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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.
Introduction
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.
ENCYCLOPEDIA OF LIFE SCIENCES / & 2002 Macmillan Publishers Ltd, Nature Publishing Group / www.els.net
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.
ENCYCLOPEDIA OF LIFE SCIENCES / & 2002 Macmillan Publishers Ltd, Nature Publishing Group / www.els.net
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.
ENCYCLOPEDIA OF LIFE SCIENCES / & 2002 Macmillan Publishers Ltd, Nature Publishing Group / www.els.net
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
nongenetic.
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 / www.els.net
Future Challenges
Ageing and Reproduction
ENCYCLOPEDIA OF LIFE SCIENCES / & 2002 Macmillan Publishers Ltd, Nature Publishing Group / www.els.net
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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 / www.els.net