Abstract
Lay Summary: An evolutionary mechanism of aging was hypothesized 60 years ago to be the genetic trade-off between early life fitness and late life mortality. Genetic evidence supporting this hypothesis was unavailable then, but has accumulated recently. These tradeoffs, known as antagonistic pleiotropy, are common, perhaps ubiquitous.George Williams’ 1957 paper developed the antagonistic pleiotropy hypothesis of aging, which had previously been hinted at by Peter Medawar. Antagonistic pleiotropy, as it applies to aging, hypothesizes that animals possess genes that enhance fitness early in life but diminish it in later life and that such genes can be favored by natural selection because selection is stronger early in life even as they cause the aging phenotype to emerge. No genes of the sort hypothesized by Williams were known 60 years ago, but modern molecular biology has now discovered hundreds of genes that, when their activity is enhanced, suppressed, or turned off, lengthen life and enhance health under laboratory conditions. Does this provide strong support for Williams’ hypothesis? What are the implications of Williams’ hypothesis for the modern goal of medically intervening to enhance and prolong human health? Here we briefly review the current state of knowledge on antagonistic pleiotropy both under wild and laboratory conditions. Overall, whenever antagonistic pleiotropy effects have been seriously investigated, they have been found. However, not all trade-offs are directly between reproduction and longevity as is often assumed. The discovery that antagonistic pleiotropy is common if not ubiquitous implies that a number of molecular mechanisms of aging may be widely shared among organisms and that these mechanisms of aging can be potentially alleviated by targeted interventions.
Highlights
THE PUZZLE OF AGINGThe logic of evolution by natural selection is straightforward
When George Williams first proposed his theory of antagonistic pleiotropy in 1957, he concocted a hypothetical example of a gene that hastened the calcification of arteries during development but led to the calcification of arterial walls in later life
In the past 20 or so years, molecular biology has presented us with a cornucopia of such genes, and of nine predictions Williams made about senescence and aging, six have proven correct over the last six decades [4]
Summary
The logic of evolution by natural selection is straightforward. Within any population, the alleles of individuals that produce the most breeding descendants will increase in frequency in successive generations at the expense of the alleles of individuals less successful at reproduction. To be successful at leaving descendants requires that organisms be successful at surviving—so that they live long enough to reach reproductive age and afterward continue reproducing. By this logic and process, natural selection produces individuals superbly designed to survive and reproduce in their environment.
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