EVOLUTION OF AGING

There are remarkable differences in observed aging rates and longevity records across different biological species (compare, for example, mice and humans). These differences are a result of what is known as the evolution of aging, a result of the processes of mutation and selection. The attempt to understand the biological evolution of aging and life span was sparked, in part, by the puzzling life cycles of some biological species. For example, a bamboo plant reproduces vegetatively (asexually) for about one hundred years, forming a dense stands of plants. Then, in one season, all the plants flower simultaneously, reproduce sexually and then die. About one hundred years later the process is repeated. This and the observation of other "suicidal" life cycles of various species, such as salmon, promoted the idea that sexual reproduction may come at the cost of species longevity. Thus, in addition to mutation and selection, the reproductive cost, or, more generally, the trade-offs between different traits of organisms, may contribute to the evolution of species aging and longevity. The evolution of aging is also related to the genetics of aging, because it studies the evolution of heritable manifestations of aging in subsequent generations.

For many decades, the evolution of aging was a puzzling phenomenon, especially in light of the Darwinian theory of evolution by natural selection. Darwin's theory is based on the idea of random and heritable variation of biological traits between individuals (caused by mutations), with subsequent natural selection for preferential reproduction of those individuals who are particularly fit to live in a given environment. Therefore, it is expected (and observed) that biological evolution acts to increase the fitness and performance of species evolving in successive generations. From this optimistic perspective, it was difficult to understand why natural selection seemed to result in such bizarrely injurious features as senescence and late-life degenerative diseases, rather than eternal youth and immortality. How does it happen that the developmental program formed by biological evolution—after having accomplished the miraculous success that leads from a single cell at conception, to a subsequent birth, then to sexual maturity and productive adulthood—fails to maintain the accomplishments of its own work? Another theoretical difficulty in understanding the evolution of aging was the timing problem—many manifestations of aging happen after the reproductive period of evolving organisms, at ages that are beyond the reach of natural selection.

The problem of biological evolution of aging has been studied over the years in a purely theoretical and abstract way by August Weismann (1889), Ronald Fisher (1930), Peter Medawar (1952), George Williams (1957), William Hamilton (1966), Brian Charlesworth (1994) and other researchers. The resulting evolutionary theory of aging has been partially tested by direct evolutionary experiments on laboratory fruit flies and on natural populations of guppies. Researchers found that aging and life span do evolve in subsequent generations of biological species in the expected direction, depending on particular living conditions. For example, a selection for later reproduction (artificial selection of late-born progeny for further breeding) produced, as expected, longer-lived fruit flies, while placing animals in a more dangerous environment with high extrinsic mortality redirected evolution, as predicted, to a shorter life span in subsequent generations. Therefore, the early criticism of the evolutionary theory of aging as merely a theoretical speculation, with limited and indirect supporting evidence obtained from retrospective and descriptive studies, has been overturned. On the contrary, the evolutionary plasticity of aging and longevity is now an established experimental fact.

The evolutionary theory of aging may be considered as part of a more general life history theory, which tries to explain how evolution designs organisms to achieve reproductive success (that is, to avoid extinction). Life history theory is based on mathematical methods of optimization models with specific biological constraints. Among the questions posed and answered by the life history theory are: Why are organisms small or large? Why do they mature early or late? Why do they have few or many offspring? Why do they have a short or a long life? Why must they grow old and die?

The latter two questions represent the entire scientific agenda of the evolutionary theory of aging. Therefore, it could be said that the evolutionary theory of aging is a subset of the life history theory. On the other hand, the evolutionary theory of aging is considered to be the intellectual core of the biodemography of aging and longevity. Biodemography is a multidisciplinary approach, integrating methods of biological and social sciences in an attempt to explain demographic data (e.g., life tables) and processes (e.g., mortality trends).

Current evolutionary explanations of aging and limited longevity of biological species are based on two major evolutionary theories: the mutation accumulation theory (Medawar) and the antagonistic pleiotropy theory (Williams). These two theories are based on the idea that, from the evolutionary perspective, aging is an inevitable result of the declining force of natural selection with age. For example, a mutant gene that kills young children will be strongly selected against (will not be passed to the next generation), while a lethal mutation with effects confined to people over the age of eighty will experience no selection because people with this mutation will have already passed it to their offspring by that age. So, over successive generations, late-acting deleterious mutations will accumulate, leading to an increase in mortality rates late in life (mutation accumulation theory). Moreover, late-acting deleterious genes may even be favored by selection and be actively accumulated in populations if they have any beneficial effects early in life (antagonistic pleiotropy theory).

Note that these two theories of aging are not mutually exclusive—both evolutionary mechanisms may operate at the same time. The main difference between the two theories is that in the mutation accumulation theory, genes with negative effects at old age accumulate passively from one generation to the next, while in the antagonistic pleiotropy theory these genes are actively kept in the gene pool by selection. The actual relative contribution of each evolutionary mechanism in species aging has not yet been determined, and this scientific problem is now the main focus of research of evolutionary biologists.

Interestingly, since the 1950s no fundamentally new evolutionary theories of aging have been proposed. There have been, however, attempts to find a better name for the antagonistic pleiotropy theory, and to specify in more detail how one and the same gene could have both deleterious and beneficial effects. The disposable soma theory, which was proposed by Thomas Kirkwood in 1977 and developed further by Kirkwood and Robin Holliday in 1979, considered a special class of gene mutations with the following antagonistic pleiotropic effects: mutations that save energy for reproduction (positive effect) and other accuracy promoting devices in somatic cells (negative effect). The authors of the disposable soma theory argued that "it may be selectively advantageous for higher organisms to adopt an energy-saving strategy of reduced accuracy in somatic cells to accelerate development and reproduction, but the consequence will be eventual deterioration and death." While discussing the disposable soma theory, it is important to keep in mind that it was initially proposed to provide evolutionary justification for another (failed) theory of aging—the error catastrophe theory, which considered aging as a result of breakdown in accuracy of macromolecular synthesis within somatic cells. Most researchers agree that the disposable soma theory is a special, more narrowly defined variant of the antagonistic pleiotropy theory of aging. According to Kirkwood and Holliday, "the disposable soma theory is, in a sense, a special case of Williams's (1957) pleiotropic gene hypothesis [antagonistic pleiotropy theory], the gene in question controlling the switch to reduced accuracy in somatic cells. The good effect of the gene is the reduced investment of resources in the soma, while the bad effect is the ultimate somatic disintegration, or ageing."

In addition to legitimate theoretical and experimental studies of the evolution of aging, there is also a more ambitious pro-evolutionary approach that aims "to overthrow the present intellectual order of gerontology [science of aging], and to replace it with one based on evolutionary and genetic foundations" (Rose).

This ambitious pro-evolutionary approach considers all other theories of biological aging— such as the free-radical theory of aging (Beckman and Ames; Harman), the somatic mutation theory of aging (Morley), the reliability theory of aging (Gavrilov and Gavrilova, 1991; 2001), the mitochondrial theory of aging (Gershon), the waste accumulation theory of aging (Terman), and the error catastrophe theory of aging—as far less important to gerontology: "the evolutionary biology of aging, rather than, for example, cell biology, should be the intellectual core of gerontology" (Rose).

Apparently, this ambitious pro-evolutionary doctrine is based on a literal interpretation of the following statement by Theodosius Dobzhansky (1900–1975) : "Nothing in biology makes sense except in the light of evolution" (Rose).

The claim has been made that a simple evolutionary model can explain even the observed age-trajectory of mortality curves, including the late-life mortality plateaus (the tendency of mortality curves to level off at advanced ages), but other investigators have found these claims to be unsubstantiated. Thus, declarations that the evolutionary theory of aging should have a dominating status among other biological theories of aging remain to be justified.

Evolution of scientific ideas on the evolution of aging

Genetic program for death. August Weismann, the great German theorist of the nineteenth century, was one of the first biologists to use evolutionary arguments to explain aging. His initial idea was that a specific death-mechanism exists, designed by natural selection to eliminate the old, and therefore worn-out, members of a population. The purpose of this programmed death of the old, Weisman thought, was to make space and resources available for younger generations. He probably came to this idea while reading the notes of Alfred Russel Wallace (one of Darwin's contemporaries and a co-discoverer of natural selection), which he later cited in his essay "The Duration of Life" (1889): "Wallace wrote that when one or more individuals have provided a sufficient number of successors, they themselves, as consumers of nourishment in a constantly increasing degree, are an injury to those successors. Natural selection therefore weeds them out, and in many cases favors such races as die almost immediately after they have left successors." Weismann enthusiastically accepted and developed further this idea, which also corresponded well with the hiring practices of German universities of that time, whereby a new candidate had to wait for the death of an old professor to obtain a position.

Suggesting the theory of programmed death, Weismann had to think about the exact biological mechanisms executing this death program, and he came to the idea that there is a specific limitation on the number of divisions that somatic cells can undergo. Specifically, he suggested "that life span is connected with the number of somatic cell generations which follow after each other in the course of an individual life, and that this number, like the life span of individual generations of cells, is already determined in the embryonic cell" (Weismann, 1892). Weismann tried to explain "the different life span of animals by making it dependent on the number of cell generations which was the norm for each different species" (1892). Remarkably, his purely theoretical speculation on the existence of a cell division limit was experimentally confirmed many decades later by H. Earle Swim (1959); and this scientific discovery was then successfully developed and publicized by Leonard Hayflick (Gavrilov and Gavrilova, 1991).

Weismann eventually stopped writing about the "injuriousness" of the old and changed his evolutionary views, considering old organisms not to be harmful, but simply neutral for the biological species: "In regulating duration of life, the advantage to the species, and not to the individual, is alone of any importance. This must be obvious to any one who has once thoroughly thought out the process of natural selection. It is of no importance to the species whether the individual lives longer or shorter, but it is of importance that the individual should be enabled to do its work towards the maintenance of the species. . . . The unlimited existence of individuals would be a luxury without any corresponding advantage" (Weismann, 1889).

Subsequent studies confirmed that Weismann's decision to abandon the initial idea of programmed death was a wise one. Many scientific tests of the programmed death hypothesis have been made, and some of them are summarized here.

One way of testing the programmed death hypothesis is based on a comparison of life-span data for individuals of a single species in natural (wild) and protected (laboratory, domestic, civilized) environments. If the hypothesis is correct, there should not be very large differences in the life spans of adult individuals across compared environments. Indeed, for a self-destruction program to arise, take hold, and be maintained in the course of evolution, it must at least have some opportunity, however small, of expression in natural (wild) conditions. Consequently, the age at which such a program is "switched on" cannot be too high, otherwise (because of the high mortality in the wild from predators, hunger, infections, and harsh natural conditions) no one would live to the fateful age, and the self-destruction mechanism would not be able to be expressed. It follows from this that life spans, in even the most favorable conditions, cannot significantly exceed the ages reached by the most robust individuals in the wild—if, of course, the concept is correct.

The analysis of the actual data reveals, however, a picture completely opposite to what would be expected from the programmed death theory: the life spans of organisms in protected environments greatly exceed the life spans observed in natural (wild) conditions. For example, the chaffinch (Fringilla coelebs ) can live for twenty-nine years in captivity. However, in the wild this is practically impossible, since about a half of all of these birds perish during their first year from hunger, cold, diseases, and attacks by predators, and the mean life span is only about 1.4 to 1.5 years. As a result of this high mortality, only 0.1 percent of the initial number of chaffinches survives to age eleven in the wild. Similar observations were made for field voles (Microtus arvalisPall). In protected laboratory conditions, the average life span of voles is about seven or eight months, while individual specimens survive to twenty-five months. In the wild, however, the average life span of voles is only 1.2 months, and only 0.1 percent survive to ten months. Observations like these are common for many biological species. Thus, if one attempts to estimate the age of programmed death on the basis of life spans in laboratory conditions, it becomes clear that no death program could arise or be maintained in evolution, if only because it would not be able to come into operation in natural conditions, where practically no individual lives to the required age.

The same conclusion is reached from an analysis of data on the human life span. At present, the mean life expectancy in developed countries is between seventy and eighty years, while the documented record for longevity is 122 years. If we take these figures as an estimate for the age range in which the death program is switched on, we are forced to admit that such a program could not have arisen in human evolution, since, according to paleodemographic data, virtually nobody survived to such an age. For example, only half of those born in the Late Paleolithic era (30,000–10,000 B.C.E.) reached eight or nine years, and only a half of those born in the Neolithic era (6,000–2,000 B.C.E.) reached twenty-six years. Even in the Middle Ages, life expectancy at birth was no greater than twenty-nine years. Investigations of the skeletons of American Indians have shown that just two centuries ago only 4 percent of the population survived to age fifty. Note for comparison, that the probability of surviving to this age in developed countries today is 94 to 96 percent. If these facts are compared, it is difficult to refrain from posing the following question: can the guaranteed destruction of a few old people, who are chance survivors and doomed in the wild, be a sufficient evolutionary basis for the formation and preservation of a special self-destruction program in the human genome? Viewed in this light, the inconsistency of the programmed death hypothesis becomes obvious.

In addition, if the question of whether death is programmed is approached from the evolutionary point of view, it becomes obvious that special mechanisms for the termination of life could hardly help an individual to fight successfully for his survival and the survival of his progeny. On the contrary, those individuals in whom the action of such a program had been impaired by some spontaneous mutation would quickly displace all the remaining individuals, since in their longer life span they would produce more offspring, or at least could increase the survival of their offspring by providing longer parental support.

In 1957, George Williams, the author of another evolutionary theory of aging summarized the critical arguments against the programmed death theory (called Weismann's theory for historical reasons). Here is a partial list of his most forceful critical arguments:

1. The extreme rarity, in natural populations, of individuals that would be old enough to die of the postulated death-mechanism
2. The failure of several decades (now over a century) of gerontological research to uncover any death mechanism (the discovery of apoptosis, or programmed cell death, is irrelevant to this discussion, which is focused on the whole organism rather than some of the organisms somatic cells)
3. the difficulties involved in visualizing how such a feature could be produced by natural selection

There is, however, one good reason why this dead theory of programmed death should not be ignored as outdated and should not be forgotten—the ghosts of the theory can still be found in many publications, including the Encyclopaedia Britannica which states: "Locked within the code of the genetic material are instructions that specify the age beyond which a species cannot live given even the most favorable conditions," (Encyclopaedia Britannica, 15th ed., 1998, p. 424.)

As for August Weismann, he should be credited with at least four significant contributions to aging studies:

1. Suggesting the first evolutionary theory of aging that attracted the attention of other researchers
2. Abandoning his own theory when he understood that it was incorrect—this honest decision allowed new evolutionary theories of aging to develop
3. Correctly predicting the existence of a cell-division limit—without having any data at all
4. Discriminating between germ cells and the somatic cells ("soma"), with a prophetic understanding of "the perishable and vulnerable nature of the soma." (Weismann, 1889); this idea is related to the more recent disposable soma theory of aging

Mutation accumulation theory of aging

The mutation accumulation theory of aging, suggested by Peter Medawar in 1952, considers aging as a by-product of natural selection (similar to the evolutionary explanation for the blindness of cave animals). The probability of an individual reproducing depends on his age. It is zero at birth and reaches a peak in young adults, after which it decreases due to the increased probability of death linked to various external (predators, illnesses, accidents) and internal (senescence) causes. In such conditions, deleterious mutations expressed at a young age are severely selected against, due to their high negative impact on fitness (number of offspring produced). On the other hand, deleterious mutations expressed only later in life are rather neutral to selection, because their bearers have already transmitted their genes to the next generation.

Mutations can affect fitness either directly or indirectly. For example, a mutation increasing the risk for leg fracture, due to a low fixation of calcium, may be indirectly as deleterious to fitness as a mutation directly impairing the eggs nesting in the uterus. From an evolutionary perspective, it does not really matter exactly why the organism is at risk not to reproduce—either because many spontaneous abortions occur, or because it becomes an easy prey for a predator (in nature) or for a criminal (in society).

According to this theory, persons loaded with a deleterious mutation have fewer chances to reproduce if the deleterious effect of this mutation is expressed earlier in life. For example, patients with progeria (a genetic disease with symptoms of premature aging) live only for about twelve years, and, therefore, they cannot pass their mutant genes to the next generation. In such conditions, the progeria stems only from new mutations and not from the genes of parents. By contrast, people expressing a mutation at older ages can reproduce before the illness occurs, as it is the case with familial Alzheimer's disease. As an outcome, progeria is less frequent than late diseases, such as Alzheimer's disease, because the mutant genes responsible for the Alzheimer's disease are not removed from the gene pool as readily as progeria genes, and can thus accumulate in successive generations. In other words, the mutation accumulation theory predicts that the frequency of genetic diseases should increase at older ages.

Mutation accumulation theory allows researchers to make several testable predictions. In particular, this theory predicts that the dependence of progeny life span on parental life span should not be linear, as is observed for almost any other quantitative trait demonstrating familial resemblance (e.g., body height). Instead, this dependence should have an unusual nonlinear shape, with increasing slope for the dependence of progeny life span on parental life span for those with longer-lived parents. This prediction follows directly from the key statement of this theory that the equilibrium gene frequency for deleterious mutations should increase with age at onset of mutation action because of weaker (postponed) selection against later-acting mutations. (The term equilibrium gene frequency refers here to the ultimate time-independent gene frequency, which is determined by mutation-selection balance [equilibrium between mutation and selection rates]; see Charlesworth, 1994).

According to the mutation accumulation theory, one would expect the genetic variability for life span (in particular, the additive genetic variance responsible for familial resemblance) to increase with age. (Additive gene variance refers to a variance of additive genetic origin; that is, a variation due to additive effects of genes on the studied trait in genetically heterogeneous populations. This variance increases with an increase in mutation frequencies.) The predicted increase in additive genetic variance could be detected by studying the ratio of additive genetic variance to observed phenotypic variance. This ratio (the so-called narrow-sense heritability of life span) can be easily estimated as the doubled slope of the regression line for the dependence of offspring life span on parental life span. Thus, if age at death were indeed determined by accumulated late-acting deleterious mutations, one would expect this slope to become steeper with higher parental ages at death. This prediction was tested through the analysis of genealogical data on familial longevity in European royal and noble families, data well known for their reliability and accuracy. It was found that the regression slope for the dependence of offspring life span on parental life span increases with parental life span, exactly as predicted by the mutation accumulation theory (see Gavrilova et al.). Thus, the current status of the mutation accumulation theory could be characterized as a productive working hypothesis, pending further validation.

Antagonistic pleiotropy theory of aging ("pay later" theory)

The theory of antagonistic pleiotropy is based on two assumptions. First, it is assumed that a particular gene may have an effect not only on one trait, but on several traits of an organism (pleiotropy). The second assumption is that these pleiotropic effects may affect individual fitness in opposite (antagonistic) ways. This theory was first proposed by George Williams in 1957, who noticed that "natural selection may be said to be biased in favor of youth over old age whenever a conflict of interests arises" (Williams, 1957).

According to Williams, this conflict arises from "pleiotropic genes . . . that have opposite effects on fitnesses at different ages. . . . Selection of a gene that confers an advantage at one age and a disadvantage at another will depend not only on the magnitudes of the effects themselves, but also on the times of the effects. An advantage during the period of maximum reproductive probability would increase the total reproductive probability more than a proportionately similar disadvantage later on would decrease it. So natural selection will frequently maximize vigor in youth at the expense of vigor later on and thereby produce a declining vigor (aging) during adult life." (Williams). These verbal arguments were later proved mathematically by Brian Charlesworth (1994).

Williams was suggesting the existence of so-called pleiotropic genes (those demonstrating favorable effects on fitness at a young age and deleterious ones at old age), which could explain the aging process. Such genes are maintained in the population due to their positive effect on reproduction at a young age, despite their negative effects at a post-reproductive age (their negative effects in later life will look exactly like the aging process).

For the purpose of illustration, suppose that there is a gene that increases the fixation of calcium in bones. Such a gene may have positive effects at a young age, because the risk of bone fracture and subsequent death is decreased, but negative effects in later life, because of increased risk of osteoarthritis due to excessive calcification. In the wild, such a gene would have no actual negative effect, because most animals would die long before its negative effects could be observed. There is then a trade-off between an actual positive effect in young individuals and a potential negative one in old individuals: this negative effect may become important only if animals live in protected environments such as zoos or laboratories.

Antagonistic pleiotropy theory explains why reproduction may come with a cost for species longevity, and may even induce death (see the story on bamboo plants and salmon life cycles at the beginning of this article). Indeed, any mutations favoring more intensive reproduction (more offspring produced) will be propagated in future generations even if these mutations have some deleterious effects in later life. For example, mutations causing overproduction of sex hormones may increase the sex drive, libido, reproductive efforts, and reproductive success— and therefore be favored by selection, despite causing prostate cancer (in males) and ovarian cancer (in females) later in the life. Thus, the idea of reproductive cost, or, more generally, of trade-offs between different traits follows directly from antagonistic pleiotropy theory.

The trade-offs between reproduction (reproductive success, fitness, vigor) and longevity were predicted by Williams as "testable deductions from the theory." Specifically, he predicted, "rapid individual development should be correlated with rapid senescence. Reproductive maturation is the most important landmark in the life-cycle for the evolution of senescence. Senescence may theoretically begin right after this stage in development. So the sooner this point is reached, the sooner senescence should begin, and the sooner it should have demonstrable effects." Another prediction of the trade-offs between reproductive capacity (vigor) and longevity was made by Williams in the following way: "successful selection for increased longevity should result in decreased vigor in youth."

These predictions were confirmed later in selection experiments using the fruit fly, Drosophila melanogaster. By restricting reproduction to later ages, the intensity of selection on the later portions of the life span was increased. This selection for late reproduction extended the longevity of the selected populations. Furthermore, a reduced fecundity was observed among the long-lived flies, supporting the idea of a trade-off between fertility and survival, as predicted by the antagonistic pleiotropy theory. A similar trade-off between fecundity and longevity was observed when fruit flies were selected directly for longevity. In another selection experiment with different levels of extrinsic mortality, the descendants from populations with low extrinsic mortality demonstrated increased longevity, longer development times, and decreased early fecundity. The general finding from these selection experiments in fruit flies is that increased longevity is associated with depression of fitness (vigor) in early life, just as Williams predicted.

Trade-offs between longevity and reproduction have also been found in experiments with soil-dwelling round worms (the nematode Caenorhabditis elegans ), where a number of long-lived mutants have been identified. When long-lived mutants were reared together with normal (wild-type) individuals under standard culture conditions, neither of them exhibited a competitive advantage, contrary to theoretical predictions. However, when cultures were exposed to starvation cycles (alternatively fed and starved)— mimicking field conditions in nature—the wild type quickly outcompeted (outnumbered) the long-lived mutant. These findings demonstrate that mutations that increase life span do indeed exhibit some fitness cost, thereby supporting the antagonistic pleiotropy theory of aging.

Studies on humans, however, have been less convincing. One study found that long-lived people (women in particular) did have impaired fertility at a young age—as predicted, in general, by antagonistic pleiotropy theory, and in particular, by disposable soma theory. However, serious methodological flaws were later found in that study, and its findings proved to be inconsistent with findings of many other researchers, including historical demographers analyzing human data (see reviews in Gavrilov and Gavrilova, 1999; Le Bourg, 2001). Therefore, more additional studies on this subject are required.

Implications for aging research

Evolutionary biologists have always been very generous with gerontologists in providing advice and guidance on how to do aging research "in directions that are likely to be fruitful" (Williams). Surprisingly, this generous intellectual assistance proved to be extremely injurious for aging studies in the past. This happened because evolutionary theory was interpreted in such a way that the search for single-gene mutations (or life-extending interventions) with very large positive effects on life span was considered a completely futile task, destined for failure for fundamental evolutionary reasons. Researchers were convinced by the forceful evolutionary arguments of George Williams that "natural selection will always be in greatest opposition to the decline of the most senescence-prone system" and, therefore, "senescence should always be a generalized deterioration, and never due largely to changes in a single system. . . . This conclusion banishes the fountain of youth to the limbo of scientific impossibilities where other human aspirations, like the perpetual motion machine and Laplace's 'superman' have already been placed by other theoretical considerations. Such conclusions are always disappointing, but they have the desirable consequence of channeling research in directions that are likely to be fruitful."

As a result of this triumphant evolutionary indoctrination, many exciting research opportunities for life span extension were squandered for a half a century, until the astonishing discovery of single-gene mutants with profoundly extended longevity was ultimately made (see Lin et al., 1997; 1998; Migliaccio et al.), despite all discouraging predictions and warnings based on evolutionary arguments.

Recent discoveries of life-span-extending mutations are spectacular. A single-gene mutation (daf-2) more than doubles the life span of nematodes, keeping them active, fully fertile (contrary to predictions of the disposable soma theory), and having normal metabolic rates. Another single-gene mutation, called methuselah, extends the average life span of fruit flies by about 35 percent, enhancing also their resistance to various forms of stress, including starvation, high temperature, and toxic chemicals. Finally, a single-gene mutation was found in mice, extending their life span by about 30 percent and also increasing their resistance to toxic chemicals. Researchers involved in these studies came to the following conclusion:

The field of ageing research has been completely transformed in the past decade. . . . When single genes are changed, animals that should be old stay young. In humans, these mutants would be analogous to a ninety year old who looks and feels forty-five. On this basis we begin to think of ageing as a disease that can be cured, or at least postponed. . . . The field of ageing is beginning to explode, because so many are so excited about the prospect of searching for—and finding—the causes of ageing, and maybe even the fountain of youth itself. (Guarente and Kenyon).

Now, when single-gene, life-extending mutations are found, evolutionary biologists are presented with the task of reconciling these new discoveries with the evolutionary theory of aging. They are certain to succeed in this task, however, as evolutionary theories of aging are very flexible and can be adjusted to almost any new finding.

However, gerontologists will also have to learn their lessons from the damage caused by decades of misguided research, when the search for major life-extending mutations and other life-extension interventions was equated by evolutionary biologists with the construction of a perpetual motion machine. Perhaps some leads for getting wisdom from this lesson can be found in the title of a recent scientific review on evolution of aging: "Evolutionary Theories of Aging: Handle With Care" (Le Bourg, 1998).

Natalia S. Gavrilova Leonid A. Gavrilov

See also Genetics; Longevity: Reproduction; Longevity: Selection; Mutation; Theories of Biological Aging.

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