Table Of ContentInterdisciplinary Topics in Gerontology
Editor: T. Fulop
Vol. 39
Aging
Facts and Theories
Editors
L. Robert
T. Fulop
EVOLUTION
G E N E T I C S
ENVIRONMENT
C E L L AG I N G
LONGEVITY
FREE RADICALS
Aging: Facts and Theories
Interdisciplinary Topics in
Gerontology
Vol. 39
Series Editor
Tamas Fulop
Sherbrooke, Que.
Aging
Facts and Theories
Volume Editors
Ladislas Robert
Paris
Tamas Fulop
Sherbrooke, Que.
32 figures and 9 tables, 2014
Basel · Freiburg · Paris · London · New York · Chennai · New Delhi ·
Bangkok · Beijing · Shanghai · Tokyo · Kuala Lumpur · Singapore · Sydney
Ladislas Robert, MD Tamas Fulop, MD
Hôtel Dieu Hospital Department of Geriatrics
Univ. Paris V University of Sherbrooke
France Sherbrooke, Que., Canada
Library of Congress Cataloging-in-Publication Data
Aging (Robert)
Aging : facts and theories / volume editors, Ladislas Robert, Tamas Fülöp.
p. ; cm. -- (Interdisciplinary topics in gerontology, ISSN 0074-1132
; vol. 39)
Includes bibliographical references and index.
ISBN 978-3-318-02652-8 (hbk. : alk. paper) -- ISBN 978-3-318-02653-5
(e-ISBN)
I. Robert, Ladislas, editor. II. Fülöp, Tamas, 1953- editor. III. Title.
IV. Series: Interdisciplinary topics in gerontology ; v. 39. 0074-1132
[DNLM: 1. Aging--physiology. 2. Cell Aging--physiology. W1 IN679 v.39
2014 / WT 104]
QP85
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2014007997
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Contents
VI Preface
Robert, L. (Paris); Fulop, T. (Sherbrooke, Que.)
1 The Commitment of Human Cells to Senescence
Holliday, R. (Canberra)
8 Evolutionary Theories of Aging Can Explain Why We Age
Le Bourg, E. (Toulouse)
24 Control of Cell Replication during Aging
Macieira-Coelho, A. (Versailles)
45 Cell Senescence: Role in Aging and Age-Related Diseases
Campisi, J. (Novato, Calif.); Robert, L. (Paris)
62 Aging of Cell Membranes: Facts and Theories
Zs.-Nagy, I. (Debrecen)
86 Oxidative Stress, Mitochondrial Dysfunction and the Mitochondria Theory of
Aging
Kong, Y.; Trabucco, S.E.; Zhang, H. (Worcester, Mass.)
108 Aging of Connective Tissues: Experimental Facts and Theoretical
Considerations
Labat-Robert, J.; Robert, L. (Paris)
142 Aging of Cell Communication: Loss of Receptor Function
Robert, L. (Paris); Fulop, T. (Sherbrooke, Que.)
163 On the Immunological Theory of Aging
Fulop, T. (Sherbrooke, Que.); Witkowski, J.M. (Gdansk); Pawelec, G. (Tübingen);
Alan, C. (Sherbrooke, Que.); Larbi, A. (Singapore)
177 Aging of the Brain, Dementias, Role of Infectious Proteins: Facts and Theories
Morinet, F. (Paris)
187 Aging as Alteration
Miquel, P.-A. (Toulouse)
198 Longevity and Its Regulation: Centenarians and Beyond
Robert, L. (Paris); Fulop, T. (Sherbrooke, Que.)
212 Subject Index
V
Preface
Speculations on aging are certainly an ancestral preoccupation of humanity. There
are reliable traces of such reflections on people having reached very old age, from the
ancient civilizations of Egypt and Mesopotamia where writing was invented, from
about 4,000 years before modern times. We had the opportunity (L.R.) to write a book
on the ‘invention’ of time and of its theorization by early civilizations up to modern
times [1] . The Egyptians invented millennia ago the widely used sentence pronounced
frequently all over the world as a birthday wish: ‘…I wish you to live up to 120 years…’
Closer to us, in the well-known N atural History of Pliny the Elder [ 2] with a long chap-
ter on very old people, as also in the Bible, with poetic exaggerations. But Pliny was
critical of such exaggerations and did not hide his skepticism about personalities of
exceptionally long life [ 2] . Citing Hesiod, he states: ‘The question “who are the men
who enjoyed the longest life?” is covered by a considerable uncertainty, both to the
location of the country as well as the diverging matters on this subject, pouring out
on human life several facts I consider fantasist …’
The more or less unconscious motivation for such exaggerations is certainly the
ancestral fear of death. The extraordinary development of the human brain as com-
pared to the one of our closest relatives, the higher anthropoids compared with the
chimpanzee, endowed humans with the capacity to realize our finitude, the fear of
death. The minimal difference between the human and chimp genomes was enough
to endow the human brain through an extraordinary complexification of its wiring
with new ‘inventions’, such as aggressiveness within the species and the fear of death.
This was however also the motivation for continued search for and ‘inventions’ of
natural ‘drugs’, mostly from plant extracts, aimed at the fight against disease, and
most importantly, at achieving longevity. Surprisingly, this tendency did not disap-
pear with higher civilization and scientific technology. Even in our times, half a cen-
tury since the discovery of the double helix and the genetic ‘program’, several recent
books, some written by well-known scientists, predict the possibility to live up to 150
or even 250 years in a near future. Such predictions are in sharp contrast with the re-
cent evolution of human longevity, and the number of ‘supercentenarians’, aged 110
years, is not increasing in the predicted proportions. Recent statistics put their num-
ber worldwide at less than 70. There is however a constant increase in centenarians,
VI
for reasons more closely analyzed later in this book. It is evident that the unconscious
fear of death is still at work even in some of the best minds of the scientific commu-
nity. At a more reasonable level, the new discipline of ‘anti-aging medicine’ is thriving
all over the world. When it first appeared, its initiators were the object of a lawsuit for
unethical promises, won by the suing scientific community of experimental geron-
tologists. However, this did not stop the emergence of this ‘new’ medical discipline,
promising longer and healthier life, based on hormones, improved cosmetics and
neutraceuticals. Beyond well-founded criticism, these facts can be considered as a
proof that a large part of the society is striving for longer and happier life.
Experimental and clinical gerontology has achieved considerable progress in un-
derstanding the cellular-molecular aspects of the aging process as well as the etiology
and treatment of age-related diseases. This progress, to which all coauthors of this
volume contributed in their respective fields, renders reasonable a conceptual appre-
ciation and evaluation of these advances, from the genetic-cellular level to clinical
diagnostics. Speculation is welcome but only if it is based on experimental or clinical
acquisitions, ‘facts’. By facts we mean repeated, confirmed observations and experi-
ments on age-related modifications of biological processes. Some of these underlie the
age-dependent increasing susceptibility to disease, the decay of the organism. One of
these relationships between age-dependent modifications at the cellular-molecular
level and altered health and diseases explains the distinction between longevity and
aging, often confounded but deserving separate analysis as will be discussed later in
this volume.
Before closing this introduction, let us restate the basic philosophy of this volume.
Gerontological literature is quite rich both in conceptualization as well as in experi-
mental reports. Experimental scientists often consider theorization as sheer specula-
tion. Theoretically minded scientists are closer to philosophy than to experimental
science and ignore sometimes basic well-proven experimentally established facts. In
between, scientific epistemology takes advantage of the positive sides of these two op-
posite tendencies. Speculation is welcome if it is based on knowledge obtained in ex-
perimental sciences. Sheer unfounded speculation is out of our approach in this vol-
ume. Hypotheses and theorization do however underlie and necessarily precede ex-
perimentation. No experiment can be valid, if not based on a solid working
hypothesis. This type of theoretical basis of experimental sciences should not be ig-
nored. Similar considerations hold also for the interpretation of experimental results.
Interpretations followed in most cases by predictions fall again in the realm of epis-
temology. It should however – and this is the great advantage of experimental science
compared to shear speculation – propose a new approach, a new project for further
experimentation. This repeated succession of theoretical considerations resulting in
a working hypothesis and experimentation to verify it is the essential proposition of
the most popular philosophy of science as proposed by Karl Popper in his famous
treatise The Logic of Scientific Discovery [ 3] . According to Popper, the theoretical in-
terpretation of experiments is valid only if it can propose further experiments con-
Preface VII
ceived to overthrow and invalidate the previous interpretations. The history of any
experimental science proves the validity of Popper’s concept. For these reasons, we
asked our colleagues who kindly accepted to contribute with chapters to this volume
to follow this ‘popperian’ concept and approach in their areas of specialization. As
experimental gerontology has considerably increased over the last decades, both in
breadth and depth, only some of its branches could be covered in this volume. We
hope however that all our colleagues will find this volume stimulating for their field
of research and for the interpretation of their observations.
Ladislas Robert , Paris
Tamas Fulop , Sherbrooke, Que.
References
1 Robert L: Les temps de la vie. Paris, Flammarion, 3 Popper KR: Logik der Forschung. Zur Erkenntnis-
2002. theorie der modernen Naturwissenschaft. Wien,
2 Pline l’Ancien: Histoire naturelle de Pline. Paris, Springer, 1935.
Chez la veuve Desaint, tome 3, 1771.
VIII Robert · Fulop
Robert L, Fulop T (eds): Aging: Facts and Theories. Interdiscipl Top Gerontol. Basel, Karger, 2014, vol 39, pp 1–7
DOI: 10.1159/000358896
The Commitment of Human Cells to
Senescence
Robin Holliday
Australian Academy of Science, Canberra , Australia
Abstract
Fifty years ago, it was demonstrated by Leonard Hayflick that human diploid fibroblasts grown in cul-
ture have a finite lifespan. Since that time, innumerable experiments have been published to discov-
er the mechanism(s) that are responsible for this ‘Hayflick limit’ to continuous growth. Much new in-
formation has been gained, but there are certain features of this experimental system which have not
been fully understood. One is the fact that different populations of the foetal lung strains WI-38 and
MRC-5 have a range in division potential of at least a millionfold. The commitment theory of cellular
aging, published more than 30 years ago, is able to explain this, but it has been consistently ignored.
The theory predicts that bottlenecks, which are transient reductions in population size, can signifi-
cantly reduce lifespan, or increase variability of lifespans. Computer simulations specify the effects of
bottlenecks on longevity, and these were confirmed in two series of experiments. Commitment to
senescence may be the loss of telomerase, which leads to the erosion of telomeres and the inability
to grow indefinitely. Many experiments have been done with skin fibroblasts from human donors of
different age, and it was originally thought that in vitro lifespan was inversely correlated with donor
age. In these experiments, a single skin biopsy produces a population of cells that are grown to senes-
cence. However, there is no reason to believe that skin fibroblasts are less variable in their in vitro
lifespan than foetal lung strains, in which case the data points with skin cells are so variable that they
may completely obscure any inverse correlation between culture lifespans and donor age.
© 2014 S. Karger AG, Basel
Fifty years ago, it was discovered by Hayflick and Moorhead that normal human dip-
loid cells grown in culture have a limited lifespan [1, 2] . After a long period of prolif-
eration, the growth of the cells slowed down and then ceased altogether. These initial
experiments were carried out with fibroblasts from foetal lung tissue. It was soon dis-
covered that fibroblasts from skin biopsies of adults also had limited proliferation. It
was proposed by Hayflick [ 2] that the aging of human cells in vitro provided a model
system for studying the ageing of cells in vivo. In the subsequent 50 years, a huge
