a rise in tempera-
ture of 10° increases the rate of development 2.86 times. This
is about the usual temperature coefficient of chemical reaction at
these temperatures.

Loeb’s argument is that if the processes which determine devel-
opment and those which determine length of life are identical, they
must have the same temperature coefficient, and since they do not,
he concludes that they must be different. Death is therefore not
the final result of development, but of specific processes quite dis-
tinct from the developmental processes. He also attempts to
account for the supposed large numbers of individuals in the animal
life of cold waters on this basis; at 10°, for example, animals develop
about one-third as rapidly but live one thousand times as long as at
20°; therefore the number of individuals alive at any given time
must be much greater at the lower than at the higher temperature.

There are several objections to this line of argument. In the
first place, the processes which immediately determine death may
be very different from those which underlie development, and still
death may be the result of the developmental processes, because
these bring the organism into a condition where the death changes
can occur. Loeb, himself, admits this when he says that the

REJUVENESCENCE AND DEATH 309

destructive processes which bring about death in the unfertilized
egg are set going by the maturation process. Maturation is a
normal feature of the life history of the egg, and to say that it leads
to death is merely to say that the end of the developmental history
is death.

As regards the conclusions drawn from the temperature coeffi-
cient of length of life, Loeb assumes that death from high tempera-
ture is identical with natural death from old age, although there is
no evidence that this is the case. Certainly there is little reason for
believing that the death of embryos in early stages or of larvae is
the same thing as the death from old age of full-grown animals.
Death in these early stages, however it occurs, is undoubtedly due
to processes different from the developmental processes, but it is at
the same time an indication that something has gone wrong and
not in any sense a natural physiological death. To make an acci-
dental process of this kind the basis for conclusions concerning
length of life and physiological death under natural conditions is
certainly not warranted until convincing proof that the two are
identical is presented. Loeb has failed completely to show that
the processes which bring about death at high temperature have
anything to do with physiological death in nature and he has
presented no evidence to show that physiological death is not the
result and final stage of development.

CONCLUSION

As regards the relation between senescence, death, and rejuve-
nescence, the higher animals and man differ from the lower organisms
in the limitation of the capacity for regression and rejuvenescence
under the usual conditions. Senescence is therefore more continu-
ous than in the lower forms and results in death, which is the final
stage of progressive development. These characteristics of man
and the higher animals are connected with the evolutionary increase
in the physiological stability of the protoplasmic substratum and
the higher degree of individuation which results fromit. Neverthe-
less, some degree of rejuvenescence occurs, even in man, and differ-
ent tissues differ as regards their capacity for rejuvenescence, the
central nervous system being apparently least capable of regressive

310 SENESCENCE AND REJUVENESCENCE

changes. This characteristic of the nervous system suggests the
probability that the natural or physiological length of life in these
forms is determined primarily by the length of life of the nervous
system and that physiological death is primarily the death, as the
final stage of senescence, of the nervous system. This view is
supported by various facts of observation.

Physiological or natural death is not something which has
originated in the course of evolution from the lower to the higher
forms. All organisms, from the lowest to the highest, from the
simplest to the most complex, undoubtedly die of old age, unless
senescence is compensated by rejuvenescence. In the lower forms
the death point may never be attained under the usual conditions
because the low stability of the substratum and the consequent
low degree of individuation permit the frequent occurrence of a high
degree of rejuvenescence. In the higher forms death becomes
inevitable and necessary because the capacity for rejuvenescence
is limited by the greater stability of the substratum. For his high
degree of individuation man pays the penalty of individual death,
and the conditions and processes in the human organism which
lead to death in the end are the conditions and processes which
make man what he is. The advance of knowledge and of experi-
mental technique may make it possible at some future time to
bring about a greater degree of rejuvenescence and retardation of
senescence in man and the higher animals than is now possible, but
when we remember that the present condition of the protoplasmic
substratum of these organisms is the result of millions of years of
evolutionary equilibration, we cannot but admit that this task may
prove to be one of considerable difficulty.

REFERENCES
BENEDICT, F. G. '

1907. ‘The Influence of Inanition on Metabolism,” Carnegie Inst. Publ.,
No. 77.
tots. “A Study of Prolonged Fasting,” Carnegie Inst. Publ., No. 203.

Campy, C.
1913. ‘‘La différenciation des tissus cultivés en dehors de l’organisme,”
Bibliogr. Anat., XXTII.
1914. ‘Notes de biologie cytologique. Quelques résultats de la méthode
de culture de tissus: ITI, Le rein,” Arch. de zool. exp., LIV.

REJUVENESCENCE AND DEATH 311

DEMANGE. |
1886. Etude clinique et anatomo-pathologique de la vieillesse.
Dottey, D. H.
1914. ‘On a Law of Species Identity of the Nucleus-Plasma Norm for
Nerve Cell Bodies of Corresponding Type,” Journal of Comp.
Neurol., XXIV.
Harms, W.
1g12. “‘Beobachtungen iiber den nattirlichen Tod der Tiere. I. Mitt.
Der Tod bei Hydroides pectinata Phil., nebst Bemerkungen iiber
die Biologie dieses Wurmes,”’ Zool. Anzeiger, Bd. XL.
Logs, J.
1902. “Uber Eireifung, natiirlichen Tod und Verlingerung des Lebens
beim Seesternei,”’ Arch. f. d. ges. Physiol., XCIII.
1908. “Uber den Temperaturkoeffizienten fiir die Lebensdauer kalt-
blutiger Tiere und iiber die Ursache des natiirlichen Todes,”’
Arch. f. d. ges. Physiol., CXXIV.
Loranp, A.
tg11. Das Altern, seine Ursachen und seine Behandlung. Leipzig.
METCHNIKOFF, E.
1903. The Nature of Man. English translation: New York and London.
1910. The Prolongation of Life. English translation: New York and
London.
Minor, C.S.
1908. The Problem of Age, Growth and Death. New York.
1913. Moderne Probleme der Biologie. Jena.
Mont1, R.
190s. “Il rinnovamento dell’ organismo dopo il letargo.”” Monitore Zool.
Ital., XVI.
Morcuts, S.
tg11. “Studies of Inanition in Its Bearing upon the Problem of Growth,”’
Arch. f. Entwickelungsmech., XOCXII.
1913. ‘The Influence of Protracted and Intermittent Fasting upon
Growth,” Am. Nat., XLVII.
Mtutmann, M.
1900. Uber die Ursache des Alters. Wiesbaden.
toro. ‘Das Altern und der physiologische Tod,” Sammlung anat. u.
physiol. Vortr., XI.
1914. ‘‘Beitrige zur Frage nach der Ursache des Todes,” Arch. f. Pathol.
(Virchow), CCXV.

tgoo. ‘La réparation compensatrice aprés la jeune,” Compt. rend. de la
Soc. biol., LIT.

312 SENESCENCE AND REJUVENESCENCE

PemBrey, M. S., and Sprices, E. I.
1904. ‘‘The Influence of Fasting and Feeding upon the Respiratory and
Nitrogenous Exchange,” Jour. of Physiol., XXXI.
RipzBert, H.
1908. Der Tod aus Altersschwiche. Bonn.
Rusner, M.
1908. Das Problem der Lebensdauer und seine Beziehungen 2u Wachstum
und Ernéhrung. Miinchen.
1909. Kraft und Stoff im Haushalte der Natur. Leipzig.
SEELAND, VON.
1887. “Uber die Nachwirkung der Nahrungsentziehung auf die Ernah-
rung,” Biol. Centralbl., VII.

VERWORN, M.

1909. Allgemeine Physiologie. V.Auflage. Jena.
WEISMANN, A.

1882. Uber die Dauer des Lebens. Jena.

1884. Uber Leben und Tod. Jena.

1892. Das Keimplasma. Jena.

1904. Vortrége iiber Descendenztheorie. II. Auflage. Jena.

ZIEGLER, E.
rgo1. Allgemeine Pathologie. X. Auflage. Jena.

PART IV

GAMETIC REPRODUCTION IN RELATION TO THE AGE CYCLE

CHAPTER XIII

ORIGIN AND MORPHOLOGICAL AND PHYSIOLOGICAL CONDITION
OF THE GAMETES IN PLANTS AND ANIMALS

THE THEORETICAL SIGNIFICANCE OF GAMETIC ORIGIN

The question of the origin of the gametes or sex cells derives its
chief importance from the germ-plasm theory, first advanced by
Galton (’72) and Jager (’77) and later developed by Weismann
(85, ’92), which postulates the continuous existence of a germ plasm
independent of the soma—that is, of other parts of the organism—
except for nutrition, and giving rise to the gametes. If such a
germ plasm exists and is continuous from generation to generation
we should expect to find in at least some organisms indications of
the separate existence of germ plasm and soma, even in early stages
of development. An early segregation of the germ plasm from the
somatic cells has been recorded for various animals and these facts
have commonly been regarded as affording support to the germ-
plasm hypothesis. Other facts, such as the formation of gametes
and the occurrence of regeneration from apparently differentiated
cells in some animals and in plants, forced Weismann to assume the
existence of a ‘‘supplementary germ plasm”’ which was supposed to
exist in the nuclei of many differentiated cells and which might be
“activated”? under the proper conditions and give rise to new
embryonic cells, or even to gametes. The existence of this supple-
mentary germ plasm may be assumed wherever it is necessary for
the theory, so that a vicious circle is established.

But when we consider the facts apart from theoretical considera-
tions, we find that the gametes appear to be integral parts of the
organism when they arise, that they become highly specialized and
differentiated cells, and that fertilization, whatever the nature of
its mechanism, initiates a process of dedifferentiation and rejuve-
nescence which is followed by another period of differentiation and
senescence. This and the two following chapters are concerned
with the development of this point of view.

315

316 SENESCENCE AND REJUVENESCENCE

-THE ORIGIN OF THE GAMETES IN PLANTS

Thus far no evidence has been discovered among the plants of an
early separation of the primitive germ cells from other so-called
somatic portions of the organism, such as has been described for
various animals (see pp. 323-33). No Keimbahn or germ path
exists in the plants, that is, the germ cells cannot be followed through
the developmental history as cells or protoplasmic regions distinct
from other parts of the body.

In that group of the green algae known as fhe Conjugales,
which includes Spirogyra and the desmids, in the diatoms, and
in most of the ciliate infusoria among the animals, the cell which
constitutes the body of the organism becomes the gamete without
any or with comparatively little visible structural change; two

‘such cells conjugate, and their contents fuse to form the
zy gospore.

Tn other algae and in those fungi in which gametic reproduction
is known to occur, the gametes are always more or less different
both in morphological structure and behavior from other parts of
the organism, but they originate from the plant body and to all
appearances are the most highly specialized parts of, the species,
and, finally, in most cases, show a high degree of sexual differentia-
tion, as the following figures show. Fig. 123 shows the young egg
cell of Volvox, Fig. 124 a Volvox spermatozoid, Fig. 125 the o6gonium
and antheridium of the alga Oedogonium with female and male
gametes, Fig. 126 the sex organs of Chara with the single egg in the
odgonium, and Fig. 127 a spermatozoid of Chara. In Fig. 128
the sex organs of the fungus Saprolegnia and their relation to the
vegetative part of the plant are shown. Im all these cases
the gametes show the same sort of sexual differentiation as in the
multicellular animals. In the mold Mucor, however, the ends of
two hyphae enlarge and come together, and a gametic cell is sepa-
rated from each (Fig. 129), but the two cells are not, so far as
known, sexually differentiated. These two cells increase in size
(Fig. 130) and unite to form the zygospore (Fig. 131). In none
of these cases is there any trace of an early segregation of the germ
cells from the rest of the plant. The sex organs and germ cells
appear only when the plant attains a certain physiological condition.

THE GAMETES IN PLANTS AND ANIMALS 317

Fics. 123-127.—Gametes of various algae: Fig. 123, young egg cell of Volvox
aureus, connected with surrounding vegetative cells by numerous plasmatic strands
(from Klein, ’89); Fig. 124, spermatozoid of Volvox aureus (from Klein, ’89); Fig. 125,
part of filament of Oedogonium, showing odgonium with large egg and below three
antheridia, from two of which spermatozoids have escaped (from Coulter, etc., ’10);
Fig. 126, branch of Chara, bearing oégonium, og, containing a single egg and antherid-
ium, an (after Sachs, from Coulter, etc., 10); Fig. 127, spermatozoid of Chara (from
Belajeff, ’94).

318 SENESCENCE AND REJUVENESCENCE

In the mosses and ferns the separate history of the germ cells
may in the male extend back to an early stage in the development
of the male sexual organ, the antheridium, where the sperma-
togenous cell or cells become separated from the cells of the
antheridial wall. Fig. 132 shows the stage of development of the
antheridium in which the spermatogenous cells first become segre-
gated in Riccia, one of the liverworts. After their segregation

Fics. 128-131.—Gametes of fungi: Fig. 128, odgonium of Saprolegnia, contain-
ing several eggs and antheridial tube piercing its wall in fertilization (from Coulter,
etc., 10); Figs. 129-131, three stages in formation and union of gametes in Mucor
(from Brefeld, ’72).

the spermatogenous cells undergo numerous divisions and finally
give rise to spermatozoids.

The female gamete, on the other hand, is not separated from
other non-gametic cells until the last division preceding fertilization.
Figs. 133-39 show the development of the archegonium of Riccia.
The divisions of the central cell in Fig. 135 produce the four neck
canal cells and the ventral cell (Fig. 137). Fig. 138 shows the
division of the ventral cell which gives rise to the ventral canal

THE GAMETES IN PLANTS AND ANIMALS 319

cell and the egg. The fully developed archegonium, containing
the egg o, is shown in Fig. 139. The canal cells take no part in
reproduction, but degenerate before fertilization.

FIGs. 132-139.—Stages of gamete formation in the liverwort Riccia: Fig. 132,
antheridium in stage at which spermatogenous cells become segregated from cells
of wall; Figs. 133-139, formation of archegonium and egg, 0,in Riccia. From Coulter,
etc., ’I0.

320 SENESCENCE AND REJUVENESCENCE

In the seed plants the whole gametophyte generation is greatly
reduced and represents scarcely more than specialized male and
female organs of the plant. In the lower seed plants, the gymno-
sperms, a considerable number of nuclear divisions may occur in
the development of the gametophyte, and the female gamete is
separated from other cells at some stage of this development.
In the male gametophyte of the gymnosperms the number of
divisions varies, but is always small, and in the course of these
divisions the male gamete is separated from non-reproductive
cells.

And finally in the angiosperms, which represent the final stage
in reduction of the gametophyte, the development of the male
gametophyte—the mature pollen
grain—from the microspore con-
sists, with one exception, of only
two nuclear divisions, of which the
first separates the primary sper-
matogenous cell from the tube
nucleus and the second divides
the spermatogenous nucleus into
two male gametes, so that the
male gametophyte contains only
three nuclei (Fig. 140).

Fic. 140.—Pollen grain of Silphium The course of development of
terebinthinaceum, showing rounded i
vegetative nucleus and the two elon- the female gametophyte, which is
gated male nuclei. FromMerrell,’0o. the embryo sac within the ovule,

is indicated in Fig. 141. The
nucleus of the megaspore (A) divides and the two daughter nuclei
pass to opposite poles (B); a second division occurs in each (C),
and a third follows (D), so that eight nuclei are present, four at each
pole, but without cell boundaries. Two nuclei, one from each group
of four, move toward the middle of the embryo sac and fuse to form
the primary endosperm nucleus. About the three nuclei at the
micropylar end (the upper end in the figures) three naked cell bodies
arise, and these three cells are the egg and the two synergids (£).
The three nuclei at the opposite pole form the three antipodal cells
which are usually ephemeral but may persist. Thus the germ

THE GAMETES IN PLANTS AND ANIMALS 321

plasm is segregated only at the last division preceding the final
differentiation of the egg.

Fic. 141.—Development of female gametophyte and formation of egg in the
higher seed plants: A, megaspore in the ovule; B, first division; C, second division;
D, third division; E, mature gametophyte: 0, egg; s, synergids; a, antipodals; f,
primary endosperm nucleus. After Coulter, etc., ’10.

322 SENESCENCE AND REJUVENESCENCE

The whole process of development of the gametes in the plants
bears all the marks of a highly specialized process, far removed from
anything which occurs in unspecialized embryonic cells, and no-
where do we find a separation of the gametic from the somatic
material before the later or final stages of the developmental
process.

The occurrence among mosses, ferns, and seed plants of what is
known as apogamy, i.e., the formation of a sporophyte without
fertilization from a vegetative cell of the gametophyte instead of
from the egg,’ is of interest in this connection. In apogamous
ferns the embryo apparently may rise from any vegetative cell of
the prothallium, which is the gametophyte, and in seed plants it
may arise either from the synergids or the antipodals of the embryo
sac, or from both. In some cases also among angiosperms sporo-
phytes may arise from cells of the nucellus or of the integument
adjacent to the embryo sac. These cells are not even parts of the
gametophyte, but belong to the sporophyte generation, yet in the
region of the embryo sac they may produce embryos and sporo-
phytes as does the egg. In such cases the gametophyte generation
is omitted from the life history.

All of these cases of non-sexual development from vegetative or
“somatic” cells of the sporophyte—the generation which usually
develops from the fertilized egg—indicate that the capacities of the
egg are not fundamentally different from those of other cells of the
gametophyte and of some cells of the sporophyte. It is of course
easy to assume with the Weismannians that, in spite of their
visible differentiations, all such cells contain an undifferentiated
germ plasm, but, so far as scientific analysis is concerned, this
assumption is equivalent to begging the whole question. A simpler
view and one much more nearly in accord with the facts of observa-
tion and experiment is that which is held by most botanists, viz.,
that many, or in some plants all, specialized or differentiated cells
may under proper conditions lose their specialization and become
embryonic and so give rise to new individuals.?

tSee Winkler, ’o8, for a general survey and bibliography of the subject.

2In the usual course of development all the cells of the gametophyte have the
reduced or haploid number of chromosomes like the animal egg after maturation,

THE GAMETES IN PLANTS AND ANIMALS 323

It was shown in an earlier chapter (pp. 245-47) that dediffer-
entiation undoubtedly occurs very commonly in plants, especially
in connection with adventitious and experimental reproduction.
The new plants thus formed from cells previously differentiated as
parts of other plants possess the capacity to form gametes. In
other words, gametes may very often arise from cells which form
differentiated parts of the plant body, and there is no evidence of
the continuous existence of any germ plasm in the theoretical sense
in such cells.

To sum up, we find in the plants no indication of continued or
early segregation of germ plasm from somatic plasm. In most
cases the gametes are not separated from somatic cells until the final
stages of their developmental history, and on the other hand
differentiated cells, in many cases every cell of the plant, may
undergo dedifferentiation and redifferentiation into new indi-
viduals capable of producing gametes. Either all the cells of the
plant contain germ plasm or there is no continuity of germ plasm
in the plant. The facts point to the second of these alternatives.
The gametes arise in the course of development like other specialized
parts, and like these also possess a definite history of differentiation.

THE ORIGIN OF THE GAMETES IN ANIMALS

In many of the unicellular animals, as in the unicellular plants,
the cell which constitutes the organism becomes the gamete. In
others the gametes are different in form from the vegetative stages,

the process of reduction occurring in the formation of the spores which give rise to the
gametophyte. But in various mosses and ferns apospory may occur, i.e., the gameto-
phyte may arise from other cells of the sporophyte without the occurrence of chromo-
some reduction, in which case the cells of the gametophyte, including the egg, possess
the full or diploid number of chromosomes. Where the gametophyte possesses the
haploid number of chromosomes, apogamy gives rise to a sporophyte with the haploid
number, half the number characteristic of sporophytes, but when the gameto-
phyte cells are diploid, the sporophyte which arises apogamously or parthenogeni-
cally possesses the full number. Various other combinations of apospory, apogamy,
parthenogenesis, and fertilization have been recorded. In certain mosses, for example,
the aposporous formation of diploid gametes, followed by fertilization and the develop-
ment of a tetraploid sporophyte, has been observed (Marchal, ’o07,’og,’11,’12). The
number of chromosomes is evidently not connected in any essential way either with
the differentiation of sporophyte and gametophyte or with the formation of the
gametes, since any of these stages may possess either the diploid or haploid number.

324 SENESCENCE AND REJUVENESCENCE

and sometimes spermatozoa and eggs approaching in morphological
differentiation those of the multicellular forms appear. In the
multicellular animals the process of gamete formation differs in
certain respects from that in the plant. There is in the animal no
developmental history with cell division, growth, and differentiation
between maturation and fertilization, corresponding to the gameto-
phyte generation in plants. The gametic cells are segregated from
other cells long before the maturation divisions occur. Since the
germ-plasm theory has found its adherents chiefly among zodlogists,
it is natural that the attention of zodlogical investigators should
have been attracted to the question of the early segregation of the
germ cells from the somatic cells. If the germ plasm is really a
distinct and separate entity independent of the soma and is con-
tinuous from one generation to another, we should expect the germ
cells to be segregated from the somatic cells at the beginning of
embryonic development. Thus far, however, no case has been
discovered in which such a segregation occurs, although in various
animal groups a more or less complete segregation apparently does
occur at an early stage of development. In other groups, among
the animals, no indication of such segregation has ever been ob-
served, although theoretical considerations have led many zodlo-
gists to believe that even in such cases a segregation occurs, but
without visible differences between germ cells and other cells.

To discuss this subject at length is beyond the present purpose,
but some of the more important cases of early segregation must be
briefly considered.t| Perhaps the most striking case of early segre-
gation of germ cells is that in the parasitic worm Ascaris megalo-
cephala, first described by Boveri and later confirmed by other
investigators, but recently denied by Zacharias. As every zodlo-
gist knows, the process of segregation of the germ cells in this
species begins at the first cleavage of the egg and is accompanied
by the peculiar process of “diminution” of the chromatin in the
somatic cells. Diminution, which occurs first in one cell of the

™For general surveys of the subject with bibliographies see Korscheldt and
Heider, ’o2, pp. 368-77; Waldeyer, ’06; Felix and Biihler, ’06; Hicker, ’12a, ’12b;
Hegner, ’14¢.

2 Boveri, ’87, 99, 04; zur Strassen, ’96; Zacharias, 13; Zoja, ’96.

THE GAMETES IN PLANTS AND ANIMALS 325

two-cell stage, consists in the separation of the large club-shaped
ends of the chromosomes, their exclusion from the nucleus of the
following resting stage, and their gradual disappearance in the
cytoplasm. At the same time the remaining portions of each
chromosome break up into a number of smaller chromosomes and
in following divisions of this cell similar small chromosomes appear,
and the nuclei of the resting stages are relatively small and poor
in chromatin. In the other cell, however, diminution does not
occur, the chromosomes retain their original form and large size,
and the resting nucleus is large and rich in chromatin. In the
second cleavage this cell gives rise to one cell which undergoes
diminution and one which does not, and in the third and fourth
cleavages also one cell remains with chromatin undiminished. In
the fifth cleavage the undiminished cell divides into two equal cells,
and these are, according to Boveri and others, the primitive germ
cells. Here then we can trace the line of descent of the germ cells,
the germ path (Keimbahn), from the first cleavage. The germ
path and the fates of the various cells which undergo diminution
are indicated in Fig. 142.

The process of early segregation of germ cells in Ascaris has been
very generally regarded as constituting almost a demonstration
of the continuity and independence of the germ plasm, but as a
matter of fact it is far from being anything of the kind. In the
first place, while it seems fairly certain that the reproductive organs
of Ascaris do arise from the undiminished cell line of descent, it is _
not known whether these cells give rise merely to the germ cells or
to the walls of the reproductive organs as well. In the latter case
the germ path of early cleavage has not resulted in the segregation
of germ plasm from the soma, but merely in the segregation of
different organs, for the walls of the reproductive organs are not
germ plasm.

Moreover, the whole process is very different from what we
should expect in a segregation of germ plasm from the soma. If
the germ plasm is a distinct entity, why should it not become
segregated in the first division instead of in the fourth? The first
four cleavages are really segregations into different cells, not simply
of germ plasm, but of various parts of the body, as Fig. 142 shows.

326 SENESCENCE AND REJUVENESCENCE

The diminished cell S, of the two-cell stage produces a definite part
of the ectoderm, and the cells S.,, S;, and S, of following generations
each have a definite fate. In other words, various portions of the
soma or body are segregated before the so-called germ plasm.

LN
\ IAMS

Ectoderm I

e
. \ I\ | :
oS C-oO 0
Entoderm II Entoderm Mesoderm I
and and

Mesoderm III Stomodeum
e e
——S

eo) O

Primitive germ cells Mesoderm II

Fic. 142.—Diagram of the cell lineage in the early cleavage of Ascaris megalo-
cephala: the black circles represent cells before chromatin diminution and the primitive
germ cells which do not undergo diminution; the unshaded circles with four black dots
about them represent the cells which undergo diminution, and the unshaded circles
alone, the cells after diminution. The further history of the various groups of cells
is indicated by the words, ‘‘ectoderm,”’ etc. After Boveri, ’10.

The undiminished cells show in all cases a slower rate of division
than those in which diminution has occurred, and there is no evi-
dence to show that the differences in the behavior of the chromatin
are anything more than visible indications or expressions of differ-
ences in rate of metabolic activity. It is quite possible that the
undiminished cells become germ cells because they have a low

THE GAMETES IN PLANTS AND ANIMALS 327

rate of metabolism and are not involved in the early differentiations,
but differentiate later.

A recent study of modified cleavage made by Boveri (’10) on
polyspermic and centrifuged eggs of Ascaris has proved beyond a
doubt that the occurrence or non-occurrence of chromatin diminu-
tion in a nucleus depends, not upon its qualitative constitution,
but upon its cytoplasmic environment. Ii this is true, persistence
of the undiminished condition is not a segregation of preformed
germ plasm, but a nuclear reaction to cytoplasmic conditions. The
‘germ path” is a feature of the cytoplasm, not of the nucleus, and
the cytoplasm is not, properly speaking, a part of the germ plasm
at all, but represents the soma of the cell. Which nuclei shall

Fics. 143, 144.—First and second division in egg of Cyclops, showing at one pole
of spindle the granules which mark the germ path. From Amma, ’11.

become the nuclei of germ cells is determined, not primarily by
the nuclei themselves, but by the soma of the cell; the germ plasm
is not then an independent entity, but is determined by correlative
factors, like any other part of the organism, except the apical or
head region.

Hicker (’97, ’02) has described a germ path for Cyclops and other
copepod crustacea, and his observations have been confirmed by
Amma (11). The germ path in this case is characterized by cer-
tain granules which appear at one pole of the first cleavage spindle
(Fig. 143), pass into one of the two daughter cells, and later aggre-
gate into larger masses and disappear. At the second division
(Fig. 144) and also at the third and fourth divisions similar granules

328 SENESCENCE AND REJUVENESCENCE

appear at one pole of the spindle of the cell to which the granules
passed in the preceding division, and in each case pass into one of
the two daughter cells, which continues the germ path. But in
the cell of the fifth generation the granules appear all around the
mitotic figure and pass into both daughter cells, which are according
to Hacker the primitive germ cells. Here the germ path is charac-
terized, not by peculiar nuclear features, but by cytoplasmic differ-
entiations which are products of metabolism: the germ cells are
evidently an integral physiological part of the organism. Some-
what similar germ paths have been described for various other
crustacea.

The early segregation of the primitive germ cells in Sagztta has
been noted by several authors, and Buchner (’10) has recently
discovered the beginning of the germ path in the granules resulting
from the degeneration of a nutritive cell taken up by the egg in
the ovary, again a cytoplasmic not a nuclear basis of segregation,
although the granules in this case may be of nuclear origin. Ina
discussion of other cases Buchner concludes that determination of
the germ path in this way is of very general occurrence.

In many insects a distinct germinal path with early segregation
of the primitive germ cells has been observed. Among the diptera
all forms carefully examined show some sort of germ path. In the
gnat Chironomus, for example (Hasper, ’11), the primitive germ
cell is segregated in the second cleavage (Fig. 145), and in the fly
Miastor (Kahle, ’08; Hegner, ’12, ’14@, ’14c) the segregation of the
mother germ cell occurs in the third cleavage, one nucleus of this
cleavage becoming imbedded in a peculiar cytoplasmic region at the
posterior end of the egg, and giving rise later to the germ cells,
while all the other nuclei undergo a process of diminution of chro-
matin somewhat similar to that occurring in Ascaris.

A cytoplasmic germ-path determinant in the form of a peculiar
granular cytoplasmic region at the posterior pole of the egg, which
during cleavage becomes nucleated and separates off as the primi-
tive germ cells, has recently been described for several chrysomelid
beetles, including the potato beetle, by Hegner (’o9, ’11, ’14@).
This author concludes with Boveri that the cytoplasm, not the
nuclei, determines which cells shall become germ cells, but this

THE GAMETES IN PLANTS AND ANIMALS 320

means that the germ cells are probably determined in essentially
the same way as other parts of the organism. In various other
insects also a germ path has been described. In certain hymenop-
tera Hegner (’146) finds that the granules of the polar cytoplasmic

region are derived from the disinte-
grated nucleus of a nutritive cell taken
up by the egg during its growth, an
origin very similar to that which
Buchner described in the case of Sagztta.

In all these cases among the inverte-
brates the factors determining what
shall become germ cells and what
somatic structures apparently exist in
the cytoplasm and not in the nuclei.
Moreover, the cytoplasmic regions
which determine the germ cells are not
directly related to the cytoplasm of pre-
existing germ cells, but very evidently
are simply regions where certain special
metabolic conditions exist. Cells
arising from these regions become germ
cells, just as those arising from other
regions become one part or another of
the body. It is of interest to note that
very generally the germ cells arise from
regions of the egg with a relatively low
metabolic rate. They very commonly
divide more slowly than other cells.
In fact, it seems possible that this low
metabolic rate, rather than any specific
character, determines that they shall
not take part in the early development
of the body, because other cells react

Fic. 145.—Early cleavage of
Chironomus, a gnat: the spindle
at the lower end of the egg
represents the primitive germ
cell; the cytoplasm about this
spindle separates with it from
the remainder of the egg and
divides into two cells, each of
which divides farther: From
Hasper, 711.

more rapidly than they do. They are, so to speak, left behind
and only later become an active functional part of the organism.

Among the vertebrates comparatively early segregation of the
primitive germ cells is apparently of wide occurrence in fishes,

330 SENESCENCE AND REJUVENESCENCE

amphibia, and reptiles. More than thirty years ago Nussbaum
(’80) described the early differentiation of the sex cells in fishes
and amphibia. Later, Eigenmann (’92, ’96a) described the early
segregation of germ cells in fishes and found that the primitive
germ cells in the fish Cymatogaster were segregated in the fifth cell
generation of cleavage, and Wheeler (’oo) found a relatively early
differentiation of the germ cells in the lamprey. Two years later
Beard (’o2), as the result of his work on selachians, reached the
conclusion that the germ cells are independent unicellular organisms
which pass a part of their life in the multicellular sterile soma.
This conclusion rests on*the occurrence in embryonic stages of
certain large cells seen by various investigators in certain regions
of the embryo and which are described as migrating to the position
of the sexual organs and later becoming the germ cells. Since
Beard’s paper, a large number of similar observations have been
made by various authors on fishes, amphibia, and reptiles.

As regards all these data on germ-cell segregation in the verte-
brates, the first question is the correctness of the observations.
Much time has been devoted to the observation of these cells in
the embryonic stages and but little to the details of their later fate.
Moreover, the extensive migrations described from various regions
of the embryo to the position of the sexual organs are in all cases
inferences from the examination of fixed and stained material.
But granting that the observations are correct, the segregation of
the germ cells is no earlier in most cases than that of many other
parts of the body, and such cases afford no valid evidence against
the view that the germ cells are integral, specialized parts of
the body like other organs. In most cases these early germ
cells in vertebrates are, like those of invertebrates, apparently
cells with a lower rate of metabolism than other parts of the
embryo. Often they retain yolk granules later than other cells,
and in all respects appear to be less active during early stages
(Eigenmann, ’96d).

At present the only conclusion possible from all these observa-
tions on germ paths and germinal segregation is that while the data,
if correct, as they probably are in at least many cases, do indicate
that in various forms the germ cells become more or less distinctly

THE GAMETES IN PLANTS AND ANIMALS 331

segregated from other cells at early stages of development, they do
not in any way constitute a valid argument for the independence
and continuity of the germ plasm.

Moreover, there are many animals in which up to the present
time no indication of early segregation of germ cells has ever been
found by any investigator. In some of these forms, e.g., certain
flatworms and the polychete annelids, the sex organs appear only
at a certain stage of development, or periodically, and before or
between the periods of their occurrence no traces of anything
representing germ cells can be found. The assumption has often
been made that in such cases the germ plasm is segregated in cer-
tain cells, but that these cells possess no characteristic visible features
distinguishing them from other cells or.tissues. In the turbellaria,
for example, the parenchyma has often been regarded as an “‘in-
different”? tissue representing the germ plasm. But the only
justification for terming such tissues as the turbellarian parenchyma
indifferent or undifferentiated tissues lies in the fact that they give
rise to germ cells and in reconstitution to various other parts.
Morphologically they are not undifferentiated, but possess definite
histological characteristics quite different from those of cells or
tissues which are really embryonic or undifferentiated, and when
other tissues or organs arise from them they first lose these charac-
teristics and become embryonic and then undergo a new differen-
tiation. Moreover, when they undergo such changes their rate of
metabolism becomes higher, an indication that they are undergoing
dedifferentiation and becoming younger. They may be less
highly specialized than certain other tissues of the organism, but
only theoretical grounds can prevent us from admitting that where
the germ cells arise from such tissues they arise from differentiated
functional parts of the organism by a process of dedifferentiation
and redifferentiation.

In the tapeworm Moniezia, for example, the sex cells arise from
the parenchyma, and apparently any parenchymal cells which lie
within the region involved in the production of sex cells may undergo
dedifferentiation and take part in the process. Even the large
muscle cells may give rise to testes, as indicated in Figs. 146 and 147.
In such cases the muscle fiber undergoes degeneration, the vacuoles

332 SENESCENCE AND REJUVENESCENCE

disappear, and the nucleus begins to divide, apparently at first
amitotically.

In some of the lower animals new individuals arise agamically
or can be produced by
experimental isolation of
pieces from regions of the
body which do not contain
sex organs, yet these indi-
viduals are capable of pro-
ducing sex cells. To
assume that these regions
of the body contain germ
plasm in the Weismannian
sense ready to develop into
ovaries or testes when
necessary is simply to beg
the question. To all
appearances germ cells de-
velop in such cases from
more or less differentiated
cells of the region in-
volved by a process of
dedifferentiation and _ re-
differentiation, and the
assumption of a pre-
existent germ plasm is
entirely unnecessary.

It is scarcely probable
that the germ plasm is a
totally different thing in
animals and plants. In
the preceding section it

Fics. 146, 147.—Formation of a testis from a
: muscle cell in Moniesia: Fig. 146, large muscle
has been pointed out that cell with single fiber; Fig. 147, transformation
for a very large number of of muscle cell into testis.
plants the development of
germ cells from differentiated functional cells of the plant body

has been experimentally demonstrated. This fact in itself creates

THE GAMETES IN PLANTS AND ANIMALS 333

a presumption in favor of a similar origin in animals, and the pur-
pose of the present section is to show that the facts themselves,
when correctly analyzed, point to the same conclusion. The
assumption of the existence of supplementary germ plasm, i.e.,
of portions of germ plasm in the nuclei of all or certain somatic cells
or tissues, not only finds no support in the data of observation and
experiment, but deprives the germ-plasm hypothesis of all scientific
value. It is undoubtedly true that the more highly specialized
cells of an organism, be it animal or plant, do not so readily undergo
dedifferentiation and redifferentiation under altered correlative
conditions and so do not so readily give rise to germ cells or other
parts as do the less highly specialized cells; in fact, many cells,
especially in the higher forms, are probably incapable of such
change, but this does not constitute adequate grounds for the belief
that germ plasm and soma are independent entities.

Summing up, it appears that the facts afford no adequate
grounds for regarding the germ cells as anything else than an
integral part of the organism specialized in a certain direction like
other parts. But in spite of the complete absence of any trace of
early segregation of germ cells in many organisms, in spite of the
fact that the egg cytoplasm, not the nucleus, is apparently respon-
sible in most if not in all cases of early segregation, in spite of our
ignorance in many cases whether the so-called primitive germ cells
really give rise only to gametes, and, finally, in spite of the remark-
able conception of the organic world to which the germ-plasm
theory leads us—in spite of all these difficulties, the view that these
processess of early specialization in the egg constitute a spatial
morphological segregation of the independent germ plasm from the
body or soma still finds supporters, as is evident from the most
recent consideration of the subject by Hegner (’14c).

THE MORPHOLOGICAL CONDITION OF THE GAMETES

Minot (’08) has maintained on morphological grounds that the
animal egg is an old cell approaching death, but has not, so far as I
am aware, expressed any opinion regarding the condition of the
spermatozoon, although, according to his theory that increase in
the proportion of cytoplasm to nuclear substance is a fundamental

334 SENESCENCE AND REJUVENESCENCE

factor in senescence, the spermatozoon should be a very young cell,
for it is almost without cytoplasm in most cases. I have called
attention to various lines of evidence which indicate that both egg
and spermatozoon are highly differentiated, old cells (Child, ’11),
and Conklin (’12, ’13) has expressed himself as in essential agree-
ment with this view.

The process of formation of the gametes in its morphological
aspects is very evidently a process of specialization and differentia-
tion. The fully developed gametic cells are among the most highly
specialized cells, if not the most highly specialized cells of the ©
multicellular organism, but the primitive germ cells from which
they arise are minute cells without any morphological structure
beyond that common to cells in general, and with a high metabolic
rate—in short, with all the visible characteristics of embryonic or
unspecialized, undifferentiated cells. The process of development
of the gametes from such cells is a process of specialization and
morphological differentiation of the same sort as that which occurs
in other cells of the organism. Morphologically the fully formed
gamete certainly bears no resemblance to an embryonic cell. A
few figures will serve to emphasize this point.

In Figs. 123-31 (pp. 317-18) the sex organs and gametes of some
of the algae and fungi are shown. The gametes are readily dis-
tinguished from the vegetative cells and in most cases appear to be
more highly specialized and differentiated than those. Male
gametes, the spermatozoids of a few plants from other groups, are
shown in Figs. 148-53. Fig. 148 is the spermatozoid of a liverwort;
Fig. 149, a horse-tail, Equisetum; Fig. 150, a fern; Fig. 151, a
cycad, Zamia; Fig. 152 is the spermatozoid or generative nucleus
of the sunflower; Fig. 140 (p. 320) shows the pollen grain of Sil-
phium, another composite with the two elongated generative nuclei
or spermatozoids, and Fig. 153, a fully developed spermatozoid of
the same plant. These male cells are different in various ways,
but most of them possess a well-developed motor apparatus of one
kind or another.

The differentiation of the male gamete among the animals is
perhaps more uniform than among plants, but there are many
animal species with aberrant forms of spermatozoa. Figs. 154-57,

THE GAMETES IN PLANTS AND ANIMALS 335

161, and 166 show more or less “typical,” fully developed
spermatozoa from various invertebrate and vertebrate species, and

Fics. 148-153.—Male gametes of various plants: Fig. 148, Sphaerocarpus ter-
restris, a liverwort (from Land, unpublished); Fig. 149, Equisetwm (from Sharp, ’12);
Fig. 150, Nephrodium, a fern (from Yamanouchi, ’o8); Fig. 151, Zamia, a cycad (from
Webber, ’o1); Fig. 152, Helianthus, sunflower (from Nawaschin, ’oo); Fig. 153, Sil-
phium (from Merrell, ’oo).

in Figs. 158-61 four developmental stages of the guinea-pig sperma-
tozoon are given. A few of the aberrant spermatozoan forms
among animals are shown in Figs. 162-72. Figs. 162-64 are from

336 SENESCENCE AND REJUVENESCENCE

three species of turbellarian worms, forms related to Planaria;
Fig 165 is the non-motile spermatozoon of the nematode worm
Ascaris megalocephala; Figs. 166 and 167 show the two forms of
spermatozoa found in certain snails; Figs. 168, 169, and 170 are

155

Fics. 154-157.—Male gametes of various animals: Fig. 154, Nereis,
an annelid worm (from F. R. Lillie, ’12); Fig. 155, Copris, a beetle
(from Ballowitz, ’90d); Fig. 156, Raja, a fish (from Ballowitz, ’90b);
Fig. 157, Triton, a salamander (from Ballowitz, ’90b).

from various species of crustacea, and Figs. 171 and 172 from
arachnids, but Fig. 171 perhaps represents a stage of spermatozoan
development rather than the mature form.

Usually the male gamete in both plants and animals is highly
motile, and the course of its development is to a large extent a

THE GAMETES IN PLANTS AND ANIMALS 337

differentiation of the motor mechanism from a cell of the usual sort.
But in some cases, as in the angiosperms among plants (Figs. 152,

153), in Ascaris (Fig. 165), and in the
crustacea (Figs. 168-70) among animals,
the male gamete is almost or quite non-
motile. Even in such cases, however,
it is none the less a highly specialized
cell. In the angiosperms among plants
a morphologically differentiated cyto-
plasmic mechanism is absent, but the
history, form, and behavior of the
nucleus attest its specialization. In
Ascaris (Fig. 165) the peculiar structure
of the cell shows that it has departed
far from the generalized form of the
embryonic cell. In the crustacean sper-
matozoa (Koltzoff, ’06a) the skeletal or
supporting structures are extensively
developed, but according to Koltzoff
(’06b, ’08), such structures are present
in other spermatozoa also. Ballowitz’
(’86-’08) extensive studies of the finer
structure of the spermatozoa also
demonstrate the morphological com-
plexity of these remarkable cells. In
the more highly differentiated forms
there remains no trace of the ordinary
amorphous cytoplasm of the cells from
which they arise: all has either under-
gone breakdown as a source of energy
or has been transformed into the fibrillar
or other structures of the spermatozoon.

The development of the female
gamete follows a very different course,
but is none the less a process of spe-
cialization and morphological differen-
tiation. Figs. 123, 125, 126, and 128

Fics. 158-161.—Develop-
ment of spermatozoon from
spermatid in the guinea-pig:
Fig. 158, beginning of trans-
formation; Fig. 159, beginning
of development of tail; Fig. 160,
side view after formation of
the thin flat head; Fig. 161,
mature spermatozoon. From
Meves, ’99.

338 SENESCENCE AND REJUVENESCENCE

(pp. 317-18) show the female gametes in some of the algae and
fungi. The development of the female cell in the liverwort Riccia

163

164

162

Fics. 162-167.—Some peculiar forms of spermatozoa from the lower inverte-
brates: Fig. 162, Plagiostomum, a turbellarian (from Bohmig, ’90); Fig. 163, Castroda,
a turbellarian (from Luther, ’04); Fig. 164, Mesostomum, a turbellarian (from Luther,
04); Fig. 165, Ascaris megalocephala, nematode worm (from Scheben, ’o5); Figs. 166,
167, the two forms of spermatozoa in Paludina, a snail (from Meres, ’o3).

is outlined in Figs. 133-39. Fig. 173 shows the archegonium of the
fern Nephrodium, containing the large egg; Fig. 174 is the fertilized

THE GAMETES IN PLANTS AND ANIMALS 339

egg of the cycad Zamia; Fig. 175, the archegonium of a conifer,
Torreya taxifolia, containing the large egg: incidentally this figure

also shows the pollen tube
with the two small male
nuclei near the tip. The

development of the female

gamete in the angiosperms
isoutlined in Figs.141, A-E
(p. 321). Fig. 176 is the
embryo sac of the sun-
flower at the time of ferti-
lization, and Fig. 177, that
of the coneflower, another
composite, at the same
stage. The eggs in all
these plants are manifestly
highly specialized cells
which have undergone
great changes from the
embryonic condition.
The animal egg usually
exhibits an even greater de-
gree of morphological
specialization than that of
the plant because it is
loaded to a greater or less
degree with granules or
masses of yolk substance
which becomes available
as a nutritive supply at
the beginning of embry-
onic development. The
accumulation of yolk is
often so great that the egg
cell attains an enormous

Fics. 168-172.—Peculiar forms of sperma-
tozoa from the arthropods: Figs. 168, 169, 170,
Pinnotheres, Maja, and Munidia, all crustacea
(from Koltzoff, ’o6a); Figs. 171, 172, Acanto-
lophus, Agalena, both spiders (from Bésenberg,
05).

size, the bird’s egg representing the extreme of development in
this direction. Since the period of growth and differentiation of

340 SENESCENCE AND REJUVENESCENCE

the animal egg as a single cell involves so much more extensive
and conspicuous change than in the plant, it has attracted much
attention and the course of odgenesis has been described for many
animal species. The following figures include characteristic stages
in the differentiation of a few animal eggs. Figs. 178-80 show
the egg of the fresh-water hydra, first at the beginning of its
growth as a small cell lying between the cells of the ectoderm
(Fig. 178); secondly, as a large amoeboid cell in the ovary
(Fig. 179); and, thirdly,
as a full-grown egg, still
in the ovary, with large
yolk spheres in the
cytoplasm. Figs. 181
and 182 show the primi-
tive germ cells and the
final stage of odgenesis
in the liver fluke Fasciola
hepatica, a parasitic flat-
worm. In most of the
flatworms the egg
accumulates little or no
yolk within its own
cytoplasm, but other
nutritive cells contain-
ing yolk are inclosed in
Fics. 173-174.—Fig. 173, archegonium of Nephro- the capsule with it be-

dium, a fern, containing the egg,o (from Yama- fore it is extruded. In
nouchi, ’o8); Fig. 174, fertilized egg of Zamia, these forms the egg cell

a cycad (from Webber, ’or). \ 5

itself remains of small
size and its growth history is relatively simple. In this and in
various other animals the egg as it grows develops a stalk (Fig. 182)
by which it is connected with the ovarian wall and through which
it probably receives most or all of its nutrition. Fig. 183 shows
an ovary of the bryozoan Plumatella fungosa, with eggs in various
stages of growth and differentiation. These eggs develop succes-
sively from the primitive cells, and each egg in turn is displaced
by the growth of another behind it.

THE GAMETES IN PLANTS AND ANIMALS 341

The interesting odgenesis of Sternas pis scutata, a peculiar marine
annelid, is shown in Figs. 184 and 185. The eggs arise from cells
on the walls of certain blood vessels and as they grow develop a
stalk containing a loop of the blood vessel, so that blood flows

directly through the
basal end of the egg.
Fig. 184 shows the egg
at the beginning of yolk

formation: the cyto- .

plasm contains a few
yolk granules and shows
a strongly radiate
structure centering
about the vascular loop.
In the full-grown egg
the cytoplasm is loaded
with numerous large
yolk spheres (Fig. 185)
except at the basal end,
where there is an area
of granular cytoplasm.
At this stage the egg
becomes free from the
stalk, which undergoes
atrophy and resorption.

A different type of
odgenesis is shown in
Fig. 186, an ovarian
tubule from the water
beetle Dytiscus margi-
nalis. Here growing

Fic. 175.—Female gametophyte of Torreya, a
conifer, showing the egg, 0, and above it the pollen
tube with the two male nuclei, sp. From Coulter
and Land, ’os.

eggs alternate with groups of so-called nurse cells, which serve as a
food supply and are used up during the growth of the egg.

Three stages of ascidian odgenesis are shown in Figs. 187-89.
The first, the young ovotestis, the animals being hermaphroditic,
with a young egg cell at the left, the second, the growing egg sur-
rounded by its follicle from which the so-called test cells—cells

{

342 SENESCENCE AND REJUVENESCENCE

which enter the cytoplasm of the egg and serve as food—are begin-
ning to arise. The third figure (Fig. 189) shows a segment of the
egg at a still later stage with follicle and test cells in the peripheral —
cytoplasm and yolk masses forming below them. Figs. 190, 191

Fics. 176, 177.—Embryo sacs of Helianthus (sunflower) and Rudbeckia (cone-
flower) at time of fertilization, showing egg, 0; two male nuclei, s:, s$2; embryo sac
nucleus, ev. From Nawaschin, ’oo.

are two stages in the odgenesis of a fish egg, the first showing the
young egg at the beginning of yolk formation, the second, a later
stage in which the cytoplasm is loaded with numerous yolk spheres.

In various invertebrate groups the same individuals produce at
different times parthenogenic eggs, i.e., eggs which develop without

THE GAMETES IN PLANTS AND ANIMALS 343

fertilization, and zygogenic eggs which require fertilization before
development. It is a fact of great interest that in such cases the
parthenogenic eggs usually differ morphologically from the zygo-
genic eggs. In Sida crystallina, one of the cladoceran crustacea, for
example, the parthenogenic eggs are smaller and contain less yolk

Fics. 178-180.—Three
stages in the differentiation
of the egg, 0, of Hydra.
From Downing, ’og.

than the zygogenic eggs. Fig. 192 shows an ovarian tubule of this
species containing various stages of parthenogenic odgenesis. The
primitive cells (pc), formed at the upper end of the tubule, after
the period of division is over arrange themselves in groups of four
(g, g) of which the third from the upper end develops into an

344 SENESCENCE AND REJUVENESCENCE

egg (0) and the other three become nurse cells, which supply the egg
with nutrition. Three of these nurse cells thus contribute to the
formation of one parthenogenic egg. The zygogenic egg, however,
uses up not only three nutritive cells, but often several other cell
groups, including the young egg cells, i-e., a much larger amount of
nutritive material contributes to its formation than to that of the
parthenogenic egg. Fig. 193 shows the lower end of an ovarian

. tubule containing a zygogenic egg.
It is much larger than the par-
thenogenic egg and contains more
yolk.

Among the insects, the plant
lice also produce both partheno-
genic and zygogenic eggs. In this
case the difference between the
two kinds of eggs is very marked,
the parthenogenic egg being much
the smaller and containing little
yolk (Fig. 194) as compared with
the zygogenic egg (Fig. 195).
Even the nurse cells, which here
form a sort of gland with which
the egg cell is connected by a pro-
toplasmic strand, are larger and
more highly developed in the latter

Fics. 181, 182.—Primitive germ case. Similar differences have
cells and full-grown egg of Fasciold been observed in other forms pro-
(liver fluke), with ftalke of attachment. ducing the two kinds of eggs. If
From Schubmann, ’o5. 4

the process of odgenesis is a pro-
cess of differentiation and senescence, we must conclude that in these
cases the parthenogenic egg does not proceed so far in development
as the zygogenic egg. Morphologically it is evidently less highly
differentiated and younger.

Among the bees, however, where eggs which produce males,
i.e., the drones, apparently develop parthenogenically, while the
females, both workers and queens, develop from fertilized eggs, no
characteristic morphological differences between the partheno-

THE GAMETES IN PLANTS AND ANIMALS 345

genic, male-producing, and the zygogenic, female-producing, eggs
have, so far as I am aware, been described. But the morphological
differences in the daphnids and plant lice are evidently extreme,

Fics. 183-185.—Fig. 183, ovary
of Plumatella (bryozoan), showing
eggs in various stages of growth
and differentiation. From Braem,
’97; Figs. 184, 185, growing egg
of Sternaspis (annelid), attached
to a stalk which contains a vas-

* cular loop; full-grown egg.

and it is possible either that much less conspicuous morphological
differences exist in the bees, or that the physiological differences
are so slight as to be morphologically inappreciable; probably

346 SENESCENCE AND REJUVENESCENCE

Fic. 186.—Part of an ovarian
tubule of Dyliscus (beetle), show-
ing eggs alternating with groups of
nutritive cells: the dark regions of
the eggs are dense aggregations of
granules derived from the nutritive
cells. From Korschelt, ’gr.

the physiological condition of the
bee’s egg is so near the boundary
line between parthenogenesis and
zygogenesis that slight differences
suffice to determine it one way or
the other.

Many other interesting cases of
odgenesis might be added to the few
described here, but the fact that the
formation of the female gamete in
organisms is a process of growth and
morphological differentiation requires
no further evidence.

The gametes then in both plants
and animals are to all appearances
the final stages of a period of growth
and differentiation. Except in a few
of the unicellular organisms where
body and gamete are the same cell,
the gametes are highly specialized
cells, different from any other cells
of the body and bearing not the
slightest resemblance to embryonic
or undifferentiated cells. Of course
it is possible to assume with Weis-
mann and others that, in addition
to the odgenic and spermatogenic

- protoplasm which is responsible for

the differentiation, the cells each con-
tain “undifferentiated germ plasm,”
but. we can find neither morpho-
logical nor physico-chemical support
for such an assumption. Not only
is such germ plasm not visible, but
from a physico-chemical point of
view it is difficult to conceive how it
could continue to exist through the
course of differentiation of the

THE GAMETES IN PLANTS AND ANIMALS 347

gametic cells. The only conclusion in agreement with the facts
is that the gametes are physiologically integral parts of the
organism, that they are, like other parts of the organism, more or

“ily

Fics. 187-191.—Odgenesis of ascidian and fish: Fig. 187, ovotestis of young bud
of Distaplia (ascidian) with primitive egg cell, 0; Fig. 188, growing egg with test
cells and follicle; Fig. 189, portion of half-grown egg, showing follicle, test cells, and
formation of yolk (from Bancroft, ’99); Figs. 199, 191, Two stages in the growth
and differentiation of the egg of Rhombus (fish) (from Cunningham, ’97).

less highly differentiated cells, and that, like other parts, they
undergo differentiation because of the conditions to which they
are subjected in the organism and not because of peculiar, inherent
properties.

SENESCENCE AND REJUVENESCENCE

Fics. 192-195.—The differentiation of parthenogenic and zygogenic eggs: Fig.
192, ovarian tubule of Sida (daphnid crustacean), showing primitive germ cells, pc,
and groups, g g, of eggs, 0, and nurse cells; Fig. 193, part of a tubule containing a
zygogenic egg, 0; Fig. 194, ovarian tubule of Melanoxanthium (plant louse), showing
nutritive gland, o gi, parthenogenic egg, 0, and embryo, em; Fig. 195, ovarian tubule
of Melanoxanthum, showing nutritive gland, o gi, and zygogenic egg, 0. Figs. 192, 193,
from Weismann, ’77; Figs. 194, 195, from Tannreuther, ’07.

THE GAMETES IN PLANTS AND ANIMALS 349

THE PHYSIOLOGICAL CONDITION OF THE GAMETES

If the gametes are highly differentiated cells—the final stages of
a period of growth and progressive development—they must be
physiologically in an advanced stage of senescence. Their rate of
metabolism and rate of growth must have been high at the beginning
of the period of differentiation and have undergone decrease during
this period.

As regards these points, our positive experimental knowledge
is very slight, but various facts of observation point very clearly
to certain conclusions. Growth has ceased in the fully developed
gametes, but the earlier stages of their development are periods of
rapid and extensive growth, and in the plants there is usually more
or less cell division in the earlier stages of gametic development.
In the female gamete growth is usually considerable, often very
great in amount. In many of the lower plants the cytoplasm of
the egg becomes loaded with nutritive substance, as in the case of
the yolk-bearing animal egg, but in the higher plants development
follows a different course and the embryo obtains its food to a large
extent from other cells. The rate of growth in the developing
gamete is apparently higher in the earlier than in the later stages,
but Iam unable to cite any exact observations upon this point.

The course of development in the male gamete usually differs
very widely from that in the female. Growth occurs, but it is much
less in amount, and instead of the accumulation of inactive sub-
stance in the cytoplasm, a transformation of the cytoplasm into a
morphological mechanism, usually motor in function, occurs. In
the fully developed male gamete, as in the female, growth has
ceased. In most cases the general metabolic substratum of the
cell has to a large extent or wholly disappeared and the cell has very
evidently progressed as far as is possible in a certain direction.

As regards the metabolic condition of the gametes of plants,
G. Maige (’og, ’11) has shown that the rate of respiration decreases
in the anther during the development of the pollen grain from the
spore. The rate of respiration in the pistil, however, is usually
higher than in the anther and frequently increases during the
development of this organ. The changes of rate in the embryo sac
alone have not been determined, but it seems probable that the

350 SENESCENCE AND REJUVENESCENCE

high rate and the increase in rate in the pistil as a whole are asso-
ciated with the reproductive processes concerned in the formation
of the ovules and embryo sacs within them, processes which involve
much more extensive growth than the development of the pollen
grain. The volume and weight of these parts in relation to total
volume and weight of the pistil increases as development goes on,
and this change is undoubtedly sufficient to account for the increase
in respiratory rate in the whole pistil in those cases where it occurs.
Probably the rate of respiration in the embryo sac decreases as its
development proceeds. Fertilization occurs and embryonic devel-
opment begins in the seed plants without any considerable period
of rest, and this fact may also play a part in determining a high
respiratory rate in the pistil during the later stages of its existence.

Determinations of the rate of oxygen consumption or production
of carbon dioxide or other metabolic products have not been made
for different stages of gametic development in animals, but as
regards the egg there can be little doubt that the rate of metabolism
decreases as development proceeds and that in the fully developed
egg very little chemical activity is going on. The male gamete, on
the other hand, usually shows very great motor activity, often con-
tinuing over a long period of time, and at first glance there may
seem to be little reason for regarding it as a physiologically old,
highly specialized cell, approaching death. It must be remem-
bered, however, that, except in some of the less highly differentiated
male cells of the unicellular organisms and the lower plants, the
motor activity of the sperm is wholly or in large degree due to
external stimulation. In this respect the sperm resembles volun-
tary muscle. In both cases the fully differentiated cell or tissue is
capable, when stimulated, of a very high rate of reaction, perhaps
higher than that in the sperm mother cell or the embryonic muscle
cell, but it is certain that the self-determined inherent rate of meta-
bolic change without stimulation in the differentiated cell is a much
more exact measure of its physiological condition or its stage of
senescence as compared with the embryonic cell. In the ‘‘resting”’
muscle and in the motionless spermatozoon the metabolic rate is
undoubtedly lower than in the undifferentiated cells from which
they arose.

THE GAMETES IN PLANTS AND ANIMALS 351

It is a question of some interest whether the energy expended
in the movements of the spermatozoon is derived entirely from its
own substance or whether in any case it obtains nutritive material
from the fluids in which its movement occurs. It is difficult to
understand how some of the more highly specialized forms of
animal spermatozoa can contain a sufficient amount of material to
furnish energy for their long-continued activity. If the sperma-
tozoon does obtain nutrition from the external world after its
isolation from the parent body, it may perhaps undergo some
degree of senescence even during this period.

Tests of the susceptibility to cyanide of various developmental
stages of the gametes have given uniform results. Thus far I have
made susceptibility tests on the female cells of the starfish and sea-
urchin, of various marine annelids, and of the fish Tautogolabrus,
and upon both female and male cells of the nematode worm Ascaris
megalocephala. Ascaris is a particularly favorable form for tests
of this sort, first, because ovaries and testes are tubular organs
lying in the body cavity and can readily be removed; secondly,
because all stages in the development of the male and female
gametes can be obtained from a single individual of the proper sex
at any time; and, thirdly, because the spermatozoa are non-motile.
In both male and female the primitive mother cells in the uppermost
or innermost portion of the tubular testis or ovary, where growth
and cell division are still occurring, show very high susceptibility
like that of embryonic cells; lower down in the tube, where the
growth and development of the gametes begin, the susceptibility
begins to decrease, and the decrease is progressive as gametic devel-
opment proceeds, until in the fully developed gamete the suscepti-
bility is exceedingly low. In a potassium cyanide solution, 0.005
mol., the primitive female mother cells underwent the death change
and disintegrated almost at once, the earlier stages of the growth
period in fifteen to thirty minutes, somewhat later stages in one to
two hours, while the fully formed eggs showed in most cases no
changes until after twenty-four to forty-eight hours in the solution
and did not actually disintegrate for several days. Numerous other
stages were tested, and in all cases the susceptibility was found to
undergo a progressive decrease. The male cells show essentially

352 SENESCENCE AND REJUVENESCENCE

the same progressive change in susceptibility, although it is very
difficult to determine with certainty when death occurs in the
mature spermatozoon.

In the other forms examined attention has been directed chiefly
to the female cells, because the different stages of development are
readily distinguishable by size and because in the male the cells are
minute, the different stages being in most cases less readily dis-
tinguishable in the living cells, except under very high powers, and
finally the spermatozoa are motile and it is practically impossible
to eliminate the motor activity without injuring the sperm or
altering its physiological condition. In all cases where female
cells were examined the results are similar to those with Ascaris
cells. The susceptibility of the primitive mother cells is high,
approaching that of embryonic cells, and decreases progressively
during development of the gamete, and that of the full-grown egg
is exceedingly low—lower than that of most differentiated cells.
Wherever the stages of spermatogenesis could be clearly distin-
guished the same results have been obtained for the non-motile
stages.

The susceptibility to cyanide of conjugating infusoria (Colpid-
ium) is very distinctly lower than that of non-conjugating and divid-
ing stages (see p. 381). The conjugating stages in these animals
are comparable to the fully developed gametes of multicellular
forms, and their low susceptibility indicates that their rate of
metabolism is lower and they are physiologically older than other
stages.

If the susceptibility method can be trusted, and a large and
increasing volume of evidence indicates that it can, the development
of the gametes in animals is associated, as the decrease in suscep-
tibility indicates, with a decrease in rate of metabolism—a process
of senescence—and the fully developed gamete is physiologically
an old cell approaching death.

Chemical analysis of heads of spermatozoa, so far as it throws
any light on the question, indicates that at least some spermatozoa

t The literature of the subject, including the pioneer work of Miescher and A. P.
Mathews’ analyses (Mathews, ’97), is discussed by Burian, ’o4, ’06. Recently
Steudel (’11¢, ’11b, ’13) has made new analyses with improved methods.

THE GAMETES IN PLANTS AND ANIMALS 353

are highly specialized and that this specialization has been in the
direction of a chemical simplification, at least during the later
stages. Apparently the proteid constituents may undergo more
or less breakdown during spermatogenesis. According to Burian,
this process of breakdown of the proteid constituents may differ in
degree in different spermatozoa. So far as our knowledge goes,
the spermatozoa of vertebrates, except the fishes, contain typical
proteids as constituents of their nucleoproteids, while in the fishes
these are replaced by the simpler histones or the still simpler
protamines, and in some cases the histones are formed during
spermatogenesis, the protamines in the fully developed sperma-
tozoa. The nucleoproteids of the nuclei of other cells of the body
sometimes contain typical proteids, sometimes histones, in com-
bination with the nucleic acid, but the process of proteid breakdown
does not go as far as the formation of protamines. From this point
of view, the differentiation of spermatozoa is apparently not funda-
mentally different from that of other cells, but some spermatozoa
seem to be more highly specialized than other cells.

As regards the eggs, it is evident that, at least in those cases
where they contain yolk, a progressive change in chemical consti-
tution of the whole cell must occur during the course of differentia-
tion: the most striking feature of this change is the increase in
lipoids, which form an important constituent of the yolk. Con-
cerning changes in chemical constitution of the egg nucleus we know
practically nothing.

THE SIGNIFICANCE OF MATURATION

At some point in the life history between successive generations
of gametes the process known as maturation occurs. In most
cases, both in animals and in plants, the process of maturation
consists of two nuclear and cell divisions during which the number
of chromosomes in the nucleus is decreased one-half more or less
(haploid number). In fertilization the normal or diploid number
is restored by the union of the two gametes each with the haploid
number. In spite of years of investigation and discussion, cytolo-
gists appear to be almost as far as ever from an agreement as to
what really occurs in the maturation divisions; indeed, it is still a

354 SENESCENCE AND REJUVENESCENCE

question whether the maturation divisions or either one of them
are in any way fundamentally different from other nuclear divi-
sions. They are believed by many to be of great importance in
heredity, but until the problem of their cytological character is
solved any consideration of their significance for heredity must
remain in the field of speculation.

The question of the physiological significance of maturation has
attracted little attention, but as a matter of fact it is in the answer
to this question that we shall find the key for the solution of the
other problems which have arisen in connection with maturation.
At least one of the maturation divisions, the so-called heterotypic
division—but whether the first or the second, opinions differ—has
commonly been supposed to be distinguished from ordinary divi-
sions by the behavior of the chromosomes, and much has been made
in a theoretical way of this difference. But with the extension of
our knowledge, one feature after another which was believed to be
characteristic of the maturation division has been found in other
divisions which have nothing to do with the development of the
gametes. The peculiar behavior of the chromatin, consisting in
premature division and agglutination of chromosomes to form rings
or other figures, which has been regarded as a characteristic feature
of the so-called “heterotypic” maturation division, has been
observed by Hicker, Bonnevie, and others in cleavage stages of
various forms, has also been found in the cells of malignant tumors,
and has been experimentally induced by the use of ether and chloro-
form and as a result of injury to the parent body.t. Hicker is
inclined to believe that this heterotypic behavior of the chro-
mosomes indicates a low degree of differentiation, hence its occur-
rence in gametic history, in early cleavage, and in cancer cells
which are often regarded as a product of dedifferentiation. Hicker
was led to this conclusion by his belief, based on theoretical grounds,
that the gametes are undifferentiated cells containing germ plasm,
but from a physiological point of view both the stages in gametic
history where maturation occurs and the early cleavage stages are
stages of relatively high differentiation.

?

« Bonnevie, ’08; Farmer, Moore, and Walker, ’o4; Hicker, ’oo, ’o4, ’07;
? + ? ? rf ? , ? ? ,

Schiller, ’o9.

THE GAMETES IN PLANTS AND ANIMALS | 355

It is evident that whatever the cytological or hereditary signifi-
cance of the chromosome behavior in maturation, this behavior
must have a physiological basis, it must be associated with certain
physiological conditions. The discovery of similar behavior in
other cells and the experimental production of it serve at least to
pave the way for the determination of its physiological significance.
The fact that the “‘heterotypic’’ behavior can be experimentally
induced by means of narcotics seems to show that its occurrence
is connected with a low rate of metabolism. In maturation, both
in plants and in animals, it occurs at the end of a developmental
period. In most plants with alternation of generations the matura-
tion divisions occur in the formation of the spores, and a more or
less extended period of dedifferentiation, cell division, and pro-
gressive development, i.e., the gametophyte generation, occurs
between maturation and fertilization. In animals, on the other
hand, no cell division occurs between maturation and fertilization.
But the important point is that in all cases the maturation divisions
occur in cells which are in an advanced stage of developmental
history and physiologically old and which therefore possess a low
metabolic rate. The occurrence of heterotypic behavior in cancer
cells is probably likewise due to a low metabolic rate, though not
in consequence of differentiation and advanced age, but because
of partial asphyxiation or intoxication of certain cells in the rapidly
growing cell mass.

According to this conception, then, the peculiar characteristics
of the maturation divisions find their physiological basis in a low
metabolic rate which may result from differentiation and senescence
or be induced experimentally or otherwise. Other features of
maturation which indicate a low metabolic rate are the absence
of the usual nuclear growth between the first and second divisions
and, in animal eggs, the slow progress of maturation and its frequent
cessation until a further stimulation from without occurs, and the
very slight influence of the nuclear division upon the cytoplasm, the
cytoplasmic divisions resulting in the formation of the minute polar
bodies and leaving practically the whole volume of the egg intact.

In the animal egg, where maturation occurs after the enormous
growth of the egg cell is completed, the process appears to be

356 SENESCENCE AND REJUVENESCENCE

initiated either by the physiological or physical isolation of the egg
cell from its source of nutritive supply in the parent body, or often
by its extrusion from the body into water, or in many cases only
after the spermatozoon has entered the egg. In most cases the egg is
incapable of even the maturation divisions, except after some degree
of excitation, and in some eggs the isolation from the parent body
is sufficient, while others require the additional stimulation of
extrusion into water, and for still others the further change result-
ing from entrance of the sperm is necessary. In the formation of
the megaspore and microspore in plants and in the spermatogenesis
of animals the period of growth between other divisions and matura-
tion is slight or practically absent, and with rare exceptions the cells
divide equally in the maturation divisions. Whether in these cases
also the maturation divisions are initiated by a stimulation of the
cells from without is not known, but the probability suggests itself
that they occur as the result of a physiological or physical isolation
of the cells.

From this point of view the maturation divisions appear to be
divisions occurring in relatively old differentiated cells as a reaction
to physiological or physical isolation from the parent body, or to
this factor in combination with others. Their peculiar features
are apparently associated with the low metabolic rate in the cells
concerned. In the mosses and ferns the spores resulting from the
maturation divisions undergo rejuvenescence and begin a new
developmental and vegetative cycle without fertilization, but in
the seed plants the degree of rejuvenescence is apparently slight
in most cases and the divisions few in number, and in animals,
except in the case of parthenogenic eggs, rejuvenescence occurs
only after fertilization.

CONCLUSION

In the present chapter the attempt has been made to show that
the developmental history of the gametes affords no adequate
grounds for the belief that germ plasm is something independent
of the rest of the organism. There is no proof of the “segregation
of the germ plasm” as an independent entity in embryonic develop-
ment, but the germ cells are very evidently determined like other

THE GAMETES IN PLANTS AND ANIMALS 357

parts of the body by correlative factors. Moreover, the course of
development of the gametes bears every indication of being a pro-
gressive differentiation and senescence, not fundamentally different
from that of other organs of the body, and the fully developed
gametes are physiologically old, highly differentiated cells, which
are rapidly approaching death and in most cases actually do die
soon after maturity unless fertilization occurs. Whatever their
significance for inheritance may prove to be, the peculiar features
of the maturation divisions are apparently associated with the
condition of advanced physiological age and low metabolic rate
in the cells where they occur. These cells, whether they are
the spore mother cells of plants or the gamete mother cells of
animals, are advanced stages of a period of progressive develop-
ment and must undergo dedifferentiation and rejuvenescence
before they can enter upon a new period of development. In the
plants this may occur to a greater or less extent without fertiliza-
tion in the development of the gametophyte, but in the gametes of
animals, with the exception of parthenogenic eggs, dedifferentia-
tion and rejuvenescence occur only after fertilization.

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Cyclops,” Arch. f. Entwickelungsmech., XXVII.

SCHUBMANN, W.
1905. “Uber die Eibildung und Embryonalentwicklung von Fasciola
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SHarp, L. W.
1912. “‘Spermatogenesis in Equisetum,’’ Bot. Gazette, LIV.

STEUDEL, H.
tg11a. “Zur Histochemie der Spermatozoen.” I. Mitt. Zeitschr. f.
physiol. Chem., LX XII.
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LXXIII.
1913. ‘‘Zur Histochemie,” etc. III. Mitt. Zeitschr. f. physiol. Chem.,
LXXXIII.

THE GAMETES IN PLANTS AND ANIMALS 363

ZUR STRASSEN, O.
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1908. “Uber Parthenogenesis und Apogamie im Pflanzenreiche,” Pro-
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CHAPTER XIV
CONDITIONS OF GAMETE FORMATION IN PLANTS AND ANIMALS

In all organisms the production of the gametes or sexual cells,
the condition known in the higher forms as sexual maturity, is
apparently associated with certain other physiological conditions
which, at least in the higher animals, are characteristic of relatively
advanced stages of development. The present chapter is an
attempt to establish a general foundation for the interpretation of
the various data of observation and experiment. This foundation
is in brief the view that the production of gametes is simply one
feature of the orderly development of the organism and is therefore
associated with certain conditions in other organs and is related
to processes of differentiation and senescence in the organism as a
whole.

CONDITIONS OF GAMETE FORMATION IN THE ALGAE AND FUNGI

It was formerly believed that the essential factors determining
reproduction, and particularly gametic or sexual reproduction in
plants were internal, and that external factors had but little to do
with the process. But various investigators, and particularly
Klebs, have demonstrated that the sequence of events in the life
cycle of plants can, to a very large extent, be controlled by external
factors. Klebs’s work along this line has been discussed in chap. x
in connection with agamic reproduction (pp. 249-52), and here only
certain points which concern the formation of gametes need be
considered. Klebs mentions the fact that where spore formation
or gamete formation or both occur in cultures of Vaucheria and
Saprolegnia, in addition to what he calls growth, which is what I
have called vegetative reproduction, these more specialized repro-
ductive processes occur on the older parts of the plant body and
the vegetative on the younger. He also concludes that the attain-
ment of a certain concentration of the organic substances in the
plant is an essential condition for such reproductive processes and
that for gametic reproduction the concentration must be higher

364

CONDITIONS OF GAMETE FORMATION 305

than for spore formation. According to Klebs, these differences
in concentration concern primarily the nutritive substances, but
it seems probable that the protoplasm of the cells may also be
involved. Ihave endeavored to show that vegetative reproduction,
in consequence of the regressive changes associated with it, retards
or inhibits the progress of senescence (pp. 237-55). The conditions
which bring about the formation of gametes in Klebs’s experiments
decrease or check vegetative growth, and the cells of the plant
accumulate organic substance and so attain a condition of greater
physiological age with a lower rate of metabolism than during active
vegetative reproduction. Apparently spore formation occurs at an
earlier, and gamete formation at a later, stage of this process of
senescence.

In the algae and fungi, with their low degree of individuation,
certain parts of the plant may under certain conditions become old
while others remain young, and in such cases gamete formation
and vegetative reproduction may occur simultaneously, the one in
the older, the other in the younger, parts. The results of Klebs’s
experiments do not then indicate that the plant has no definite life
history, but merely that because of its capacity for vegetative
reproduction it can be prevented indefinitely from attaining the
later stages. But when it, or a part of it, attains these stages, the
more specialized reproductive processes appear, and the formation
of gametes is apparently characteristic of a more advanced stage
than spore formation. Even after gamete formation, however,
the plant does not necessarily die, but under the proper conditions
may resume vegetative reproduction or spore formation. In those
cases where gametic reproduction may be induced before vegetative
reproduction has continued for any considerable length of time it is
probable that the conditions bring about premature aging, and the
plant very soon attains a certain physiological state which under
other conditions may arise only after a long time or not at all.

The process of aging in these lower plants is then very inti-
mately associated with external conditions. Under certain con-
ditions progressive senescence and gamete formation, under others
a balance between senescence and rejuvenescence, with continuous
vegetative reproduction, may occur. A life cycle exists as a

366 SENESCENCE AND REJUVENESCENCE

possibility for the lower plant, and gamete formation is a feature
of its later stages, but since physiological progression may be
experimentally accelerated, retarded, or inhibited by controlling the
relation between progression and regression, the life cycle does not
appear as a definite, uniform, internally determined sequence of
events such as occurs in the higher animals.

CONDITIONS OF GAMETE FORMATION IN MOSSES AND FERNS

In mosses and ferns the life cycle is complicated by an alternation
of sporophyte and gametophyte generations, each of which possesses
a characteristic different structure. The gametophyte produces
sexual organs in which the gametes develop, and the gametes after
fertilization give rise to the sporophyte which produces asexual
spores, and these produce another gametophyte generation. In
mosses the gametophyte is the vegetative generation, and the sporo-
phyte does not lead an independent life but develops upon the
gametophyte. In the ferns, on the other hand, both the sporo-
phyte, the fern plant, and the gametophyte, the prothallium, lead
an independent vegetative life.

In both mosses and ferns the production of sexual organs and
gametes on the gametophyte occurs only after a certain period of
vegetative activity which may vary in length with external con-
ditions; in other words, gamete formation seems to be characteristic
of a certain physiological condition which does not exist in the early
life of the gametophyte but arises only later. This condition evi-
dently corresponds to the condition of sexual maturity in the higher
animals. Moreover, after producing sex organs and gametes the
gametophyte dies, except where parts of it produce new gameto-
phytes asexually.

Vegetative agamic reproduction in the gametophytes occurs
very widely and in a great variety of forms among both mosses and
ferns and leads directly to the formation of new gametophyte indi-
viduals. In certain species, or under certain external conditions,
vegetative reproduction of the gametophyte may continue indefi-
nitely, and sex organs and gametes do not appear or appear very
rarely. This is conspicuously the case in many of the so-called
true mosses, the Bryales, in which the degree of individuation in the
gametophyte is evidently very slight, and vegetative reproduction

CONDITIONS OF GAMETE FORMATION 367

occurs by the isolation of leaves, branches, specialized gemmae,
etc., and in many cases from single cells of various regions of the
gametophyte. In many such species sex organs and gametes appear
only occasionally, or very rarely, and vegetative propagation of the
gametophyte may continue indefinitely.

If the viewpoint developed in preceding chapters has any
foundation in fact, we must believe that in every one of these
vegetative reproductions a new individuation and some degree of
reconstitutional change in the cells involved occur. And again, if
this is the case, the new individuals resulting from reproduction
are, at least to a slight degree, younger physiologically. than the
individual of which they originally formed a part. The result of
continued vegetative reproduction, whether it is induced by external
factors or determined by a low degree of individuation in the
species, is then to prevent the gametophyte generation from attain-
ing physiological maturity; consequently the specializations and
morphological differentiations characteristic of maturity, viz., the
development of sex organs and gametes, do not take place, or take
place only rarely when individuals in consequence of external or
internal conditions happen to reach maturity.

Various botanists have suggested that in such cases the vege-
tative reproduction is the consequence of the failure to produce
sex organs and gametes, but the facts point to the opposite con-
clusion—that the continued vegetative reproduction with the
accompanying reconstitution simply prevents the individual from
attaining maturity. Whether in any case the capacity for gamete
formation has been lost or is disappearing, can be determined only
after the most extensive and intensive research. But the low degree
of individuation accounts without difficulty for the preponderance
of vegetative reproduction, and there is no reason for believing that
a loss in the capacity for gamete formation has occurred. Failure to
produce gametes in such cases probably means only that the indi-
vidual never attains the physiological condition of which that par-
ticular process is a feature.

The occurrence of apogamy in the ferns‘ indicates, as already
pointed out (p. 322), that there is no segregation of germ plasm

t Farlow, ’74; de Bary, ’78; Heim, ’96; Farmer and Digby, ’07; Woronin, ’08;
Winkler, ’o8.

368 SENESCENCE AND REJUVENESCENCE

in the gametes alone. Apparently the sporophyte may arise from
any vegetative cell of the gametophyte. But the fact that apoga-
mous development of a sporophyte often begins as a transformation
of the sex organs either antheridia or archegonia, or is correlated
with the incomplete development or degeneration of the sex organs
or of the eggs, suggests that some sort and some degree of phys
iological correlation exists between apogamy and formation oi
gametes. It seems not improbable that the degree of individuation
is in such cases not quite sufficient to carry the organism through
the entire cycle, and the physiological isolation of vegetative cells
in the stages near maturity leads to reproduction of a sporophyte,
i.e., the vegetative cells have the same developmental capacity as
the egg, but are less specialized and so do not require fertilization.
Up to the present, however, other aspects of the process of apog-
amy have received much more attention than its physiology and
relation to the individuation of the organism in which it appears,
and any attempt at physiological interpretation must at present
be a mere guess.

CONDITIONS OF GAMETE FORMATION IN THE SEED PLANTS

In the mosses, ferns, and related forms the two generations, the
asexual sporophyte and the gametophyte which produces sexual
organs and gametes, are more or less distinct and separate organisms
with different morphological structure and different habit. In the
seed plants, however, the sporophyte generation has become by far
the most conspicuous feature of the life cycle, and the gametophyte
generation is reduced to the pollen grain and the embryo sac of the
flower. The flower is commonly defined as an axis or shoot of
which some parts bear sexual organs. The flower, like the vegeta-
tive shoots, arises from an agamic bud, but this bud is evidently
more highly specialized than the vegetative buds, for its parts are
variously modified and differentiated in various directions into the
parts of the flower. Moreover, the axis which produces the flower
usually does not continue to grow for a long time, or indefinitely,
but the growth is narrowly limited and the development of the
flower ends under the usual conditions in death. Evidently the
flower represents the most advanced or the highest stage in the

CONDITIONS OF GAMETE FORMATION 369

differentiation of the plant body. Both morphologically and
physiologically it is a much more highly differentiated and special-
ized system than the vegetative axes of the plant.

This being the case, we should expect to find the flower as the
final stage of development, as the expression of maturity of the
plant. Among the flowering plants this appears in general to be
the case. The young plant grows, produces new vegetative axes,
and in most cases becomes what the zodlogist would term an asexual
colony, but after a longer or shorter period of such vegetative growth
and reproduction, varying in different plants from a few weeks to
many years, flower buds appear in place of certain or all of the
vegetative buds, gametes are produced, and seeds are formed.
In many plants vegetative growth ceases when flowering occurs,
and flowering is followed by death of the whole plant, except the
seeds, but in others the sequence may be repeated an indefinite
number of times during the life of the plant.

To all appearances then these plants have a definite life history,
vegetative growth and reproduction of vegetative axes being
characteristic of the earlier stages and the development of flowers
and gametic reproduction of the later stages. In those plants
where the sequence is repeated periodically, different shoots or axes,
that is, different plant individuals, are concerned in each pericd.
Moreover, it is a well-known fact that in general cuttings from
plants in bloom or ready to bloom are likely to bloom earlier than
cuttings from plants which are still in the stage of active vege-
tative growth. Such facts indicate clearly that flowering is an
expression of internal conditions which are characteristic of a rela-
tively advanced stage in the life of the plant or in a seasonal or
other period of metabolic activity and growth.

But certain facts of observation and experiment have often been
regarded as pointing to a somewhat different conclusion. First
among these is the familiar fact, to which attention has already been
called (pp. 239-44), that many plants live and grow indefinitely
without sexual reproduction. This is true, not only of many
rhizome plants, in which the rhizome or rootstock grows con-
tinuously and produces new buds and roots, and from time to
time branches, while at the other end death continually advances,

370 SENESCENCE AND REJUVENESCENCE

but it apparently holds for at least many other plants as
well. Propagation by cuttings may be continued for a large
number of generations and probably indefinitely in many
plants, and some plants are not known to reproduce sexually in
nature.

Many of our cultivated plants have been bred agamically,
either wholly or to a large extent, for a long period of years. The
banana is one of the most conspicuous examples, the sugar cane
another, and in various species of willow and poplar and many
plants grown from bulbs or tubers, e.g., the potato, the agamic
method of propagation is the usual one.

Mobius (’97) has brought together a large number of these cases,
and has considered particularly those in which agamic propagation
for a longer or shorter time was apparently followed by the deteriora-
tion or the dying out of the stock. In many cases parasitic diseases
are responsible for this result, in other cases climatic or other ex-
ternal factors, and Mobius concludes that there are no grounds for
believing that agamic propagation necessarily results in an aging,
deterioration, and death of the stock.

Mobius has also discussed the facts bearing on the question
whether continued agamic propagation may lead to loss of the power
of gametic reproduction and concludes that, in at least most cases,
gametic reproduction is prevented by external factors and agamic
reproduction takes its place. It is an undoubted fact that plants
which do not reproduce sexually usually show a high degree of
agamic reproductive capacity of one form or another. While it is
not possible at present to analyze most of these cases, they all fall
readily into line with the view that gametic reproduction is char-
acteristic of a certain relatively advanced stage of the life history
of the individual, and that the individual cannot attain this stage
under conditions which bring about a continued or periodic breaking
up, physiologically speaking, into new individuals. If conditions
in nature or under cultivation favor continued vegetative growth,
new individuations continually occur and the reconstitutional
changes connected with this continued agamic reproduction prevent
any individual from attaining the condition of maturity. Or the
conditions may decrease the degree of individuation of the species

CONDITIONS OF GAMETE FORMATION 371

by altering the rate of metabolism, or in some other way, and so
lead to vegetative or other forms of agamic reproduction.

From this point of view, the absence or rare occurrence of
gametic reproduction in various plants, either in nature or under
cultivation, is not in any sense the factor which determines increased
agamic reproduction, but the agamic reproduction prevents the
organism from attaining the physiological condition in which
gametic reproduction occurs. Teleological interpretation of such
cases is entirely unnecessary and beside the point. Whether one
form of reproduction or another occurs depends upon the physi-
ological condition of the individual. In the physiologically
young, immature individual, whether it be a unicellular plant, a
single plant axis, or a whole multiaxial plant, reproduction, when it
occurs, is agamic, while the formation of gametes occurs in the older,
mature individual.

This conclusion may seem at first glance to conflict seriously with
certain other observational and experimental data concerning the
occurrence and experimental production of flowers. Flowers appear
frequently, either as an anomaly in nature or under experimental
conditions, on plants which, as regards length of time from the seed,
as well as size and morphological condition, are in an early stage
of development and young. The experimental investigations of
Véchting, Klebs, and others have demonstrated that the occurrence
of flowering may be controlled within wide limits by means of
various external conditions."

Voéchting’s experiments on Mimulus tilingii show very clearly
the significance of light for flowering. In a certain low illumination
in which vegetative growth is possible the inflorescence begins to
develop, but the preformed flower buds cease their development at

1 The following references will serve as a guide to the literature of the subject.
Mobius (’97) presents and describes numerous facts, largely observational rather
than experimental, bearing upon the problem. Diels (’06) has brought together many
cases of premature flowering or “nanism,” both from his own observations and from
the literature. The experimental investigations of Véchting (’93), Klebs (’o3, ’o4,
’06), and others demonstrate that the occurrence of flowering may be controlled within
wide limits by means of external factors. Jost (’08, pp. 439-46) gives a good general
survey of the subject. Additional references are Benecke, ’06; Doposcheg-Uhlar, ’12;

A. Fischer, ’05; Goebel, ’08, pp. 6, 10, 117, 190; Loew, ’05. These papers contain
further references.

372 SENESCENCE AND REJUVENESCENCE

an early stage, and instead of flowers axillary buds become active
and grow out into vegetative branches and the inflorescence is
transformed into a vegetative complex and the formation of gametes
does not occur. It should be noted that in this case it is only the
later stages of flower development which are inhibited by the low
light intensity. The specialization or change, of whatever character
it may be, which determines the development of an inflorescence
has occurred in these plants, but it stops at a certain stage and with
its cessation new vegetative individuals arise in consequence of
physiological isolation, and the vegetative life is resumed.

Klebs records similar results for various species and states that
in all plants which do not possess a considerable volume of reserves
a decrease in illumination suppresses the formation of flowers.
According to Klebs, this influence of illumination on flowering is
essentially a matter of photosynthesis. Blue light, which decreases
photosynthesis, acts like decreased illumination on flowering, while
in red light, by which photosynthesis is less affected, flowering
occurs.

Various other conditions—temperature, water, nutritive salts,
etc.—have been found to influence the occurrence of flowering. In
summing up his experiments on flowering plants in general Klebs
says: ;

For the formation of flowers the relations between the internal physico-
chemical conditions must be different from those in which vegetative growth
occurs. I believe that a quantitative increase in concentration of the organic
substances, with all its physical and chemical consequences, plays an essential
part in the transition from growth to reproduction. All external factors may
influence the occurrence of flowering favorably or unfavorably, according to
their intensity, their interrelations with each other, and the specific nature of
the plant, their effect depending upon the relations among the internal con-
ditions which they bring about.?

In a later paper Klebs states the results of his extensive experi-
- ments on Sempervivum funkii in somewhat more definite form. He
says:

I begin with a vigorous, previously well-nourished rosette which is ready

to bloom and make the experiments which determine its fate before or during
the primordial stages of flower development. The results are as follows:

? Klebs, ’04, pp. 553-54-

CONDITIONS OF GAMETE FORMATION 373

1. In bright light with active photosynthesis and intense absorption of
water and salts active vegetative growth results.

2. In bright light with active photosynthesis but with limited absorption
of water and salts profuse flowering results.

3. With a medium water and salt absorption the intensity of photosyn-
thesis determines whether vegetative growth or flowering shall occur. When
the production of organic substance is decreased, e.g., in blue light, vegetative
growth results, and when it is increased, flowering occurs.*

These results have in general been confirmed by the observations
and experiments of others, so that it seems to be a well-established
fact that the development of flowers depends upon different meta-
bolic conditions from those which determine vegetative growth.
Observation and experiment agree, moreover, in indicating that
flowering is determined by the accumulation in the plant of organic
substances which, because of insufficiency of water and salts, are
not completely transformed into metabolically active protoplasm
or its products, and so do not simply produce growth, but rather
a change in metabolic conditions in the direction of differentiation
and senescence.

If the formation of a new vegetative tip, i.e., a new vegetative
axis, is the generalized form of reproduction in the flowering plant
(cf. pp. 238-39), then there can be no doubt that the flowering is a
specialized type of reproduction. The flower certainly shows a
much higher degree of differentiation of its parts than does the
vegetative axis. Moreover, the metabolic conditions which favor
flowering are conditions which cannot arise at once in a plant indi-
vidual beginning its development and dependent upon external
sources of nutrition. At least certain stages of metabolic history
must be passed through before the plant is capable of being brought
into the flowering condition. Authorities in general agree that a
certain amount of vegetative growth must occur before the plant
can be induced to bloom. In other words, the plant must appar-
ently attain a certain stage of development, a certain physiological
age, before flowering is possible. But this stage having been
attained, the further metabolic conditions which favor flowering
are similar in character to those which bring about morphological
differentiation and senescence in animals, for they consist in the

t Klebs, ’06, pp. 105-6.

374 SENESCENCE AND REJUVENESCENCE

accumulation of inactive or relatively inactive organic substances
in the cells and consequently a decrease in metabolic rate. We see
also that such internal conditions bring about a higher degree of
differentiation in the plant than the conditions accompanying
vegetative growth. Moreover, the parts particularly involved in
this differentiation—the inflorescence axis or the flower—do not
under the usual conditions undergo any further vegetative growth,
but, after their development is completed, die a natural death,
and in many cases this natural death involves the whole plant,
the seeds only remaining alive.

The evidence seems then to point very clearly to the conclusion
that flowering in the plant is characteristic of an advanced stage
in the life cycle—that the blooming plant is physiologically rela-
tively old. The conditions which prevent flowering and favor
vegetative growth are simply such as keep the plant in a relatively
young condition by preventing the accumulation of the organic
substances and bringing about repeated vegetative reproduction
in consequence of growth.

It may seem at first glance that the metabolic conditions in the
flower are not in accord with the conclusion that the flower is the
product of advanced age in the plant. The flower, particularly in
its earlier stages, is usually the seat of a very intense respiratory
activity and often possesses a higher rate of oxidation than any
other part of the plant.t. If blooming is a feature of advanced age
and if rate of oxidation is in any way associated with age, it would
seem that we ought to find a low rate of oxidation in the flower.
Such a conclusion, however, ignores completely the fact that the
formation of the flower is a complex reproductive process and
unquestionably involves a greater or less degree of rejuvenescence
which appears in increased respiratory activity, and that in the
formation of the pollen grains in the anther and the ovules and
embryo sacs in the ovary extensive reproduction again occurs.
Moreover, in the developing flower the proportion of actively grow-
ing cells to the total weight is greater than in the vegetative por-
tions of the plant, with the exception of the embryonic growing

™See A. Maige, ’06, ’07; G. Maige, ’o9, ’11, and, for further references, Pfeffer,
97; Nicolas, ’og.

CONDITIONS OF GAMETE FORMATION 375

regions. In consequence of this condition the flower may be
expected to show a relatively high rate of respiration.

The accumulation of organic material and the relatively low
metabolic rate in the vegetative parts of the plant are probably
factors in making possible the high rate in the flower, which develops
at the expense of the nutritive substances in other parts. The
flower is a new individual or system of individuals, which arises
under conditions of low metabolic rate in other parts, and such
conditions favor the establishment in it of a high rate of metabolism
and growth. Evidently the flower is a more stable structure than
most of the vegetative parts of the plant and it undergoes rapid
progressive differentiation and aging. These characteristics are
also doubtless associated, on the one hand, with metabolic condition
of advanced age in other parts and, on the other, with its own high
metabolic rate.

In most flowers the rate of respiration decreases from relatively
early stages onward, but in some cases it undergoes increase or
remains almost constant up to the time of opening. These differ-
ences are probably associated with differences in the size and
amount of growth of the ovary and its contents as compared with
other parts of the flower. It was suggested in the preceding chap-
ter (pp. 349-50) that the increase in rate of respiration in the pistil
during its development is connected with the increasing bulk of the
growing ovules and embryo sacs in proportion to the whole pistil.
Since it is impossible to measure the respiratory rate of single game-
tophytes (pollen grains or embryo sacs) or gametes during their
development, the available data on rate of respiration in the flower
and its parts are incomplete for present purposes. In the case of
the pistil particularly they represent measurements of rate in a
complex system in which different parts attain their maximum
activity at different times and differ in amount and rate of growth
in different cases. Nevertheless, so far as the data are applicable
they do not conflict with, but rather support, the view that the
flower is a product of relatively advanced physiological age in the
plant.

In those cases where blooming is periodically repeated in the life
of the plant, as in perennials, it must be remembered that new

376 SENESCENCE AND REJUVENESCENCE

phytoids are concerned and that each period represents the life
history of a generation of phytoids. The life of the perennial,
multiaxial plant is not comparable to the life of an individual
animal, but is made up of innumerable life cycles with senescence
and death of the more highly differentiated parts in each generation.

From this standpoint the cases of premature flowering are to be
regarded simply as cases of prematurely established physiological
conditions resembling those which usually arise only after a con-
siderable period of vegetative activity. It is impossible to con-
sider these cases at length, and in many of them the determining
conditions have not been analyzed. One interesting case recently
recorded by Doposcheg-Uhlar (’12) may, however, be mentioned.
Bulbs of a species of Begonia could be made to produce either a
vegetative shoot or an inflorescence at once according as they were
allowed to produce roots or not. The roots provided for the
entrance of water and salts and so made possible the transforma-
tion of the organic reserves in the bulb into protoplasm, and under
these conditions complete rejuvenescence to the vegetative con-
dition was possible. When, however, root formation did not occur,
the metabolic conditions in the cells were those characteristic of an
advanced stage of the life cycle under ordinary conditions and
growth from the bulb resulted in the immediate development of
the highly differentiated flower structure. The early flowering of
various other plant species grown from bulbs is probably to be
interpreted in the same way. The internal conditions in such cases
are those of relatively advanced age.

Numerous cases of the transformation of an inflorescence, a
flower or some part of a flower, into a new vegetative axis have
been recorded by various authors (see pp. 246-47), and Klebs,
Goebel, and others have induced this transformation by subjecting
the young inflorescence or flower to external conditions favorable
to vegetative growth. As Goebel (’08, pp. 117-18) suggests,
these cases are undoubtedly to be interpreted as cases of return to
a juvenile stage. The external conditions have made dedifferen-
tiation and rejuvenescence possible, even in the relatively highly
differentiated flower.

t See the references given on p. 246, and particularly Klebs,’o3, ’o6.

CONDITIONS OF GAMETE FORMATION 377

Proceeding now to the last point in our consideration, the devel-
opment of the flower is preliminary to the formation of the gamete.
The gametophytes develop as parts of the flower (see pp. 320-22),
the pollen grains being the male, the embryo sac in the ovule the
female gametophyte. Although these gametophytes are much
reduced as compared with those of the mosses and ferns, yet their
formation in the seed plants, as in the lower forms, is unquestion-
ably the result of a specialized agamic reproductive process, i.e.,
spore formation. The gametophytes arising from the spore are
certainly in the seed plants highly specialized organs or organisms.
Their development differs widely in the two sexes and in both is
very different from anything else in the development of the plant
(see Figs. 140, 141, pp. 320, 321).

It is in these highly specialized organs, or individuals, as we
choose to call them, that the gametes are formed. The whole
history of the plant leading up to the formation of the gametes
is a history of specialization and differentiation of parts, and we
have therefore every reason to regard the gametes as among the
most highly specialized and differentiated cells produced by the
_plant.

CONDITIONS OF CONJUGATION IN THE PROTOZOA

According to Weismann all protozoa are potentially germ cells.
Maupas in his investigations on the ciliates reached the conclusion
that conjugation results from internal factors which, during the
period of agamic reproduction, bring about a progressive senescence
of the stock ending in death unless conjugation occurs. Conju-
gation in some way rejuvenates the animals and so makes possible
a new series of agamic generations. But the investigations of
recent years, as noted in chap. vi, have forced a change in view."

On the one hand, the breeding experiments of Calkins, Enriques,
Woodruff, and Jennings have demonstrated that at least some races
of Paramecium and other ciliates can be bred agamically for hun-
dreds or thousands of generations, and probably indefinitely,
without the occurrence of conjugation and without loss of vigor,
provided the proper conditions are maintained in the medium.

t Among the more important references are those given in the footnotes on p. 136;
see particularly Woodruff, ’14, Jennings, ’12, ’13.

378 SENESCENCE AND REJUVENESCENCE

On the other hand, Enriques, Jennings, Woodruff, Baitsell,
and others have shown that conjugation may be induced experi-
mentally. According to Jennings, different races show great differ-
ences in their capacity or tendency to conjugate, some conjugating
every few weeks, others at intervals of a year or more, or not at all.
But in those races which conjugate readily conjugation occurs,
“not as a result of starvation, but at the beginning of a decline in
nutritive conditions after a period of exceptional richness that has
induced rapid multiplication. At the time of conjugation the
animals are often in good condition, and multiplication may still
be in progress” (Jennings, ’10, p. 298). As regards these points
Calkins is in essential agreement with Jennings. In his experi-
ments with a single race Zweibaum found that conjugation may be
induced in a great variety of ways, provided a certain nutritive
condition exists in the animals. This condition is brought about
by keeping animals which have been richly fed for some weeks in
a medium with less food and then removing to a medium containing
almost no food. Differences in the methods of Jennings and
Zweibaum may be due to differences in the races used for experi-
ment, but there is general agreement that decreased nutrition favors
the occurrence of conjugation. Woodruff has recently brought
about conjugation experimentally in the Paramecium culture which
has been bred agamically for nearly five thousand generations, and
Baitsell has also found that the occurrence of conjugation in other
infusoria can be experimentally controlled.

These recent investigators agree in general that conjugation is
not the result of a progressive senescence, and so does not represent
the end of the life history. Calkins and Gregory maintain further
“that the progeny of an ex-conjugant is not a homogeneous race,
but consists of differentiated individuals which give rise to pure
lines, some of which conjugate, others do not. In other werds,
some Paramecia are potential germ cells, others are not.”? Wood-
ruff, however, disputes this conclusion and holds that the occur-
rence or non-occurrence of conjugation depends on environmental
conditions.

In chap. vi facts are cited which indicate that some degree of
senescence occurs during the life of each generation and some

CONDITIONS OF GAMETE FORMATION 379

degree of rejuvenescence, at least in the cytoplasm, in each agamic
reproduction, and the periodic process of endomixis and the repro-
ductive rhythms associated with it were interpreted as periods of
senescence, death, and replacement of the meganucleus. Since
Woodruff and Erdmann (’14) have demonstrated, not only that
endomixis occurs periodically, but that it has no relation to the
occurrence of conjugation, we must conclude that the progressive
senescence of the meganucleus which results in endomixis is not
the essential factor concerned in bringing about conjugation.
Moreover, since conjugation is not a feature of an internally
determined invariable life cycle, but is rather associated with and
dependent upon certain environmental conditions, at least to a
high degree, it seems probable that the physiological conditions of
conjugation are primarily cytoplasmic rather than nuclear, for the
cytoplasm is more affected than the nucleus by the environmental
conditions.

Since cytoplasmic rejuvenescence occurs with each agamic
reproduction, it is evident that the physiological age of the cyto-
plasm attained in each generation may depend, at least in part,
upon the frequency of reproduction. With abundant food and
favorable medium the reconstitution associated with one repro-
duction is scarcely completed before another reproduction occurs.
Under such conditions the degree of physiological senescence be-
tween two successive fissions must be less than when the interval
between reproductions is longer. Consequently certain conditions
which retard growth and agamic reproduction, but which are not
so extreme as to bring about either complete quiescence or star-
vation and reduction, favor the attainment of a more advanced
cytoplasmic age by the individuals of each generation. Under
these conditions the parts continue to exercise their special func-
tions for a longer period before undergoing regressive changes in
connection with reproduction, and the advance of senescence in
each generation may not be balanced by the rejuvenescence
occurring in each reproduction, so that progressive cytoplasmic
senescence of the race may occur. We need not expect, however,
to find conspicuous morphological differences between such ani-
mals and those which are growing and reproducing rapidly. The

380 SENESCENCE AND REJUVENESCENCE

differences can at most be merely those between physiologically older
and younger individuals both of which have attained the adult form,
and in organisms as simple as the ciliates would be more readily
distinguishable physiologically than morphologically. But so far
as I am aware, this point has not been considered by most students
of protozoa. One author, Prowazek (’10), has stated that when
cultures of Colpidium are prevented from dividing by insufficient
nutrition, they rapidly become old. In his cultures, however, the
animals were evidently starved, for they underwent reduction in
size to a considerable extent and their susceptibility to atropin
underwent a marked increase. These changes in size and suscepti-
bility suggest that these cultures were undergoing reduction and
increase in rate of metabolism in consequence of partial starvation
(cf. chap. vii) instead of undergoing senescence. Nutrition seems
to have been insufficient in this case to permit senescence to occur;
for that the food should have been at least sufficient to prevent
decrease in size.

But the important point is that those conditions which favor a
. progressive senescence are the conditions which favor conjugation.
The facts from this point of view suggest simply that under con-
ditions which favor rapid agamic reproduction the animals have
no opportunity to attain maturity because of the frequent recon-
stitution and rejuvenescence. When agamic reproduction is
retarded or inhibited, maturity is very soon attained and conju-
gation occurs.

The occurrence of endomixis indicates, as I have pointed out,
that the meganucleus undergoes senescence in spite of agamic
reproduction. If, at the time when the meganucleus is approach-
ing death, the cytoplasm is physiologically young and in good
metabolic condition, then apparently endomixis and recovery with-
out conjugation occur, but if, at this time, the cytoplasm is also in
a condition of advanced physiological senescence, then probably
the physiological conditions for conjugation are present, and if con-
jugation is impossible, death may result. According to this view,
endomixis results from progressive senescence of a single specialized
organ, the meganucleus, and conjugation from the senescence of
both meganucleus and cytoplasm.

CONDITIONS OF GAMETE FORMATION 381

If senescence is essentially a decrease in rate of metabolism, the
stage of maturity must possess a lower rate of metabolism than the
stage in which agamic reproduction is occurring. While I have not
as yet made a systematic study of the changes in susceptibility of
ciliates with changes in medium and other conditions, certain
differences in susceptibility observed in a culture of Colpidium are
of some interest in this connection. This culture was at first under-
going very rapid agamic reproduction and the small, recently
divided individuals, as well as most of those in late stages of division,
were more susceptible to cyanide than the larger, older individuals.
In the course of a few days an acute epidemic of conjugation
occurred in the culture, and fissions almost ceased: conjugation
- was confined to the larger individuals of the culture. At this stage
the small animals were most susceptible, the large, non-conjugating
animals less susceptible, and the conjugating pairs least susceptible
ofall. The low susceptibility of the conjugants indicates that they
possess a lower metabolic rate and so are physiologically older than
the other members of the culture.

These experiments suggest that the occurrence of conjugation
is associated with the attainment of a certain physiological age, a
condition of maturity, with a relatively low rate of metabolism.
If this conclusion is correct, we must consider the question of the
influence of external conditions upon the attainment of this ma-
turity: is it possible to accelerate or retard its occurrence through
cultural or other environmental conditions? It is not to be
expected that a sudden decrease in rate of metabolism induced by
external conditions will bring about a normal maturity in a very
young individual: such a change would simply retard or inhibit its
development. But when development has reached a certain stage
and the organism is approaching maturity, then it is very probable
that a slight decrease in metabolic rate, externally induced, may be
sufficient in many cases to bring about or accelerate the change
which under constant external conditions would have occurred much
more slowly. Some of the chemical agents which Zweibaum and
others have used to induce conjugation may perhaps act in this way.

As regards the different capacity or tendency of different races
to conjugate, which has been discussed by Jennings, Woodruff, and

382 SENESCENCE AND REJUVENESCENCE

Calkins, it is possible at present only to point out certain probable
factors concerned. In the first place, the rate and coutse of indi-
vidual senescence or rejuvenescence under a given complex of con-
ditions is probably different in different races of Paramecium and
other forms, and the rate and course of individual senescence or
rejuvenescence in a given race may differ under different conditions.
Differences of this kind also appear to some extent in planarians.
In Planaria velata the course of the age cycle depends upon the
character of the food (see pp. 169-75). With some kinds of food
progressive senescence from generation to generation occurs and
in a few generations death results, while with others rejuvenes-
~ cence and senescence balance each other in each generation.
Doubtless similar relations exist in Paramecium and other ciliates
between character of food, rate of senescence in each generation,
and degree of rejuvenescence in each reproduction. And it is not
at all improbable that various other factors besides nutrition, e.g.,
many chemical agents, may influence the rate, degree, and course
of development, senescence, and rejuvenescence.

Whether, as Calkins believes, some races of Paramecium and
other ciliates are not even potentially capable of conjugation can
be determined only by extensive investigation, and then only with
a certain degree of probability. It is of course conceivable that
in organisms with great capacity for agamic reproduction the
capacity to attain gametic maturity may not be realized under
ordinary conditions (see chap. x), but as yet we have no adequate
basis for maintaining that the potentiality is absent in such cases.

In the higher animals a definite sequence of events is a funda-
mental characteristic of the life cycle, and it seems not wholly
logical to maintain that a sequence is entirely absent in the simpler
forms. We can scarcely doubt that an individual Paramecium,
continuing to live without reproduction and with sufficient food
for maintenance in a constant medium which does not inhibit
metabolism, will undergo certain more or less definite changes, and
will show a life history. And it seems probable that if these changes
proceed sufficiently far without interruption by reproduction or
change in external conditions, the individual may attain maturity—
the physiological condition in which conjugation occurs—or may

CONDITIONS OF GAMETE FORMATION 383

even die of old age. But the more readily agamic reproduction
occurs in consequence of either internal or external factors, the less
likely is the life history of the individual to attain its later stages.

In the case of the protozoa the question of progressive race
senescence has occupied the minds of most investigators to the
exclusion of individual senescence. Apparently, however, the
solution of the whole problem is to be found in the relation between
individual senescence and rejuvenescence under different conditions.
If progressive senescence in a race, ending in conjugation or death,
does not occur in a race bred agamically, it is not because the
individuals do not undergo senescence, but rather because the
cytoplasmic senescence in each generation is compensated by
rejuvenescence in each agamic reproduction and because senescence
of the meganucleus is compensated by the process of nuclear reor-
ganization which Woodruff and Erdmann have called endomixis.

CONDITIONS OF GAMETE FORMATION IN THE MULTICELLULAR ANIMALS

Our knowledge concerning the physiological conditions which de-
termine the formation of gametes in the lower multicellular animals
is as yet very fragmentary. As regards many forms we do not even
know whether sexual maturity occurs once or periodically in the
life cycle, or whether its appearance is merely a reaction to external
conditions. Observation of the animals in nature seems to indicate
clearly enough that in general the formation of gametes occurs only
when a period of vegetative growth, with or without agamic repro-
duction, is approaching or has reached its end. In the case of the
fresh-water hydra considerable experimental work has been done,*
and most authors agree that low temperature determines sexual
maturity, although different species appear to differ to some extent
as regards the effective temperatures. Nussbaum maintains that
starvation or at least decrease in nutrition is the essential factor,
but other authors do not agree with him. These results do not
afford us any very deep insight into the physiology of gamete
formation. They merely indicate that a relatively low rate of
metabolism favors or even determines gamete formation, but
whether gamete formation ever occurs without the aid of external

tR. Hertwig, ’06; Krapfenbauer, ’08; Frischolz,’09; Nussbaum, ’og; Koch, ’11.

384 SENESCENCE AND REJUVENESCENCE

factors which decrease metabolism we do not know. It may be
that such processes as budding and the replacement of differ-
entiated old cells by young cells from the interstitial tissue prevent
progressive development in hydra beyond a certain point under
the usual conditions, in which case low temperatures by decreasing
the rate of metabolism may bring about essentially the same changes
that would occur in further development determined by internal
factors. In many if not in all of the coelenterates, however, there
are indications that the formation of gametes is associated with an
advanced stage of the life cycle.

One of the most interesting cases is that of certain jelly-fishes
or medusae belonging to the family Margelidae (Chun, ’96; Braem,
08). These medusae reproduce agamically by budding, and buds
arise in a definite order upon the proboscis and develop from the
ectoderm alone instead of from both body layers, as do other coelen-
terate buds. The young medusa gives rise to these buds, but as it
grows older sex organs begin to appear from the same body layer
and in the same region as the buds and sometimes in place of them.
Fig. 196 shows the proboscis of one of these medusae on which
both buds and ovaries containing eggs are present. After the sex
organs once appear the buds gradually cease to form and only
gametes are produced in later stages.

In these medusae the same region and layer of the body and,
so far as we can determine, cells of exactly the same character, give
rise in the younger animal to agamic buds and in later stages to
gametes. Very evidently the physiological condition of these cells
undergoes change during the life history of the animal. Braem
regards this case as indicating that the agamic buds as well as the
gametes arise from germ plasm, but it seems rather to indicate that
gametes as well as agamic buds may arise from cells which are
functional, more or less specialized parts of the organism, and that
the gametes are more highly specialized cells and arise later in the
life history than those which develop into buds.

As regards the planarian worms a few facts are at hand. Atten-
tion has already been called (pp. 99, 125) to the fact that Planaria
dorotocephala is not known to reproduce sexually at all in the locality
where I have collected material. But in stocks which are kept in

CONDITIONS OF GAMETE FORMATION 385

the laboratory under uniform conditions, provided with abundant
food and prevented from undergoing fission, the animals often con-
tinue to grow until they are fully twice as large as the largest found
under natural conditions, and a considerable number of these very
large animals develop the hermaphroditic sexual organs character-
istic of the species, become sexually mature, and lay eggs. Often

Fic. 196.—Manubrium of female Lizzia (jelly-fish), showing agamic buds and
eggs: in addition to the four large eggs, 0, those regions which are occupied by dis-
tinctly differentiated ovarial cells are indicated by drawing in cell outlines and nuclei;
in the dotted regions are cells which may become either buds or ovarian cells: roman
numerals I, III, IV, V, VII, indicate buds in the order of their formation, bud I having
already become free and buds II and VI being on the other side of the manubrium;
the point * indicates the position where the eighth bud should appear. From Braem,
708.

sexually mature animals can be made to undergo fission simply by
transferring them to another perfectly clean aquarium without
slime on its walls, and when the level of fission is anywhere near t he
openings of the sexual ducts, which lie a short distance behind the
mouth, the openings and all the terminal organs disappear.

The very low susceptibility of the sexually mature animals to
cyanides, as compared with that of the largest animals in nature,

386 SENESCENCE AND REJUVENESCENCE

indicates that physiologically they are very much older than the
latter. In consequence of continued feeding and growth and the
absence of the reconstitutional changes connected with fission,
these animals have evidently attained a stage of development which
is not reached by the animals in nature.

The conditions in nature which prevent the animals from
attaining the later stages of development and sexual maturity are
less abundant food and consequently greater activity, which in
turn determines more frequent fission, so that the animals are
almost continuously undergoing reconstitution. Moreover, the
animals are subjected more or less periodically to periods of partial
starvation. Insufficiency of food may arise from the rapid increase
in numbers of the animals by fission during the summer, perhaps
also from the slow reproduction of the food animals in winter.
These two facts, fission and repeated partial starvation, contribute
to keep the animals physiologically young and so prevent them
from attaining the age and physiological condition in which sexual
maturity occurs.

Planaria maculata becomes sexually mature in some localities
and not, or only very rarely, in others (Curtis, ’o2). In the latter
localities the factors which prevent the occurrence of sexual ma-
turity are undoubtedly the same as those which produce the result
in P. dorotocephala, i.e., repeated fission and periodical or occasional
partial starvation.

In a stock of P. maculata kept in the laboratory I found that
sexually mature individuals, after egg laying, lose the sexual organs
and undergo a considerable reduction in size. During this period
they take little or no food, but after a time begin once more to feed
and grow, and if growth is rapid they may reproduce agamically,
while if it is slow they may in some cases become sexually mature
again without passing through any period of agamic reproduction.

The differences in susceptibility of the animals at these different
periods indicate that the sexually mature stages are physiologically
older than others, and that after egg laying they undergo a consider-
able degree of rejuvenescence during the reduction, and once more
begin to undergo senescence when they begin to feed. Whether
they remain asexual or become sexually mature depends on the

CONDITIONS OF GAMETE FORMATION 387

amount and uniformity of the food supply and the rate of growth.
There is no question that in P. maculata, as well as in P. doroto-
cephala, sexual maturity represents a condition of greater physio-
logical age than the asexual stage.
The case of P. velata is somewhat different. Under the con-
ditions where it is usually found in nature, as well as in the labora-
tory, this form unquestionably grows old, ceases to feed, and
undergoes fragmentation in each generation without becoming
sexually mature. Apparently sexual reproduction has no place in
the life cycle of this species. If it were not for the fact that the
animal stops feeding and ceases to grow before fragmentation
occurs we might believe that the life cycle of the individual is sim-
ply interrupted as in P. dorotocephala and in many plants by the
agamic reproduction, but as a matter of fact the period of develop-
ment and growth is apparently completed before fragmentation
begins. Thus far it has not been possible to induce sexual maturity
experimentally in this species. It seems probable, however, that
certain of the feeding experiments already described afford a clue
to the understanding of this case. It was pointed out that the
length of the growth period and the amount of growth before
fragmentation differ very widely with different foods. In other
words, the rate of senescence differs according to character of food.
This suggests the possibility that with certain foods growth might
continue and fragmentation be delayed until attainment of the
stage of sexual maturity, but only further experiment can throw
light upon the question.
As regards the parasitic groups of flatworms, the flukes and the
tapeworms, there can be no doubt that formation of gametes and
sexual reproduction is characteristic of an advanced stage in the
life of the individual. Such parasites are subjected to but little
change in external conditions, especially those living in the bodies
of mammals, and yet they pass through a definite life history, ending
in the development of gametes and, following this, the death of the
individual. In some of the flukes the number of larval generations
_between the egg and the development of the sexual organs may
differ according to external factors, but the relation between
sexual maturity and relatively advanced age is unmistakable.

388 SENESCENCE AND REJUVENESCENCE

In other animal groups in which agamic reproduction is a more
or less characteristic feature of the life cycle—certain families of
annelids, the bryozoa, and the tunicates—it is in general true
that agamic precedes gametic reproduction in the life history, and
in some of these forms, notably in certain annelids, agamic repro-
duction may apparently continue indefinitely under certain con-
ditions without the attainment of sexual maturity.

Among the higher invertebrates, and among the vertebrates,
the definite character and internal determination of the life history
become in most cases even more apparent. In many forms, as in
most of the insects, development ends in a single period of gametic
production followed by death. In many other forms, after ma-
turity is once attained, the production of gametes is periodic or
continuous and the animal may live for a long time and may also
undergo extensive growth, as do most of the mollusks after the
first period of sexual maturity. In such cases growth, as well as
gamete production, appears to be periodic, and the formation of
gametes follows, at least in most cases, the growth period.

Periodicity of this sort in the organism is commonly associated
with periodicity in the environment, e.g., with seasonal or other
periodic changes. The environmental periodicity may determine
slight alterations of senescence and rejuvenescence as perhaps in
the case of the mollusks, where growth periods ending with or
followed by gamete formation occur or in other cases the activity
of the sexual organs may be directly influenced by nutritive con-
dition, temperature, etc.

That the vertebrates pass through a definite developmental
history, with sexual maturity as a comparatively late stage, and
that this history is primarily determined by factors within the
organism rather than environmental conditions is sufficiently
evident. Here agamic reproduction does not occur, except in a
few cases in early embryonic stages, and the life history is without
the complications which arise in lower forms to prevent, balance,
or retard progressive development. Even among the vertebrates,
however, the appearance of sexual maturity may be hastened or
retarded by the character and amount of the food and by various
other environmental conditions. The tadpoles of frogs and sala-

CONDITIONS OF GAMETE FORMATION 389

manders, for example, may be made to undergo metamorphosis
into the adult form at a very small size or to attain giantism without
metamorphosis by controlling the character of the food (Guder-
natsch, ’12,’14; Romeis, ’14), and their development may be modi-
fied in various other ways. Even in man the age in years at which
sexual maturity occurs varies somewhat widely with climatic and
other factors. But none of these facts indicate anything more than
that a certain physiological condition of the organism may be
attained sooner or later according to the nature of the environment.

In various species among both invertebrates and vertebrates
cases of premature sexual maturity may occur while the animal is
still morphologically a larva, as in the so-called axolotl form of
certain salamanders; or after sexual maturity in the larval stage
the sex organs may disappear and the animal undergo meta-
morphosis to the adult form, after which new sex organs arise
and a second period of sexual maturity occurs, as in certain
ctenophores.

Evidently the sex organs may mature and produce gametes
at various stages of morphological development, but we know
nothing of the physiological conditions in these cases. In the light
of the facts already cited, however, it is probable that, whatever
the morphological stage at which sexual maturity occurs, certain
physiological conditions must exist in the organism which make its
appearance possible and that these are conditions which ordinarily
arise relatively late in development. In other words, the cases
of premature sexual maturity are probably cases of accelerated
physiological senescence.

PARTHENOGENESIS AND ZYGOGENESIS

In several of the invertebrate groups, viz., the rotifers, the clado-
cera among the crustacea, and the plant lice and related families
among the insects, the eggs of a single individual or of successive
generations differ in behavior, some developing parthenogenically
into females or males, and others zygogenically, i.e., requiring
fertilization for development.

Within recent years members of the crustacean group of
cladocera, the daphnids, have been the subject of extensive

390 SENESCENCE AND REJUVENESCENCE

investigation along these lines,* and while different authorities are
not as yet in full agreement, evidence which points to a definite
conclusion is accumulating.

It is well known that the daphnid females produce three kinds
of eggs, parthenogenic eggs which produce females, parthenogenic
eggs which produce males, and zygogenic eggs which produce
females. Both the female- and male-producing parthenogenic
eggs develop at once and are commonly known as “‘summer eggs.”
The zygogenic eggs, on the other hand, are surrounded by a thick
shell and hatch only after a quiescent period which often, but not
necessarily, coincides with the winter season, hence they are known
as “‘winter eggs.”” The problem to which attention has been
chiefly directed is that of the relative importance of external and
internal factors in determining the production of these three kinds
of eggs. Weismann believed that a fixed cycle of generations |
determined by inheritance existed in each species quite independ-
ently of external factors; according to this view a certain number
of generations of parthenogenic females were produced, then males
developed from parthenogenic eggs and zygogenic eggs were pro-
duced, which after a quiescent period developed into parthenogenic
female-producing females, and these began the cycle anew.

Later investigators have found that the cycle of generations is
far from being hereditarily fixed and that it can be greatly modified
by external factors. Under certain conditions, e.g., with high tem-
perature and abundant nutrition, parthenogenic reproduction may
continue indefinitely. Other conditions, such as low temperature
and lack of food, favor the production of males and zygogenic eggs.
In general, males and zygogenic eggs are produced under similar
conditions. Moreover, Woltereck has found that after producing
males the females may again begin to produce females partheno-
genically without producing winter eggs, and the same change may
occur even after the production of winter eggs. Kuttner showed,
however, that the cycle of generations may occur independently
of change in external conditions.

t Some of the more important papers are the following: Issakowitsch, ’06, ’o8;
Kuttner, ’09; Langhans, ’09; Papanicolau, ’10a, ’10b, ’11; von Scharfenberg, ’10;
Strohl, ’07, ’08; Weismann, ’80; Woltereck, ’og, ’11.

CONDITIONS OF GAMETE FORMATION 391

Woltereck’s extensive investigations, together with the evidence
from the work of others, seem to show very clearly that, while
differences exist in different races and species, nevertheless a cyclical
change affecting the character of the eggs produced does occur in
these animals independently of external factors, although it may
be modified by temperature, nutrition, and chemical constitution
of the medium in which the animals live. Woltereck divides the
cycle into three periods, the first including the early generations of
females following the winter eggs. These females are predomi-
nantly parthenogenic and female-producing, at least until late in
life, and external factors have no effect on the character of the eggs.
After this follows a second period in which external conditions
determine to a very large extent whether parthenogenic eggs pro-
ducing females, or parthenogenic eggs producing males and zygo-
genic eggs are produced, and finally a third period occurs in which
parthenogenic eggs producing males and female-producing zygogenic
eggs appear independently of external conditions.

Von Scharfenberg and Papanicolau found that a change in egg
character occurred, not only in the course of successive generations,
but also in the course of single generations, i.e., the eggs produced
early in the life of a female are more likely to develop partheno-
genically into females and those produced later in life into males
or to be zygogenic winter eggs. In the earlier generations of a
cycle the male-producing and zygogenic eggs appear later in the
life of the individuals, in later generations earlier. Moreover,
the same three periods appear more or less clearly in the repro-
ductive cycle of the single females as in the cycle of generations.

This reproductive cycle appearing both in single individuals
and in successive generations is in certain respects analogous to the
cycle of agamic and gametic reproduction in many of the lower
animals. In the early stages of the cycle the daphnids, although
producing what we call eggs, are really reproducing agamically,
since the eggs develop parthenogenically, but in later generations,
as well as later in the life of the individual, they become sexually
mature, and males and females appear and the eggs require ferti-
lization. ‘There seems to be a progressive change in physiological
condition in these animals, both individually and in successive

392 SENESCENCE AND REJUVENESCENCE

generations, which corresponds to the aging and the attainment of
sexual maturity in other forms. The parthenogenic female-
producing egg is apparently characteristic of the young animal
and the earlier generations in a cycle, the parthenogenic male-
producing egg and the zygogenic female-producing egg of a more
advanced age in the individual and in the generations. Richard
Hertwig (’12) in discussing these facts says: ‘‘It is therefore possible
to speak in a double sense of an aging of the daphnids and of a
change in the constitution of the eggs determined by it.”

Woltereck has found that an individual may pass through
more than one of these reproductive cycles. Even after producing
winter eggs, females may again pass through a labile period in
which the character of the eggs can be influenced by external con-
ditions and still later attain a condition in which the eggs are
parthenogenic and female-producing in spite of external conditions.
In other words, they become physiologically young again. But it
has been shown in earlier chapters that such rejuvenescence occurs
in many forms. In the case of the daphnids it does not proceed
as far as in many of the lower animals, for these may lose their
sexual organs entirely and return to reproduction by budding or
fission, while in the daphnids we find only a return from the produc-
tion of zygogenic to the production of parthenogenic eggs.

As regards the rotifers, in certain species of which partheno-
genesis and bisexuality exist, the various investigators’ still differ
widely in their opinions as to the determining factors. The effect-
ive factor in determining parthenogenesis and bisexuality is accord-
ing to Maupas temperature, and according to Nussbaum nutrition,
while Punnett finds that neither of these external factors is con-
cerned, but that the character of the eggs is hereditarily determined.
Whitney regards the age of the family, that is, the position in the
cycle of generations, as the important factor, although he admits
the influence of external conditions. And, finally, Shull has demon-
strated the influence ef external factors in the environmental
medium, apparently of chemical nature, but believes that internal
factors are also involved. With such differences of opinion it

™Maupas, ’91; M. Nussbaum, ’97; Punnett, ’06; Shull, ’1o0, ’r1a@, ’11b, ’12;
Whitney, ’o7, ’12a, ’12b.

CONDITIONS OF GAMETE FORMATION 393

seems at least probable that internal physiological conditions,
which are not yet clearly recognized, are the real determining
factors, and that the various external factors merely modify their
action. As Woltereck (’11) has pointed out, there is every reason
to believe that the relation between parthenogenesis and bisexu-
ality is essentially the same in the rotifers as in the daphnids.

Parthenogenesis and bisexuality are also found among the
plant lice and various other related forms among the hemiptera.
In these cases, as in the daphnids, bisexuality appears later in the
cycle than parthenogenesis, but concerning the influence of external
conditions in modifying the usual course of events, our knowledge
is fragmentary. Low temperature or lack of food may apparently
at times induce bisexuality, as in the daphnids. All that we know
suggests that in this, as in other cases, bisexuality is a feature
of more advanced age than parthenogenesis, and that the aging
may be accelerated or retarded, perhaps reversed, by external
conditions.

The parthenogenic egg is apparently a less highly specialized,
physiologically younger cell than the egg requiring fertilization.
Morphologically it is less highly differentiated, at least in many
cases, than the zygogenic egg (see pp. 342-46), and when isolated
from the parent body it is capable of developing at once without
fertilization (cf. pp. 406-8). If such eggs are produced by animals
in the earlier stages of their adult life history or by the earlier
generation of a cycle, we are forced to the conclusion that the germ
cells undergo differentiation and aging like the rest of the body.
In short, the egg produced by the older organism is itself older
and more highly specialized than that produced by a younger.

The physiological character of the action of external conditions
in modifying the eggs can at present only be surmised. Woltereck
suggests that the differences in the eggs are due to differences in the
intensity of assimilation in the ovary, high intensity determining
parthenogenic female-producing eggs and low intensity bisexual
eggs. A decrease in intensity of assimilation is, however, a char-
acteristic feature of senescence and may result from internal as
well as from external conditions. Apparently the external factors,
whatever the exact mechanism of their action, either accelerate,

394 SENESCENCE AND REJUVENESCENCE

retard, or reverse the life cycle of the whole animal and so affect the
character of the eggs, or else they alter conditions in the ovaries
so that eggs are isolated from the parent organism earlier or later
in their development.

If the external conditions decrease the general metabolism, they
may bring about physiological conditions which would arise without
their action in more advanced stages of senescence, but if their
effect is to increase metabolism, they may make the animal some-
what younger physiologically by increasing breakdown and elimi-
nation, or they may at least retard or inhibit senescence. In this
manner the character of the eggs may be influenced through the

physiological condition of the whole animal.

It is probable, however that the physiological age and condition
of the egg do not necessarily correspond in all cases to the physio-
logical age of the egg-producing organism. Under certain conditions,
such as abundant nutrition or high temperature, the development of
successive eggs may be so rapid that each egg is forced down the
ovarian tubules and isolated before its growth is completed, even
though the animal itself is physiologically old. Such an egg must
be physiologically younger than one which undergoes more growth
before isolation. Probably the action of external factors in deter-
mining parthenogenesis and bisexuality is sometimes of this charac-
ter, and a high rate of egg production results in younger eggs, a
low rate of egg production in older eggs.

Summing up, this point of view seems to afford a basis for
reconciling the apparently conflicting data, and for further analytic
investigation. The parthenogenic egg in the daphnids and rotifers
is apparently physiologically younger and less highly differentiated
than the zygogenic; the physiological age, both of the individual
and of the race, and probably also the rate and conditions of egg
production, are factors in determining whether parthenogenic or
zygogenic eggs shall be produced; and, finally, external factors act
by accelerating, retarding, or reversing the course of the life history
in the individual or race, or by influencing the rate and other
conditions of egg production in the ovary.

It seems to be definitely determined that among the bees the
males arise from parthenogenic eggs, the females from fertilized

CONDITIONS OF GAMETE FORMATION 395

eggs, as Dzierzon maintained more than sixty years ago." The
queen bee is apparently capable of producing drone eggs at any
time, or at least repeatedly, during her life. It is conceivable that
all eggs produced by the queen are potentially parthenogenic and
so male-producing, but that when fertilized they produce females
(see pp. 344-45), but if the parthenogenic eggs are physiologically
different from the zygogenic in this case, it seems probable that the
former are at least slightly younger than the latter when they
leave the ovary. If, as suggested above, not only the physio-
logical age of the animal, but the conditions in the ovary determining
the rate of egg production—the abundance of nutrition, etc.—are
factors in the determination of parthenogenic and zygogenic eggs,
old queens may produce parthenogenic or young queens zygogenic
eggs under certain conditions. Only under fairly constant external
conditions could a definite, fixed relation between physiological
condition of the egg and physiological age of the parent be expected.

In certain of the parasitic flatworms—the digenetic trematodes
—two or more larval generations occur between the fertilized egg
and the adult stage. The first of these larval generations arises
from the egg as a single individual which contains within its body
certain cells known as germ cells. Each of these germ cells develops
within the parent body into a larval individual of the second genera-
tion, and in many cases these larvae likewise contain germ cells
which give rise to a third larval generation: sometimes the process
may continue still farther, but in any case the final larval generation
undergoes transformation into a single adult individual and becomes
sexually mature.

The germ cells in the bodies of these trematode larvae have
commonly been regarded as eggs, and the development of the second
and following larval generations as cases of parthenogenesis. The
observation of Cary (’og) that these germ cells resemble partheno-
genic eggs in giving rise to a single polar body before beginning
development gives further support to this view. If these cells are
actually parthenogenic eggs or approach such eggs in their charac-
teristics, their appearance during or immediately after the embryonic

t The latest studies on the subject, Nachtsheim, ’13, Armbruster, 713, give an
extensive bibliography.

396 SENESCENCE AND REJUVENESCENCE

period seems to conflict with the conclusion reached in the
present chapter that the formation of gametes is a feature of
relatively late stages in the life history of the individual. This
conflict, however, is apparent rather than real. Each larval genera-
tion has a life history of its own not essentially different from that
of other animals: during this period it undergoes progressive differ-
entiation and growth, but the rate of growth decreases and the
larva finally dies, apparently of old age. I have determined the
changes in susceptibility to cyanides of two of the larval generations
of certain species and have found that a marked and rapid decrease
in susceptibility occurs in each generation and that the early stages
of each generation show a much higher susceptibility than the late
stages of the preceding generation. This means that each genera-
tion undergoes a rapid senescence and that rejuvenescence occurs
during each reproduction, but there is some evidence that progressive
senescence from generation to generation also occurs to some extent.

During the earlier stages of the life of a larva the cells which
later become germ cells undergo division and so increase in number,
but they do not become mature and begin independent development
into new individuals until a relatively late larval stage of larval
life is reached. The period of reproduction through the germ cells
is in fact a feature of advanced age in the life of the larva. The cells
resemble eggs in possessing a low metabolic rate before beginning
development because they are parts of a physiologically old body,
and it is probable that the occurrence of a maturation division with
the formation of a polar body is connected with this condition (see
pp. 353-56). What we commonly call the life history of these
worms is then in reality a series of life histories with alternating
periods of senescence and rejuvenescence. Each period of senes-
cence is accompanied in its later stages by reproduction through
cells which resemble parthenogenic eggs more or less closely, but
only in advanced age of the final generation, the adult form, do
sexual maturity and fertilization occur. Certain other points in
these life histories are of interest in connection with the problem of
the life cycle, but this brief consideration is perhaps sufficient to
show that the peculiar larval reproduction of these species is a
feature of advanced age like gametic reproduction in other forms.

CONDITIONS OF GAMETE FORMATION 397

CONCLUSION

It is apparently true for both animals and plants that the pro-
duction of gametes is associated with certain internal conditions
which are characteristic of an advanced physiological age. But
since the course of the age cycle may be accelerated, retarded, or
reversed by the action of external factors, the formation of gametes
in the lower organisms, where the influence of external factors is
relatively great, may often appear to be largely dependent upon
these external factors. Not only is gamete production a feature
of relatively advanced age, but in some cases the physiological
age of the egg—parthenogenic or zygogenic character—apparently
depends to some extent on the physiological age of the parent.

The association of gamete formation with advanced physio-
logical age is a fact of great importance, for it indicates that the
“germ plasm” is an integral physiological part of the organism
and that the formation of the gametes is the final stage of a period
of progressive development in the reproductive cells. In the earlier
stages of the life history of the organism isolated cells or cell masses
may react to isolation by dedifferentiation and reconstitution to a
new individual, i.e., agamic reproduction occurs. The partheno-
genic egg is apparently a cell which has undergone a considerable
degree of differentiation as a gamete, but has not lost the capacity
to react to isolation by dedifferentiation and reconstitution. And,
finally, the zygogenic gamete has attained a stage of differentiation
and senescence in which it is no longer capable alone of reacting to
isolation, but can undergo dedifferentiation and reconstitution only
when fertilization occurs. If there are any cells in the organism
which do not contain “undifferentiated germ plasm,” the gametes
certainly seem to be among those cells.

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CHAPTER XV

REJUVENESCENCE IN EMBRYONIC AND LARVAL
DEVELOPMENT

If the gametes are physiologically old cells, rejuvenescence must
occur during embryonic development, for the organism when it
begins its active independent life at the end of the embryonic
period is certainly very much younger in every respect than the
gametes before fertilization. It now remains to consider the
evidence bearing upon this point. This evidence is chiefly zod-
logical rather than botanical, for in most of the plants the early
embryonic stages cannot readily be isolated for experimental
purposes.

THE EFFECT OF FERTILIZATION

To attempt any consideration of the problem of fertilization
itself would lead us too far afield; moreover, no well-established
and generally accepted theory of fertilization has as yet emerged
from the great mass of often conflicting experimental data and
opinions. It is the effect of fertilization rather than the process
itself with which we are primarily concerned.

Whatever the nature of the process, it is a self-evident fact that
the union of the two gametes is usually the starting-point of a
new period of activity and change in the resulting cell. It is true
that in some cases among both plants and animals fertilization is
followed after a short period of activity by a quiescent period, but
we know that in certain of these cases the cessation of activity is
due to incidental or external factors, such as the presence of an
impermeable shell or envelope of some sort which cuts off the supply
of oxygen or water, or otherwise interferes with dynamic activity
until it is removed in one way or another, or gamete formation may
occur at seasons of the year or under external conditions which
retard or inhibit metabolic activity. In the delayed germination
of plant seeds,’ in the quiescent encysted periods of certain protozoa

™See, for example, Crocker, ’06, ’07, 09; and references to literature in these
papers.
403

404 SENESCENCE AND REJUVENESCENCE

after union of the gametes, and in the cessation of development of
the ‘‘winter eggs” of flatworms, rotifers, crustacea, and insects,
the presence of shells or envelopes of some sort is undoubtedly the
chief factor in retarding or inhibiting the metabolic activity. Even
in those animal eggs which, like some seeds, must before they will
hatch be subjected to certain external conditions, such as freez-
ing temperature or desiccation, or in the case of Branchipus, the
fairy shrimp, apparently to both, there is good reason to believe
that the effect of these conditions in altering or disintegrating the
egg envelope is much more important than any effect which they
may have upon the protoplasm itself. These, however, are cases
of the cessation of development rather than of its failure to begin.

There are some cases where gametic union does not result in a
period of increased activity and where internal rather than external
factors seem to be responsible. Jennings (’13), for example, has
found that in Paramecium the effects of conjugation are by no
means uniform, for many of the ex-conjugants show decreased rather
than increased activity and some die, while others do exhibit an
increased rate of growth and division. It is probable that this lack
of uniformity in the results of gametic union is connected with the
fact that the body and the gamete are the same cell. Different
individuals become specialized in different directions and the
physiological effect of gametic union must vary widely, for in some
cases the two protoplasms are incompatible in some way, or a sum-
mation of their physiological defects occurs, while in others the
result is the opposite. In the multicellular organisms, however,
where the gametes develop as specialized parts of the body more or
less remote from the influence of factors external to the organism,
their course of development and consequently the effects of their
union are much more definite and uniform, but even here the results
of gametic union may vary to some extent, although increased
dynamic activity following union is the usual result.

There are in fact very few exceptions to the rule that gametic
union is followed by increased dynamic activity, and it is probable
that most, if not all, of these exceptions will prove to be apparent
rather then real. We may say then with Loeb that fertilization
in some way saves the life of the gametes. If the gametes are highly

REJUVENESCENCE IN EMBRYO AND LARVA 405

differentiated, physiologically old cells, approaching death, an
increase in dynamic activity can scarcely mean anything else than
the beginning of a period of rejuvenescence and dedifferentiation.

The increase in the dynamic activity of the sea-urchin egg after
fertilization has been determined in various. ways by various inves-
tigators.. Lyon found that the susceptibility of the eggs to cyanide
was greater after than before fertilization. Measurements of the
oxygen consumption of the egg of the Neapolitan sea-urchin
(Strongylocentrotus lividus) by Warburg showed that after fertiliza-
tion the oxygen consumption was between six and seven times as
great as before, and Loeb and Wasteneys found that in an American
sea-urchin (Arbacia punciulata) the fertilized egg consumed three
to four times as much oxygen as the unfertilized.?, In a study of
heat production in the sea-urchin egg Meyerhof finds the heat
production per hour between four and five times as great in fer-
tilized as in unfertilized eggs.

In the starfish egg, however, according to Loeb and Wasteneys
(’12), the oxygen consumption is about the same before and after
fertilization. This difference in behavior between starfish and sea-
urchin eggs is undoubtedly connected, as Loeb (’11) suggested,
with the fact that in the starfish the extrusion of the eggs from the
ovaries into sea-water starts the maturation divisions, while in the
sea-urchin maturation has occurred and the egg is quiescent when
the sperm enters it. But the unfertilized starfish egg dies very
soon unless, according to Loeb, its oxidation processes are inhibited
by lack of oxygen or by cyanide. As a matter of fact, the starfish
egg is almost a parthenogenic egg, as Mathews (’or) has shown.
By experimental means its development can readily be initiated
without fertilization. But, left to itself, it is apparently not quite
able to begin normal development; something goes wrong and
death soon follows. The unfertilized sea-urchin egg, on the other
hand, which remains almost quiescent after extrusion from the

t Loeb, ’10; Loeb and Wasteneys, ’10, ’11; Lyon, ’02; Meyerhof, ’11; Warburg,
708, ’I0.

2 There are certain sources of error in the method used for determining oxygen

consumption which make it possible that these values are too high, but that an increase
occurs cannot be doubted.

3 Loeb, ’11; Loeb and Wasteneys, ’12.

406 SENESCENCE AND REJUVENESCENCE

ovary and does not begin development until the sperm enters, may
live for a week or more. The death of the unfertilized starfish egg
is not comparable to death from old age in organisms in general,
but is the result of the peculiar physiological condition of the egg
almost on the boundary line between parthenogenesis and zygo-
genesis. The conclusions concerning natural death which Loeb
has drawn from the behavior of this egg are certainly not applicable
to death from old age (see pp. 307-9). A few other eggs show
somewhat similar behavior, but in all of them a more or less similar
physiological condition exists and their behavior cannot be made the
basis for conclusions as to the nature of death in general.

In experiments of my own the susceptibility of various animal
eggs to cyanide before and after fertilization has been tested, both
by observing the occurrence of the death changes and by determin-
ing the limits of recovery in a given concentration. The sea-urchin
egg and the eggs of Nereis, Chaetopterus, and Hydroides, among the
annelids, are all somewhat more susceptible to cyanide after ferti-
lization than before, although the difference is not very great. In
the starfish egg, however, the susceptibility increases markedly in
unfertilized eggs when maturation begins, and there is little or
no further change on fertilization. Since increased susceptibility
means increase in rate of metabolism, these results agree in general
with those obtained by other methods, although the increase in
susceptibility to cyanide is not as great as might be expected if the
rate of oxidation increases from three to six times with fertilization.
The results with the starfish egg indicate, as Loeb suggested, that
here the chief increase in rate of oxidation occurs with maturation.

PARTHENOGENESIS

The naturally parthenogenic egg is evidently a cell which pos-
sesses the capacity to react to its physiological or physical isolation
from the parent body or from the former source of nutrition or
to the change of conditions associated with its extrusion from the
body by the initiation of a normal development. Although oxygen
consumption and susceptibility of parthenogenic eggs before and
after isolation have not been determined, the observations on the
starfish egg which is on the verge of parthenogenesis and the very

REJUVENESCENCE IN EMBRYO AND LARVA 407

evident increase in activity in parthenogenic eggs during and after
maturation leave no room for doubt that the physiological changes
which occur in zygogenic eggs after the entrance of the sperm occur
in parthenogenic eggs independently of the sperm. Moreover,
among animals most parthenogenic eggs undergo only one matura-
tion division before beginning development. It was also pointed
out in chap. xiii that in many cases parthenogenic eggs are appar-
ently less highly differentiated morphologically, and younger phys-
iologically, than zygogenic eggs of the same species.

The obvious conclusion in the light of the various facts is that
eggs which are capable of parthenogenic development in nature are
less highly specialized as gametic cells than those which require
fertilization. They react to isolation by undergoing dedifferentia-
tion and reconstitution into new individuals, and in this respect
they resemble the pieces from the bodies of many lower animals,
such as Planaria, which undergo reconstitution when isolated.
The capacity of parts of the body for reacting to physiological
or physical isolation by dedifferentiation varies inversely as the
degree of physiological stability of the structural substratum (see
Pp. 39-42). But physiological stability of the substratum appar-
ently increases during individual development and also during the
course of evolution, and often varies to a considerable extent in
related species. Since the development of the primitive egg cell
into an egg is apparently subject to the same laws as the develop-
ment of other parts of the body, the parthenogenic egg must repre-
sent an earlier stage of development than the zygogenic egg of the
same species. But it does not by any means follow that the eggs
of all species would develop parthenogenically if they were iso-
lated at a sufficiently early stage. Since the bodies of different
species and the different tissues of the same individual possess very
different degrees of reconstitutional capacity, we must expect to
find differences of the same sort in eggs. Moreover, since the
formation of gametes is characteristic of relatively late stages in
the individual life history, we should expect a rather high degree
of physiological stability in the eggs of most species and partheno-
genesis in comparatively few. Asa matter of fact, parthenogenesis
occurs only here and there among organisms, but it is of interest to

408 SENESCENCE AND REJUVENESCENCE

note that it is relatively frequent in the lower plants, the algae and
fungi. To what extent it may occur among the lower animals is
not fully known, though apparently it appears chiefly as a charac-
teristic of certain groups without relation to their systematic posi-
tion. Finally, we cannot expect to find parthenogenesis ne cessarily
associated with a high degree of reconstitutional capa city in other
parts of the body, for the physiological condition of the primitive
germ cells from which eggs are formed, the rate of growth of the
egg, the character and amount of its nutrition, and dou btless many
other factors, must be concerned in determining whether it shall be
parthenogenic or zygogenic.

From this point of view the parthenogenic egg is a cell which
has undergone more or less development as a gamete but still re-
tains the capacity to initiate dedifferentiation and reconstitution
independently of union with a male gamete. In this respect it
resembles the less highly specialized cells of other tissues rather
than the gametes.

Much evidence has accumulated to show that in the higher seed
plants reproduction of a new sporophyte generation very often
occurs in various other ways than by the fertilization of a zygogenic
egg. In some cases the reproductive cell is not the egg cell, but a
vegetative cell of the gametophyte and the reproductive process is
known as apogamy; in other cases the maturation divisions char-
acteristic of spore formation do not occur, i.e., there is apospory,
but a gametophyte containing a parthenogenic egg is formed; in
still other cases the reproductive cell is not even a part of the
gametophyte, but a cell of the nucellus which corresponds to the
sporangium. There can be little doubt that in such cases the
reproductive cell does not attain the specialized condition and
advanced age characteristic of the zygogenic egg. The final stages
of progressive development are omitted in one generation or the
other.

THE EXPERIMENTAL INITIATION OF DEVELOPMENT

Through the extensive investigations of Loeb, Delage, Bataillon,
and many others during the last twenty years it has been demon-
strated that the eggs of various species of animals which in nature

REJUVENESCENCE IN EMBRYO AND LARVA 409

require fertilization for their development can be induced experi-
mentally to develop without fertilization. General agreement has
not yet been reached as to the nature of the changes concerned in
the initiation of development, but there can be no doubt that the
increased metabolic activity which in nature follows fertilization
may be brought about by the action of certain experimental con-
ditions. A great variety of agents and conditions have been em-
ployed in these experiments. Harvey (’10) has tabulated the
different methods. A few of these methods bring about in certain
species a normal, orderly development like that which occurs after
fertilization. With many of the so-called parthenogenic agents,
however, and in some species with all, the changes which are initi-
ated differ more or less widely from normal development. In some
cases development may proceed more or less normally through
the earlier stages, but ends in death at or before a certain stage;
in others the forms produced are clearly abnormal from the begin-
ning; in still others only a few divisions, or only changes in the
membrane, occur before death. In certain cases also some degree
of differentiation without any cell division results from the use of
these agents.

All of these experimental effects have very commonly been
regarded as initiation of development, but if the term ‘“‘develop-
ment’ means anything, it means an orderly series of events leading
to a certain definite result. The course of events and the result
attained are subject to more or less variation, and it is not always
possible to make a sharp distinction between what is and what is
not development. Nevertheless, it is evident that many of these
experimental treatments of the egg do not initiate development,
but a change which lacks some of the essential features of develop-
ment and soon leads to death. To maintain that any experimental
agent or condition which brings about some degree or kind of
cellular activity in the egg initiates development is to lose sight
entirely of the fundamental characteristics of development; and to
use such experimental data indiscriminately as a basis for con-
clusions concerning the nature of fertilization is certainly not a
justifiable procedure. It cannot be doubted, however, that devel-
opment in the strictest sense is initiated experimentally in certain

410 SENESCENCE AND REJUVENESCENCE

cases and by certain methods, and no criticism can detract from
the importance and interest of this fact.

The questions which have been most widely discussed in con-
nection with this field of investigation, viz., the nature of the
changes produced in the egg and the manner in which the experi-
mental conditions act to produce them, are outside the range of
the present discussion. The point to which I desire particularly
to call attention is the difference in the reaction of the eggs of
different animals to the experimental conditions. Some eggs react
readily to a variety of experimental conditions and give 100 per
cent, or nearly, of normal embryos or larvae, while others, even in
the most favorable cases, give only a small percentage of normal
forms, or react only to certain experimental conditions, and still
others are refractory to all methods and have never been known
to develop except when fertilized. In the egg of the starfish, for
example, which is on the verge of natural parthenogenesis, develop-
ment can apparently be initiated by almost any slight stimulus,
while the egg of the sea-urchin is somewhat less susceptible to the
various agents and conditions employed to initiate development,
and many other eggs are only slightly or not at all susceptible.
Our knowledge along this line is as yet somewhat fragmentary, for,
although changes of some kind and degree have been experimentally
induced in the eggs of many different species of invertebrates and a
few vertebrates, no systematic comparative study along these lines
has yet been attempted. But that great differences in the capacity
to begin development without fertilization exist in different eggs
is a demonstrated fact, and the probability that these differences
are associated with the different degrees of specialization and differ-
entiation of eggs at once suggests itself. If the eggs of different
species represent various degrees of specialization, all gradations
from natural parthenogenesis through the various degrees of sus-
ceptibility to experimental parthenogenic agents to the strictly
zygogenic condition, in which the egg reacts only to the entrance
of the sperm, must be expected to occur. Apparently some eggs
can be aroused from their quiescent condition and started along the
course of development in a great variety of ways, some of which may
differ widely from the process of fertilization, while others can be

REJUVENESCENCE IN EMBRYO AND LARVA AII

aroused only by experimental conditions which approximate more
closely the conditions of fertilization, and still others only by
fertilization itself, or conditions essentially identical with it. More-
over, it is by no means certain that the conditions concerned in
fertilization are exactly the same in all cases. The morphological
differences in the gametes of different species show clearly enough
that the course of gametic development is not always the same,
and the assumption that the action of the sperm is always the same
seems to be unjustified. The result is, of course, essentially similar
in all cases, i.e., increased metabolic activity, transformation of
nutritive substances, and cell division, but different factors or
combinations of factors may be concerned in producing it in differ-
ent cases. The differences in the reaction of different eggs to the
experimental parthenogenic agents suggest that various degrees of
specialization exist in the process of fertilization itself. The con-
ception of the gametes as highly specialized, physiologically old
cells places the whole problem of the initiation of development by
either experimental or natural means in a new light.

‘OXYGEN CONSUMPTION AND HEAT PRODUCTION DURING EARLY
STAGES OF DEVELOPMENT

The first stage of development is a period of repeated cell
division, the cleavage period, during which the proportion of
active cytoplasm and nuclear substance increases at the expense
of substances which were accumulated in the egg during its growth
and have been previously inactive; or in some organisms, where
the egg itself contains but little nutritive material, it becomes
dependent at an early stage on nutriment from without.

Authorities are generally agreed that during at least some part
of this period an acceleration in the rate of metabolism occurs.’
According to Warburg and Loeb and Wasteneys the oxygen con-
sumption of sea-urchin eggs increases during the course of cleavage.
In the egg of the mollusk Aplysia limacina Buglia found that the
oxygen consumption decreased slightly while carbon-dioxide pro-
duction remained uniform during the earliest stages of cleavage,
but in later embryonic stages both underwent a marked increase

1 Buglia, 08; Loeb and Wasteneys, ’11; Meyerhof, ’11; Warburg, ’o8, ’10.

412 SENESCENCE AND REJUVENESCENCE

and finally became nearly uniform again in early larval stages.
Meyerhof has shown that the heat production of the sea-urchin
egg increases steadily up to the larval stage; at the sixty-four-cell
stage it is about twice as great as during the first hour after fertili-
zation; when the larva begins to swim it is three times as great,
and at a stage four hours later, four times as great. Heat produc-
tion in the A plysta embryo decreases during the first few cleavages,
then increases rapidly to the larval stage, when it becomes nearly
uniform, i.e., the changes in heat production in Aplysia are essen-
tially parallel to the changes in oxygen consumption and carbon-
dioxide production as determined by Buglia.

All of these data indicate that at least the oxidation processes
increase in rate during the earlier stages of development, and the
general behavior of the developing embryo, the increase in the
amount of metabolically active cytoplasm and nuclear substance,
and the decrease in amount of yolk where yolk is present suggest
that not merely oxidation but metabolic activity in general
undergoes a marked increase during this period. In short, this is a
period of physiological rejuvenescence.

CHANGES IN SUSCEPTIBILITY DURING EARLY STAGES

Lyon (’o2) found that the susceptibility to cyanide of the sea-
urchin egg underwent a gradual increase during the course of
cleavage, and I have determined the susceptibility to cyanide dur-
ing early development in a number of animal species. In these
experiments the susceptibility was measured in most cases by the
limits of recovery, that is, the length of time in the cyanide solu-
tion at which recovery ceased to occur on return to water. It was
also possible in most cases to determine the survival time by
observing the death changes in the cyanide. A part of the results
of these experiments appear in the following tables. For the sake
of simplicity only the average survival times are given, viz., the
average length of time in cyanide necessary to prevent any visible
degree of recovery after return to sea-water. These tables serve
merely to give a general idea of the changes in susceptibility and
do not show the differences or the differe nt rates of change in the
susceptibility of different regions of the embryos.

REJUVENESCENCE IN EMBRYO AND LARVA 413

In both starfish and sea-urchin the susceptibility increases very
greatly, and more in the starfish than in the sea-urchin, up to the
early gastrula stage and then begins to decrease slightly as the
larval structure begins to develop. At this stage the cells have
lost the differentiation of the egg, the chemically active protoplasm
has undergone great increase at the expense of the inactive substance
and has attained the maximum, and from this stage on the develop-
ing organism begins to grow old.

TABLE VIII
StarFIsH (A sterias forbesii)
KCN o0.or1 mol.

Stage of Average Survival Time
Development in Hours and Minutes
Unfertilized egg undergoing maturation... ..11.30
30 minutes after fertilization.............. II.30
2=8. CéllS3 igs chad Dae ee eee oiaeltss 10.30
64-128 CElISy cc cae tn dtann dee cota eeeeeay 5.30
Blastulae before movement ............... I.15
Early gastrulae.... 12.2.2 .- cece eee eee eee 1.35
Advanced gastrulae.............-...-005- 1.20
Young bipinnaria larva................... 3.00

TABLE IX

SEa-UrcHIN (Arbacia punctulata)
KCN 0.005 mol.

Stage of Average Survival Time
Development in Hours and Minutes
Untertilized eg ..i4 coke sassadsderees ees 8.15
20 minutes after fertilization.............. 6.45
AB CelISs oie 5 ibs a alee PARSON As Meee eas 5.45
Late Cleavage..c.i4 08 casas aad eee es 3.30
Barly gastrulae sc syacsg eae w un ond eaaleen's 2.15
Advanced gastrulae..................004. 3.00
Prepliteush cca cess ue jase da ee ew senses 3.30

In this connection it is of great interest to note that in the starfish
and sea-urchin and various other species the late blastula and early
gastrula stages appear to be critical stages in development under
many experimental conditions, e.g., in experimental partheno-
genesis, in many hybrids and under the action of various external
agents. Development may proceed with little or no disturbance

414 SENESCENCE AND REJUVENESCENCE

up to these stages and then stops or becomes abnormal. If these
stages are passed successfully, further development is likely to
follow its usual course. It is easy to see why, if anything is wrong,
it should become evident during these stages, for they represent
the period when the intrinsic metabolic activity of the cells is greater
than at any other period of the life history, and the physical condi-
tion of the protoplasm which is of course correlated with the high
rate of metabolism must likewise be most susceptible to change at
this time. Internal or external factors, which produce little or
no effect when the metabolic and protoplasmic susceptibility is
lower, may at this time bring about changes which either lead to
death or profoundly modify the further course of development.

The different behavior of the two eggs in relation to fertilization
which was mentioned in an earlier section (pp. 405-6) appears in
the tables. The starfish egg shows scarcely any increase in sus-
ceptibility just after fertilization, while in the sea-urchin egg the
increase is marked.

TABLE X
Nereis limbata
KCN 0.005 mol.

Stage of Average Survival Time
Development in Hours and Minutes
9=4 CellSeveg tay esuyesp ea eucee veda sieass 13.45
Early gastrulae...............22. eee ceee II.30
Early larvae hatching.................... 7.30
Larvae 8 hours after hatching............. 3.30
Larvae with two pairs of setae............ “45
Full-grown larvae.... 0.2.0.2... eee eee I.40
Advanced Jarvae.................000005. 2.30

In Nereis, an annelid worm, the susceptibility increases up to the
larval period and during this period begins to decrease. Undoubt-
edly the great increase in susceptibility in the early larval stages is
due in part to the appearance and increase of motor activity and
functional stimulation. The larva is a highly organized animal
with sense-organs and muscles, and its rate of metabolism is higher

‘than that determined by conditions existing within its cells because
it reacts to external stimuli. But even during the larval period
very considerable changes in susceptibility occur which must belong

REJUVENESCENCE IN EMBRYO AND LARVA 415

to the age cycle. In the earlier larval stages the animal is stil]
growing young, while in the later stages it is growing old.

Between Nereis and another annelid, Avenicola cristata, an
interesting difference exists. During the period of rejuvenescence .
the Nereis embryo obtains its nutritive material from the yolk in
the egg, but this material is used up before the end of the larval
period, and metamorphosis from the Jarval to the adult form does
not occur unless the larva can obtain food from without. The
egg of Arenicola, however, contains sufficient yolk to carry
development completely through the larval period and meta-
morphosis to the stage of a worm with five or six segments, after
which food from without is necessary. In both these forms the
embryonic period of increase in susceptibility, i.e., of rejuvenescence,
ends at about the stage when the last of the yolk is used up: the
Nereis embryo continues to grow younger only up to the larval
stage, while rejuvenescence in Arenicola continues through the
larval stage, the metamorphosis, and up to the six-segment stage
of the worm. During this period yolk is being transformed into
chemically active nuclear substance and cytoplasm, and the pro-
portion of chemically active to inactive substance increases to a
certain point where the accumulation of new structural substance,
together with any part of the old that may remain, balances the
synthesis of active protoplasm.

Susceptibility determinations have been made for only two other
species of annelids, Chaetopterus pergamentaceus and Hydroides
dianthus, and in both rejuvenescence takes place during the embry-
onic period, as in Nereis, but the stage at which rejuvenescence
gives place to senescence was not determined in these forms.

Among the vertebrates the eggs of two species of fish have been
used for susceptibility determinations. In contrast to the holo-
blastic egg of the starfish, sea-urchin, and annelid in which the
yolk is in all or some of the cells and the whole egg divides, the fish
eggs are meroblastic, most of the yolk being separated from the
active protoplasmic part of the egg, and only the latter divides.
In such eggs the embryo begins at a rather early stage to feed on
the yolk outside its own cells, and its relation to the nutritive supply
becomes similar to that of the animal developing from a holoblastic

416

egg which has used up all its yolk.

SENESCENCE AND REJUVENESCENCE

It is a point of some interest

to determine at what stage the embryonic period of rejuvenescence

ends in such cases.

given in Tables XI and XII.

TABLE XI

Fundulus heteroclitus
Saturated Phenyl Urethane in Sea-Water

The survival times for these two forms are

Stage of Development

Length of Time after
Fertilization in

Average Survival
Time in Hours and

Hours and Minutes Minutes
DB COUS soe cc isides Hae Bagg seta 3.30 Il.45
Advanced periblast......... 24 4.30
Embryo just appearing ..... 45 5.30
Embryo with 3-4 somites... . 69 6.00
Embryo with heart beating. . 117 7.30
At time of hatching........ 408 2.00

TABLE XII

Tautogolabrus adspersus
KCN 0.005 mol.

Stage of Development

Length of Time after
Fertilization in

Average Survival
Time in Hours and

Hours and Minutes Minutes
15 minutes after fertilization 6,25 10.45
12, COS hei cais eae RH Beatenee 0.50 I0.10
=O COUS 555 ct sees oti seesesiieia hans 2 7.30
Many cells................ IS 6.35
Penblastccocisiiacee enone 7 5-45
Embryo just appearing...... 20 0.45
Heart beating............. 42 0.15
Newly hatched............ 55-60 0.20

Phenyl urethane was used instead of cyanide in determining the

susceptibility of the Fundulus egg, because the membrane of this
egg is impermeable to cyanide, as it is to many other substances, so
that even in high concentrations development is not retarded, while
for phenyl urethane the permeability is practically complete.

Rejuvenescence occurs in Fundulus during the early stages of

development, as indicated by the increase in susceptibility, but
as soon as the embryo begins to form, it gives place to senescence.
The great increase in susceptibility between establishment of the

REJUVENESCENCE IN EMBRYO AND LARVA 417

heart-beat and hatching is probably due in part to increased func-
tional activity and stimulation, but it may be largely the con-
sequence of the increasing lipoid content of the nervous system in
connection with medullation of the nerves, a change which would
increase the relative concentration of phenyl urethane in the
nervous system and so might intensify its action (see pp. 75-76).
In the vertebrates particularly these changes in the nervous system
make the use of the susceptibility method with highly fat-soluble
substances difficult in the later stages of development. If this
second increase in susceptibility is due to the increase of fatty
substances in the nervous system, it of course does not mean that a
second period of rejuvenescence occurs, but rather that the sus-
ceptibility to phenyl urethane is not a measure of the metabolic
condition at this stage. In all probability senescence and decrease
in metabolic rate continue from the stage where the susceptibility
first begins to decrease.

In Tautogolabrus the period of increasing susceptibility con-
tinues up to the time of hatching, and almost all of the increase
occurs before movement or special function of organs begins. At
the periblast stage, where Fundulus shows the highest suscepti-
bility, Tautogolabrus has undergone only half of its increase and the
total increase of susceptibility in the latter is about twice that
in the former. These differences between the two forms are
undoubtedly associated with differences in the course of develop-
ment. The second column of Tables XI and XII shows that
Tautogolabrus develops three or four times as rapidly as Fundulus,
and its development up to the time of hatching occurs very largely
at the expense of nutritive material in the protoplasmic part of the
egg, but little of the separate yolk mass being used during this
stage, while in Fundulus most of the yolk is used before hatching.
It is also evident that the protoplasms of the two species differ
widely in capacity for growth, for the egg of Fundulus is very much
larger and the adult usually much smaller than that of Tautogola-
brus. Apparently the differences between the two eggs determine
that the degree of rejuvenescence is much greater and that the
period of rejuvenescence extends to a much later stage of develop-
ment in Tautogolabrus than in Fundulus.

418 SENESCENCE AND REJUVENESCENCE

In the frog and salamander, the only other vertebrates for which
embryonic susceptibilities have been determined, the changes are
very similar to those described for other forms. From the time of
fertilization on, through cleavage, gastrulation, and the formation
of the embryo, and somewhat beyond the stage of hatching, the
average susceptibility increases. As in the fishes, the results in the
later stages are perhaps complicated by the increased metabolic
activity connected with the functional activity of special organs
and with movement, or by changes in the nervous system, but as
regards the earlier stages this is certainly not the case.

All of these data, as well as those on oxygen consumption, are
in full agreement with the observed facts of development. It is
well known that as cleavage goes on the rate of cell division is
accelerated and other developmental changes proceed more and
more rapidly up to a certain stage. In general the rejuvenes-
cence of certain parts of the embryo, and particularly of the apical
region, where the metabolic rate is originally highest, proceeds more
rapidly than that of other parts and is completed earlier.

THE MORPHOLOGICAL CHANGES DURING EARLY DEVELOPMENT

The morphological changes during the period of increasing
susceptibility consist in an increase of nuclear as compared with
cytoplasmic substance and in the decrease and disappearance of
the yolk in the cytoplasm and the increase of the amorphous,
undifferentiated, or embryonic cytoplasm; often also, particularly
in the later stages, the new morphological features connected with
the new process of differentiation begin to appear. The increase,
both absolute and relative, in total nuclear volume is a character-
istic feature of embryonic development in animals and is evident
from observation. It has often been stated that the nuclear
volume or nuclear substance increases in geometrical progression
during this period, but measurements, so far as they have been
made, indicate that this is by no means always the case. Godlewski
(’o8) has found that in the sea-urchin from the four-cell to the
sixty-four-cell stage the nuclear volume does increase almost in
geometrical progression, while from the sixty-four-cell stage on
there is but little further increase. During the period of nuclear

REJUVENESCENCE IN EMBRYO AND LARVA 419

increase there is no increase, but rather a decrease, in total cyto-
plasmic volume, for the nuclear substance is formed at the expense
of the cytoplasm or of substances contained in it; consequently
the relative increase in nuclear substance is somewhat greater than
the absolute. According to Erdmann (’o8), the nucleoplasmic
relation, that is, the volume of the nucleus in relation to the volume
of the cytoplasm, undergoes very great increase from the four-cell
stage to the gastrula in the sea-urchin, and the volume of the
chromosomes, in relation both to cell volume and to nuclear volume,
also increases during this period. Conklin (’12), in a study of the
mollusk Crepidula, also finds an increase in total nuclear volume
during cleavage, though by no means so great as that found in the
sea-urchin.

The change in the nucleoplasmic relation during this period is
evidently in the reverse direction from that which it underwent
during the growth period of the gametes. Undoubtedly the
increase in relative nuclear volume during early development is, as
Conklin points out, an important factor in the acceleration of meta-
bolic activity, but it is not the only nor even the primary factor,
for the acceleration may begin before the nuclear increase, and
under other conditions acceleration of metabolism may occur with-
out such increase. The increase in nuclear volume is an indication
rather than a cause of the metabolic changes which the embryo is
undergoing during this period. Moreover, as regards the sperma-
tozoon, entrance into the egg constitutes a sudden and enormous
increase in cytoplasmic volume, yet the spermatozoon undergoes
regressive changes as well as the egg. The general significance of
the nucleoplasmic relation for the problem of age is considered in
chap. xvi (see also pp. 284-86).

In most animal eggs the cytoplasm contains more or less fatty
substance—the yolk—in the form of granules, droplets, or large
masses, and in such eggs the most conspicuous cytoplasmic change
during the early stages of development is the gradual disappearance
of this yolk. But even in eggs which contain no visible yolk the
cytoplasm becomes more homogeneous in appearance, and cyto-
plasmic strands, granules of various sorts, and other structural
features of the egg disappear wholly or in part. At the same time

420 SENESCENCE AND REJUVENESCENCE

that these regressive processes are going on, progressive changes
are occurring and new structural features are beginning to appear.
In some embryos these do not become visible or conspicuous until
the regressive changes are far advanced, while in others, such, for
example, as certain annelids and mollusks, in which larval forms
differentiate very early in development, they may begin to appear
during the first few divisions following fertilization, or some of the
structural features of the egg may be carried over into the larva.
In short, both the degree and rate of morphological regression, as
well as the degree and rate of rejuvenescence during early stages,
vary greatly in different forms.

LARVAL STAGES AND METAMORPHOSIS

In many animals the form hatching from the egg is widely
different, both in structure and in behavior, from the adult, and is
known as a larva: sooner or later this form undergoes either a
gradual or a somewhat abrupt transformation or metamorphosis
into the adult form. The question as to the nature of larval
metamorphosis and the internal and external conditions which
determine it has been much discussed, and various hypotheses
have been advanced. Here, however, the purpose is only to present
a few suggestions rather than to attempt extended discussion.

In the first place the term “larva” is a loose biological term with
little physiological significance. The larva is merely a form differ-
ent from the adult and appearing before it in the life history. But
the larva of an annelid which develops during the first few cell
divisions after fertilization is very different from the larva of an
insect or a frog which appears only after thousands of divisions and
extensive differentiation. The larval form may represent an
earlier or a later stage in the developmental history.

In many invertebrates, e.g., in the annelid Nereis, the larval
form develops during the period of rejuvenescence. So far as I
have been able to determine, the eggs or embryos of all species
in which the larval form arises very early possess a strongly marked
axial gradient and individuation progresses rapidly, while in those
where the larval period occurs at a later stage the gradient is much
less clearly marked in early stages and develops only gradually.

REJUVENESCENCE IN EMBRYO AND LARVA 421

The larval form of the annelids, mollusks, crustacea, and some
other invertebrate groups represents chiefly the head and anterior
regions of the body, and metamorphosis consists, not only in changes
in the parts already formed, but in the addition of new segments
from a growing region just in front of the posterior end. The fully
developed larva of the annelid Nereis, for example, consists of the
head and the first three segments, as indicated in Fig. 197, and during
the transformation of this free-swimming form into the worm new
segments are added successively at the posterior end. In this and

Fic. 197.—Trochophore larva of Nereis. After E. B. Wilson, ’92

in other related species the axial gradient, which is so clearly marked
during prelarval stages, becomes less and less distinct in the larva,
until, as metamorphosis approaches, the growing region at the
posterior end shows the highest metabolic rate of any part of the
body. These changes enable us to gain some insight into the
process of formation of new segments. The head-region under-
goes rejuvenescence and begins senescence before other parts, so
that in the larval stage its metabolic rate begins to decrease before
that of the more posterior regions. But even before its metabolic

422 SENESCENCE AND REJUVENESCENCE

rate begins to decrease, the rate in more posterior regions is in-
creasing more rapidly than in the head, and the result is a partial
physiological isolation of the posterior region and the formation
of a new segment. Similarly, physiological isolation of the pos-
terior region from the first segment results in the formation of the
second, and isolation from the second in the formation of the
third. But by this time the rate of metabolism in the head-region
is decreasing, and a little later it begins to decrease in the first,
then in the second and the third segments. Sooner or later this
process leads to partial physiological isolation of the posterior end
and, if food is present to provide energy and substance for growth,
another segment is added posteriorly, and so on.

In the crustacea the process is essentially similar. In the lower
crustacea the earliest larval stage represents, as in Nereis, the head,
and three segments with their appendages, and new segments are
added successively at the posterior end. Fig. 198 shows a stage in
the metamorphosis of the fairy shrimp Branchipus. The original
larval form in this case consisted of the head and the first three
segments to which the three pairs of large appendages are attached
in the figure, and to this new segments are successively added at
the posterior end. The figure shows a stage in which a large
number of segments have already formed, but are not yet fully
developed.

In the insects and vertebrates the formation of the segments
occurs before hatching, but is in all probability a similar process.
The changes called metamorphosis in the insects belong to a much
later stage of development. Here the larval form, which has fed
and grown for a time and has acquired a large nutritive reserve,
undergoes transformation into the mature form, the imago, during
the pupal stage which usually shows little or no movement and does
not feed. In this case the changes seem to be the result of aging
of certain of the larval organs in consequence of which growth and
development of certain parts previously inhibited now becomes
possible. In some insects many of the larval organs actually die
and undergo complete resorption or degeneration. In some other
invertebrates parts of the larva die and are cast off bodily when
metamorphosis begins.

REJUVENESCENCE IN EMBRYO AND LARVA 423

Apparently in all these cases metamorphosis is a partial physio-
logical disintegration of the individual resulting from changes in
the axial gradient during the earlier stages of development, or from
the aging and death of certain larval organs. Where the larval

Fic. 198.—Larval metamorphosis of Branchipus (fairy shrimp)

period occurs at a very early stage of development a well-marked
axial gradient and a relatively high degree of individuation are
present at the beginning, or at a very early stage, of embryonic
development.

424 SENESCENCE AND REJUVENESCENCE

Metamorphosis in the amphibia is evidently a process associated
with progressive development and physiological senescence, and it
may be hastened or delayed by external factors which accelerate or
retard development; but the physiological factors immediately
concerned in bringing about the changes which occur are still
obscure. Metamorphosis unquestionably results in a higher degree
of physiological integration, particularly in the higher amphibia,
the frogs and toads; in fact, it is in a sense a new integration
within the previously existing individual. In the substitution of
physiologically younger for older organs and parts, which apparently
occurs in amphibian metamorphosis, differences in metabolic rate
may play a part, but our knowledge is at present too incomplete
to permit definite conclusions.

EMBRYONIC DEVELOPMENT IN PLANTS .

In most plants embryonic development takes place within
special organs of the parent plant, and the embryonic stages are
not accessible to physiological investigation as are those of many
animals. Moreover, the plant ovum does not in most cases accumu-
late a large supply of nutritive substance within its own body, but
is nourished by other cells. Only in certain algae and fungi, where
embryonic development occurs apart from the parent body, is
there any considerable accumulation of nutritive material in the
egg itself.

So far as I am aware, no determinations of oxygen consumption,
carbon-dioxide production, or susceptibility have been made upon
the embryonic stages of plants, but observation indicates clearly
enough that the metabolic changes during these stages are not
fundamentally different from those in animals. Fertilization in the
plant, as in the animal, initiates an increased activity in the pre-
viously quiescent ovum, repeated division occurs with an absolute
and relative increase of nuclear substance, and, where nutritive
substances are present in the egg, they gradually disappear. As
in the animal, the cells resulting from the successive divisions
become more or less completely ‘‘embryonic” or undifferentiated
in appearance, and from such cells the new plant individual arises.
There is, in short, every visible indication of a process of regression

REJUVENESCENCE IN EMBRYO AND LARVA 425

and rejuvenescence in the early stages of plant development. The
youngest stage physiologically is probably earlier in some and later
in other plants, as in different animals, but, as pointed out in
chap. x, certain parts in most plants remain physiologically young
for a long time, or indefinitely, and well-marked differentiation
and senescence are confined to other parts.

THE DEGREE OF REJUVENESCENCE IN GAMETIC AND AGAMIC
REPRODUCTION

“In gametic reproduction the organism begins its life history as
a single cell resulting from the union of two highly specialized,
old cells, and the earlier part of this history is a period of dediffer-
entiation, cell division, and rejuvenescence. In many cases of
agamic reproduction also the life history begins with a single cell,
but in many others the reproductive body is a cell mass often con-
taining various differentiated organs. Evidently in those cases
where a single specialized cell is the starting-point, the degree of
reconstitutional change involved in the formation of a new indi-
vidual is in general greater than where the individual arises from a
large mass of cells, for in the latter case some of the cells or organs
are incorporated as parts of the new individual with but little
change. It has been shown in chap. v, for example, that in Planaria
the degree of reconstitution and rejuvenescence varies inversely
as the size of the isolated piece: in the large piece, while certain cells
may become embryonic, these rapidly differentiate and grow old
and the total rejuvenescence is slight, while in the smaller piece the
cells undergo more change and the total rejuvenescence is greater
in amount. In the single cell which gives rise to a new individual
the changes are still greater, and the degree of rejuvenescence of
the whole must also be greater, because the reconstitutional changes
are very extensive and involve the cell as a whole. Moreover, if
it is true that the gametes are more highly specialized than single
cells which reproduce agamically, we must conclude that the degree
of rejuvenescence is in general greater in gametic than in any
form of agamic reproduction, that is, in multicellular organisms.

If, however, the same degree of rejuvenescence occurs in suc-
cessive agamic generations, even though it is much less than that

426 SENESCENCE AND REJUVENESCENCE

occurring in gametic reproduction, the agamic process may be
repeated indefinitely without race senescence. The failure of
agamic reproduction after a larger or smaller number of agamic
generations is not due to the fact that there is less rejuvenescence
connected with it than with the gametic reproduction, but rather
to the fact that under the existing conditions senescence in each
agamic generation is not entirely compensated by rejuvenescence
in each reproduction, and race senescence results. In such cases
of course a substitution of gametic for agamic reproduction will
rejuvenate the race and make possible a new series of agamic
generations. This course has from time to time been followed with
the potato, when a particular race has seemed to show signs of
decrease in vitality or commercial value, and often with good results.
There is, however, every reason to believe that a change of the
right kind in conditions of cultivation would accomplish the same
result without breeding from the seeds instead of the tubers.
Doubtless the gametic process affords a less difficult and more
rapid method of accomplishing the desired result, but it is probably
not the only method.

In many organisms, under the ordinary conditions of nature,
senescence is evidently not completely compensated by the reju-
venescence occurring in agamic reproduction, and progressive
senescence of the race or colony occurs. This is apparently the
case among both plants and animals, but, as already pointed out,
experimental investigation has shown for many of these cases that
under the proper conditions progressive senescence does not occur,
and these results make it probable that we shall find this true for
many other cases. It may be, however, that in some forms senes-
cence progresses in spite of agamic reproduction and independently
of external conditions, and if so the agamic period must in any case
sooner or later come to an end in such forms. Perhaps some of
the higher animals, where agamic reproduction occurs only as
polyembryony or in the early stages of postembryonic life, consti-
tute cases of this sort.

The point of chief importance is, however, that the difference
between agamic and gametic reproduction is, as regards the rela-
tion between senescence and rejuvenescence, one of degree rather

REJUVENESCENCE IN EMBRYO AND LARVA 427

than of kind, and that there is much more difference in this respect
between different forms of agamic reproduction than between
agamic reproduction from single cells and small cell masses and
gametic reproduction. From the physiological point of view the
reproductive process is fundamentally the same wherever it occurs
in nature: it is in all cases the reconstitution of a new organism from
a part of one previously existing, but the starting-point of the new
individual and consequently the degree of reconstitution and the
result differ in different forms and with different conditions.

CONCLUSION

It is only necessary to point out the close agreement between
all the different lines of evidence in indicating that the early stages
of development from the egg in both animals and plants constitute
a period of rejuvenescence in every sense. Minot (’08) has already
advanced this view on the basis of the changes in the nucleoplasmic
relation, but has failed to present any of the physiological evidence
in support of it. The nucleoplasmic relation is a rather unsafe
criterion of physiological age, but it is interesting to see that in the
present case it leads to the same conclusion as the physiological
evidence.

From this point of view gametic reproduction differs from
agamic only in the greater degree of specialization of the reproduc-
tive cells and the special conditions necessary to initiate the pro-
cess of dedifferentiation and rejuvenescence. The same periodic
changes, the same life cycle and age cycle, occur in both. We
can dispense entirely with that remarkable conception, the germ
plasm of the Weismannian theory, and say that germ plasm is
any protoplasm capable under the proper conditions of undergoing
dedifferentiation and reconstitution into a new individual of the
species. Reproduction, whether it is the process of reconstitution
in a piece experimentally isolated from an animal or plant body,
or the process of development from the fertilized egg, is funda-
mentally the same physiological process and involves both regressive
and progressive changes, both rejuvenescence and senescence.

A recent attempt by Godlewski (’10) to compare the process of
regeneration with gametic reproduction requires mention here.

428 SENESCENCE AND REJUVENESCENCE

Godlewski found that in the earlier stages of regeneration the
epithelial cells of amphibia show an increase in cytoplasmic in
relation to nuclear volume as compared with the cells of differen-
tiated normal epithelium, and that the nucleoplasmic relation
gradually approaches the norm as regeneration proceeds. From
these facts he concludes that the earlier stages in regeneration cor-
respond to the period of odgenesis, and particularly that stage of
it in which the egg cytoplasm increases in amount, while the later
stages of regeneration correspond to the period of embryonic
development in which nuclear substance undergoes relative increase.
These conclusions only serve, I think, to show how unsafe the
nucleoplasmic relation is as a criterion of physiological condition.
It is probable that the first effect of stimulation and increase
in metabolic rate in these cells is some degree of hypertrophy
(pp. 43-44) with increase in the relative volume of cytoplasm, but
this is soon followed by divisions with increase in relative nuclear
volume. This is the period of dedifferentiation and rejuvenescence
and corresponds not to the growth period of the egg, but to the
period of rejuvenescence in embryonic development, while the later
stages of regeneration correspond to the period of morphogenesis
and senescence in the later stages of development.

REFERENCES
Bucii, G.
1908. ‘‘Sullo scambio gassoso delle uove di ‘Aplysia limacina’ nei vari
periodi dello sviluppo,” Arch. di fisiol., V.
ConkLIN, E. G.
t9r2. “Cell Size and Nuclear Size,” Jour. of Exp. Zool., XII.
Crocker, W.
1906. “‘Rédle of Seed Coats in Delayed Germination,” Bot. Gazette, XLII.
1907. ‘‘Germination of Seeds of Water Plants,” Bot. Gazette, XLIV.
1g09. “Longevity of Seeds,” Bot. Gazette, XLVII.
ERpMANN, RuHopa.
1908. ‘“‘Experimentelle Untersuchung der Massenverhiltnisse von
Plasma, Kern und Chromosomen in dem sich entwickelnden
Seeigelei,” Arch. f. Zellforsch., II.
GopLEewskI, E., Jr.
1908. ‘“‘Plasma und Kernsubstanz in der normalen und der durch dussere
Faktoren verdnderten Entwicklung der Echiniden,” Arch. f.
Entwickelungsmech., XXVI.

REJUVENESCENCE IN EMBRYO AND LARVA 429

GopLEwskI, E., Jr.
1910. ‘‘Plasma und Kernsubstanz im Epithelgewebe bei der Regeneration
der Amphibien,” Arch. f. Entwickelungsmech., XXX.
Harvey, E.N.
tgio. “Methods of Artificial Parthenogenesis,” Biol. Budll., XVIII.
Jenninecs, H. S.

1913. “The Effect of Conjugation in Paramecium,” Jour. of Exp. Zool.,

XIV.
Logs, J.

gto. “Die Hemmung verschiedener Giftwirkungen auf das befruchtete
Seeigelei durch Hemmung der Oxydationen in demselben,”
Biochem. Zeitschr., X XIX.

tgtr. ‘Auf welcher Weise rettet die Befruchtung das Leben des Eies ?”’
Arch. f. Entwickelungsmech., XXXI.

Logs, J., und WasTENEYS, H.

igto. ‘“‘Warum hemmt Natriumcyanide die Giftwirkung einer Chlor-
natriumlosung fiir das Seeigelei?’’ Biochem. Zeitschr., XXVIII.

igiz. “Sind die Oxydationsvorginge die unabhangige Variable in den
Lebensercheinungen ?”’ Biochem. Zeitschr., XXXVI.

ig12. ‘‘Die Oxydationsvorgange im befruchteten und unbefruchteten
Seesternei,” Arch. f. Entwickelungsmech., XXXV.

Lyon, E. P.

1902. ‘‘Effects of Potassium Cyanide and of Lack of Oxygen upon the
Fertilized Eggs and the Embryos of the Sea Urchin (Arbacia
punctulata),”” Am. Jour. of Physiol., VII.

Matuews, A. P.

tgor. ‘Artificial Parthenogenesis Produced by Mechanical Agitation,”

Am. Jour. of Physiol., VI.
MEVERHOF, O.
1gt1. ‘Untersuchungen iiber die Warmeténung der vitalen Oxydations-
vorginge in Eiern, I-III,” Biochem. Zeitschr., XXXV.
Munor, C. S.
1908. The Problem of Age, Growth and Death. New York.
Warsore, O.

1908. “Beobachtungen iiber die Oxydationsprozesse im Seeigelei,”’
Zeitschr. f. physiol. Chem., LVII.

tg1o. ‘Uber die Oxydationen in lebenden Zellen nach Versuchen am
Seeigelei,” Zeitschr. f. physiol. Chem., LXVI.

WItson, E. B.
1892. ‘‘The Cell-Lineage of Nereis,” Jour. of Morphol., VI.

PART V

THEORETICAL AND CRITICAL

CHAPTER XVI

SOME THEORIES OF SENESCENCE AND REJUVENESCENCE

The present chapter makes no attempt at a complete historical
review of the various ideas and theories concerning the nature
of the age process: it is merely a brief critical consideration, in
the light of the preceding experimental data, of some of the more
recent theories and suggestions.

SENESCENCE AS A SPECIAL OR INCIDENTAL FEATURE OF LIFE

The popular belief, which is of course based on the phenomena
of old age and death in man and the higher animals, is that the
process of aging is a wearing out and death a final breakdown of the
organic mechanism, or some essential part of it. This idea has
from time to time found scientific support, chiefly among those
who have considered the problem of senescence primarily in rela-
tion to man. Among the earlier authorities of the modern era in
science Lotze (’51, ’84) is one who holds this view, and recently
Magnus-Levy (’o7) has expressed the same opinion. While the
phenomena of senile atrophy in extreme old age in man and the
higher animals may perhaps be interpreted as in some sense a
wearing out (see pp. 288-89), they represent only the final stages
of senescence and are the result of what has happened during the
earlier life of the organism. Both man and animals grow old
throughout the course of progressive development, as the decrease
in rate of metabolism indicates.

Speculative attempts have been made to show that age and
death are associated in some way with the reproductive function.
Weismann regards the limitation of life as an adaptation which has
arisen by the action of natural selection, because continued life of
the individual after the reproductive period is a ‘‘senseless luxury”
for the species. Weismann’s views are discussed in another
chapter (see pp. 304-5). In opposition to this hypothesis Goette
(’83) maintains that reproduction is the real cause of age and death
of the parent individual and at the same time brings about rejuve-
nescence in the offspring. The foundation of Goette’s hypothesis

433

434 SENESCENCE AND REJUVENESCENCE

is the fact that reproduction in many of the simpler organisms
involves a disintegration of the original individual and the origin
of new individuals from its parts or certain of them. According
to von Hansemann (’93, 09), it is the atrophy of the sexual organs,
the final elimination of the germ plasm, which brings about the
changes of old age ending in death. These hypotheses are little
more than guesses based on observation of the life histories of
various organisms.

Various authors have suggested that conjugation and fertiliza-
tion bring about rejuvenescence in some way. Maupas (’88, 89)
believed that the infusoria grow old and may finally die of old age
in the course of repeated agamic reproductions and that conjuga-
tion renews their capacity for growth and division, but later
investigators do not confirm these conclusions (see pp. 136-45).
Bernstein (’98) suggests that certain internal conditions whose
nature is unknown act as inhibitors of the growth impulse, and
that their effect increases during life and finally brings about death.
Fertilization, however, weakens or inhibits the inhibitors, and
growth proceeds anew until again gradually inhibited. According
to Buhler (’04) the molecular constitution of the organic substance
undergoes gradual change during life and becomes less and less
capable of metabolism, and fertilization re-establishes the original
constitution. Rubner (’89) has advanced a very similar view.
These hypotheses are merely statements of a supposed fact and do
not throw any light upon the problem of the nature of the processes
concerned in either senescence or rejuvenescence.

The idea that age and death are the results of an intoxication,
a poisoning of the organism in one way or another, has been ad-
vanced by various authors, among whom Metchnikoff (’o03, ’10)
has received most attention. According to Metchnikoff man is
slowly poisoned by resorption of the products of bacterial activity
in the large intestine. One result of this intoxication is arterio-
sclerosis; another is that some of the phagocytes, the white blood
corpuscles, under the influence of the poisons depart from their
proper function as scavengers and protectors of the tissues and
begin to devour the cells of the highest organs of the body, even
those of the nervous system. While Metchnikoff’s ideas have

SOME CURRENT THEORIES 435

aroused great popular interest, largely because of his scheme for
prolonging life by preventing the intestinal intoxications, they
have received little support among scientists. The evidence for
the universal or almost universal occurrence of chronic intoxica-
tion in man, and of arteriosclerosis as a result of it, is far from
convincing, and the hypothesis of the action of the phagocytes
under such conditions has proved even less acceptable. At best
Metchnikoff’s hypothesis is not widely applicable, for many animals
which possess no large intestine grow old and die. But, as is evi-
dent from his statement that natural death occurs very rarely,
Metchnikoff is really concerned with certain pathological aspects
of advanced life in man and not at all with the problem of physio-
logical senescence. While his ideas may or may not be of practical
value, they have no general theoretical significance.

According to Jickeli (’02) metabolism is an incomplete process
and injurious substances accumulate in the cell because of this
incompleteness of metabolism. The secretions of cuticular sub-
stances, cysts, cellulose membranes, etc., the formation of hair,
feathers, and various other products of cellular activity represent
these injurious substances of which the cell attempts to rid itself
by excretion, or the body by giving rise to parts which are sooner
or later cast off. In other cases the cells react to the accumulation
of injurious substances by increased rate of division, which results
in increase of surface and so in greater possibility of excretion.
The accumulation of the injurious substances brings about senes-
cence and death, and excretion by the cell, or the casting off of
parts by the organism, is a process of rejuvenescence. This
hypothesis is based entirely on a teleological conception of the cell
and the organism and cannot be regarded as in any real sense
physiological, although in his fundamental idea that senescence
results from accumulation of substances in the cell and rejuvenes-
cence from their elimination Jickeli approaches my own position.
But for him the substances concerned are not the protoplasmic
substratum of the cell, but something “injurious” which remains
in the cell only because metabolism is an incomplete process, and
the cell and the organism are all the time struggling, apparently with
superhuman intelligence, to rid themselves of their burdens.

436 SENESCENCE AND REJUVENESCENCE

More’ recently Montgomery (’06) advanced a somewhat simi-
lar hypothesis. He believed that waste products accumulate in
the cells as life continues and that some of them are toxic. Senes-
cence and death are the result of the insufficiency of the excretion
process. Reproduction is in general an escape or separation of some
parts from ‘‘an empoisoned mass,” and the part which is thus
separated is capable of repeating the life history. But Mont-
gomery does not make it clear why the part or parts which separate
as reproductive elements do not carry their share of the poisonous
substances with them. This is the most important point, for if
the reproductive elements do not free themselves from these poisons
they, as well as other parts, must die, and there seems to be no
reason except a teleological one why parts should separate as repro-
ductive elements at all. Here, as in Jickeli’s hypothesis, certain
cells free themselves, voluntarily as it were, from the poisonous
substances which are killing the organism. The chief difference
between Jickeli and Montgomery is that for the one rejuvenescence
is an excretory process and may occur in somatic as well as in
reproductive cells, while the other maintains that only the repro-
ductive elements rejuvenate, and that they somehow leave the
poisonous substances behind in the body or in a residuum.

SENESCENCE AS A RESULT OF ORGANIC CONSTITUTION

Most of those who have considered the problem of age from any
general viewpoint have maintained that the conditions which
determine senescence and death are found in the physiological
constitution of the organism. Seventy years ago Johannes Miiller
(’44) expressed this opinion; some forty years later Cohnheim (’82)
took the same position, and in more recent years this view has found
numerous supporters.

Butschli’s suggestion (’82) that death is due to the exhaustion
of the supply of a certain substance—the “‘life ferment’’—which is
gradually used up during life, and that the protozoa and the germ
cells of multicellular forms do not die because they are capable of
producing the substance anew, is not much more than a statement
that death is the result of life without rejuvenescence. Cholod-
kowsky (’82), on the other hand, suggested that death was rather

SOME CURRENT THEORIES 437

the result of the multicellular condition with its accompanying
differentiation. In such organisms the struggle for existence among
the parts which Roux (’81) believed to be of such fundamental
importance in organic life must lead finally to the death of the
whole.

The change in the relation between surface and volume in the
cell and the organism during growth has often served as the founda-
tion for speculations concerning growth and its cessation, aging and
death, and cell division. Since the volume of the cell or the
organism increases more rapidly than its surface, and since nutrition
and oxygen enter through the surface, it is argued that as the cell
or the organism increases in size the amount of nutrition and oxy-
gen which can enter through the surface must become less and less
adequate for the needs of the growing cell mass. Sooner or later
a stage may be reached where only the superficial parts of the cell
receive sufficient nutrition, and finally the death of the cell may
result from the starvation of the parts farthest from the surface.
Various authors, among them Herbert Spencer, Bergmann and
Leuckart, and later Verworn, have called attention to the biological
importance of this relation between surface and volume and have
employed it as a basis for theoretical considerations concerning
one aspect or another of life. Recently Miihlmann (’oo, ’10, ’14)
has advanced a theory of senescence and death based upon this
principle. According to Miihlmann growth brings about senescence
and death because it leads sooner or later to starvation of the parts
of the cell or the organism farthest from the surface. In the uni-
cellular forms the nucleus reacts to the extreme stage of starvation
by division, which is followed by cell division, and so an increase
of nutritive surface is produced; but in multicellular organisms,
where the cells do not separate from each other, cell division only
leads to further growth and so to starvation, which is most extreme
in the part farthest from the surface. Old age is then a condition
of starvation which according to Miihlmann is most extreme in the
central nervous system, the part farthest removed from the nutri-
tive surfaces, and death is consequently primarily a death of the
nervous system. Death for Miihlmann is not only the cessation
of life, as it occurs in man and the higher animals, but the division

438 SENESCENCE AND REJUVENESCENCE

of the cell is the death of the individual cell. The changes in the
cells during their development, the appearance of metaplasmic
structural substances, which is usually regarded as differentiation,
Miihlmann interprets as a dedifferentiation and regression from
the embryonic condition and as a secondary result of the gradual
starvation of the cells.

As regards the biological importance of the relation between
surface and volume, I am not aware that it has been proved in
any case to be a fundamental factor in limiting growth. Growth
is not simply a matter of nutrition: in the higher animals a very
definite limit of size exists, no matter how great the supply of
nutrition, and in many lower animals extensive reconstitutional
growth may occur, even in a stage of extreme reduction from star-
vation. On the other hand, the growth of embryonic cells may
be inhibited by correlative influences from other parts, even
though an abundant supply of nutrition is present. In many cases
animal eggs receive their nutrition chiefly or wholly through a
minute fraction of their surface (see Figs. 184, 185, p. 345) yet
are able to attain an enormous size as compared with other cells
of the body. Similarly, in many cells of the multicellular body,
the nutritive surface is evidently only a small fraction of the total
surface of the cell, e.g., in many glandular tissues, yet life and
function continue. And in the unicellular infusoria food enters
through a definite mouth and passes into the entoplasm, where a
nutritive surface is formed about each food particle. In such cases
the externa] surface of the cell has no relation to its capacity for
ingesting food. Oxygen doubtless enters through the cell surface,
but it undoubtedly enters more or less rapidly according to con-
ditions in the cell. In fact, the whole theory of the biological
importance of the relation between surface and volume rests rather
upon a process of logic than upon the data of observation and
experiment, and when we examine the behavior of cells and organ-
isms it is difficult to find adequate support for it.

As regards Miihlmann’s hypothesis, the conclusion that old age
is an advanced stage of cell starvation rests chiefly upon assertion
rather than proof. As a matter of fact, in starvation the nervous
system loses less than other tissues, while in old age, according to

SOME CURRENT THEORIES 439

Miihlmann, it suffers most of all. That accumulation of structural
substance and so-called metaplasm in the cells is the result of a
gradual starvation is difficult to believe in view of the fact that
during actual starvation in the lower animals these substances may
disappear to a greater or less extent. And the fact that cell division
can be inhibited by starvation is scarcely in agreement with Miihl-
mann’s assertion that cell division results from starvation of the
nucleus. Miihlmann regards all that is commonly called progres-
sive development as a regression or involution from the embryonic
condition and maintains that the only progress is the reproduction
of embryonic cells, but here again we have merely assertion, not
evidence. In what way progress is involved in the reproduction
of embryonic cells he does not attempt to show. And his assertion
that cell division and the cessation of life are both death leaves the
idea of death without any physiological significance, for cell division
and the cessation of life are certainly two very different processes.
In the one an increase in metabolism apparently occurs, while in
the other metabolism ceases.

More than twenty years ago Richard Hertwig (’89) advanced the
opinion, based on studies of certain protozoa, that ‘‘depression” and
‘physiological degeneration”? of the cell—conditions supposedly
more or less closely identical with senescence and natural death—
are associated with an increase in the size of the nucleus relatively
to the cytoplasm, and in later papers (’03, ’08) he has attempted to
show that the nucleoplasmic relation, i.e., the size ratio of nucleus
to cytoplasm, varies and regulates itself within definite limits for
each particular kind of cell and that its variation is an index of
the functional condition of the cell. This idea has been further
developed by some of his students and others, but has also been
rather widely criticized, and many investigators have not been
able to find the definiteness of relation which Hertwig believes to
exist. Conklin (12), for example, concludes from an extensive
study of the nucleoplasmic relation in the development of the
mollusk Crepidula, that it is neither a constant nor a self-regulating
ratio and not a cause of cell division, as Hertwig believes, but
rather a result. As a matter of fact differentiation and senescence
in the higher animals are associated in most tissues with an increase

440 SEN. ESCENCE AND REJUVENESCENCE

in the relative volume of the cytoplasm rather than of the nucleus.
Hertwig assumes that the cell is able to regulate its own nucleo-
plasmic relation, at least within certain Jimits, but the origin and
nature of the nucleoplasmic tension which he postulates as the
basis of this regulation, as well as the physiological mechanism of
regulation, remain obscure. In short, the hypothesis has not a
physiological foundation and apparently is not in complete agree-
ment with the facts.

Minot’s views, which are fully stated in his recent publications .
(Minot, ’o8, ’13), are almost diametrically opposed to those of
Hertwig, as regards the direction of change in the nucleoplasmic
relation during senescence. Minot attempts to show that the
growth and differentiation of the cytoplasm are the fundamental
factors in senescence and death. In the young cell the amount of
cytoplasm in relation to the amount of nuclear substance is least,
but during development it increases and undergoes differentiation,
““cytomorphosis ” occurs, and brings about senescence.

According to Minot this is a universal law, but his evidence is
taken almost entirely from the higher animals. In many of the
lower animals no marked proportional increase in the amount of
cytoplasm occurs during development, and in the plants differ-
entiation is in general accompanied, not by increase in the cyto-
plasm, but by vacuolization. Therefore the size relations of the
cytoplasm and nucleus, while they may serve to some extent as an
index of age in the higher animals, cannot by any means be regarded
as a universal factor in senescence. But the differentiation of the
cytoplasm undoubtedly is a very important factor in senescence,
and as regards this point my own view agices closely with Minot’s.

The changes in the substratum of the cells are merely the con-
ditions or one aspect of senescence, they are not senescence itself,
for that is a change in the dynamic processes of the organism which
ends in their cessation. Minot, however, has not told us what
senescence is nor how the cytoplasmic changes bring it about. I
have attempted to show that senescence is a decrease and rejuve-
nescence an increase in rate of metabolism associated with changes.
in the cellular substratum which themselves result from the relation
between substratum and metabolism (Child, ’11, ’14). In his

SOME CURRENT THEORIES 441

latest paper Minot has criticized this view on the ground that if it
were correct we must be growing alternately old and young. While
I am quite ready to admit that this is to a certain extent the case,
it does not by any means follow, as Minot has asserted, that every
change in metabolic rate is either senescence or rejuvenescence.
Undoubtedly it is often impossible to draw a sharp line of distinc-
tion between the age changes and many other periodic changes in
the organism (see pp. 187-93), yet in general] senescence and reju-
venescence are relatively slow and gradual changes in metabolic
rate associated with certain changes in the cellular substratum,
which do not undergo rapid reversal or regression. Minot’s criti-
cism is quite beside the point. There is nothing in his own theory
that is in conflict in any way with the idea that senescence and
rejuvenescence, viewed in their dynamic aspects, are changes in
rate of metabolism, for it is concerned with certain conditions and
indications of senescence in the cells rather than with the process
of senescence itself.

According to Minot, dedifferentiation and rejuvenescence do
not occur in the body cells. At various points in the present book
(see especially chaps. v—vii, x, xii) I have endeavored to show that
dedifferentiation and rejuvenescence occur very widely in body
cells. No further discussion, therefore, is necessary here. Minot
believes, however, that the egg differs from all other cells in that it
undergoes rejuvenescence after fertilization. The basis for this
conclusion is the increase during this stage in the amount of
nuclear substance in relation to cytoplasm. As regards the
occurrence of rejuvenescence in the embryo, I am in essential
agreement with him, but my conclusions are based on the changes
in metabolic rate rather than size relations of nucleus and cyto-
plasm. Minot, however, has made no mention of the spermatozoon.
According to his view it should be one of the youngest cells in
existence, since it possesses in most cases practically no cytoplasm.
As a matter of fact, however, it shows none of the characteristics
of a young cell. It is if anything more highly specialized than the
egg, and has ceased entirely to grow; moreover, when it enters the
egg it loses its morphological characteristics and to all appearances
also undergoes dedifferentiation and rejuvenescence into an ordinary

442 SENESCENCE AND REJUVENESCENCE

nucleus. It would be of interest to know how Minot regarded
this cell.

Delage (’03) believes that age and death are the result of differ-
entiation. In the course of differentiation the cells lose the capacity
for reproduction and finally for growth, and no cell is able to live
indefinitely without either growing or dividing. The idea that
cell reproduction prevents or retards senescence seems to be involved
in this view, but Delage does not attempt to develop it.

Jennings has recently advanced a view very similar to that held
by Delage. Age and death, according to Jennings (’12, ’13), are
the result of the increased differentiation of the higher organisms.
The infusoria do not necessarily die or undergo progressive race
senescence, as Maupas believed. In the more complex and highly
organized body of the higher animals the greater degree of differ-
entiation brings about loss of capacity to carry on the fundamental
vital processes, and so death finally results. Jennings fails to
note that the higher organisms differ from the protozoa, not merely
in the degree of structural differentiation, but in the absence or
limitation of agamic reproduction. As I have endeavored to show
(pp. 136-45), it is the repeated process of reproduction rather than
their low degree of differentiation which prevents progressive race
senescence and death in the protozoa. Each division brings about
some degree of rejuvenescence, which may balance the senescence
during the interval between divisions. Doubtless the capacity of
the protozoa to reproduce agamically and their low degree of differ-
entiation are associated with each other as results of a common
cause, but it is the repeated interruption of progressive develop-
ment by regression that prevents or retards old age and death.

It remains to consider certain hypotheses which concern them-
selves more directly with the metabolic aspects of the age changes.
In his Allgemeine Biologie (1899), Kassowitz has attempted a
general consideration of biological phenomena on the basis of a
theory of metabolism which assumes that all metabolism consists
in the synthesis and destruction of the protoplasm molecule. All
non-protoplasmic (metaplasmic) substances, such for example as
fat, glycogen, starch, etc., which appear in the cell, must first have
formed part of the protoplasm molecules, and their formation is the

SOME CURRENT THEORIES 443,

result of chemical decomposition of these molecules. When the
cells are strongly stimulated, as they are during active function,
the protoplasmic molecules break down into substances which are
eliminated from the cell, such as carbon dioxide and the nitrogenous
excretion products. This Kassowitz terms active breakdown. But
even when the cells are not stimulated and functionally active to
any marked degree, protoplasmic breakdown still occurs, although
slowly and incompletely, and this inactive breakdown gives rise in
large part to the metaplasmic substances which accumulate in the
cell. The metaplasmic substances are, according to Kassowitz,
either quite incapable of further change in the cel] after they are
once formed, or must be slowly transformed by the action of
enzymes before they can again take part in the synthesis of new
protoplasmic molecules. The presence of these metaplasmic
substances in the cell interferes with the passage of oxygen to the
labile molecules and with the transmission of stimuli and so favors
further inactive, as opposed to active, breakdown of protoplasmic
molecules. Consequently, when metaplasmic substances appear
in the cell, the inactive breakdown increases and this in turn leads
to further accumulation of metaplasm and so on. The result is a
decrease in functional activity and, sooner or later, death. From
this point of view senescence and death are the result of a progres-
sive increase in the inactive breakdown and the metaplasmic sub-
stances formed by it. Death from old age finds its determining
factors in the chemical and physical constitution of protoplasm.
In this theory the ideas of the accumulation of substance in the
cell and its effect upon metabolism as a basis for senescence is very
clearly and fully developed. And while there are various reasons
for dissenting from Kassowitz’ theory of metabolism based on the
labile protoplasmic molecule (see pp. 13-18) and from the sharp
distinctions made between active and inactive breakdown and
between protoplasm and metaplasm, we can agree with him that
senescence and death are fundamental features of life and are
associated with an increase in stability of substratum of the cell.
As regards rejuvenescence, Kassowitz is much less clear,
although he has in his ideas a satisfactory foundation for a theory
of rejuvenescence. In referring to Weismann’s ideas concerning

444 SENESCENCE AND REJUVENESCENCE

the immortality of the protozoa, he points out that since a rapid
growth of protoplasm precedes each cell division, and since growing
protoplasm with its large volume of active breakdown is an unfavor-
able substratum for the accumulation of metaplasm, therefore when
such growth occurs the organism may frequently remain young.
He apparently fails entirely to note that, according to his own
hypothesis, elimination from the cell of metaplasmic substances
should make the cell more capable of active breakdown, and so
younger.

Enriques (’07, ’0g) lays stress upon the decrease in assimilatory
capacity, and this capacity he believes decreases as differentiation
increases. Death is not a necessary consequence of life, for the
unicellular forms and also many plants may continue to live indefi-
nitely. Enriques cites some chemical analyses of plants in support
of his view that the nitrogenous substances become ‘“‘diluted”’
during development by the deposition in the cells of carbohydrates.
Moreover, he finds that the changes in the nitrogenous substances
precede the changes in other substances, and this confirms his
belief that the assimilatory capacity of the cells decreases, for the
nitrogenous substance is the assimilating substance. In other
words, a decrease in the proportion of chemically active protoplasm
occurs during development. My own views are in essential agree-
ment with those of Enriques, but I have endeavored to proceed
a few steps farther and to show how rejuvenescence occurs and its
significance in retarding and preventing senescence and death.

Conklin (’12, ’13) has expressed himself as in essential agreement
with my own conclusions concerning the nature of senescence and
rejuvenescence, but he lays particular emphasis upon the inter-
change between nucleus and cytoplasm as the fundamental condi-
tion of constructive metabolism, and concludes that “‘anything
which decreases the interchange between nucleus and protoplasm
leads to senility; anything which increases this interchange renews
youth.” This conclusion seems to me not sufficiently broad in
one sense and too broad in another. It can scarcely be doubted
that at least some degree of cytoplasmic or nuclear senescence may
occur independently of the metabolic interchange between nucleus
and cytoplasm, perhaps as a result of colloid or other changes in

SOME CURRENT THEORIES _ 445

the substratum. Such a change will doubtless decrease nucleo-
plasmic interchange, but this decrease will be secondary rather than
primary in the senescence process. Nucleoplasmic interchange
depends upon the metabolic conditions in the cytoplasm and in the
nucleus and may be altered by changes in either or both. The
primary metabolic changes of age must occur throughout the proto-
plasm. On the other hand, to say, as Conklin does, that anything
which decreases nucleoplasmic interchange leads to senility and
anything which increases it renews youth is manifestly not true,
for low temperature may decrease and high temperature increase
the interchange, but such metabolic changes do not, properly
speaking, constitute senescence and rejuvenescence, although they
may in some cases result sooner or Jater in one or the other.

The advances during recent years in our knowledge of the
colloids and the very natural and entirely justifiable desire to apply
the principles and conclusions of colloid chemistry to the living
organism have led various authors to suggest that senescence in
organisms is fundamentally a colloid change. In chaps. i, ii, and
viii I have called attention to these colloid changes and their impor-
tance for the problems of senescence and rejuvenescence. It can
scarcely be doubted that the colloid substratum of the organism
does undergo changes which are not essentially different from those
in non-living colloids and that such changes play an important
role in the process of senescence. They are perhaps, as I suggested
(pp. 49-50), the primary changes in embryonic protoplasm which
lead to decrease in metabolic rate and so initiate the processes of
differentiation and senescence. But something more than these
changes is involved in at least most cases of senescence, for differ-
entiation occurs, new structural substances are produced and
accumulate in the cell, and its metabolic activity often becomes
very different in character from that of the embryonic cell. While
these changes may depend in large measure upon colloid changes,
it is probable that changes in the chemical constitution of the
substratum may also contribute to its increasing stability and so
play a part in senescence.

The occurrence of rejuvenescence has not, so far as I know,
been considered in connection with the suggestions that senescence

446 SENESCENCE AND REJUVENESCENCE

is a colloid change, but from this point of view rejuvenescence
would naturally be regarded as a reversal of the change concerned
in senescence in consequence of altered conditions. As I have
pointed out (pp. 56-57), however, rejuvenescence is not necessarily
a reversal of senescence, but rather, to a large extent at least, the
substitution of a new substratum or protoplasm for the old, which
may serve in greater or less part as a source of energy and of
material. Here certainly chemical decomposition and synthesis
are the important factors, although reversible colloid changes may
be concerned to some extent.

Life is not entirely a matter of colloid condition, nor is it entirely
a matter of chemical reaction: it is rather in the interrelations
between chemical reaction and colloid substratum that we find the
fundamental characteristics of life. If, as I have attempted to
show, the age cycle is life itself, viewed from a certain standpoint,
we must look to these interrelations for any adequate conception of
the changes of senescence and rejuvenescence.

THE CONCEPTION OF GROWTH AS AN AUTOCATALYTIC REACTION AND
THE RESULTING THEORY OF SENESCENCE

Within the last few years various authors’ have suggested that
growth is essentially an autocatalytic reaction. Loeb has made
this suggestion in several papers concerning the process of nuclein
synthesis in the developing egg, and Robertson, Wolfgang Ostwald,
and Blackman have attempted to show that the processes of growth
in general follow the laws of autocatalysis. An autocatalytic
reaction is one in which one or more of the products of the reaction
act as catalyzers and so increase the velocity of the reaction. In
such a reaction the velocity of the transformation at any instant is
proportional to the amount of material undergoing change and to
the amount of material already transformed. This remains true
until products of the reaction begin to decrease its velocity. The
curve of such a reaction is in general an S-shaped curve, like
Fig. 199, at first concave to the axis of ordinates as the velocity of
reaction increases and finally becoming convex to this axis as
the velocity decreases.

1 Blackman, ’09; Loeb, ’06, ’08, ’0g; Wolfgang Ostwald, ‘08; Robertson, ’o8¢,
08), 713.

SOME CURRENT THEORIES 447

Grams

15,000

10,000

4,000

12345678910 I 2 3 4
Months (birth) Years after birth

Fic. 199.—Curve of human growth for the embryonic period and the first four
years after birth, drawn from the absolute increments of weight in Table XIII: each
vertical interval indicated on the axis of ordinates represents an absolute increase of
weight of 1,000 grams; on the axis of abscissae the ten short intervals at the left repre-
sent the nine months of the embryonic period and the month of birth, and each of
the following intervals represents one year.

448 SENESCENCE AND REJUVENESCENCE

If growth is a process of this kind, the rate of growth must
increase up to a certain maximum as growth proceeds and then,
after maintaining this maximum for a longer or shorter time, must
decrease. Both Robertson and Ostwald present a great variety of
data from various sources to support their conclusions, and many
of Ostwald’s curves are very characteristic curves of autocatalysis.
Robertson has attempted to show further that in any growth-cycle
of an organism, tissue, or organ, the maximum increase in volume or
weight in a unit of time occurs when the total growth of the cycle is
half completed. From this point of view senescence consists merely
in the retardation during the later stages of a growth-cycle of the
rate of reaction by the accumulation of the products of reaction.
Senile atrophy and death are not a feature of the reaction and must
be due to special conditions not directly connected with growth.
Rejuvenescence, so far as it occurs, must consist of a reversal of the
reaction and consequently a removal of the accumulated products
which were responsible for the retardation.

The foundation upon which this conception of growth rests
consists of the observational, statistical data of the increments of
growth or of certain growth-components, such as weight, length,
water-content, etc., in various organisms. Ostwald has shown that
the absolute increments of growth or growth-components show very
generally an increase during the earlier and a decrease during the
later portion of the growth-cycle under consideration and so when
graphically presented appear as an S-shaped curve like the curve
of autocatalysis. Robertson’s conclusions rest on the same basis
as Ostwald’s. Stated in general terms these results mean simply
that up to a certain point, the larger, or heavier, or longer the
organism becomes, the greater its absolute increase in a given time,
but beyond that point the absolute increase in a given time becomes
smaller, although the total size, or weight, or length is still in-
creasing.

The same statistical data may be handled in another way.
From the absolute increments we may determine the relative
increments of weight, length, etc., that is, the increase in a given
period of time in proportion to the weight or length at the beginning
of that time. This relative increment may be expressed as a per-

SOME CURRENT THEORIES 449

centage of the total weight or length at the beginning of each period
and may be called for convenience the percentage increment. The
percentage increments for different periods enable us to compare
the activity of the organic substance per unit of weight or length
in adding to the weight or length in each period, and we find that
in growth the percentage increments may decrease while the
absolute increments are stillincreasing. In other words, as growth
proceeds, the absolute increment in grams or millimeters may
become greater, but the growth-activity of each unit of weight or
length already present is decreasing.

TABLE XIII

WEIGHTS OF THE HUMAN EMBRYO AND OF THE CHILD DURING
THE First Four YEARS AFTER BIRTH

Age Weight inGrams| yatrement | Increment
2 months Bol eo wen tile sal Saree x eainee ¢
a 20 16 400
4 -% 120 I00 500
i 285 165 137-5
6 1 635 350 123
ie, is I,220 585 92
8 Z I,700 480 39
ae 2,240 540 32
TO. (birth)... .. 3,250 I,O10 45

4 year. ..... ss... 5,620 2,370 73

Lee ee 75350 1,730 31 a

Be area Seaeaie 8,820 1,470 20
Te a atia ikl aiats 9,920 I,100 12.5
Tah weenie ayes 10,720 800 8
Eg he Pag elects etal ars 11,520 800 7.5
Reap oats Sawa dai 12,020 500 4-3
QE ee aed as 12,620 600 5
Be ca tiva Saas tesiens 14,820 2,200 14.5
Be) SR Shia Nd eetotiasaN 16,320 1,500 I1.2

An example from among the data used by Ostwald will make the
matter clear. Table XIII gives in the second column the weights
in grams of the human embryo at monthly intervals from the
second month to birth, as determined by Fehling, and of the child
after birth at intervals of three months during the first two years
and of one year each during the third and fourth years, as deter-
mined by Camerer. The third column of the table gives the absolute

450 SENESCENCE AND REJUVENESCENCE

increments in grams for each period as determined from the differ-
ences in weight, and the fourth column the percentage increments,
i.e., the increments expressed as percentages of the total weight at
the beginning of each interval. It is evident at once that the
absolute increments in the third column increase during the first
seven months of the embryonic period, and that after birth there
is at first an increase and then a decrease, with slight irregularities.
But the percentage increments show an increase only from the
third to the fourth month and afterward a decrease. In comparing
the increments before and after birth it must be remembered that
the time intervals from birth to two years are three times and those
from two to four years twelve times as long as those before birth,
so that we must divide the increments given in the table for these
periods by three and by twelve respectively to make them com-
parable to the increments for the embryonic period.

If from the growth-increments we plot a curve of growth, using
the time intervals as abcissae and the increments as ordinates, the
form and direction of the curve will be very different, according
as we use the absolute or the percentage increments. The curve
which results when the absolute increments are used is shown in
Fig. 199. This is an S-shaped curve and is similar to the curve of
an autocatalytic chemical reaction. Ostwald and Robertson have
used the absolute increments in their studies of growth and have
obtained similar curves for a variety of data.

But if we use the percentage increments the curve is of the kind
shown in Figs. 200 and 201. Fig. 200 is the curve for the embry-
onic period and Fig. 201 for the period after birth, the former being
on a larger scale than the latter in order to show its character
more clearly. This method of graphic presentation of the data
gives a descending curve, which expresses the fact that the rate of
increase in weight as a percentage of total weight decreases from a
very early period on. The other data of growth used by Ostwald
and Robertson give essentially similar results, with here and there
slight irregularities resulting from larval moultings, changes in
relation to environment, etc. Donaldson’s and Minot’s curves of
rate of growth were also drawn from percentage in crements."

t See Donaldson, ’95; Minot, ’91, ’08; and also pp. 274-77 above.

SOME CURRENT THEORIES 451

Evidently there must be no conflict between the conclusions
which we may draw from the two kinds of increments or the two
kinds of curves, since both are obtained from the same statistics.

Per cent
500 T

400 T

300 F

200 f

100 +

In the one case growth
resembles an autocata-
lytic reaction, in which
the amount of substance
added in a given time
increases up to a certain
point and then de-
creases, while in the
other we observe that
the rate of growth, or,

.in other words, the

growth activity per unit
of weight, decreases
from a very early period
on. A. W. Meyer (’14)
has criticized Ostwald
and Robertson for using

Months

2

)

pe ee
6 7 8 9

Fic. 200.—Curve of human growth for the embryonic period and the month of
birth, drawn from the percentage increments of weight in Table XIII: each vertical
interval indicated on the axis of ordinates represents an increment of 100 per cent in
weight, and each horizontal interval on the axis of abscissae, one month.

absolute instead of percentage increments of growth as the basis
of their curves.’ This criticism is somewhat beside the point, for it
must be remembered that the absolute and relative increments
represent simply different aspects of the same process.

452

SENESCENCE AND REJUVENESCENCE

The general resemblance of the growth process to an autocata-
lytic reaction is self-evident: in the first place one result of growth

Per cent
150

140

130

120

IIo

Ioo

go

80 }

70

60

50

40

30

204

10

Years

is an increase in the amount of protoplasm,
and the greater the amount of protoplasm
the greater the amount of growth in a given
time. Or more specifically, assuming what
is undoubtedly true, that growth is dependent
directly or indirectly upon the presence of
certain enzymes, then it is evident that
greater amounts of growth are possible as
growth proceeds, for the necessary enzymes
are one of the products of growth.
Doubtless certain reactions concerned in
growth are autocatalytic reactions, but it
seems obvious that growth is very much more
than an autocatalytic reaction and that
certain processes which do not follow the
laws of autocatalysis are much more impor-
tant in relation to the more conspicuous
characteristics of growth than those which
do or seem to. Growth produces other sub-
stances besides active protoplasm or enzymes,
viz., substances which play little or no part
in bringing about further growth, but form

I 2 3

Fic. 201.—Curve of human growth from birth to three years, drawn from the
percentage increments of weight in Table XIII: each vertical interval indicated on
the axis of ordinates indicates an increment of ro per cent in weight, each horizontal
interval on the axis of abscissae, three months.

more or less stable structural constituents of the organism.
As growth proceeds, the proportion of these substances to the total

SOME CURRENT THEORIES 453

weight or volume undergoes more or less continuous increase and
the proportion of active substance to total weight or volume becomes
less and less. Consequently the percentage increment of growth
decreases more or less continuously from the beginning of these
changes, and the absolute increment, while at first increasing, must
sooner or later decrease. It is, in fact, not the increase in the
autocatalyst of growth, but the increase of other products of reac-
tion and the transformation of active protoplasm into other less
active forms which retards growth, and these changes are going on
and the proportion of these substances is increasing more or less
continuously from the beginning of the growth period. Enriques
(’o9), in a critique of the autocatalytic theory of growth, has
emphasized the fact that in consequence of differentiation a “‘dilu-
tion” of the actively growing substance occurs and the rate of
growth decreases, until finally the total growth is insufficient to
balance the losses, and senile atrophy occurs. Senescence, senile
atrophy, and death result from changes of this kind, not from the
autocatalytic changes, and there is no need of assuming, as the
adherents of the autocatalytic theory of growth are forced to do,
that the conditions which determine senile atrophy are different
from those which are concerned in growth. Senile atrophy is in
reality merely the necessary result of continued growth in organisms
with a relatively stable substratum.

Growth is not a simple chemical reaction and cannot be con-
sidered as such: it is a complex physico-chemical process in which
changes in the physical character of the substratum as well as
chemical conditions are concerned. The rate of growth is deter-
mined, not simply by the laws of autocatalysis, but by a complex
of factors of different kinds. The decrease in the absolute growth-
increment in later stages does not represent approach toward a
chemical equilibrium, but rather a continued dilution and physical
change of the protoplasm.

The question whether reduction and dedifferentiation are
reversals in the chemical sense of growth and differentiation has
already been raised (see pp. 38, 56). If it were possible to regard
the whole life cycle of the organism as a reversible chemical reac-
tion it would doubtless simplify very greatly our conception of

454 SENESCENCE AND REJUVENESCENCE

living things. But the organism cannot be compared to a chemical
reaction; it consists of a multitude of chemical reactions and
physical changes interrelated and localized and controlled by their
relations to a peculiar physical environment or substratum, which
in turn is the product of the reactions and is modified by them.
Many factors not concerned in simple chemical reactions i vitro
are present in living organisms, and to ignore them can only result
in failure to gain an adequate conception of what life is.

Recently Robertson (13) has attempted to develop the auto-
catalytic theory of growth still farther and to show that lecithin, or
the substances of the phospholipine group to which lecithin belongs,
are the autocatalysts of growth. Robertson points out that two
kinds of autocatalytic growth are possible, one the autostatic in
which the autocatalyst is decreasing in amount, the other the auto-
kinetic in which it is increasing in amount. He believes that the
early period of embryonic development in which the nuclear sub-
stance is increasing and the yolk decreasing is of the autostatic
type, while the later period of cytoplasmic growth and differentia-
tion is of the autokinetic type. These two periods correspond
in general to the periods which I have distinguished as the periods
of rejuvenescence and senescence in the life cycle. The grounds
for his conclusion that lecithin is the autocatalyst are: first, that
the amount of lecithin in the sea-urchin egg decreases during early
stages of development (Robertson and Wasteneys, ’13); secondly,
that lecithin added to the sea-water retards, or, as he believes, may
even reverse, the development of the sea-urchin in early stages;
thirdly, that lecithin accelerates the growth and development of
amphibian larvae in later stages preceding metamorphosis.

It is of course true that the amount of lecithin decreases during
early embryonic development, for the yolk is rich in lecithin, and
during this period yolk is the source of nutrition, and it is also true
that the formation of nuclear substance undergoes marked accelera-
tion at the same time, but there is also increase in the volume of
active cytoplasm. In contrast to the period of senescence there is
during this period of rejuvenescence an increase in concentration,
so to speak, of the active substance of the organism at the expense
of the yolk, and this increase in concentration is continuous through-
out the period, which is brought to an end, not by the decrease in

SOME CURRENT THEORIES 455

lecithin, specifically, but by the disappearance of the yolk as a
nutritive supply. If the organism obtains nutrition from without,
the formation of both nuclear substance and cytoplasm may go on
for a long time, but sooner or later the gradual ‘‘dilution” of the
protoplasm begins to make itself felt. It may be that the synthesis
of the nuclein of the nucleus is, as Loeb has suggested, an auto-
catalytic reaction, but the important point is that any attempt to
interpret the period of early embryonic development as a whole in
terms of autocatalysis fails to take account of features of great
biological importance.

As regards Robertson’s further evidence, his experiments on
the retardation of development by means of lecithin must be pre-
sented in much more complete form before they can be regarded
as convincing. To establish as a fact a change so important as the
reversal of embryonic development requires extended and careful
experimentation. There is no evidence, from Robertson’s descrip-
tion, of anything more than a toxic effect of the lecithin preparation,
and for the present we can only regard his conclusion as based on
very inadequate evidence.

While the autocatalytic theory of growth is interesting and
doubtless of value as regards certain aspects of growth, it is at best
only a partial theory and can never be applied to the growth process
asawhole. The great periodic changes in growth during senescence
and rejuvenescence not only do not follow the laws of autocatalytic
reactions, but are determined by a complex of factors of which some
are only indirectly connected with chemical reactions of any kind.
From the laws of simple chemical reactions alone we can never
hope for anything more than partial and inadequate interpretations
of the complex biological processes, such as growth and reduction,
differentiation and dedifferentiation, senescence and rejuvenescence.

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BERNSTEIN, J.
1898. ‘Zur Theorie des Wachstums und der Befruchtung,” Arch. f.
Entwickelungsmech., VII.

BLACKMAN, F. F.
1909. ‘‘The Manifestations of the Principles of Chemical Mechanics in
the Living Plant,” Report of the 78th Meeting of the Brit. Assoc.
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BUHLER, A.
1904. ‘Alter und Tod,” Biol. Centralbl., XXIV.
BUrTscuLt, O.
1882. ‘“‘Gedanken iiber Leben und Tod,” Zool. Anzeiger, V.
Cuitp, C. M.
tg11. ‘‘A Study of Senescence and Rejuvenescence Based on Experi-
ments with Planarians,” Arch. f. Entwickelungsmech., XXX.
1914. ‘Starvation, Rejuvenescence and Acclimation in Planaria doroto-
cephala,” Arch. f. Entwickelungsmech., XX XVIII.
CHOLODKOWSEY, N.
1882. ‘Tod und Unsterblichkeit in der Tierwelt,” Zool. Anzeiger, V.
CoHNHEIM, J.
1882. Vorlesungen tiber allgemeine Pathologie. II. Auflage. Berlin.
ConkLIy, E. G.
1912. ‘Cell Size and Nuclear Size,” Jour. of Exp. Zool., XII.
1913. ‘‘The Size of Organisms and of Their Constituent Parts in Relation
to Longevity, Senescence and Rejuvenescence,” Pop. Sci. Monthly,
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DELAGE, Y.
1903. L’ Hérédité et les grandes problémes de la biologie. Paris.
Dona tpson, H. H.
1895. The Growth of the Brain. London.
ENRIQUES, P. ;
1907. ‘‘La morte,” Rivista di Scienza. Ann. I.
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XXIX.
GoETTE, A.
1883. Uber den Ursprung des Todes. Hamburg.
HANSEMANN, D. VON.
1893. Studien iiber die Spezifitat, den Aliruismus und die Anaplasie der
Zellen. Berlin.
1909. Descendenz und Pathologie. Berlin.
HERTWIG, R.
1889. “Uber die Kernkaonjugation der Infusorien,” Abhandlungen d.
Bayer. Akad. d. Wissensch., 1. K1., XVII.
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fiir die geschlechtliche Differenzierung und die Teilung der Zelle,”
Biol. Centralbl., XXIII.
1908. ‘Uber neue Probleme der Zellenlehre,” Arch. f. Zellforsch., I.
JENNINGS, H. S.
1g12. “Age, Death and Conjugation in the Light of Work on Lower
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SOME CURRENT THEORIES 457

JENNINGS, H. S.
1913. ‘‘The Effect of Conjugation in Paramecium,” Jour. of Exp. Zool.,

XIV.
JICKELI, C. F.
1902. Die Unvollkommenheit des Stoffwechsels. Berlin.
Kassowirz, M.
1899. Allgemeine Biologie. Bande I und II. Wien.

Logs, J.
1906. ‘Weitere Beobachtungen iiber den Einfluss der Befruchtung und
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Zeitschr., II.
1908. ‘Uber den chemischen Character des Befruchtungsvorgangs und
‘seine Bedeutung fiir die Theorie der Lebenserscheinungen,” Vortr.
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1909. Die chemische Entwicklungserregung des tierischen Eies. Berlin.

Lorze, R. H.
1851. Allgemeine Physiologie des kérperlichen Lebens. Leipzig.
1884. Microcosmus. IV. Auflage. Leipzig.

Macnus-Levy, A.
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Maupas, E.
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ciliés,”” Arch. de zool. exp., (2), VI.
1889. ‘“‘La Rajeunissement karyogamique chez les ciliés,” Arch. de zool.
exp., (2), VII.

METcHNIKoFF, E.
1903. The Nature of Man. English translation. New York and London.
1910. The Prolongation of Life. English translation. New York and
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Mever, A. W.
1914. “Curves of Prenatal Growth and Autocatalysis,” Arch. f. Ent-
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Minor, C. S.
1891. ‘Senescence and Rejuvenation,” Jour. of Physiol., XII.
1908. The Problem of Age, Growth and Death. New York.
1913. Moderne Probleme der Biologie. Jena.

Montcomery, T. H., Jr.
1906. ‘On Reproduction, Animal Life Cycles and the Biological Unit,”
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Miutmuann, M.
, 1900. Uber die Ursache des Alters. Wiesbaden.
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(Virchow), CCXV.
MULLER, J.
1844. Handbuch der Physiologie des Menschen. IV. Auflage. Coblenz.
OsTWALD, WOLFGANG.
1908. ‘‘Die zeitlichen Eigenschaften der Entwicklungsvorginge,” Vorir.
u. Aufs. ii. Entwickelungsmech., H. V.
ROBERTSON, T. B.
1908a. ‘‘On the Normal Rate of Growth of an Individual and Its Bio-
chemical Significance,” Arch. f. Entwickelungsmech., XXV.
1908). “Further Remarks on the Normal Rate of Growth of an Indi-
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lungsmech., XXVI.
1913. ‘‘On the Nature of the Autocatalyst of Growth,” Arch. f. Entwicke-
lungsmech., XXXVILI.
RoBERTSON, T. B., and WaAsTENEYS, H.
1913. ‘On the Changes in Lecithin-Content Which Accompany the
Development of Sea-Urchin Eggs,” Arch. f. Entwickelungsmech.,

XXXVII.
Roux, W.
1881. Der Kampf der Teile im Organismus. Leipzig.
Rusner, M.

1909. Kraft und Stoff im Haushalte der Natur. Leipzig.

CHAPTER XVII

SOME GENERAL CONCLUSIONS AND THEIR SIGNIFICANCE FOR
BIOLOGICAL PROBLEMS

It remains only to review briefly in a connected way some of the
more important conclusions of the preceding chapters and to make
a few further suggestions as to their bearing upon certain biological
problems. In the first place, a full consideration of the facts leads
unmistakably to the conclusion that the age cycle is simply one
aspect of the developmental cycle, or we might even say that the
developmental cycle is an aspect of the age cycle. Senescence
and rejuvenescence do not include special processes, they are
merely certain aspects of the relations between the metabolic reac-
tions and the protoplasmic substratum. The progressive changes
with which physiological senescence is associated are changes in
the direction of greater physiological stability of the protoplasm
and decreased dynamic activity. The regressive changes which
bring about rejuvenescence are not necessarily reversals in the
chemical sense of the progressive changes, but rather a substitution
of a new substratum for an old. Asastructure built by man, when
it is no longer suited to existing conditions, may be torn down and
some parts of it used, together with new material, for building a new
structure which meets the demands of the new conditions, so in
organisms structural features built up under certain physiological
conditions may under others be broken down, and some of their
constituents may take part in the formation of a new structure.

Both progression and regression are undoubtedly going on at
all times in the active organism, but under the usual conditions of
vegetative life the progressive changes overbalance greatly the
regressive because building material in the form of nutrition is
being added. But while growth and progressive development,
with its specialization and differentiation of parts, is the more con-
spicuous feature of the life cycle, reduction and regression are none
the less essential parts of it. The life cycle consists of one or more
periods of senescence and one or more periods of rejuvenescence.

459

460 SENESCENCE AND REJUVENESCENCE

When the organism is adding to its structural substance, and trans-
formation from more active to less active physical and chemical
conditions takes place, senescence occurs. When conditions change
so that previously formed structure is wholly or in part broken
down and replaced by a new structural substratum, rejuvenescence
occurs.

Senescence occurs chiefly during the vegetative life of the indi-
vidual, while rejuvenescence is usually associated with reproduc-
tion, although various other conditions, such as starvation in which
extensive breakdown of previously formed structure occurs, may
bring it about. Reproduction may be defined as the regression or
dedifferentiation and reconstitution into a new individual of a
physiologically or physically isolated part of a pre-existing indi-
vidual. In agamic reproduction the changes result from the isola-
tion of the part without further external action, but in gametic
reproduction specialization of the part concerned, i.e., the gamete,
has proceeded so far that the union of the two widely different cells
is necessary—except in parthenogenic eggs—to initiate the regres-
sive and reconstitutional changes.

The occurrence of reproduction of one kind or another depends
on various physiological conditions, the degree of individuation,
physiological age, etc. In general the vegetative forms of agamic
reproduction occur in relatively young organisms, the more spe-
cialized agamic reproductions, such as formation of spores, gem-
mules, etc., are characteristic of somewhat later stages with a
lower metabolic rate, and finally gametic reproduction is a feature
of relatively advanced age and the gametes are cells which have
reached the end of their progressive developmental history, have
no further function in the parent organism, and are cast off as
waste products or remain as physiologically isolated quiescent cells.
Before their isolation they were integral physiological parts of the
organism, and they represent a more highly specialized, physio-
logically older condition than those parts which when isolated
develop agamically. .

The degree of physiological integration or individuation in-
creases in general and up to a certain limit with increasing stability
of the structural substratum. In general, also, the greater the

SOME GENERAL CONCLUSIONS 461

degree of physiological integration, the more continuous the prog-
ress of senescence and the less frequently does vegetative agamic
reproduction occur. In the plants and lower animals conditions
which decrease physiological dominance and integration bring
about reproduction of one kind or another. Senescence is itself
such a condition, and in many organisms senescence may result
automatically in the physiological isolation of parts, or the disinte-
gration of the individual into fragments or cells, and so in repro-
duction.

Senescence is a characteristic and necessary feature of life and
occurs in all organisms, but in many of the lower forms it may be
more or less completely balanced by rejuvenescence in connection
with reproduction or other regressive changes, so that there is
little or no progressive senescence from one generation to another,
or in the case of colonial forms, such as multiaxial plants, of the
colony as a whole. Life in such cases consists of brief alternating
periods of progression and regression, of senescence and rejuvenes-
cence, which in some cases apparently balance each other for an
indefinite period, while in other cases a slow progressive senescence
may occur, extending through many generations.

Death is the inevitable end of the process of senescence when
regression and rejuvenescence do not occur. In the lower forms,
where agamic reproduction is frequent, or where other conditions,
such as starvation, bring about regression periodically or occasion-
ally, death does not necessarily occur. But in the higher forms,
where progression and senescence are more nearly continuous, the
life of the individual usually ends in death, though even in these
forms some degree of rejuvenescence may occur.

If these conclusions are correct, agamic and gametic reproduc-
tion are fundamentally similar processes, except for the fact that in
gametic reproduction specialization of the reproductive cells has
proceeded so far that the peculiar conditions associated with ferti-
lization are necessary for the initiation of the process of regression
and rejuvenescence. And if we accept this theory of reproduction,
the Weismannian conception of germ plasm as a self-perpetuating
entity, independent of other parts of the organism except as regards
nutrition—in short, a sort of parasite upon the body—becomes not

462 SENESCENCE AND REJUVENESCENCE

only unnecessary but impossible. Germ plasm is any protoplasm
capable, under the proper conditions, of undergoing regression,
rejuvenescence, and reconstitution into a new individual, organism,
or part. In other words, germ plasm becomes merely an abstract
idea which connotes the sum-total of the inherent capacities or

“potencies”? with which a reproductive element of any kind, natural _

or artificial, agamic or gametic, giving rise to a whole or a part,
enters upon the developmental process. Germ plasm is then
merely another term for heredity. The process of inheritance is
concerned in every case of reproduction, whether it be agamic or
gametic, partial or total, and both experimental reproduction and
agamic reproduction in nature present opportunities for the study
of the process and mechanism of inheritance, which have thus far
been almost entirely neglected, but which are not found in con-
nection with the much more highly specialized process of gametic
reproduction. And, admitting that every reproductive element
of any kind is, before reproduction begins, an integral physiological
part of an organic individual, we may define heredity more briefly
as the capacity of a physiologically or physically isolated part for
reconstitution into a new individual or part.

It does not by any means follow from this theory of reproduction
and inheritance that all the characteristics of the individual shall
reappear in the following generation. Many individual charac-
teristics which are the result of action of external factors or of
special functional activity of certain parts—such, for example, as
calloused areas in the skin, the functional hypertrophy or atrophy
from disuse of certain muscles, and many others—are evidently the
result of local quantitative changes in metabolism and as such
cannot be expected to alter at once the equilibrium of the whole
protoplasmic system in such a way that they will be reproduced
in following generations in the absence of the special conditions
which determined their first appearance. This is equally true for
agamic and for gametic reproduction. Nevertheless, since every
reaction represents to some extent a reaction of the whole organ-
ism and no change is purely local or entirely independent of
other changes, it is conceivable that if the special external or func-
tional conditions act in the same way through a sufficient number

SOME GENERAL CONCLUSIONS 463

of generations, they may in time bring about an appreciable lasting
change in the whole system of such a kind that the characteristics
produced by them will become hereditary. And if the cells which
give rise to gametes are integral parts of the organism, such a
change must sooner or later affect them as well as other parts. It
is quite impossible to discuss at this time the great mass of evidence
for and against the inheritance of these so-called acquired charac-
ters. In general, biologists have been slow to admit the possibility
of such inheritance, largely because it conflicts with the Weisman-
nian theory, but if we admit that the gametes are integral parts of
the organism, there is no theoretical difficulty in the way of such
inheritance. Whatever the theoretical possibilities may be, it is in
my opinion quite impossible to account for the course of evolution
and particularly for many so-called adaptations in organisms with-
out the inheritance of such acquired characters, but since thousands
or tens of thousands of generations may be necessary in many cases
for inheritance of this kind to become appreciable, it is not strange
that experimental evidence upon this point is still conflicting.

The morphological parallelism between the course of individual
development and the course of evolution have long been familiar
to biologists and have been the subject of much discussion and
speculation. While departures from this parallelism are numerous
and often conspicuous, nevertheless the so-called biogenetic law
that embryology repeats phylogeny, i.e., the development of the
individual repeats evolutionary history, still remains a striking
biological fact. Moreover, a physiological parallelism seems to
exist to some extent. In the individual we see advancing diversity
and specialization of function, apparently associated with increas-
ing stability of the structural substratum, and in evolution a similar
series of changes. The question at once arises: Can we not find a
clue in individual development to certain factors concerned in
evolution ?

In earlier chapters I have attempted to show that individual
development and senescence are associated with the increase in
stability of the substratum, while regression and rejuvenescence
involve a return to the original ‘‘undifferentiated”’ active proto-
plasmic condition. It is of course not necessary to assume that in

464 SENESCENCE AND REJUVENESCENCE

all cases exactly the same condition is attained in each successive
regression and rejuvenescence. It is quite conceivable, indeed
probable, that, in spite of the successive regressive changes in each
generation, there may be some slight, more or less continuous, pro-

gressive change, which perhaps becomes appreciable only after
many generations. Have we, in fact, any right to assume that
the organism returns to exactly the same condition in each succes-
sive regression? Is it not probable that a gradual, progressive
senescence of protoplasm has occurred in the course of evolution ?
These questions have already been touched upon in chap. viii, and
here it need only be said that the facts point very definitely in the
direction of an affirmative answer.

If protoplasmic senescence is the essential factor in progressive
evolution, then evolution is, like individual development, to a
large extent internally, rather than externally, determined. We
can accelerate, retard, or alter the course of individual development
experimentally, but in spite of all such changes it retains a remark-
able constancy of character. Have we not in evolution a somewhat
similar process, a progressive change, a secular differentiation and
senescence of protoplasm along lines which are determined primarily
by the constitution of protoplasm rather than by external factors ?
In our attempts to modify experimentally the course of evolution
are we not merely bringing about minor changes in a process
which, like individual development, is internally determined, rather
than determining the essential factors in evolution? Here again
the facts seem to suggest an affirmative answer.

If evolution is in some degree a secular differentiation and
senescence of protoplasm, the possibility of evolutionary rejuvenes-
cence must not be overlooked. Perhaps the relatively rapid rise and
increase of certain forms here and there in the course of evolution
may be the expression of changes of this sort. Perhaps also those
forms which have been, so to speak, left behind as the lower organ-
isms in evolutionary progress are forms in which senescence
and rejuvenescence more nearly balance than in those that have
gone on.

Even if evolution is a process of this kind we must believe that
environmental factors affect its course to a greater or less extent,

SOME GENERAL CONCLUSIONS 405

as they do the course of individual development, and we must admit
the possibility of sudden changes of considerable magnitude, so-
called mutations, although even these may be determined by pre-
viously existing internal conditions, as, for example, metamorphosis
in individual development which is primarily the result of internal
factors. And, finally, as our ability to control the process of indi-
vidual development has increased so greatly with the advance in
knowledge of experimental methods, we may perhaps expect that
in the course of time our ability to control the evolutionary pro-
cess may increase, although the difficulties involved in controlling
and modifying to any very great degree internal conditions which
are the result of millions of years of alternating progressive and
regressive change will perhaps make progress in this direction slow.
Senescence and rejuvenescence result from a combination of
factors which is found nowhere except in organisms, but there is no
reason to believe that any one of the factors which make up the
complex is peculiar to living things. Changes in the permeability
of membranes and other changes in aggregate condition of the
colloids, changes in proportion of active and inactive substance in
chemical systems, changes in water-content—all these and many
others occur in non-living as well as in living systems. But we
may make our basis of comparison broader than this and use for
definitions somewhat more general terms than heretofore. In such
terms senescence is a retardation resulting from continued dynamic
activity under certain conditions in a system, and rejuvenescence
an acceleration resulting from elimination or transformation
of the retarding factors under altered conditions. These defini-
tions still hold good for the organism, but they also apply to many
other changes in nature. Senescence and rejuvenescence in this
sense are going on all about us, in some cases with short, in others
with very long, periods. The age changes in the organism are
merely one aspect of Werden und Vergehen, the becoming and
passing away, which make up the history of the universe.

INDEX

INDEX

Nortr.—References give the number of the page on which the matter referred to begins.

Acclimation: in relation to concentra-
tion of reagent, 72; in relation to age,
82; in relation to temperature, 84;
in relation to nutrition, 84, 165; in rela-
tion to metabolic rate, 164. See also
Susceptibility.

Age: physiological and morphological,
58, 85; criteria of, 85, 178; in relation
to time, 87, 97; in relation to hydranth
and medusa buds in Pennaria, 151,
256; in relation to vegetative repro-
duction in plants, 239; in relation to
spore formation in plants, 247; of
gametes, 349; in relation to matura-
tion, 355; in relation to gamete forma-
tion, chap. xiv; in relation to partheno-

genesis and zygogenesis, 393. See
also Age cycle; Rejuvenescence;
Senescence.

Age cycle: occurrence of, 59; in relation
to endomixis, 143, 379; in relation to
character of nutrition, 169, 179; in
relation to reproduction, 178, 239, 2473
in relation to other periodicities, 187,
192; in relation to spore formation,
254; individual and racial, in relation
to parthenogenesis and zygogenesis,
389; in relation to larval stages and
metamorphosis, 420; as one aspect of
developmental cycle in world in gen-
eral, 465. See also Age; Life cycle;
Rejuvenescence; Senescence.

Alternation of generations: in relation
to age cycle in plants, 253; in mosses
and ferns, 254, 366; in seed plants, 254,
320, 368.

Anabolism, 14, 43.

Anophthalmic form in Planaria doroto-
cephala, 112, 223.

Antheridium: in algae, 316; in mosses
and ferns, 318.

Apical region: metabolic rate in, 202,
204; independence of, 210, 213, 215;
dominance of, 213, 215, 216; limit of
dominance in, among plants, 232, 238;
physiological condition of, in plants,
240, 244. See also Axial gradient;
Axis. :

Aplysia limacina, oxygen consumption
and carbon-dioxide production during
early development in, 411.

Apogamy: origin of embryo in, 322; in
relation to segregation of germ plasm,
367; in seed plants, 408.

Apospory, 322 footnote 2, 408.

Arbacia punctulata: increase in oxygen
consumption of, after fertilization,
405; increase in susceptibility of,
during early development, 413, 414.
See also Sea-urchin.

Archegonium: of mosses, 316; of fern,
338; of Torreya taxifolia, 339.

Arenicola cristata: period of developmen-
tal rejuvenescence in, compared with
that of Nereis, 415.

Arteriosclerosis in relation to senescence,
287, 301, 434.

Ascaris megalocephala: germ path in,
324; spermatozoon of, 336; suscepti-
bility of gametes of, 351.

Asterias forbesit, susceptibility of, during
early development, 413. See also
Starfish.

Atrophy: senile, 2, 287, 301; from dis-
use, 45, 185, 287; difference between,
and reduction, 288; of sex organs as
condition of senescence, 434.

Autocatalyst, lecithin as, of growth, 454.
See also Autocatalytic reaction.

Autocatalytic reaction: growth as, 446,
452; nature of, 446; curve of, 446;
autostatic and autokinetic, 454; leci-
thin in, of growth, 454.

Axial gradient: in Planaria dorotocephala,
122, 202; in Stenostomum, 135; in
other forms, 203; along polar axis,
202, 243; along axis of symmetry, 203;
changes in, during development, 203,
207; in rate of growth, 204; in animal
morphogenesis, 204; origin of, 207;
persistence of, through reproduction,
209; establishment of, 209; in relation
to organic axes, 209; as basis of indi-
viduation, 225; maintenance of, 226;
of eggs in relation to larval develop-
ment, 420; change in, during larval
development of Nereis, 421. See also
Dominance; Individual; Individua-
tion.

Axiate.
tion.

See Axis, Individual, Individua-

469

470 SENESCENCE AND REJUVENESCENCE

Axis, organic: presence of, 200, 203; of
polarity and symmetry, 200, 201, 203;
as metabolic gradient, 209, 225. See
also Axial gradient.

Axolotl, 389.

Banana, vegetative propogation of, 239,
370.

Bee, parthenogenesis in, 345, 395.

Begonia: dedifferentiation in, 246; con-
trol of flowering in, 376.

Biaxial forms: in Tubularia, 210; in
Planaria dorotocephala, 213; in Plana-
ria simplicissima, 215.

Biogene hypothesis, 15.

Biogenetic law, significance of, 463.

Biometer, 73, 156, 160, 202.

Branchipus: conditions of hatching in,
404; larval metamorphosis in, 422.
Budding: in hydra, 145; in Pennaria,
147, 150; in plants, 231, 239; adven-

titious, in plants, 229, 246.

Carbon-dioxide production: decrease of,
in narcosis, 71; estimation of, 73, 202;
during starvation in Planaria doro-
tocephala, 161; decrease of metabolic
rate by, 188; in nervous system of
Limulus, 273; in early development of
Aplysia limacina, 411. See also Meta-
bolic rate; Oxidation; Oxygen con-
sumption.

Cassiopea, reduction of, during starva-
tion, 163.

Catalysis: réle of colloids in, 25; retar-
dation of, 67, 184; by products of
reaction, 446. See also Autocatalytic
reaction.

Cell: embryonic or undifferentiated, 48,
51, 242; differentiation and dedifferenti-
ation of, 52, 57, 239, 245, 257, 286, 294;
metabolic conditions in, 39, 51, 183;
relation of, to life, 41; division of, in
infusoria, 137; in starvation, 155;
cyclical changes in, 189, 297; axes of,
200; plant spore as specialized, 247,
253; nucleoplasmic relation in, 284,
285, 418, 430, 440; length of life of,
307; origin of gametic, in plants, 316;
differentiation of gametic, in plants,
316, 334, 337; origin of gametic, in
animals, 323; differentiation of gametic
in animals, 334, 339. See also Dediffer-
entiation; Differentiation; Gamete for-
mation; Gametes; Infusoria; Nervous
system.

Chaetopterus pergamentaceus: axial gradi-
ent in embryo of, 203; susceptibility in

eggs of, after fertilization, 406; reju-
venescence during early development
of, 415.

Chara, gametes of, 316.

Chironomus, germ path of, 328.

Chromatin, diminution of, 324, 328.

Chromosomes, haploid and diploid num-
ber of, 322 footnote 2, 353.

Chrysanthemum, dedifferentiation in, 246.

Clavellina, dedifferentiation in, 258.

Colloids: characteristics of, 21; suspen-
soid, 21; emulsoid, 21; significance of,
for morphogenesis, 22; réle of, in life in
general, 22, 26; in relation to water and
salts, 24; membranes composed of, 24;
as catalyzers, 25; rdle of, in transmis-
sion, 26; in relation to substratum, 41;
in relation to differentiation, 48; coagu-
lation of, in relation to temperature, 49;
changes of, with time, 50, 184. See
also Proteids; Substratum.

Colony: in Pennaria, 148; in plants,
237, 369.

Colpidium: rejuvenescence of, in agamic
reproduction, 141; susceptibility of, at
time of conjugation, 352, 381; effect
of prevention of agamic reproduction
on, 380.

Conducting paths: in relation to physio-
logical correlation, 217, 260; in ani-
mals, 218, 224, 268; in plants, 238;
See also Conductivity; Dominance,
Transmission.

Conductivity, 217, 218, 227, 232, 260,
268. See also Dominance; Trans-
mission.

Conjugation: Maupas’ conclusions con-
cerning, 64, 377, 434; breeding with-
out, in Paramecium, 136, 377; experi-
mental determination of, 378; in
relation to endomixis, 379, 380; capa-
city of different races for, 381; effect of,
404. See also Fertilization.

Correlation, physiological: mechanical,
217; chemical, 217, 224; transmissive,
217; increase in complexity of, in
higher animals, 266. See also Domi-
nance; Individual; Individuation;
Isolation.

Correlative differentiation, 50. See also
Differentiation. .

Corymorpha palma: susceptibility in
relation to age of, 101; rejuvenescence
in reconstitution of, r10.

Crepidula, nucleoplasmic relation in, 419.
439.

Cyclops, germ path in, 327

Cymatogaster, germ path in, 330.

Cytomorphosis, 284, 440.

Dedifferentiation:

INDEX

Daphnid crustacea, parthenogenesis and
zygogenesis in, 389.

Death: absence of, 1, 260, 303; chemical
conceptions of, 15, 306; disintegration
as criterion of, in lower animals, 74;
from starvation, 156, 298, 302; in re-
lation to character of nutrition in
Planaria velata, 170, 174; of parts in
plants, 239, 241; of cells in animals,
257; necessity of, in higher animals,
270; conditions of, in higher animals,
301; physiological or natural, 301, 309;
various views concerning, 301, 304,
306, 307, 308, chap. xvi; in relation
to nervous system, 301, 307; from
exhaustion in animals, 302; appearance
of, in evolution, 304; in unfertilized
starfish egg, 307, 405; temperature
coefficient of, in sea-urchin larvae,
308, of flower in plants, 368; from old
age in infusoria, 382; after experi-
mental treatment of eggs, 409; at
critical stage of development, 414;
of larval parts, 422; as result of ex-
haustion of ‘life ferment,” 436; as
result of differentiation, 436, 442;
Miihlmann’s theory of, 437; in relation
to autocatalytic theory of growth, 448;
as end of senescence, 461. See also
Age; Age cycle; Dedifferentiation;
Development; Differentiation; Re-
juvenescence; Senescence.
Decrement, in transmission, 209, 217, 268.
See also Transmission.

definition of, 54;
process of, 55; conditions of, 57;
course of, 58; experimental evidence
for, 179, 180, 294, 295; as a condition
of reproduction, 234; in vegetative
life of plants, 239; in plant cell, 245,
252; observational evidence for, in
animals, 257; limited capacity for, in
higher animals, 267, 286; in striated
muscle, 294; in nerve, 295; in ex-
planted kidney cells, 295; after hiber-
nation, 296; in embryos of starfish and
sea-urchin, 413; in early embryonic
development of animals, 418, 420; in
early embryonic development of plants,
424. See also Reconstitution; Reduc-
tion; Rejuvenescence.

Dendrocoelum lacteum, susceptibility of,
in relation to age, Ior.

Development: reversibility of, 56, 64,
155, 446; progressive, 57; regressive,
57, 155; in relation to age cycle, 182;
orderly character of, 199; law of
antero-posterior, 204; repetition in, 220,
269; continuity of, 239, 247, 267, 270;
temperature coefficient of, 308; of

47t

gametes as process of specialization,
316, 333; stage of, in relation to
flowering, 373; initiation of, in rela-
tion to fertilization, 403; initiation of,
in parthenogenesis, 400; experimental
initiation of, 408; experimental treat-
ment of eggs in relation to, 409;
critical stages in, 413; increase in sus-
ceptibility during early embryonic,
412; different rate of, in Tautogolabrus
and Fundulus, 417; nucleoplasmic
relation in early embryonic, 418; cyto-
plasmic changes during early embry-
onic, 419; embryonic, in plants in
relation to age cycle, 424; Miihlmann’s
conception of, 439; reversal of, by
lecithin, 454. See also Differentiation;
Reconstitution; Senescence.
Differentiation: as general characteristic
of organisms, 1; chemical conception
of, 17; physico-chemical conception
of, 23; physical analogy to, 28; defini-
tion of, 46; quantitative factors of, 47;
in relation to metabolic rate, 47, 51, 53;
factors of, 51; different degrees of,
53, 286; reversibility of, 56, 64, 155,
440; not primarily dependent on
chemical correlation, 224; quantity
and quality in, 226; in plants, 240,
242, 244, 245; in higher animals, 267,
286; in gametes of plants, 316, 334,
337, 346; in gametes of animals, 334,
339, 346; in relation to chemical con-
stitution of sperm head, 353; of
flower, 368, 373, 375; in early embry-
onic development, 420; as determin-
ing senescence, 442; secular, in
evolution, 464. See also Dedifferen-
tiation; Development; Gametes; Re-
constitution; Senescence.
Diminution: of chromatin in Ascaris
megalocephala, 324; dependence of,
on cytoplasmic environment, 327;
of chromatin in Miastor, 328.
Dominance, physiological: in relation to
apico-basal axis, 54, 213, 215, 216; in
relation to metabolic rate, 216; in
relation to chemical correlation, 217;
in relation to transmission, 217, 224;
limit of, 217, 219, 220, 223, 268: exten-
sion of, during development, 219, 231,
232, 238, 268; spatial factor of, in posi-
tion of parts, 222; nature of, 225; in
embryonic tissue of plants, 243. See
also Axial gradient; Individual; Indi-
viduation.
Dytiscus marginalis, odgenesis of, 341.

Egg. See Fertilization; Gamete forma-
tion; Gametes; Parthenogenic egg;

472

Reproduction,
egg.

Embryo sac, development of, 320. See
also Gametophyte.

Encystment: in Planaria velaia, 131;
in relation to character of nutrition in
Planaria velata, 169; in relation to age
cycle, 255, 256; influence of envelope
in, 404.

Endomixis: process of, 143; in relation to
age cycle, 143; in relation to conjuga-
tion, 379, 380.

Entelechy, 9, 54.

gametic; Zygogenic

Enzymes: colloid character of, 25; re-

tardation of action of, 67, 184; stabil-
ity of substratum in relation to, 41.

Epigenesis, 46.

Equisetum, spermatozoid of, 334.

Evolution: increase in physiological
stability of substratum during, 45,
53, 194, 267, 298, 304, 460; increase
in differentiation during, 53, 286;
limitation of dedifferentiation during,
57, 230, 267, 286; increase in degree
of individuation, during 227, 266, 304;
senescence and rejuvenescence in, 193;
course of, in plants, 241; appearance
of death during, 304; of length of life

and of death, 304; interpretation of, :

from individual development, 463;
as a secular senescence of protoplasm,
464; possibility of control of, 464.
Exhaustion: distinction between, and
fatigue, 297; distinction between, and
senility, 297; as cause of death, 302.

Fasciola hepatica, odgenesis of, 340.

Fatigue: nature of, 188, 297; distinction
between, and exhaustion, 297; mental,
297; in relation to senility in nerve
cell, 297.

Fertilization: rejuvenescence in con-
nection with, 307, 434; prevention of
death by, 307, 404; absence of, in
apogamy in plants, 322; effect of, 403,
424; quiescent period following, 403;
metabolic rate in animal eggs after,

405, 413. See also Conjugation;
Gametes; Parthenogenesis; Partheno-
genic egg.

Fission: act of, in Planaria dorotocephala,
124; prevention of, in Planaria doroto-
cephala, 125; in Stenostomum, 135;
in infusoria, 137; in consequence of
decreased metabolism, 232.

Fission plane: in Stenostomum, 135; in
infusoria, 138.

Flower: rate of oxidation in, 349, 374;
definition of, 368; differentiation of,
368, 373, 375; Origin of, 368; limited

SENESCENCE AND REJUVENESCENCE

growth of, 368; transformation of,
into vegetative shoot, 376. See also
Flowering.

Flowering: in relation to senescence, 368;
early, in cuttings from blooming plants,
369; influence of light on, 371; experi-
mental control of, 372; physiological
conditions of, 373; periodic repetition
of, 375; premature, 376.

Fragmentation: in Planaria velata, 130;
in relation to character of nutrition,
169; in relation to age cycle, 255, 256,
259.

Functional hypertrophy, 43.

Fundulus heteroclitus: susceptibility dur-
ing early development of, 416; period
of developmental rejuvenescence in,
compared with that in Tautogolabrus,
417.

Gamete formation: in algae and fungi,
316; in mosses and ferns, 318; in seed
plants, 320, 377; asa process of special-
ization, 322, 330; conditions of, in
lower plants in relation to age, 364;
conditions of, in mosses and ferns
in relation to age, 366; loss of capacity
for, 367, 370; conditions of, in seed
plants, 368; conditions of, in protozoa,
377; conditions of, in hydra, 383; con-
ditions of, in margelid medusa, 384;
conditions of, in planarians, 384;
conditions of, in parasitic flatworms,
387; conditions of, in other inverte-
brates, 388; conditions of, in verte-

brates, 388; premature, 389; in
trematode larvae, 395. See also
Gametes.

Gametophyte: in relation to life cycle,
253; in mosses and ferns, 253, 366;
development of, in seed plants, 320,
377; omission of, 322, 408.

Gametes: physiological condition of,
270, 460; morphological condition of,
270, 316, 333; theoretical significance
of origin of, 315; of algae and fungi,
316; of mosses and ferns, 318; in seed
plants, 320; origin of, in animals, 322;
differentiation of parthenogenic and
zygogenic, 343; metabolic rate in
development of, 349; motor activity
in male, 350; susceptibility of, 351;
physiological conditions of maturation
in, 353; different specialization of, in
infusoria, 404. See also Fertiliza-
tion; Gamete formation; Germ path;
Germ plasm; Reproduction, gametic.

Gemmules of sponges, in relation to age:
cycle, 256, 259.

INDEX

Germ path: absence of, in plants, 316;
in Ascaris megalocephala, 324; deter-
mined by cytoplasmic conditions, 327,
328, 329; in Cyclops, 327; in Sagitta,
327; in Chironomus, 328; in Miastor,
328; in chrysomelid beetles, 328;
in hymenoptera, 329; in vertebrates,
329; absence of, in certain animals,
331. See also Gamete formation,
Gametes.

Germ plasm, 2, 3, 55) 64, 179, 315, 322,
330, 332, 346, 356, 397, 461; supple-
mentary, 315, 333; no segregation of,
in plants, 316; question of continuity
of, in plants, 323; supposed segregation
of, in animals, 323; not an independent
entity in Ascaris megalocephala, 327;
definition of, 462. See also Gametes;
Germ path; Reproduction, gametic.

Gliadin, in nutrition experiments, 278.

Gonophore of hydroids, dedifferentiation
of, 258.

Growing tip: in Planaria dorotocephala,
124; in plants, 204, 216, 221, 229, 232,
238, 240, 244, 246; inhibition of, 221,

231.
Growth: as general characteristic of
organisms, 1; chemical conception of,
16, 38; in organism and in crystal, 16;
definitions of, 34, 37; changes in water
content during, 36; reversibility of,
38; different processes of, 38; proteid
synthesis in, 39; in relation to rate of
oxidation, 43, 279; rate of, in relation
to age, 86, 96, 240, 273, 282; of new
tissue in reconstitution of Planaria
dorotocephala, 103; axial gradients in
rate of, 204; beyond limit of individual
size, 220, 229, 231; in relation to
agamic reproduction in plants, 239;
limitation of, by differentiation in
higher animals, 223, 230, 268; correct
measure of rate of, 273; periodic, 276,
388; difference between, and mainte-
nance, 278; during partial starvation in
mammals, 280; senescence in mammals
without, 282; after starvation in birds
and mammals, 298; after starvation
in amphibia, 300; energy requirement
for, in mammals, 305; rate of, in
gametes, 349; in relation to gamete
formation in algae and fungi, 364;
limitation of, in flower, 368; cessation
of, at flowering, 369; in relation to
surface and volume, 438; as an auto-
catalytic reaction, 446, 452; founda-
tion of autocatalytic theory of, 448;
significance of absolute and relative
increments of, 449; inadequacy of
autocatalytic theory of, 452, 4553

_Hydroides dianthus:

473

lecithin as autocatalyst of, 453. See
also Reduction.

Growth impulse: assumption of, un-
necessary, 45; supposed location of,
in mammals, 280; senescence as inhi-

bition of, 434.

Headless form in Planaria dorotocephala,
112.

Heat production: in relation to body sur-
face, 272; during early embryonic
development of sea-urchin, 412.

Heredity: in relation to germ plasm, 462;
definition of, 462.

Heterotypic mitosis: in maturation, 334;
occurrence and experimental produc-
tion of, in other cells, 334.

Histone, in sperm head, 353.

Hordein, in nutrition experiments,
278.

Hormones, 224. See also Correlation.

Hydra: susceptibility of, in relation to
age, IoI; rejuvenescence of, in recon-
stitution, 110; budding in, 145; reju-
venescence of, in agamic reproduction,
145; odgenesis of, 340; conditions of
gamete formation in 383.

susceptibility of

eggs of, after fertilization, 406; rejuve-
nescence during early development of,
41s.

Increment: absolute and relative, in
growth, 273, 449; decrease in relative,
of growth during senescence, 274.

Individual, organic: nature of, 54, 225;
agamic formation of, in Planaria doro-
tocephala, 122; definitions of, 199, 225;
characteristics of, 199; radiate type of,
200; axiate type of, 200, 225; inade-
quacy of current theories of, 201;
axial gradients in, 202; dominance
and subordination in, 210; limit of
dominance and size of, 217; other
factors limiting size of, 223, 230, 268;
in the plant body, 237. See also
Dominance; Individuation; Isolation,
physiological.

Individuation: in posterior region of
Planaria dorotocephala, 123; different
kinds of, 199; nature of, 225; degree
of, 227, 239, 240, 266, 304, 460; of
plant as a whole, 237; in vegetative
reproduction in plants, 238; in spore-
bearing parts of plants, 241; in embry-
onic tissue of plants, 243; in plant
spore, 252; in relation to death, 304.
See also Dominance; Individual;
Isolation, physiological.

474

Infusoria: age changes in, 136; agamic
reproduction in, 137; endomixis in,
143; rhythms of growth and division
in, 143; immortality of, 145.

Inhibition: in production of subnormal
forms in Planaria, 113; of senescence,

167, 239, 257; 279, 303-

Integration, physiological, 224, 227,
267, 424, 460. See also Dominance;
Individuation; Isolation, physiologi-

cal; Reconstitution; Reproduction,
agamic, experimental.

Intelligence: in construction of machine,
29; in organism, 30; in relation to
structure, 30. :

Involution in Planaria velata, 172.

Irritability, Winterstein’s conception of,
70.

Isolation, physiological: in Planaria
dorotocephala, 124; in Planaria velata,
130; in Tubularia, 220; in plants, 221,
239; as condition of reproduction, 229;
by increase in size, 229, 231, 239;
by decrease of dominance, 229, 231;
effect of, 230, 239; by decrease in con-
ductivity, 232; by direct action of
external factors, 232; infrequency
of, in higher animals, 268; in partheno-
genesis, 406; in segmentation of Nereis
larva, 422. See also Dominance;
Individual; Individuation.

Katabolism: 14, 43, 278.

19, 38. See also

Lability, 14, 17, 18,
Substratum.

Stabihty, physiological;

Larva: «f trematodes, 395: of Nereis,
414, 421; characteristics of, 420;
metamorphosis of, 420; segmentation
in, 421.

Lecithin: as autocatalyst of growth,
454; reversal of development by, 454;
disappearance of, in early development,

454.
Life: neo-vitalistic conception of, 9;
chemical conception of, 15; physico-
chemical conception of, 19, 26; relation
to colloids, 22, 26; substratum and
reactions both neceisary for, 26; be-
ginning of, 26; indissociability of
structure and function in, 28; relation
of intelligence to, 30, 31; Huxley’s
conception of, 41; cyclical character
of, 59; temperature coefficient of
length of, 68, 308; without gametic
reproduction, 99, 130, 136, 239, 366
369, 386, 387, 388; length of, in higher
animals, 301; factors in length of, 302;
relation of length of, to time, 303;
theories of length of, 304. See also Age;

SENESCENCE AND REJUVENESCENCE

Age cycle; Death; Dedifferentiation;
Differentiation; Life cycle; Rejuvenes-

cence; Senescence, individual, racial,
evolutionary.
Life cycle: occurrence of, 59; in rela-

tion to age cycle, 182; of plants, 252,
254, 365, 369; of infusoria, 382; of
daphnid crustacea, 389; of rotifers,
392; of digenetic trematodes, 395.
See also Life.

Limulus polyphemus: in relation to evolu-
tionary senescence, 193; carbon-dioxide
production in nervous system of, 273.

Lingula, in relation to evolutionary
senescence, 193.

Lipoids: in membranes, 25; rdle of, in
narcotic action, 69, 75; increase of, in
animal odgenesis, 353.

Lumbriculus, rejuvenescence of, in recon-
stitution, 110.

Maintenance: difference between, and
growth, 278; energy requirement for,
in mammals, 306.

Maturation: as a cause of death, 307,
309; in relation to life cycle in plants
and animals, 324; cytology of, 353;
heterotypic division in, 354; physio-
logical interpretation of, 355, 356; con-
ditions of, in animal egg, 355; in germ
cells of trematode larvae, 395; differ-
ent conditions of, in sea-urchin and
starfish, 405; increase of oxidation
during, 405, 406, 413; in partheno-
genic animal eggs, 407.

Meganucleus: division of, 137; behavior
of, in endomixis, 143.

Megaspore, of seed plants, 320.

Meristematic tissue, 244, 246.

Mesostomatidae, susceptibility of, in
relation to age, 101.

Metabolic rate: in relation to age, 65,
178, 183, 186, 271; in relation to sus-
ceptibility, 66, 71, 72, 73, 79, 82;
susceptibility methods of comparing,
73, 77, 82; increase in, during recon-
stitution in Planaria dorotocephala,
106; increase in, during reconstitution
in various other forms, 110; increase
in, in agamic reproduction in infusoria,
142; increase in, during starvation in
Planaria dorotocephala, 156; decrease
in, during loading of pancreas cell, 189;
in axial gradients, 202, 243; in biaxial
forms of Tubularia, 211; in relation to
dominance, 216, 224; in relation to
position of parts, 222; in relation to
transmitted changes, 225; in relation
to degree of individuation, 228; in
relation to physiological isolation, 232;

INDEX

in relation to age in plants, 2309, 243,
246. 255; in relation to spore formation
in plants, 248, 251; in nervous system,
267; in relation to body surface, 271;
in relation to senile atrophy, 287;
during starvation in man, 298; during
starvation in fishes, 300; determined
largely by internal factors in warm-
blooded animals, 303; in differentiation
of gametes, 349, 350, 351; in flower
and its parts, 349, 374; in conjugating
infusoria, 352, 380; at stage of
maturation, 355; in plant at time of
flowering, 375; during development of
flower, 375; in relation to gamete for-
mation in hydra, 383; in germ cells of
trematode larvae, 396; after fertiliza-
tion in sea-urchin and starfish eggs,
405; after fertilization in annelids, 406;
evidence for increase of, during early
embryonic development of animals,
411, 412; in larva of Nereis, 414;
in relation to nuclear and cytoplasmic,
volume during early development, 410.
See also Metabolism; Susceptibility.

Metabolism: chemical conception of, 14;
Hoéber’s conception of, 19; physical,
of stream, 28; production of water in,
37; substratum as sediment of, 41; as
a reaction system, 43; change in char-
acter of, during differentiation, 50; in
relation to narcotic action, 67; in-
complete character of, 435; Kassowitz’
theory of, 442; constructive, in relation
to nucleoplasmic interchange, 444. See
also Metabolic rate; Susceptibility.

Metamorphosis, larval: in Nereis, 421;
in Branchipus, 422; in insects, 422;
as a partial physiological disintegration
of individual, 423; in amphibia, 424.

Metaplasm, 52, 439, 442. See also Cell;
Differentiation; Protoplasm.

Miastor, germ path in, 328.

Micronucleus: division of, 137; behavior
of, in endomixis, 143.

Microspore, of seed plants, 320.

Mimulus tilingii, influence of light on
flowering in, 371.

Mnemiopsis leidyi, susceptibility of, in
relation to age, Ior.

Moniezia: dedifferentiation of paren-
chyme cells of, 258; origin of gametes
in, 331.

Mucor: spore formation in, 248; gametes
of, 316.

Narcotic action: general character of, 66;
theories of, 67; effect of, on transmis-
sion in nerves, 218; effect of, on recon-
stitution in Planaria dorotocephala, 222.

475

Nephrodium, archegonium and egg of,
338.

Nereis: axial gradient in embryos of, 203;
susceptibility of eggs of, after fertiliza-
tion, 406, 414; increase in suscepti-
bility during early development of,
414; metabolic rate in larva of, 414;
period of developmental rejuvenescence
in, compared with that of Arenicola,
415; segmentation in larva of, 421.

Nervous system: of Planaria doroto-
cephala, 92; structure of, in relation
to degree of reconstitution in Planaria
dorotocephala, 111; in relation to devel-
opmental gradients, 205; transmission
in, 218, 227, 230; in relation to physio-
logical integration, 224; physiological
stability of, 281, 297; water content
of, in relation to senescence, 283; nu-
cleoplasmic relation in cells of, during
development, 284; morphological age
changes in cells of, 287; dedifferentia-
tion in, 295; rejuvenescence in, 297;
in relation to death, 3or.

Normal form, in reconstitution of
Planaria dorotocephala, 111.

Nucleoplasmic relation: Minot’s views
concerning, 284, 440; in development
of nerve cells, 285; in early embryonic
development, 418; R. Hertwig’s views
concerning, 439; in relation to senes-
cence, 439.

Nutrition: Piitter’s views concerning,
164; character of, in relation to age
cycle, 169, 179, 276, 388; difficulties of
experimental control of, 277; effect of
qualitatively inadequate, 278; effect
of quantitatively insufficient, 280;
effect of excess of, 298; in relation to
conjugation, 378; in relation to par-
thenogenesis and zygogenesis, 390,
392, 408; in relation to surface and
volume, 438. See also Reduction;
Starvation.

Oedogonium: conditions of spore forma-
tion in, 252; gametes of, 316.

Oligochetes: susceptibility of, in relation
to age, 102; increase in susceptibility
of, in reconstitution, 110; increase in
susceptibility of, in agamic reproduc-
tion, 136; axial gradient in, 203, 205.

Odgenesis: in animals in general, 340;
in hydra, 340; in Fasciola hepatica,
340; in Plumatella fungosa, 340; in
Sternaspis scutata, 341; in Dytiscus
marginalis, 342; in ascidian, 342;
in fish, 342; in Sida crystallina, 343;
in plant lice, 344. See also Gamete
formation; Gametes.

476

Odgonium, in algae, 316.

Organism: neo-vitalistic conception of, 9;
corpuscular conception of, 11; com-
pared with crystal, 16, 199; com-
pared with flame, 27; compared with
flowing stream, 27, 41, 58, 226; com-
pared with machine, 29; Huxley’s
conception of, 41; construction of, by
function, 44. See also Individual;
Individuation.

Oxidation: in relation to structure, 28;
rate of, in relation to growth, 43;
effect of cyanides and narcotics on, 66;
decrease in, during narcosis, 68, 71;
rate of, in young and old parts of plants,
239; raté of, in flower and its parts,
349, 374;. change in rate of, during
development of flower, 375; rate of,
after maturation and fertilization in
sea-urchin and starfish, 405; increase
in rate of, during early embryonic
development in animals, 412. See
also Metabolic rate; Metabolism.

Oxygen consumption: decrease of, during
narcosis, 68; increase of, in stimulated
gland cell, 189; after fertilization in
sea-urchin and starfish, 405; during
early embryonic development, 411.
See also Oxidation.

Paramecium: agamic breeding of, 136;
conjugation in, 136; agamic reproduc-
tion in, 137; aurelia and caudatum, 138,
143; rejuvenescence of, in agamic
reproduction, 141; endomixis in, 143;
effect of conjugation in, 404.

Parthenogenesis: in plants, 322 footnote 2,
408; in bee, 345, 395; in relation to
zygogenesis in invertebrates, 389, 410;
in relation to physiological age, 393,
406; in relation to rate of egg produc-
tion, 394, 395, 408; in trematode
larvae, 395; artificial, 405; resem-
blance of, to agamic and experimental
reproduction, 407; conditions deter-
mining, 407; “artificial,”’ 408; grada-
tions between, and zygogenesis, 410.
See also Fertilization; Gametes.

Parthenogenic egg: odgenesis of, com-
pared with that of zygogenic egg, 343:
female-producing and male-producing,
390; younger than zygogenic egg, 393,
407, 410; germ cell of trematode larva
as, 395; general characteristics of, 408.

Parthenogenic female, in crustacea, 390.

Penicillium, spore formation in, 248.

Pennaria tiarella: susceptibility of, in
relation to age, Io1; agamic reproduc-
tion in, 148, 150; rejuvenescence of,
in agamic reproduction, 149, I5I.

SENESCENCE AND REJUVENESCENCE

Periodicity: in organisms in general, 187,
296, 297; in accumulation of carbon
dioxide, 188; in fatigue and recovery,
188, 297; in pancreas cell, 189, 296; in
plants, 191; in gametic reproduction,
192, 388; in growth, 276, 388; in
flowering, 375. See also Age cycle;
Life cycle.

Permeability: réle of, in organisms, 24;
theories of, 25; in relation to narcotic
action, 69.

Phagocata gracilis, susceptibility of, in
relation to age, Ior.

Phytoid, 237, 239.

Plagiostomum girardi, axial develop-
mental gradients in, 205.

Planaria dorotocephala: reduction of,
during starvation, 35, 157; structure
of, 92; susceptibility of, in relation to
age, 99; reconstitution of, 103; change
in susceptibility of pieces of, after sec-
tion, 105; reconstitution of, in relation
to internal and external factors, 111;
degrees of reconstitution of, 111;
rejuvenescence of, in experimental
reproduction, 116; rejuvenescence of,
in repeated reconstitution, 118; agamic
reproduction of, 122; act of fission in,
124; prevention of fission in, 125;
rejuvenescence of, in agamic repro-
duction, 126; rejuvenescence of, during
starvation, 157; rate of reduction of,
in starvation, 162; acclimation of,
during starvation, 165; axial gradients
in, 202; dominance and subordination
during reconstitution of, 213; limit
of dominance in agamic reproduction
of, 221; reconstitution of, in narcotics,
222; spatial factors of dominance in,
222; conditions of gamete formation

“in, 384.

Planaria maculata: susceptibility of, in
relation to age, 93; time not a measure
of age in, 97; agamic reproduction in,
124; rejuvenescence of, in agamic
reproduction, 126.

Planaria simplicissima, biaxial posterior
ends in, 215.

Planaria velata: susceptibility of, in
relation to age, 101; agamic reproduc-
tion of, 130, 169; rejuvenescence of,
in agamic reproduction, 132; inhibi-
tion of senescence in, 165; senescence
of, in relation to character of nutrition,
169; involution in, 171.

Plumatella fungosa, odgenesis of, 340.

Polarity, physiological, occurrence of,
200. See also Axes: Dominance;
Individual; Individuation.

INDEX

Pollen grain: development of, 320;
rate of oxidation in development of,
349, 374.

Polyembryony: in armadillo, 231, 269;
in insects, 268.

Preformation, 46.

Primitive germ cell. See Germ path.

Progression, 57. See also Development;
Differentiation; Senescence.

Protamine, in sperm head, 353.

Proteids: occurrence of, in organisms,
14; labile molecule of, 14, 19; dis-
tinction between living and dead, 15;
changes in, at death, 16; significance
of, for life, 20; molecular constitution
of, 20, 277; colloid character of, 20;
synthesis of, in growth, 39, 278; physio-
logical stability of, 39; nutrition
experiments with specific, 278; changes
in proportional amount of, during
senescence, 283, 444; in differentiation
of sperm head, 353. See also Colloids;
Stability, physiological; Substratum.

Prothallium, 238, 245, 366.

Protoplasm: chemical conception of, 14;
physico-chemical character of, 19;
undifferentiated, 48, 51, 245; changes
in aggregation of, 50; evolutionary
senescence of, 194, 464. See also
Colloids; Proteids; Substratum.

Protozoa: agamic reproduction and
rejuvenescence in, 136; division in,
137; occurrence of death in, 305. See
also Infusoria.

Radiate, 200.

Reconstitution: in Planaria doroto-
cephala, 103; rejuvenescence in, 107,
IIO, 114, 116, 118, 180, 240; in rela-
tion to internal and external factors,
ii1; degrees of, 111; repeated, in
Planaria dorotocephala, 118; resem-
blance of, to agamic reproduction, 126,
132, 135, 140; after partial involution
in Planaria velata, 172; termination of,
181; origin of axial gradient in, 207;
independence of apical region in, 210,
213; dominance and subordination in,
213, 215; of head in Planaria doroto-
cephala, 215; resemblance of, to embry-
onic development, 215; spatial factor
of dominance in, 222.

Redifferentiation. See Dedifferentia-
tion; Development; Senescence, indi-
vidual.

Reduction: definition of, 34, 37; chemical
conception of, 38; during starvation
in Planaria dorotocephala, 35, 44, 155;
during decreased metabolism, 45; after
fragmentation in Planaria velata, 131;

477

of cell size in starvation, 155;
variable limit of, in Planaria doroto-
cephala, 156; rate of, in starvation in
Planaria dorotocephala, 162; of bran-
chial region in Clavellina, 258; of less
stable constituents during partial
starvation, 281; difference between,
and atrophy, 288; in fishes, 300. See
also Dedifferentiation; Rejuvenescence.

Regeneration in excess, 43.

Regression, 57, 155. See also Dediffer-
entiation; Reconstitution; Reduc-
tion; Rejuvenescence; Reproduction;
agamic, gametic.

Rejuvenescence: occurrence of, in gen-
eral, 3, 4, 5, 8, 64, 178, 180, chaps. x,
xii, xv; definition of, 58; general char-
acter of, 64,186; Maupas’ conclusions
concerning, 64, 377, 434; in reconstitu-
tion in Planaria dorotocephala, 107;
in reconstitution in other forms, 110;
degrees of, in reconstitution, 114, 180;
degrees of, in experimental and gametic
reproduction, 116; in repeated recon-
stitution, 118; in agamic reproduc-

’ tion in Planaria, 126; in agamic re-
production in infusoria, 141, 378; in
relation to endomixis, 143; in agamic
reproduction in hydra, 146; in agamic
reproduction in Pennaria, 149, 151;
in starvation in Planaria, 157, 178;
in relation to acclimation during starva-
tion, 165; in relation to character of
nutrition, 169; in relation to cell
division, 182, 242; in relation to
gametic reproduction, 186, 192, 270,
chap. xv, 434;-in relation to other
periodicities, 187, 296; Braun’s ideas
concerning, 237; in vegetative life of
plants, 239; in plant cell, 245; in spore,
252, 253; in agamic reproduction in
lower animals, 255; without reproduc-
tion in lower animals, 256; morpho-
logical evidence for, in animals, 257,
294; as result of senescence, 259;
limitation of, in higher animals, 267,
270; after hibernation, 296; in nervous
system, 297; after starvation in higher
animals and man, 298; after loss of
weight in disease, 299; during starva-
tion in fishes, 300; after starvation
in amphibia, 300; in transformation
of flower into vegetative shoot, 377;
in different races of Paramecium, 382;
in daphnid crustacea, 392, 394; in
larval life history of digenetic trema-
todes, 396; evidence for occurrence
of, in embryonic development, 411,
412; period of developmental, in
Nereis and Arenicola, 416; degree and

478

period of developmental, in Tautogo-
labrus and Fundulus, 417; in relation
to segmentation in Nereis larva, 421;
in embryonic development of plants,
424; degree of, in agamic and gametic
reproduction, 425; by substitution of
gametic, for agamic reproduction, 426;
as a casting off of injurious substances,
435; Minot’s theory of, 441; nucleo-
plasmic relation in, 441; as result of
increase in nucleoplasmic interchange,
444; in relation to colloid changes,
445; aS a reversal of autocatalytic
reaction, 448; not a special process,
459; not necessarily a reversal of
senescence, 459; possibility of, in
evolution, "464; in non-living systems,
465. See also Dedifferentiation;
Metabolic rate.

Reproduction, agamic: in Planaria doro-
tocephala, 122; resemblance of, to
reconstitution, 126, 132, 135, 140; re-
juvenescence in, 126, 141, 146, 149, 151,
181, 239, 252, 255; in Planaria velata,
130; in Stenostomum, 133; in oligo-
chetes, 136; in infusoria, 137, 377, 3793
in hydra, 145; limit of ‘dominance 1 in,
220; in plants, 221, 231, 238; in rela-
tion to physiological isolation, 229; in
armadillo, 231; different forms of, in
plants, 239, 247; in relation to indi-
viduation in plants, 244; in gameto-
phyte of plants, 254, 366; various
forms of, in lower animals, 255; as
a result of senescence, 259; infre-
quency of, in higher animals, 268;
in production of gametophyte, 377; in
relation to conjugation, 377; in marge-
lid medusa, 384; degree of rejuvenes-
cence in gametic and, 425. See also,
Dedifferentiation; Reconstitution; Re-
juvenescence; Reproduction, gametic,

in general.
Reproduction, experimental: in Planaria
dorotocephala, 103, 105, 214, 222;

different degrees of, 111; in Tubularia,
210; continued, in plants, 239, 370.
See also Reconstitution; Rejuvenes-
cence; Reproduction, agamic.
Reproduction, gametic: absence of, 99,
130, 136, 239, 366, 369, 386, 387, 388;
rejuvenescence in, 186, 270; periodic,
192, 388; prevention of, by agamic
reproduction, 239, 367, 370; in relation
to senescence, 270, chap. xiv, 460;
parthenogenic and zygogenic, in inver-
tebrates, 389; degree of rejuvenescence
in agamic and, 425; Godlewski’s com-
parison of, with regeneration, 427.
See also Conjugation; Fertilization;

SENESCENCE AND REJUVENESCENCE

Gamete formation; Gametes; Par-
thenogenesis; Reproduction in general.

Reproduction in general: as characteristic
of organism, 1, 202; in relation to age
cycle, 178, 2 503 different processes of,
in plants, 238, 247; cycle of, in inver-
tebrates, 390; fundamental ’similarity
of all forms of, 427; as condition of
death and rejuvenescence, 433; defini-
tion of, 460; inheritance involved in all
cases of, 462. See also Reconstitution;
Rejuvenescence; Reproduction, agamic,
experimental, gametic.

Reproductive cycle: in daphnid crus-
tacea, 390; repetition of, 392; in
rotifers, 392; in trematodes, 395. See
also Reproduction, agamic, experi-
mental, gametic, in general.

Reversibility: of reaction, 38, 56, 67, 71;
of development, 56, 64, 155, 188; of
relative susceptibilities, 72, 82.

Riccia, origin of gametes in, 318.

Rotifers, parthenogenesis and zygo-
genesis in, 392.

Saggita, germ path in, 328.

Saprolegnia: spore formation in, 247;
conditions of spore formation in, 250;
gametes of, 316; conditions of gamete
formation in, 364. ,

Sea-urchin: axial gradient in, 203;
temperature coefficient of length of
life in eggs of, 308; susceptibility of
eggs of, 351; increase in metabolic
rate in eggs of, after fertilization, 405,
414; conditions of maturation in, 4053
oxygen consumption during early
development of, 411; heat production
during early development of, 412;
susceptibility during early develop-
ment of, 412; critical stage in develop-
ment of, 413.

Secretions, internal. See Correlation.

Segmentation: in higher animals, 269;
in larva of Nereis, 421; in larva of
Branchipus, 422.

Segregation. See Gametes; Germ path;
Germ plasm.

Self-differentiation: in general, 50, 55;
of apical region of Tubularia, 210; of
apical region of Planaria dorotocephala,
213.

Sempervivum funkii, Klebs’s experiments
on control of flowering in, 372.

Senescence, evolutionary: occurrence of,
193, 464; paleontological evidence for,
193; in evolution of higher organisms,
464; control of, 465.

INDEX

Senescence, individual: occurrence of,

in organisms, 2, 178, 461; significance *

of, 3; definition of, 58, 185; general
character of, 63, 441; morphological
changes during, 86, 284; as condition
of rejuvenescence, 133, 186, 259, 461;
in protozoa, 142, 379; in relation to
endomixis, 143; in relation to hydranth
and medusa buds in Pennaria, 151, 256;
inhibition of, 167, 239, 257, 279, 3033
in relation to character of nutrition,
169, 276; theories of, 182, chap. xvi;
changes in water content during, 184,
279, 283; in relation to other periodi-
cities, 187, 192, 296; in vegetative life
of plants, 239; in whole and parts of
plants, 239, 241, 243; in growing tips
of plants, 244; in relation to spore
formation in plants, 251, 253; as con-
dition of specialized agamic reproduc-
tion in animals, 256; in absence of
growth, 282; changes in chemical con-
stitution during, 283; atrophy in later
stages of, 287, 301; internal determina-
tion of rate of, in warm-blooded ani-
mals, 303; in development of gametes,
349; in relation to maturation, 355;
in relation to gamete formation in
algae and fungi, 364; in relation to
gamete formation in mosses and ferns,
366; in relation to flowering, 368;
as condition of conjugation, 378; in
different races of Paramecium, 382;
in relation to gamete formation in
hydra, 384; in relation to gamete
formation in margelid medusa, 384;
in relation to gamete formation in
planarians, 384; in relation to gamete
formation in other invertebrates, 387;
in relation to gamete formation in
vertebrates, 388; in relation to par-
thenogenesis and zygogenesis in inver-
tebrates, 391, 392; in larval life cycle
of digenetic trematodes, 396; suscepti-
bility in early development in relation
to, 412; larval stages and metamor-
phosis in relation to, 420; as a wearing
out, 433; as an adaptation, 433; as
result of reproduction, 433; as result
of atrophy of sex organs, 434; as
result of inhibition of growth impulse,
434; as an intoxication, 434; as result
of organic constitution, 436; in relation
to surface and volume, 437; as result of
starvation of cells, 437; nucleoplasmic
relation in, 439; in relation to cyto-
morphosis, 440; as result of differentia-
tion, 442; as result of accumulation of
metaplasm, 443; in relation to decrease
of assimilatory capacity, 444; “dilu-

479

tion” of nitrogen in plants during,
444, 453; as result of decrease in
nucleoplasmic interchange, 444; in
relation to colloid changes, 445; as
retardation of an autocatalytic reac-
tion by accumulation of products, 448;
not a special process, 459; in non-
living systems, 465. See also Age;
Age cycle; Development; Differentia-
tion; Senescence, evolutionary, racial.

Senescence, racial: in protozoa, 136, 378;
in relation to endomixis, 143; in
Planaria velata, 173, 179; in relation
to conjugation, 378, 383, 434; in
relation to parthenogenesis and zygo-
genesis in invertebrates, 390; in
potato, 426; conditions of, 426, 561.

Senility: atrophy as characteristic of,
287, 301; morphological changes in,
287; asa “wearing out” of physiologi-
cal mechanism, 288, 433; mental, 297;
in relation to fatigue and exhaustion,
297; as result of atrophy of sex organs,
434; as result of special conditions not
connected with growth, 448. See also
Death; Differentiation; Senescence;
individual.

Sida crystallina, odgenesis of, 343.

Silphium, pollen grain and spermatozoid
of, 334.

Specification, 46.

Spermatogenesis, in guinea-pig, 335. See
also Gamete formation; Gametes.
Spermatogenous cell, segregation of, in
plants, 318, 320. See also Gamete
formation; Gametes.
Spermatozoid of plants.
formation; Gametes.
Spermatozoon of animals. See Fertiliza-
tion; Gamete formation; Gametes.
Spirogyra, gametic reproduction in, 316.

Sporangium, 247, 250.

Spore formation: in plants, 233, 238, 241,
247; in relation to senescence, 241,
248; rejuvenescence in, 252, 253; in
relation to age cycle in plants, 254;
in protozoa, 255.

See Gamete

. Sporophore, 248.

Sporophyte: in relation to age cycle, 253;
in mosses and ferns, 253; origin of, in
apogamy, 322.

Stability, physiological: nature of, 35, 39;
different degrees of, 41; in relation to
starvation, 44; increase in, during
development, 50, 183, 463; in relation
to metabolic rate, 51, 279; in relation
to evolution, 53, 194, 267, 298, 304,
460, 463; in relation to individuation,
227; increase in, during partial starva,
tion, 280, 282; of skeletal substance-

480

281; of nervous system, 281, 297; of
flower, 375; in animal egg, 407. See
also Dedifferentiation; Differentiation;
Substratum.

Starfish: axial relations in, 200; axial gra-
dient in, 203; early death after matur-
ation of unfertilized egg of, 307, 405;
susceptibility of eggs of, 351, 413;
oxygen consumption in egg of, in rela-
tion to fertilization, 405, 414; condi-
tions of maturation in, 405; egg of,
almost parthenogenic, 405, 410; suc-
ceptibility during early development
of, 413; critical stage in development

of, 413.
Starvation: in Planaria dorotocephala,
35, 155, 156; reduction of nervous

system during, 35, 281; in other
planarians, 44; decrease in cell size
during, 155; death from, 156; in Cassio-
pea, 163; capacity for acclimation
during, 165; effect of partial, 167,
280, 386; stunting effect of partial, in
mammals, 281; rejuvenescence in con-
nection with, in higher animals and
man, 298, 299; increase in weight
after, 298, 300; susceptibility of fishes
during, 299; senescence as a process
of cell, 437. See also Nutrition;
Reduction; Rejuvenescence.

Statoblasts of bryozoa, in relation to
age cycle, 256, 259.

Stenostomum, agamic reproduction in,
133; increase of susceptibility during
agamic reproduction in, 135.

Stentor coeruleus: agamic reproduction
in, 138; rejuvenescence of, in agamic
reproduction, 141, 142.

Sternaspis scutata, odgenesis of, 341.

Strongylocentrotus lividus, increase in
oxygen consumption of, during early
development, 405. See also Sea-urchin.

Subordination, 215.

Substratum: in relation to reaction, 19,
42; physiological stability of, 40, 41,
50, 53, 183, 194, 227, 267, 298, 304,
460, 463; as metabolic sediment, 41;
Huxley’s conception of, 41; function
in relation to, 42; selective action of
starvation upon, 44; changes in, during
development, 45, 50, 183; embry-
onic cell as metabolic, 49; action of
narcotics on, 69, 70; in relation to
maintenance of axial gradients, 226.
See also Dedifferentiation; Differentia-
tion; Stability, physiological.

Summer egg, 390.

Surface and volume: in relation to nar-
cotic action, 75, 78; in relation to

SENESCENCE AND REJUVENESCENCE

metabolic rate, 272; in relation to
senescence, 437; significance of rela-
tion between, 438.

Susceptibility: to cyanides and narcotics,
66; in relation to metabolic rate, 66,
71, 72, 73, 79, 82; methods of use of,
73, 77, 82; in relation to carbon-
dioxide production, 73; in relation to
age in Planaria maculata, 93; in
relation to age in Planaria doroto-
cephala, 99; in relation to age in
Planaria velata, 101; in relation to age
in other forms, 101; of pieces of
Planaria dorotocephala after section,
105; in relation to different degrees of
reconstitution, 113; increase of, in
agamic reproduction in Planaria doro-
tocephala and P. maculata, 127; increase
of, in agamic reproduction in Planaria
velata, 132; increase of, in agamic
reproduction in Stenostomum, 1353
increase of, in agamic reproduction in
oligochetes, 136; increase of, in agamic
reproduction in infusoria, 141; in-
crease of, in agamic reproduction
in hydra, 146; increase of, in agamic
reproduction in Pennaria, 149, 151};
increase of, during starvation in
Planaria dorotocephala, 157; in rela-
tion to acclimation in starved Planaria
dorotocephala, 165; in relation to
axial gradients, 202; of dominant
region to external conditions, 226;
of fishes during starvation, 299; of
gametes of animals, 351; at time of
conjugation, 352, 381; of sexually
mature Planaria dorotocephala, 385;
of sexually mature Planaria maculata,
386; of different larval generations
in trematodes, 396; increase of, after
fertilization in animal eggs, 405, 406;
of different eggs to parthenogenic
agents, 410; of starfish during early
development, 413; of sea-urchin dur-
ing early development, 413; of Nereis
during early development, 414; of
Arenicola during early development,
415; of frog and salamander during
early development, 418. See also
Metabolic rate.

Symmetry, physiological: occurrence of,
201, 203; in relation to axial gradients,
204.

Tautogolabrus adspersus: susceptibility
of eggs of, 351: susceptibility during
early development of, 416, 417; period
of developmental rejuvenescence in,
compared with that in Fundulus,
457.

INDEX

Teleology: the problem of, 30; in inter-
pretation of reduction in planarians,
44; in interpretation of budding in
plants, 231; in interpretation of re-
lation between agamic and gametic
reproduction in plants, 367, 360.

Temperature coefficient: of rate of
chemical reaction, 68; of length of life
of Planaria dorotocephala in cyanides
and narcotics, 68; of length of life of
sea-urchin eggs, 308; of rate of develop-
ment, 308.

Teratomorphic form, in Planaria doroto-
cephala, 111, 223.

Teratophthalmic form, in Planaria doro-
tocephala, 111.

Torreya taxifolia, archegonium and egg
ot ee

Transmission: in relation to colloids, 26;
in relation to axial gradients, 209;
decrement in, 209, 217, 227; as means
of physiological correlation, 217; limit
of, 217, 219, 231; in nerves, 218, 230;
quantitative effect of, 225; efficiency
of, 227. See also Conducting paths;
Conductivity.

Trematode, parthenogenesis in larvae
of digenetic, 395.

Tubularia: simple individual of, 210;
reconstitution of, 210; limit of domi-
nance in agamic reproduction of, 220;
limit of dominance in reconstitution
of, 221.

481

Ulothrix, spore formation in, 247.
Urocentrum turbo, rejuvenescence of,
in agamic reproduction, 141, 142.

Vacuole, in infusoria, 137.

Vacuolization, in plant cells
differentiation, 245, 284.

Vaucheria: spore formation in, 247:
conditions of spore formation in, 250;
conditions of gamete formation in,
365.

Volume and surface. See Surface.

Volvox, gametes of, 316.

during

Water: in relation to colloids, 24; in
relation to growth, 36; production of,
in metabolism 37; in relation to senes-
cence, 184, 279, 283.

Winter egg, 390, 404.

Zamia: spermatozoid of, 334; egg of, 339-

Zooid: formation of, in Planaria doroto-
cephala, 123; formation of, in Steno-
stomum, 133; as member of animal
colony, 237.

Zodspore, 247, 252.

Zygogenesis, 343, 389; gradations be-
tween, and parthenogenesis, 410.

Zygogenic egg: odgenesis of, compared
with that of parthenogenic egg, 3433
in daphnid crustacea, 390.

Zygospore, in algae and fungi, 316.

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