Integrating evolutionary and molecular genetics of aging

Abstract

Aging or senescence is an age-dependent decline in physiological function, demographically manifest as decreased survival and fecundity with increasing age. Since aging is disadvantageous it should not evolve by natural selection. So why do organisms age and die? In the 1940s and 1950s evolutionary geneticists resolved this paradox by positing that aging evolves because selection is inefficient at maintaining function late in life. By the 1980s and 1990s this evolutionary theory of aging had received firm empirical support, but little was known about the mechanisms of aging. Around the same time biologists began to apply the tools of molecular genetics to aging and successfully identified mutations that affect longevity. Today, the molecular genetics of aging is a burgeoning field, but progress in evolutionary genetics of aging has largely stalled. Here we argue that some of the most exciting and unresolved questions about aging require an integration of molecular and evolutionary approaches. Is aging a universal process? Why do species age at different rates? Are the mechanisms of aging conserved or lineage-specific? Are longevity genes identified in the laboratory under selection in natural populations? What is the genetic basis of plasticity in aging in response to environmental cues and is this plasticity adaptive? What are the mechanisms underlying trade-offs between early fitness traits and life span? To answer these questions evolutionary biologists must adopt the tools of molecular biology, while molecular biologists must put their experiments into an evolutionary framework. The time is ripe for a synthesis of molecular biogerontology and the evolutionary biology of aging.

Figure 1

Intensity of selection on survival. The force of selection on survival rate declines as a function of age, a key insight first developed by Haldane and Medawar and later mathematically formalized by Hamilton [1, 8, 10, 38]; see Baudisch [41] for a qualifier. Haldane [8], Medawar [1], and Williams [2] realized that the declining strength of selection “opens the door” for mutations with either neutral or beneficial effects during youth, when selection is intense, but with deleterious effects at older ages, when selection is negligible (so-called “selection shadow”). Since such alleles have unchecked negative consequences at old age when selection is weak, these alleles can spread in the population and lead to the evolution of aging.