Fisher, Medawar, Hamilton and the Evolution of Aging

Abstract

THE idea that senescent decline in the performance of biological systems must have an evolutionary basis traces back almost to the beginnings of evolutionary biology (Rose 1991, Chap. 1), although Darwin does not seem to have discussed the problem. At first sight, the nearly universal existence of senescence in species of multicellular organisms is paradoxical, given that natural selection supposedly causes the evolution of increased, not decreased, fitness. As discussed by Comfort (1979), many biologists have, therefore, taken the view that senescence reflects an inevitable process of damage accumulation with age, and indeed an analog of senescence can be seen in complex machines such as cars (Gavrilov and Gavrilova 1991). But unicellular organisms, such as bacteria, which propagate simply by binary fission, and the germ lines of multicellular organisms, have been able to propagate themselves without senescence over billions of years, showing that biological systems are capable of ongoing repair and maintenance and so can avoid senescence at the cellular level. Senescence cannot, therefore, just be an unavoidable cumulative result of damage. The large amount of variation among different species in their rates of senescence also clearly indicates that aging is subject to variation and selection (Comfort 1979; Finch 1990; Rose 1991; Wachter and Finch 1997). This conclusion is backed up by the existence of both quantitative genetic variation and major gene mutations affecting the rate of aging (Finch 1990; Rose 1991; Wachter and Finch 1997). Modern evolutionary theory has demonstrated that, in species with a clearcut distinction between parent and offspring, senescence is a virtually inevitable result of the fact that genes that affect survival or fecundity only early in life have a greater selective impact than genes whose effects are manifest only late in life. The purpose of this Perspectives article is to trace the history of this idea, with especial emphasis on William Hamilton's (1966) classic paper and its influence on subsequent work. This was motivated by Hamilton's untimely death earlier this year and the fact that his work on the evolution of senescence has probably received less attention than his other seminal contributions to evolutionary theory. Fisher called r the Malthusian parameter of the population, in reference to Malthus's preoccupation with the supposedly inevitable exponential increase in numbers of the human species. Although not mentioned by Fisher, this result traces back to the work of Euler (1760) and Sharpe and Lotka (1911). r is now commonly referred to as the “intrinsic rate of increase” of the populations, and Equation 1 is often called the Euler-Lotka equation. This is the reproductive value of individuals of age x and measures their contribution to the future ancestry of a population growing at rate r, normalized to a value of unity at the time of conception. Fisher (1930) stated (p. 27), “The direct action of Natural Selection must be proportional to this contribution.” He showed a curve of reproductive value for Australian women, which rises with advancing age during childhood, reaches a maximum around 19, and then declines steadily, reaching zero at close to 50, when most women have reached menopause. He commented (p. 29), It is probably not without significance in this connexion that the death rate in Man takes a course generally inverse to the curve of the reproductive value. The minimum of the death rate curve is at twelve, certainly not far from the primitive maximum of the reproductive value; it rises more steeply for infants, and less steeply for the elderly than the curve of reproductive value falls, points which qualitatively we should anticipate, if the incidence of natural death had been to a large extent moulded by the effects of differential survival. These ideas greatly influenced Medawar (1946, 1952) when he was formulating the first explicit model of the evolution of aging. Medawar took it for granted that Fisher's reproductive value measures the relative effectiveness of selection at age x. Given this premise, a hypothetical mutant gene that increases survival over a small time interval at an age when reproductive value is high would thus have a higher net effect on fitness than a gene acting at an age when reproductive value is low. Since reproductive value declines over much of adult life, this leads to the expectation that selection will be more effective in improving performance early in adult life than late in life. He pointed out that this means that deleterious alleles with effects restricted to late stages of life would equilibrate at higher frequencies at mutation-selection balance than alleles that act earlier, the process now referred to as the “mutation-accumulation” theory of aging (Rose 1991, Chap. 4). Late-acting deleterious mutations are, of course, familiar to medical geneticists. Haldane (1941, pp. 192–194) had previously suggested that t