Evolution of Aging

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.