Table Of ContentResults and Problems in Cell Differentiation
29
Series Editors:
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Siegfried Hekimi (Ed.)
The Molecular Genetics
of Aging
With 53 Figures and 8 Tables
, Springer
Dr. Siegfried Hekimi
McGill University
Department of ßiology
1205 Ave. Docteur Penfield
Montn!al, Quebec H3A lßl
Canada
ISSN 0080-1844
ISBN 978-3-642-53686-1 ISBN 978-3-540-48003-7 (eBook)
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The molecu!ar genetics of aging/[edited by] Siegfried Hekimi. p. cm. -(Results and Problems in cen Differentiation,
ISSN 0080-1844; 29) Includes bibliographical references and index. ISBN 354066663X (hardcover) 1. Aging-Genetic
aspects. I. Hekimi, Siegfried, 1956-11. Series. QH607.R4 vol. 29 [QP86] 571.8'35 s - dc21 [571.8'78]
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Preface
The molecular genetics of aging or life-span determination is an expanding
field. One reason is because many people would consider it desirable if hu
man life span could be extended. Indeed, it is difficult not to be fascinated by
tales of the life and death of people who have succeeded in living a very long
life. Because of this, we have placed at the head of this book the chapter by
Perls et al. on Centenerians and the Genetics of Longevity. Perls and his
coauthors convincingly argue that, while the average life expectancy might be
mostly determined by environmental factors because the average person has
an average genotype, extremely long life spans are genetically determined.
Of course, studying humans to uncover the genetics of aging is not ideal,
not so much because one cannot easily perform experiments as because they
live such a long time. This is why most of this book describes the current state
of research with model organisms such as yeast, worms, flies, and mice.
Ja swinski focuses on yeast and how metabolic activity and stress resistance
affect the longevity of Saccharomyces cerevisiae. In the process, he discusses
the concept of aging as applied to a unicellular organism such as yeast and
the importance of metabolism and stress resistance for aging in all organisms.
In the following chapter, Sohal, Mockett, and Orr, whose experimental
organism is Drosophila, give us a general perspective of the role of oxidative
stress in aging. In this context, they argue that mutants whose extended life
span is concomitant with a slow rate of aging do not provide true insight into
the causes of aging because they do not alter the rate of aging with respect to
the rates of other organismal parameters such as reproduction. In other
words, mutations that make an organism live long by making it live slowly
throw out the baby with the bath. In addition, they show how experiments
with transgenic animals are subjected to many caveats. In particular, the
presence of the transgene might induce a stress response or a slowing down
of the rate of aging, that is independent of the biochemical activity of the
protein encoded by the gene. Their clear analysis is a welcome reminder to all
of us of how necessary it is to remain rigorous, in particular in a field that
easily gets people excited.
The distinction between chronologie al age and developmental age is also
addressed by Helfand and Rogina, who describe how gene expression during
aging can be studied with great precision and resolution in Drosophila,
particularly in the antennae.
VI Preface
Their work helps to address the question of whether short-lived mutants
provide insight in the mechanisms of aging. While it is clear that mutations
prolonging life span must alter a gene whose normal function limits life span,
it is much less certain that each mutation that shortens life span accelerates
the processes that normally underlie aging. Helfand and Rogina have iden
tified and studied subtle biomarkers of aging, and their analysis, and the tools
it provides, should help to assess whether a given mutation that shortens life
span is associated with an increased rate of aging or whether it shortens life
span through a novel pathology that is unrelated to the processes that occur
during senescence in wild-type animals.
The next four chapters describe work on and insights into the aging
process obtained through studies with the nematode Caenorhabditis elegans.
In recent years, C. elegans has become an important model system for the
study of aging, for two principal reasons, I believe. Firstly, worms live for
only a short time, approximately 2 weeks on average, and their life and death
is easy to score. This allows large-scale experiments to be performed and to
be repeated several times within an acceptable time frame. Secondly, C.
elegans is a self-fertilizing hermaphrodite, which means that comparisons can
be made between strains that are fully isogenic except for the mutation under
study. In the first worm chapter, I describe the action of three groups of
genes: genes that affect developmental dormancy (the dauer larva pathway
and da! genes), genes that affect the rate of living (clk genes), and genes that
affect food intake (eat genes). Mutations in these three groups have also been
studied in combination, in an effort to determine whether mutations that
alter aging can be organized into genetic pathways in the manner that has
been so successful with genes that affect development. I discuss these studies,
their findings and their limits. Finally, I try to give a global view of how the
genes under discussion might act together to determine life span by con
sidering their action in the context of the organism as a whole.
One of the criticisms of using invertebrate model systems to study aging,
as voiced by clinically inclined researchers, is that one cannot study relevant
age-associated pathologies. The chapter by Herndon and Driscoll focuses on
work in C. elegans toward understanding the genetic basis of apoptotic as weIl
as necrotic ceIl death and what the relation of these processes to organismal
aging might be. This might be particularly relevant given that some important
age-associated diseases such as Alzheimer's disease are accompanied by loss
of neuronal ceIl populations. Furthermore, recent results suggest that the
molecular mechanisms of apoptosis are involved in the mechanisms under
lying the development as weIl as the pathology of Alzheimer's. Herndon and
DriscoIl describe some of their findings with mutations that can suppress the
increased prevalence of necrotic ceIl deaths produced by genetic manipula
tions. Strikingly, these suppressor mutations also increase organismal life
span, suggesting that part of what limits life span is the increased prevalence of
necrotic ceIl deaths. This resembles what we see with people where the medical
alleviation of age-associated pathologies suffices to increase mean life span.
Preface VII
Possibly, one way forward is to explore whether a common mechanism
or theme can link the findings with various mutants in worms and other
organisms. Such thematic analyses are particularly important because of the
difficulty in distinguishing which, among the variety of phenotypes displayed
by most long-lived mutant strains, are causally linked to increased life span
and which are accompanying phenomena. Lithgow explores the theme of
stress resistance and Ishii and Hartman the related theme of the impact of
oxidative stress on life span. These phenomena have traditionally been
considered to be very important for life span and have therefore been studied
in great detail by methods that did not involve the analysis of long-lived
mutants. Testing the relevance of already well-documented phenomena by
genetic means and the analysis of mutants is proving to be very powerful in
this respect.
The last three chapters describe research using the mouse as model
system. Although any finding with mice is likely to be the most relevant to the
human condition, it is also true that mice are much larger, live much longer,
and are much more expensive to maintain than yeast, worms, or flies. Be
cause of this, it is much more difficult to use mice to carry out the sort of
experimentation (mutant screens and aging experiments with large sampIe
sizes and many different genotypes) that has been done successfully with the
invertebrate model systems. However, mice provide tools and insights that
invertebrates do not as yet, and might never, provide. These include the
possibility of doing detailed biochemistry. Not only is it difficult to obtain a
large amount of fresh material from whole animals, it is also very difficult in
flies and virtually impossible in worms to obtain enough material from single
organs. Most importantly, however, is the existence of a wealth of knowledge
about the physiology and biochemistry of the animal and each of its organs
and tissues. These features can be examined during aging and the biological
and physiological consequences of mutations and treatments can thus be
determined. All these advantages are weIl illustrated in these last three
chapters. For example, Dolle, Giese, van Steeg, and Vijg describe the elegant
and powerful techniques they have pioneered to examine genomic stability in
aging. They address this question in two ways. First, they look at the accu
mulation of somatic mutations and its relative importance for the aging
process. Second, they look into the link between mutagenesis and cancer,
which may be the single most important age-related pathology.
All mutations known to date that prolong life span displaya number of
additional phenotypes, none perhaps more strikingly than the dwarf mice
described by Bartke. It is very surprising to me that animals with such
profound anatomical and physiological defects manage to live longer than
their nonmutant counterparts. Bartke examines a number of physiological
hypotheses to explain this pattern. For example, he points out that although
individuals of larger species tend to live longer than those of smaller species
(probably because of a difference in rate of living), the smaller individuals in
a given species live longer than the larger individuals. This pattern is also
VIII Preface
seen among races of dogs. This notion seems to worry some people and I
have even been interrogated by towering giants in scientific symposia about
my opinion on the validity of this idea.
We finish the book with the chapter by Van Zant on the links between
stern cells development and aging. Van Zant discusses what stern ceUs reaUy
are and describes their behavior during aging, also touching on experimental
manipulations of telomeres and stern cells in vitro. He shows how the biology
of stern ceUs might hold part of the key to what happens in an aging animal.
These views are upheld by his identification of a genetic locus that appears to
influence stern ceU behavior and life span concurrently. It seems that in the
scientific and lay public's mind, the research subject most clearly associated
with the biology of aging is that of telomeres and stern ceUs. I suspect that the
reasons for this lie in a conceptuaUy easy idea and in the beauty of a word.
The idea is that telomere shortening represents a counting mechanism, and
the attraction is for the word "immortalized".
In a way we have come full circle. The book starts with a chapter on the
basic phenomenon that some people live longer than others, probably be
cause of their particular genetic constitution, and finishes with a chapter on a
subject regarded by many as the best hope to overcome our genetic limita
tions.
Montreal, November 1999 Siegfried Hekimi
Contents
Centenarians and the Genetics of Longevity
Thomas Perls, Dellara F. Terry, Margery Silver, Maureen Shea,
Jennifer Bowen, Erin Joyce, Stephen B. Ridge, Ruth Fretts, Mark Daly,
Stephanie Brewster, Annibale Puca, and Louis Kunkel
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
2 Are Centenarians a New Phenomenon? ............... 2
3 Centenarians Are the Fastest Growing Age Group. . . . . . . . . 3
4 Are Centenarians Different? . . . . . . . . . . . . . . . . . . . . . . . 4
5 The Centenarian Phenotype: Compressing Morbidity
Towards the End of Life . . . . . . . . . . . . . . . . . . . . . . . . . 6
6 Evidence from Centenarians Supporting a Strong
Genetic Influence upon Longevity. . . . . . . . . . . . . . . . . . . 7
7 Siblings of Centenarians Live Longer . . . . . . . . . . . . . . . . . 7
8 Parents of Centenarians also Achieve Unusually Old Age . . . . 8
9 Four Families with Clustering for Extreme Longevity ...... 8
9.1 Mathematical Analysis. . . . . . . . . . . . . . . . . . . . . . . . . . 10
10 Middle-Aged Mothers Live Longer: An Evolutionary Link
Between Reproductive Success and Longevity-Enabling Genes. 11
10.1 What Determines When a W oman Will Go Through
Menopause? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
10.2 Menopause: An Adaptive Response . . . . . . . . . . . . . . . . . . 13
10.3 Why Menopause Does Not Occur in Other Mammals? . . . . . . 13
10.4 Nonhuman Data Supporting the Association Between Delayed
Reproductive Senescence and Increased Longevity . . . . . . . . 14
10.5 Alternative Explanations for Why Menopause Occurs . . . . . . 14
10.6 Why Is the Human Life Span 122 Years and What Is the
Evolutionary Advantage for Living to Such an Age? ....... 15
10.7 What If We Removed the Selective Force
for Maximizing Life Span? ....................... 16
10.8 The Association Between Longevity-Enabling Genes
and Genes Which Regulate Reproductive Health ......... 16
11 In Our Near Future. . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
x Contents
Coordination of Metabolie Aetivity
and Stress Resistanee in Yeast Longevity
S. Michal Jazwinski
1 Introduetion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
2 Phenomenology of Yeast Aging . . . . . . . . . . . . . . . . . . . . 23
3 Genetics of Longevity .......................... 25
4 Physiological and Moleeular Meehanisms of Aging . . . . . . . . 27
4.1 Genetie Instability and Gene Dysregulation. . . . . . . . . . . . . 27
4.2 Metabolie Control . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 29
4.3 Stress Resistanee. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
4.4 Coordination of Metabolie Aetivity and Resistanee to Stress . . 34
4.5 Comparisons with Other Organisms ........ . . . . . . . . . 36
5 Primaey of Metabolie Control . . . . . . . . . . . . . . . . . . . . . 38
Referenees. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
Current Issues Coneerning the Role
of Oxidative Stress in Aging: A Perspeetive
Rajindar S. Sohal, Robin J. Moekett, and William C. Orr
1 Introduetion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
2 The Coneept of Life Span: A Cautionary Note. . . . . . . . . . . 47
3 Metabolie Rate, Stress Resistanee and Antioxidative Defenses. 49
4 Current Evidential Status of the Oxidative Stress Hypothesis
of Aging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50
5 Longevity Studies in Transgenic Drosophila ............ 53
6 Hazards of Life-Span Analysis in Drosophila . . . . . . . . . . . . 55
6.1 Compensation............................... 55
6.2 Genetic Effeets . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57
6.3 Inducible Expression Systems ..................... 59
7 Conelusions....... . . . . . . . . . . . . . . . . . . . . . . . . . . 61
Referenees. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62
Regulation of Gene Expression During Aging
Stephen L. Helfand and Blanka Rogina
1 Importanee of Examining Gene Expression During Aging 67
2 Drosophila as a Model System for Studying Gene Expression
During Aging. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67
3 Enhaneer Trap and Reporter Gene Teehniques Can Be Used
to Study Gene Expression During Aging. . . . . . . . . . . . . . . 68
4 The Level of Expression of Many Genes Is Dynamically
Changing During Adult Life in Drosophila melanogaster .... 69
