Reflections on an unsolved problem of biology: the evolution of senescence and death

William R. Clark, Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, California, 90024

ABSTRACT

The evolutionary theory of senescence is based largely on principles outlined by Williams in 1957, and consists of two relatively independent parts. The first part builds on ideas first put forward by Medawar, Haldane and others, to explain how something as negative as senescence could have been positively selected in evolution, particularly since most animals in the wild do not reach an age where senescence is expressed. Williams proposed that the genes responsible for the negative effects of senecence (senescence effector genes) were fixed in evolution by a process he called antagonistic pleiotropy, wherein a subset of genes selected because they confer a reproductive advantage early in life may have harmful effects in the post-reproductive period; negative selection against these harmful effects fails because, as pointed out by Medawar, the force of natural selection declines with age. The evolutionary history of senescence-causing genes is seen as a nondirected accumulation of genes selected on a basis independent of senescence per se. In the second portion of his paper, Williams made a series of predictions about how the age of organisms at reproductive maturity, fecundity, lifespan and the timing of the onset of senescence would all interact in the life history of a species. These latter predictions, which do not depend at all on details of the mechanisms of selection of senescence effector genes, have been validated by numerous experiments over the past several decades. On the other hand, it has become increasingly evident that the senescence effector genes did not, as would be predicted by antagonistic pleiotropy, accumulate in a random, non-directed fashion in various species over evolutionary time. Rather, everything we know about these genes suggests they were present in eukaryotic founder cells shortly after, or even congruent with, the emergence of eukaryotes from their prokaryotic ancestors, and have been stringently conserved ever since. Complicated explanations of how so-called "death genes" may have evolved in eukaryotes are thus not required. It is suggested that the evolutionary theory of senescence should be focused on those evolutionary principles that have been validated experimentally, and that the notion of antagonistic pleiotropy be dropped from theories of the evolution of senescence.

 

Some fifty years ago, Peter Medawar launched a series of lectures and discussions that led to what is generally considered the "modern era" of thinking about the evolution of senescence. Medawar summarized his early ruminations in his classic treatise, An Unsolved Problem of Biology (Medawar, 1952). The problem, as Medawar and others (e.g., Haldane, 1941) saw it, was how to explain the evolution of something as negative to the interests of the individual reproductive organism as senescence, which has death as its implicit endpoint. This is especially difficult to visualize since, in the wild, the majority of members of any given species do not live long enough for senescence ever to be expressed. Aside from humans, where senescence is now a major factor in death, senescence is largely seen only in animals kept in zoos or reared in laboratories, where they can be protected from accidental causes of death such as predation, starvation, or physical trauma. Most animals - in some species, the vast majority - die of accidental causes well before senescence begins to be expressed. How could a trait not expressed by the majority of members of a species be acted on by natural selection, and come to be fixed in the species as a whole?

Medawar was among the first to recognize what has become a foundation stone of contemporary evolutionary theories of aging: the declining force of natural selection with age of the individual. Harmful genetic events that are expressed prior to the reproductive period in an animal’s life history will be strongly selected against, whereas the expression of such genes at later stages will not be subject to negative selection. Medawar speculated that spontaneously arising variants of genes that display a harmful effect only later in life - senescence effector alleles - would simply accumulate in a species over evolutionary time; the allelic variants of the genes responsible for Huntington’s chorea and Alzheimer’s disease are often cited as examples. He also raised the possibility that late-acting, harmful genetic alterations could arise in senescence regulator genes, as well as in the senescence effector genes themselves. This concept of senescence regulator genes was not followed up for several decades after Medawar proposed it, but may be his most important contribution to thinking about the evolution of senescence.

These ideas about the origin of genes causing senescence were carried forward a few years later in a seminal paper by George Williams (Williams, 1957). Williams’ paper actually contains two mechanistically independent parts. In the first part, Williams essentially restates and refines slightly the previous ideas of Haldane, Medawar and others about the origin and evolution of genes responsible for senescence. In this context, Williams contributed the term antagonistic pleiotropy to the lexicon of discussions about the evolution of aging. This notion suggests that allelic variants of genes involved in promoting senescence would likely have been positively selected on the basis of whether or not they enhance an individual’s ability to survive until the reproductive period, and/or to carry out reproductive activities in a successful fashion. Some of these variants may, by random chance, have negative effects on the organism at later stages in life, but since there would presumably be no reproductive consequences of these negative effects, natural selection cannot operate to suppress transmission of these alleles to subsequent generations. Given that every allele in any genome can only be positively selected on the basis of its contribution to reproductive fitness, this is a relatively modest extension of previous thinking on the subject. Nevertheless, it is obvious that Williams, like Medawar, felt that an accretion of such late-acting mutations could account for the overall "program" of senescence seen in various species today.

Quite apart from his speculations on the evolutionary origin of genes responsible for senescence (Medawar’s distinction between senescence effector genes and senescence regulator genes is lost in Williams’ 1957 paper), Williams also made a series of important predictions about how reproductive timing and accidental death rates should influence fecundity, senescence and lifespan. By and large these predictions, which have stimulated a great deal of fruitful research in senescence in the past four decades, are not dependent on his ideas about the origins of senescence effector genes. Nevertheless, both sets of ideas are generally included in what is now called the "evolutionary theory of senescence" (hereinafter referred to simply as the evolutionary theory). Most of the early attempts to test the validity of the evolutionary theory were directed to those aspects dealing with the interactions between senescence and species mortality rates, or between senescence and reproductive maturity and fecundity. Such studies, which relied mostly on classical transmission and population genetics, (admirably summarized in Rose, 1991), have largely validated Williams’ predictions.

Most of the elements of the evolutionary theory were laid down at a time when molecular genetics was in its infancy, and it fails to account for a number of features of senescence that have become increasingly apparent in recent years. In particular, there are difficulties with that portion of the theory implying that senescence effector genes gradually accrued in different species over evolutionary time, in a random process not directed toward aging per se. The problem is that the senescence-related genes described so far do not behave that way at all. Recent genetic analyses have shown that the fundamental mechanisms of senescence, and the genes underlying them, are remarkably similar in virtually every eukaryotic organism studied, which is hardly consistent with a random, independent accumulation of late-acting harmful mutations over the evolutionary history of eukaryotes. Senescence does not behave like a gradually accruing genetic pattern, either in terms of fixation of the underlying genes, or of the lack of any apparent random genetic drift that might be expected in a genetically passive and unregulated phenomenon.

Thus, while the initial proposals of Haldane, Medawar, Williams and others offered a way out of a seemingly irresolvable dilemma about the origin and evolution of senescence-related genes, this portion of the resulting evolutionary theory suffers from serious genetic, molecular, and even evolutionary drawbacks. Curtsinger et al. (1994), in studying how stable polymorphisms might arise in large populations, concluded that antagonistic pleiotropy probably plays a limited role in explaining persistence of genetic variation in fitness components. They did not, however, propose explanations for the selection of senescence-related genes. I propose that instead of gradually accruing over long periods of time in a random fashion, nearly all of the genetic elements of senescence - the genes that cause senescence (senescence effector genes), and those that oppose its effects (senescence resistor genes) - were set in place very shortly after, or in some cases even before, the emergence of eukaryotes from their prokaryotic ancestors. These elements have been rigorously conserved through subsequent evolution, with very little change, and thus discussions of how they may have been selected in spite of harmful effects directed toward the individual, and how they could have been selected in individuals not living long enough to express them, must be shifted back to the context of the very earliest stages of eukaryotic phylogeny. A strong case can be made that selection of these elements was driven by two radically new biological parameters defining emerging eukaryotic life forms: endosymbiosis with oxygen-metabolizing prokaryotes, and the use of sex in reproduction. Many of the details of these phenomena that would be relevant to senescence were incompletely known to thinkers forty years ago. It is time for a fresh restatement of certain portions of the evolutionary theory in light of recent advances in molecular genetics. This Perspective is an attempt in that direction.