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Genes, Sex and Ageing
Prof Tom Kirkwood
A belief that ageing and length of life are governed by genetic factors has
led to growing excitement that research on the human genome will soon uncover
the genes for ageing and - who knows? - open the path to longer lives for us
all. What is the evidence that genes control ageing and how realistic is it to
expect that the "new genetics" can secure for us a modern-day elixir
of youth? And could it be true, as Aristotle believed, that it is sex that
ultimately causes us to age? New research reveals that there is indeed a
trade-off between reproduction and the length of life, but rest assured, sexual
activity itself is not the cause of ageing, at least in humans.
The genetics of ageing
The confidence that genes affect ageing comes from several lines of evidence.
First, different species have different life spans, and where better to look for
the underlying causes than their genomes. Second, when we look at human
longevity it really does seem to be true that the best recipe for a long life is
to choose your parents carefully. Longevity shows a statistical tendency to run
in families, and the life spans of identical (monozygotic) twin pairs are more
similar to each other than life spans of non-identical (dizygotic) twins.
Fourth, and the subject of much recent research, simple organisms like fruit
flies and nematode worms have revealed a range of gene mutations that markedly
affect the length of life. Intriguingly, however, the genetic specification of
individual life span seems rather weak. 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. So what kinds of genes control longevity? And why do
they do so in such an indecisive way?
One of the most successful tools for studying the role of genes in ageing is
the theory of evolution by natural selection. Ageing is widespread among animal
species but by no means universal, and not all species age in the gradual way
that we do. Some organisms, like the freshwater Hydra, show no signs of ageing
at all. Others like the Pacific salmon age all at once, just as soon as their
once-in-a-lifetime chance of reproduction has come and gone. In the case of the
Pacific salmon, the rapid post-reproductive death of the adult appears to be
driven by sex hormones. If a salmon has its gonads removed, it cannot of course
reproduce but it lives much longer.
So is ageing the price paid for sex? And are ageing and death programmed to
tie in with reproduction, for example, to provide living space for the next
generation? The answer to the first question, we shall see, is 'sort of'. The
answer to the second is a definite 'no'. Understanding why and how ageing
evolved will tell us much about the nature of the genes that are involved and
how these shape the life history, particularly the relationship between
reproduction and survival.
We are programmed for survival, not death
A simple observation from nature dispels the idea that old organisms are
programmed to lay down their lives in order to provide living space for their
young. Extensive field studies show that it is rare, in the wild, to find old
animals, i.e. animals in which the ageing process is significantly advanced.
Most animals in the natural world die young. Out of a population of newborn wild
mice, nine out of ten of them will be dead before age 10 months even though half
of the same animals reared in captivity would still be alive at age 24 months.
Thus, ageing is in an important sense an artifact of protected environments,
even though the potential to age is deeply ingrained.
The fact that ageing is rarely seen in natural animal populations tells us
immediately that it did not evolve to control population size. Since animals do
not, for the most part, live long enough for ageing to exert any effect on their
survival, we can discount the population-control argument. Furthermore, because
animals die young, natural selection cannot exert a direct influence over the
ageing process. It is thus hard to see how any programme for death, driven
perhaps by an 'ageing gene' might have evolved. Indeed, it is the failure of
natural selection to tightly control the late stages of the life history that
lies at the heart of the currently accepted evolutionary theory.
Instead of being programmed to die, organisms are programmed to survive. The
trouble is that in spite of a formidable array of mechanisms that strive to keep
us alive (including programmed cell death, or 'apoptosis', which in adults
serves mainly to delete unwanted or damaged cells), these mechanisms are not
good enough to allow us to last indefinitely.
The key to understanding why this should be so, and what governs how long a
survival period should be catered for, comes from looking again at the data from
survival patterns in the wild. If 90% of wild mice are dead by the age of 10
months, any investment in programming survival much beyond this point benefits
at most 10% of the population. This immediately suggests that there will be
little evolutionary advantage in building long-term survival capacity into a
mouse. The argument is further strengthened when we observe that nearly all of
the survival mechanisms required by the mouse to combat intrinsic deterioration
(DNA damage, protein oxidation, etc) require metabolic resources. Metabolic
resources are scarce, as evidenced by the fact that the major cause of mortality
for wild mice in temperate climates is cold, due to failure to maintain an
adequate body temperature. From a genetic point of view, the mouse will benefit
more by investing any spare resource into warming its body or into reproduction
rather than by boosting its DNA repair capacity to a better level than it
requires.
This concept, with its explicit focus on evolution of optimal levels of cell
maintenance, is termed the 'disposable soma' theory, an idea I first proposed in
1977. In essence, the disposable soma theory predicts that the investments in
the durability of somatic (non-reproductive) tissues are sufficient to keep the
body in good repair through the normal expectation of life in the wild
environment, but no better (although some measure of reserve capacity is to be
expected). Thus, it makes sense that mice (with 90% mortality by 10 months) have
intrinsic life spans of around three years, while humans (who probably
experienced something like 90% mortality by age 50 in our ancestral environment)
have intrinsic life spans limited to about 100 years.
The distinction between somatic and reproductive tissues is important because
the reproductive cell lineage, or germ line, must be maintained at a level that
preserves viability across the generations, whereas the soma needs to serve only
a single generation. At once, we can understand the apparent immortality of
Hydra. The usual mode of reproduction in Hydra is vegetative, by forming asexual
buds. This is facilitated by the fact that germ/stem cells permeate its body,
which gives it almost limitless powers of regeneration. Although individual
Hydra can and do die, their immortality is very real in the sense that
individuals have been observed for long periods of time without showing signs of
intrinsic ageing. The principle that absence of a clear distinction between soma
and germ line correlates with absence of ageing, and vice versa, has been
confirmed in other species.
Factors controlling length of life
The disposable soma theory identifies the level of extrinsic mortality as the
primary driver in the evolution of longevity. If the level of extrinsic
mortality is high, the average survival period is short and there is little
selection for a high level of maintenance. Any spare resources should go instead
towards reproduction. Consequently, the organism is not long-lived even in a
protected environment. Conversely, if the level of extrinsic mortality is low,
selection is likely to direct a higher investment in building and maintaining a
durable soma. Comparative studies confirm this prediction at both the ecological
and molecular level. Adaptations that reduce extrinsic mortality (wings,
protective shells, large brain) are linked with increased longevity (bats,
birds, turtles, humans). And at the molecular level, a study in my own
laboratory showed that cells from the longer-lived mammals had greater capacity
to withstand stress than the cells from the shorter-lived species. This ties in
well with a range of comparative studies demonstrating greater capacity for DNA
repair in longer-lived mammals.
The last decade has seen a surge of activity aimed at identifying genes
controlling ageing in invertebrate models such as the nematode worm Caenorhabditis
elegans and the fruit fly Drosophila melanogaster. It was in 1988
that the first gene mutation conferring an increase in life span in C.
elegans was reported and since then the number of such genes has steadily
climbed, now standing at around twenty. A particular advantage of C. elegans
for this kind of work, in addition to its short life span (around 20 days for
wild-type worms under standard culture conditions), is that this species mainly
reproduces as a self-fertilising hermaphrodite. This facilitates the isolation
of new strains with a very high degree of genetic uniformity.
By the middle 1990s it had been found that the original C. elegans
longevity mutation, appropriately named age-1, showed unusual resistance to a
wide range of stresses, including oxidative stress, heat, and UV irradiation, an
observation subsequently reproduced in many of the other longevity-conferring
mutants. This is directly consistent with our finding that longevity and
stress-resistance are positively associated in mammals. Furthermore, life
extension has since been demonstrated in nematodes and fruit flies with
phenotypically or transgenically induced up-regulation of stress-resistance
genes. A side-effect of this work has been a revival of interest in a phenomenon
known as hormesis, where a low dose of a damaging agent such as heat or
radiation increases survival. In nematodes and fruit flies, hormetic effects are
particularly clear.
The 'costs' of longevity
While the high level of genetic uniformity in nematode stocks has been of
advantage in identifying longevity-conferring mutations, a different approach
has been used to explore the genetics of ageing in fruit flies by applying
artificial selection to outbred populations. In outbred populations, the
existence of variation among genes that control rate of ageing should, in
principle, allow selection for sub-populations that age slower. There is,
however, an inherent problem in selecting for longevity. By the time you know
which flies lived the longest, they are of little use for breeding! This problem
was overcome in two ways. First, selection was applied not to longevity directly
but to the capacity to lay eggs at older ages. By discarding eggs laid before a
certain age, the experiment imposed a selection for late fecundity. After twenty
generations of selection, this procedure resulted in populations whose life span
had been increased by 30% or more, compared with controls. A different trick
exploited the fact that temperature affects fruit fly life span, flies living
longer at lower temperatures. Sibling groups of flies were divided into two sets
of sub-groups, one maintained at high temperature, the other at low temperature.
Those at high temperature died quickly, and the longest-lived sub-groups could
be quickly identified. Meanwhile their low temperature siblings were still fully
fertile and could be selected for further breeding. This second procedure worked
particularly well producing 30% life span increases within just six generations
of selection.
If selection experiments can so readily produce major increases in life span,
it might seem that longevity could be enhanced at will. But there was a price.
In the case of fruit flies, the downside of evolving longer lives was revealed
in a reduced reproductive rate. In most of the selection experiments, the
long-lived populations that were produced had significantly reduced overall
fertility, particularly in the earlier stages of life, which in nature are the
most important. Studies with mutant nematodes have shown less obvious fitness
costs from increased life span but the costs are there to be found. An
experiment that grew long-lived age-1 mutants together with the wild-type in
mixed populations found that when the worms were exposed to intermittent stress,
mimicking conditions likely to arise in nature, the wild-type won out even
though the age-1 worms have greater individual capacity to survive acute
stresses. Thus, in conditions more natural than standard laboratory culture,
something about the age-1 mutation rendered the worms less competitive.
The principle that a price is paid for longevity holds true in fruit flies
and nematode worms, but what about us? To test the possibility that humans, too,
might show a negative correlation between longevity and fertility,
epidemiologist Rudi Westendorp and I analysed birth and death records for more
than thirty thousand British aristocrats who lived and died between the 8th and
19th centuries. Although aristocrats are an atypical sub-group of the population
we chose them for our work because, firstly, they are far better documented than
the general population, and secondly, they have always enjoyed the best living
conditions. If you want to study biological determinants of longevity, it is of
little use to study a population whose lives are often truncated by hardships
associated with poverty. What we found, after allowing for historical trends in
the data set, was a statistically significant tendency for the longest-lived
individuals to have had, on average, smaller family sizes and higher levels of
infertility. Studies based on historical records are necessarily limited in the
kinds of questions they can answer. Nevertheless, our finding has since been
repeated in other populations and recently we reported evidence linking innate
immune factors to either high protection against infection at the cost of
impaired fertility, or vice versa.
Potential of the Human Genome project
Current studies in humans are focusing on the growing numbers of centenarians
among us. Centenarians are interesting for what these exceptionally long-lived
individuals might tell us about the genes influencing human longevity. Several
recent studies have found evidence for genetic differences between centenarians
and the general population. And, as has been shown in work led my colleague
Alexander Bürkle, activity levels of the key enzyme poly(ADP-ribose)
polymerase-1 (PARP-1), which reacts to DNA damage within minutes of a stress
being applied, have been shown to be higher in centenarians. This is in line
with an earlier comparative study from Bürkle's group, showing that PARP-1
activity levels correlate with mammalian species life span, longer-lived species
having higher PARP-1 levels. Thus it appears, at least in the case of PARP-1,
that the same genetic factor can contribute both to differences in life span
between and also within species.
Huge advances in our knowledge of genes involved in ageing are promised by
the Human Genome project and by similar projects in other species. But this
avalanche of data will require careful interpretation. Genes for longevity do
not simply count out our days and then kill us. They endow us with a given level
of protection against damaging factors like oxidative stress. How long we
actually keep going is then strongly influenced by things like lifestyle - the
foods we eat and the exercise we take - as well as by luck.
Conclusions
In conclusion, the major themes emerging from our present understanding of
the genes that control ageing are: (i) ageing is not programmed but results from
the gradual accumulation of random somatic damage; and (ii) the rate of ageing
(and hence longevity) is set by the efficacy of maintenance and repair
processes. A growing body of data supports these themes but a great deal more
work still needs to be done to identify the actual genes which are involved, how
they are regulated, and how they interact with each other.
Finally, what about those Pacific salmon and their sudden post-reproductive
death? Is this not programmed ageing and does it not tell us that it is sex that
is to blame? Actually the answer is 'no'. Pacific salmon belong to a group of
species that have evolved what is called a 'semelparous' life history, i.e. they
have all their offspring at once. If you evolve down the semelparous path (and
the factors driving this have been very well defined by evolutionary theorists),
your life consists mostly of acquiring resources and readying yourself for the
big day. When that day comes, it is important to mobilise all possible metabolic
resources to maximise your reproductive success, even when this is destructive
to the soma. In some species, somatic tissue is even sacrificed directly to feed
the young. In other words, the semelparous soma is the ultimate disposable soma.
The programming is not for ageing but for big-bang reproduction with death as a
side-effect of little or no consequence. We may feel sorry for the salmon that
is sex life is so intimately linked to its death but, all things considered,
there are worse ways to go.
More information:
Professor Tom Kirkwood is with the Institute for Ageing and Health,
University of Newcastle, Newcastle upon Tyne, UK. He recently presented these
findings at the Sasol Scifest in
Grahamstown, South Africa.
Further reading:
Westendorp RGJ, Kirkwood TBL. Human longevity at the cost of reproductive
success. Nature 1998;396:743-746.
Kirkwood TBL. Time of Our Lives: The Science of Human Ageing. London:
Weidenfeld & Nicolson, 1999.
Kirkwood TBL, Austad SN. Why do we age? Nature 2000;408:233-238.
Cournil A, Kirkwood TBL. If you would live long, choose your parents well.
Trends in Genetics 2001;17:233-235.
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