You are on page 1of 6

Ageing Future Directions

for Research in the Biology of

Thomas BL Kirkwood, University of Newcastle, Newcastle Upon Tyne, UK

Special article
Article Contents
. Introduction
. Understanding Why Ageing Occurs
. Cellular and Molecular Mechanisms
. Genetic Control of Lifespan
. Nongenetic Factors

An increasing fraction of the worlds population is living to an age when intrinsic biological
constraints take their toll on health and quality of life through age-related frailty. As the
number of older people increases, so does the number suffering from a wide range of ageassociated disabilities and diseases.

An increasing fraction of the worlds population is living to
an age when intrinsic biological constraints take their toll
on health and quality of life through age-related frailty. As
the number of older people increases, so does the number
suering from a wide range of age-associated disabilities
and diseases, like Alzheimers, arthritis and osteoporosis.
All of this makes it important that we should deepen our
understanding of the cellular and molecular mechanisms
that underlie human ageing.
The last decades have seen great strides in our ability to
get to grips with the complex challenges of ageing. This
results partly from the emergence of a much clearer
understanding of why ageing occurs, and partly from the
rapid advance in experimental techniques. Ageing aects
molecules, cells, organs and entire physiological systems
and needs to be understood at each of these levels.
Although there is much excitement about the possibilities for new technologies to revolutionize the ageing
process, these possibilities need to be pegged to current
understanding of the mechanisms of ageing. Considerable
further research will be needed to check the feasibility of
the proposed interventions, as well as careful ethical
assessment and debate. There are, however, immediate
benets to be realized from understanding ageing in greater
detail, not least because new knowledge provides support
for the idea that relatively simple nutritional and lifestyle
interventions, which are available immediately at modest
cost, can benet the health of older people.

Understanding Why Ageing Occurs

Ageing is not programmed
A common but generally mistaken view is that ageing is
controlled in the same way as development, i.e. that we are
specically programmed to die. A suggested advantage of
ageing is that it helps to prevent overcrowding and so

. Ageing and Reproduction

. Future Challenges

lessens the risk of severe depletion of resources. However,

there are strong objections to this idea. First, there is little
evidence that ageing contributes signicantly to mortality
in natural populations, most wild animals dying comparatively young (Kirkwood and Austad, 2000). Second, such
an advantage benets the individual only indirectly and
relies upon the troublesome concept of group selection. If
ageing had evolved to regulate population size, then any
mutant in whom the ageing process was inactivated would
enjoy an advantage and the mutant genotype would

Nonadaptive theories of ageing

If ageing is not specically programmed, then its evolution
must be explained through the indirect action of natural
selection. The nonadaptive theories of ageing are of two
types: ageing occurs because (i) the power of natural
selection declines during the lifespan; or (ii) the costs of
maintaining and repairing the body to a high enough level
that it can last indenitely are too great.
Significance of the age-related decline in the force of
natural selection
Natural selection acts through the dierential eects of
genes on reproductive tness, so the force of natural
selection declines in proportion to the remaining fraction
of the organisms total lifetime expectation of reproduction. This is true whether or not the species exhibits ageing,
since even if individuals do not age they are nonetheless
susceptible to extrinsic mortality (e.g. predation, accidents). If a gene eect is expressed early in life, it inuences
the reproductive success of a greater proportion of
individuals born bearing that gene than if it is expressed
late, when many will already have died. This inevitably
leads to attenuation in the force of natural selection with
age, so there is only loose genetic control over the late
portions of the lifespan. Two of the non-adaptive theories
follow directly from this observation.

ENCYCLOPEDIA OF LIFE SCIENCES / & 2002 Macmillan Publishers Ltd, Nature Publishing Group /

Ageing Future Directions for Research in the Biology of Ageing

The mutation-accumulation theory asserts that lateacting harmful gene mutations, whose eects are delayed
until an age when in the wild environment most individuals
would have died already, are beyond the reach of selection.
Such genes may therefore become xed in the genome
through random drift. Although of little consequence in
the wild, they will cause ageing if organisms are reared
under protected conditions.
The antagonistic-pleiotropy theory supposes the existence of genes that have good eects early in life and bad
eects later. Selection favours retention of the genes on the
basis of their early benets, but defers the time of
expression of the deleterious eects to ages when survivorship in the wild environment is low. The decline in the force
of natural selection with age ensures that even quite modest
early benets outweigh severe harmful side-eects, provided that the latter occur late enough. Again, ageing is
seen if organisms are reared under protected conditions.
Disposable soma theory
Another approach is the disposable soma theory, which
explicitly recognizes the intrinsic costs of somatic maintenance and repair and leads to specic predictions about
the biological mechanisms of ageing. The term soma is
used in the sense introduced by Weismann in the late
nineteenth century to describe those parts of the body that
are distinct from the germline that produces the
reproductive cells the sperm and the egg.
Given the continual hazard of accidental death, each
soma has only a nite expectation of life even if it does not
suer intrinsic deterioration. When the soma dies, the
resources invested in its maintenance are lost. Too low an
investment in the prevention or repair of somatic damage is
unsatisfactory because the soma may disintegrate before it
can reproduce. However, too high an investment is also
wasteful because there is no advantage in maintaining the
soma better than is necessary for it to survive its expected
lifetime in the wild environment in reasonably sound
condition. The predicted outcome is therefore that the
optimum level of somatic maintenance is less than would
be necessary to prevent intrinsic deterioration, and hence,
that ageing occurs through the progressive accumulation
of unrepaired faults.
The precise optimum investment in maintenance depends on the species ecological niche. A species subject to
high accidental mortality will do better not to invest
heavily in each individual soma, but should concentrate
instead on more rapid and prolic reproduction. A species
that experiences low accidental mortality may prot by
doing the reverse.

Tests of evolutionary theories

Model organisms have been the major means of testing the
predictions of the evolutionary theories. For practical

reasons, most research has used either the fruity

Drosophila melanogaster or the nematode Caenorhabditis
elegans, both of which combine advantages of short
lifespan, low maintenance costs and excellent background
genetics. D. melanogaster is a random-bred, diploid
organism. Its populations therefore harbour high levels
of genetic variation, like humans. C. elegans mainly
reproduces as a self-fertilizing hermaphrodite. This facilitates the creation of stocks with a very high degree of
genetic uniformity and aids the recovery of mutations.
Fruities have been used to test for evidence of
mutation-accumulation and/or trade-os between longevity and fertility (see Kirkwood and Austad, 2000). The
former tests have so far proved inconclusive, but extensive
evidence now points to the existence of trade-os. In one
series of experiments ies were bred for longevity, using
laboratory selection for late reproductive capacity.
Although the selection for longevity was therefore indirect,
the rationale behind these studies was that ies that
retained fertility at later ages might be those that aged more
slowly and would also live longer. Young lines of ies
were propagated in each generation from adults that had
just emerged from pupae, while old lines were propagated
from adults that had already been reproducing for some
time. In line with expectation, greater longevity of old
lines has consistently been found in these studies, and this
has been correlated in most studies with a decrease in earlylife fertility.
In another approach, direct selection for increased
lifespan was accomplished using an experimental design
that exploited the eect of temperature on Drosophila
longevity (Zwaan et al., 1995). The progeny from each pair
of breeding ies were divided into two groups, one of which
was maintained at 158C and the other at 298C. At 298C
maximum lifespan was less than 60 days, whereas at 158C
mean lifespan was greater than 120 days. This meant that
lifespans could be measured on the groups maintained at
298C and the longest-lived families selected, at a time when
the sibling groups kept at 158C were still reproductively
viable. Again, the selection regimen generated populations
with increased lifespans but decreased fertility.
Evidence for a trade-o between longevity and fertility
in human populations has also been reported (Westendorp
and Kirkwood, 1998, 1999).

Comparative studies of ageing and longevity

From the comparative perspective, many opportunities
exist to test the prediction that in safe environments (those
with low extrinsic mortality) ageing will evolve to be
retarded, whereas ageing should evolve to be more rapid in
hazardous environments. Adaptations that reduce extrinsic mortality (wings, protective shells, large brain) are
generally linked with increased longevity (bats, birds,
turtles, humans). Field observations comparing a main-

ENCYCLOPEDIA OF LIFE SCIENCES / & 2002 Macmillan Publishers Ltd, Nature Publishing Group /

Ageing Future Directions for Research in the Biology of Ageing

land population of opossums subject to signicant predation by mammals, with an island population not subject to
mammalian predation, found the predicted slower ageing
in the island population (Austad, 1993).
At the molecular and cellular levels, the disposable soma
theory predicts that the proportional eort devoted to
cellular maintenance and repair processes will vary directly
with longevity. Numerous studies support this idea. For
instance, the long-lived rodent species Peromyscus leucopus exhibits lower generation of the reactive oxygen species
(ROS; also known as free radicals) that are widely seen as
a major contributor to the ageing process, higher cellular
concentrations of some antioxidant enzymes, and overall
lower levels of protein oxidative damage than the shorterlived species Mus musculus (Sohal et al., 1993).
DNA repair capacity has been shown to correlate with
mammalian lifespan in several comparative studies (Promislow et al., 1995), as has the level of poly(ADP-ribose)
polymerase (Grube and Burkle, 1992), an enzyme that
plays an important role in the maintenance of genomic
integrity. Comparisons of the functional capacity of
cultured cells to withstand a variety of imposed stressors
have shown that cells taken from long-lived species have
superior stress resistance to that of cells from shorter livedspecies (Martin et al., 1996; Ogburn et al., 1998; Kapahi
et al., 1999).
The comparative studies support the idea that it is the
evolved capacity of somatic cells to carry out eective
maintenance and repair that governs the time taken for
damage to accumulate to levels where it interferes with the
organisms viability, and hence regulates longevity.

Cellular and Molecular Mechanisms

One of the most important categories of damage contributing to ageing is that caused by oxidative stress, as a
result of the production of free radicals, or reactive
oxygen species (ROS) (Martin et al., 1996; von Zglinicki
et al., 2001). ROS are byproducts of normal cellular
metabolism and they are crucial factors in late-life diseases
like dementia, heart disease and age-related blindness.
Each free radical is a tiny but highly reactive molecule and
likely to damage the rst thing it meets inside the cell. This
might be a protein, a membrane or a segment of DNA. A
vast amount of damage is done daily to DNA by ROS,
estimated at 10 000 hits per cell per day. The majority of
these hits are corrected by DNA-repair mechanisms, but a
small fraction escapes detection by the repair system and
gives rise to permanent mutation of the cells DNA. In
addition to damage by ROS, there is a variety of other
mechanisms that cause molecular damage during ageing.
Some of these mechanisms are more likely to aect dividing
cells; others are more of a threat to postmitotic cells like
neurons and muscle.

Ageing of dividing cells

In dividing cells, in addition to ROS-induced DNA
damage, errors in DNA replication can arise with each
cell division, resulting in a progressive build-up of somatic
mutations. Studies on the frequency of somatic mutations
in aged animal tissues indicate that in tissues such as liver
the frequency of somatic mutations increases exponentially with age (Dolle et al., 1997).
A particular category of DNA damage aecting dividing
cells is the progressive erosion of telomeres, repetitive
DNA structures found at the chromosome ends. In many
human somatic tissues the decline in cellular division
capacity is linked to the fact that the telomeres get
progressively shorter as cells divide (Chiu and Harley,
1997). This is due to the absence of telomerase a
specialized enzyme that overcomes a crucial shortcoming
in the normal DNA-copying process that limits its ability
to copy to the very end of the DNA strand. The main
function of telomerase is to protect the telomeres in
germline cells from getting shorter each generation. But it
does not matter greatly if telomeres get whittled away in the
soma, which after all is disposable. It turns out that
telomerase is generally switched o in somatic cells.
Telomere shortening has been suggested to act as an
intrinsic division counter, perhaps to protect us from
runaway cell division as happens in cancer (Campisi et al.,

Ageing in postmitotic cells

Postmitotic cells face other kinds of build-up of damage. In
particular, these involve accumulations of defective
mitochondria and aberrant proteins. Defective mitochondria carry mutations in the mitochondrial DNA (mtDNA)
sequence that disrupt oxidative phosphorylation and thus
impair energy generation. Aged postmitotic tissues show
increased frequencies of cells with mtDNA mutations
(Linnane et al., 1989; Brierley et al., 1998). Postmitotic
tissues are also vulnerable to the build-up of proteaseresistant denatured or aberrant protein molecules. In
dividing cells, such molecules are diluted by fresh
cytoplasmic material each time the cell divides but in
postmitotic cells they simply accumulate and may contribute to the kind of problem that is caused by the
protease-resistant b-amyloid, which is implicated in the
pathogenesis of Alzheimers disease.

Networks of damage and repair

By now it will be clear that multiple mechanisms contribute
to ageing, most being linked through a theme of stress,
damage and repair. Devising strategies for experimental
research that can unravel this complexity is not easy. An
invaluable tool is to use mathematical and computer
modelling to help understand how the dierent mechan-

ENCYCLOPEDIA OF LIFE SCIENCES / & 2002 Macmillan Publishers Ltd, Nature Publishing Group /

Ageing Future Directions for Research in the Biology of Ageing

isms interact with each other (Kowald and Kirkwood,

1996). This work is a part of the burgeoning eld of
bioinformatics, one of the fastest growing areas in biology

Genetic Control of Lifespan

Although the evolutionary theories suggest that genes that
actively promote ageing do not exist, it is clear that genetic
factors inuence the rate of ageing. First, dierent species
have dierent lifespans. Second, there are clear lifespan
dierences between dierent inbred strains of laboratory
animals, such as mice and rats. Long-and short-lived
laboratory strains are held in identical environments,
diering only in their genes. Third, human longevity shows
a statistical tendency to run in families, and the lifespans of
monozygotic twin pairs are more similar than lifespans of
dizygotic twins (Cournil and Kirkwood, 2001). Fourth,
and the subject of much recent research, simple organisms
like fruities and nematode worms have revealed a range of
gene mutations that markedly aect the length of life.
The evidence for a genetic contribution to ageing is
therefore compelling, but all these studies point to only
weak genetic specication of individual lifespan. In
humans, genes account for only about a quarter of what
determines individual length of life. In other species, the
picture is much the same (Finch and Tanzi, 1997). So what
kinds of genes control longevity?
The last decade has seen a surge of activity aimed at
identifying genes controlling ageing in invertebrate models. It was in 1988 that the rst gene mutation conferring an
increase in lifespan in C. elegans was reported and since
then the number of such genes has steadily climbed. It was
soon found that the original C. elegans longevity mutation,
age-1, showed unusual resistance to a wide range of
stresses, including oxidative stress, heat and ultraviolet
irradiation, an observation subsequently reproduced in
many of the other longevity-conferring mutants (Lithgow,
1996). It thus appears that these genes regulate longevity by
controlling the average rate at which damage can

Heritability of human lifespan

Given the dierences in methodology and the large number
of potential confounding variables in such work, there has
been surprising consistency in the estimates of the
coecient of heritability of human longevity at about
25% (Cournil and Kirkwood, 2001). Current studies on
genetics of human longevity are focusing on the growing
numbers of centenarians and have discovered statistically
signicant dierences between centenarians and the
general population in the frequencies of certain alleles at
polymorphic gene loci (e.g. Schachter et al., 1994). Further

advances in our knowledge of genes involved in human

ageing are promised by the Human Genome Project.

Functional genomics
Large amounts of data are beginning to emerge from
techniques like DNA microarray analysis that compare
patterns of gene expression in old versus young tissues or
those with and without age-related diseases. But this
avalanche of data will require careful interpretation. A
major challenge will be to determine which of the many
dierences that might be detected are primary in the ageing
process, and which are secondary. For example, gene
expression changes during ageing are as likely to be
consequences of senescence-associated damage as they are
to be causes.

Nongenetic Factors
The fact that the coecient of lifespan heritability is only
25% implies that three-quarters of what determines
longevity, and presumably also health in old age, is
One of the most important environmental variables is
the abundance of food, particularly in temperate climates
where organisms may have to adjust not only to regular
seasonal changes but also to year-on-year uctuations. In
the mid-1930s it was found that a diminished food supply
increased the lifespan of laboratory rodents, giving rise to
the major research paradigm based on the so-called
calorie-restriction model.
Not only does calorie restriction extend lifespan, it also
postpones a wide range of age-associated diseases and
biomarkers of ageing. In eect, it appears to slow the rate
of ageing by upregulating a broad spectrum of somatic
maintenance and repair systems. A similar phenomenon is
seen in other species, including C. elegans which responds
to nutritional stress by switching from the normal
developmental sequence and producing the long-lived,
highly stress-resistant dauer larva.
In addition to the eects of food quantity, there is reason
to believe that the quality of nutrition can also inuence
ageing through its eects on damage accumulation. Some
foods, e.g. those rich in sugar or saturated animal fats, have
well-recognized negative impacts on the body. Minimizing
exposure to such foodstus should slow the build-up of
damage. Likewise, certain foods are rich in components
that aid the ght against damage, such as vitamins C, E and
other antioxidants. Trace elements like selenium and zinc
are involved in essential tissue maintenance functions.
Exercise is generally good for health and longevity.
There are obvious benets from regular physical exercise
for cardiovascular and lung function, and for maintenance
of bone and muscle. There is also evidence that mental

ENCYCLOPEDIA OF LIFE SCIENCES / & 2002 Macmillan Publishers Ltd, Nature Publishing Group /

Ageing Future Directions for Research in the Biology of Ageing

exercise wards o depression and may even protect

cognitive functions. However, exercise also contributes to
wear and tear of tissues like cartilage. Prolonged exercise,
particularly of a heavy and repetitive kind, is a risk factor
for age-related osteoarthritis.
Another factor that contributes to nongenetic variation
in ageing is intrinsic chance. Although geneticists have
tended to see the explanation for phenotypic variations in
terms of genes, environment or geneenvironment interaction, intrinsic chance can be considered as a category on
its own (Finch and Kirkwood, 2000). For example, there is
pronounced variation in lifespan of individual nematode
worms even though the individuals are genetically identical
and live in a uniform laboratory environment.

when it is comparatively safe, thereby increasing the

likelihood of the mother surviving to raise her existing
ospring to independence. Additionally, postmenopausal
women may contribute to the successful rearing of their
grandchildren, by providing assistance to their own adult
ospring and thereby increasing their inclusive tness, i.e.
their overall genetic contribution to future generations
(Hawkes et al., 1998). A recent analysis suggests that a
combination of all of these factors is required to explain the
human menopause (Shanley and Kirkwood, 2001), which
may account for the lack of evidence for evolution of
menopause in other species (Packer et al., 1998).

Future Challenges
Ageing and Reproduction

Disentangling multiple mechanisms

An erroneous view, akin to the programme theory

dismissed earlier, is that ageing is necessary to rid a
population of old and worn-out individuals, which have
produced their required quota of ospring and are of no
further reproductive value. This idea is not only circular
(by assuming old individuals to be worn-out) but relies on
group selection. In fact, reproductive senescence should be
understood as a consequence, not a cause, of general
ageing. If, from the perspective of natural selection, it does
not matter that mortality increases due to the action of
ageing, then it cannot matter that fertility declines.
However, one connection between reproduction and
ageing merits particular attention. This is menopause,
which occurs uniquely in women around the age of 50. The
evolutionary puzzle about menopause is why a woman
should cease reproducing at an age when she is still far from
her biological lifespan. Oocyte depletion is the physiological trigger for menopause but this begs the question of
why natural selection has not produced a larger store of
Most attempts to explain menopause focus on the
special circumstances of the human life history, notably,
the evolution of increased brain size and sociality.
Increased neonatal brain size coupled with the constraint
on the birth canal imposed by the mechanics of a bipedal
gait has made giving birth unusually dicult for human
females. The risks of child-bearing, particularly in the
absence of modern obstetric care, would increase even
more steeply with age if fertility were to persist during the
later period of the lifespan. The problem of a large brain is
also reected in the fact that human infants are born
unusually early, relative to other species, with respect to the
completion of brain growth and development. Infants
remain highly dependent for extended periods and, in the
ancestral environment, their survival will have been
unlikely if their mother died in childbirth. There may thus
be a tness advantage in limiting reproduction to ages

There is no single mechanism of ageing. This situation is

clearly explained by the evolutionary theories, each of
which suggests that multiple genes aect longevity.
Furthermore the theories are not mutually exclusive and
in some cases, at least, there will be contributions from all
of them. On the other hand, single interventions, like
calorie restriction, can produce multiple eects. A major
challenge for future work is therefore to unravel more
completely the nature of the genetic architecture of ageing
and clarify the interactions and possible synergisms
between dierent mechanisms at the cell and molecular

Identifying the determinants of life history

Organisms often live in highly variable environments
where a single life history strategy may prove too
restrictive. This has implications for the evolution of
plasticity to allow organisms to make the best of each
dierent situation that may arise. Calorie restriction is a
striking example. If we can better identify both the ultimate
(evolutionary) and proximate (physiological) factors that
govern life history plasticity, we will gain insights that can
guide attempts to intervene in the ageing process.

Interventions against ageing

The view that ageing itself, like many age-related diseases,
is caused by progressive accumulation of cell and tissue
damage, suggests that there may be considerable overlap of
the causal pathways leading to ageing and to age-related
diseases. There is at present no known intervention
specically to extend human healthspan or lifespan by
targeting basic mechanisms of ageing, other than by
relatively nonspecic lifestyle choices, e.g. nutrition and
exercise. Interventions that postpone ageing in model

ENCYCLOPEDIA OF LIFE SCIENCES / & 2002 Macmillan Publishers Ltd, Nature Publishing Group /

Ageing Future Directions for Research in the Biology of Ageing

organisms comprise (i) articial selection to alter the

genetic make-up of a population (fruities), (ii) recovery of
gene mutations producing increased lifespan (nematodes,
fruities, yeast), (iii) transgenic manipulation, e.g. of
antioxidant defence (fruities, nematodes, yeast, mice),
(iv) calorie restriction (rodents, possibly fruities and
nematodes, primate work in progress), and (v) administration of antioxidant drugs (nematodes). Given the
importance of nding ways to enhance the quality of the
extra years of human longevity, which human ingenuity
has produced over the last century, it is essential that
research on interventions in ageing be accelerated.

Austad SN (1993) Retarded senescence in an insular population of
opossums. Journal of Zoology 229: 695708.
Brierley EJ, Johnson MA, Lightowlers RN, James OF and Turnbull DM
(1998) Role of mitochondrial DNA mutations in human aging:
implications for the central nervous system and muscle. Annals of
Neurology 43: 217223.
Campisi J, Kim SH, Lim CS and Rubio M (2001) Cellular senescence,
cancer and aging: the telomere connection. Experimental Gerontology
36: 16191637.
Chiu CP and Harley CB (1997) Replicative senescence and cell
immortality: the role of telomeres and telomerase. Proceedings of the
Society for Experimental Biology and Medicine 214: 99106.
Cournil A and Kirkwood TBL (2001) If you would live long, choose your
parents well. Trends in Genetics 17: 233235.
Dolle MET, Giese H, Hopkins CL, Martus HJ, Hausdor JM and Vijg J
(1997) Rapid accumulation of genome rearrangements in liver but not
in brain of old mice. Nature Genetics 17: 431434.
Finch CE and Kirkwood TBL (2000) Chance, Development and Aging.
New York: Oxford University Press.
Finch CE and Tanzi RE (1997) The genetics of aging. Science 278: 407
Grube K and Burkle A (1992) Poly(ADP-ribose) polymerase activity in
mononuclear leukocytes of 13 mammalian species correlates with
species-specic lifespan. Proceedings of the National Academy of
Sciences of the USA 89: 1175911763.
Hawkes K, OConnell JF, Jones NGB, Alvarez H and Charnov EL
(1998) Grandmothering, menopause, and the evolution of human life
histories. Proceedings of the National Academy of Sciences of the USA
95: 13361339.
Kapahi P, Boulton ME and Kirkwood TBL (1999) Positive correlation
between mammalian lifespan and cellular resistance to stress. Free
Radical Biology and Medicine 26: 495500.
Kirkwood TBL and Austad SN (2000) Why do we age? Nature 408: 233

Kowald A and Kirkwood TBL (1996) A network theory of ageing: the

interactions of defective mitochondria, aberrant proteins, free radicals
and scavengers in the ageing process. Mutation Research 316: 209236.
Linnane AW, Marzuki S, Ozawa T and Tanaka M (1989) Mitochondrial
DNA mutations as an important contributor to ageing and
degenerative diseases. Lancet 25: 642645.
Lithgow GJ (1996) Invertebrate gerontology: the age mutations of
Caenorhabditis elegans. BioEssays 18: 809815.
Martin GM, Austad SN and Johnson TE (1996) Genetic analysis of
aging: role of oxidative damage and environmental stresses. Nature
Genetics 13: 2534.
Ogburn CE, Austad SN, Holmes DJ, et al. (1998) Cultured renal
epithelial cells from birds and mice: enhanced resistance of avian cells
to oxidative stress and DNA damage. Journal of Gerontology 53:
Packer C, Tatar M and Collins A (1998) Reproductive cessation in
female mammals. Nature 392: 807811.
Promislow DEL, Tatar M, Khazaeli AA and Curtsinger JW (1995) Agespecic patterns of genetic variation in Drosophila melanogaster. I.
Mortality. Genetics 143: 839848.
Schachter FL, Faure-Delanef L, Geunot F, et al. (1994) Genetic
associations with human longevity at the APOE and ACE loci. Nature
Genetics 6: 2932.
Shanley DP and Kirkwood TBL (2001) Evolution of the human
menopause. BioEssays 23: 282287.
Sohal RS, Ku H-H and Agarwal S (1993) Biochemical correlates of
longevity in two closely-related rodent species. Biochemical and
Biophysical Research Communications 196: 711.
von Zglinicki T, Burkle A and Kirkwood TBL (2001) Stress, DNA
damage and ageing an integrative approach. Experimental
Gerontology 36: 10491062.
Westendorp RGJ and Kirkwood TBL (1998) Human longevity at the
cost of reproductive success. Nature 396: 743746.
Westendorp RGJ and Kirkwood TBL (1999) Human longevity and
reproductive success: response to Gavrilov and Gavrilova. Journal of
Anti-Aging Medicine 2: 125126.
Zwaan BJ, Bijlsma R and Hoekstra RE (1995) Direct selection on
lifespan in Drosophila melanogaster. Evolution 49: 649659.

Further Reading
Austad SN (1997) Why We Age: What Science is Discovering about the
Bodys Journey Through Life. New York: John Wiley.
Arking R (1998) Biology of Aging: Observations and Principles, 2nd edn.
Sunderland, MA: Sinauer.
Hayick L (1996) How and Why We Age. New York: Ballantine Books.
Holliday R (1995) Understanding Ageing. Cambridge: Cambridge
University Press.
Kirkwood T (1999) Time of Our Lives: the Science of Human Ageing.
Oxford: Oxford University Press.

ENCYCLOPEDIA OF LIFE SCIENCES / & 2002 Macmillan Publishers Ltd, Nature Publishing Group /