Aging and Death

Senescence and aging, used interchangeably here, are defined as a persistent decline in the survival probability or reproductive output of an individual because of internal physiological deterioration. In other words, we and other organisms become inherently more fragile as we age. It is important to distinguish the progressive and inherent dilapidation of aging from nonaccelerating sources of injury or death such as lightning strikes, car crashes, or falls from cliffs. Consider an analogy to a huge population of glass test tubes in a science laboratory.43 Test tubes occasionally are dropped and broken. Assume that all breakage is accidental and has nothing to do with progressive deterioration, such as a thinning of glass through handling. The test tubes will tend to decline in number at a stochastically predictable rate (like radioactive decay) and the population eventually will go extinct. However, in the absence of aging, the probability of breakage per unit time for an old codger test tube is no greater than that for a brand new one, and some test tubes by chance may survive for extremely long periods of time.

Living organisms are unlike our idealized population of test tubes. Beyond a certain age typically associated with the onset of reproductive capacity, the probabilities of death tend to increase. Consider girls and women in the United States. The lowest per capita death rates are for ten- and eleven-year-olds, but after that, mortality rates double about every eight years.44 For instance, the average risk of death for a woman of sixty-eight years is twice that of an average sixty-year-old, and a hundred and twenty-eight times that of an average twelve-year-old! Such demographics have not escaped the notice of life insurance companies, which typically double the rates for approximately every eight years of advancing age.

The marked acceleration of death probabilities with age also explains why there are no ancient humans alive today.45 Hypothetical two-hundred-year-olds would have a death rate about ten-million-fold higher than that of our twelve-year-olds. By contrast, if a fountain of youth existed such that the death rates of twelve-year-olds remained in effect forever, we would live on average about 1,200 years, and about one person in a thousand today would have been born near the end of the last Ice Age, about ten thousand years ago!

The problem of aging becomes more agonizing when we appreciate that living organisms, unlike test tubes, possess evolved capacities for self-repair. Indeed, such capacity is almost a defining criterion for life. Repair occurs at many levels, ranging from the physiological mending of cuts and broken bones, to immune-mediated recovery from infectious diseases, to the recombinational repair of molecular DNA damages. Given the evident capacity of living creatures to heal themselves, there would seem to be no exigency that individuals age and die. Yet they do. How can natural selection have permitted this state of affairs?

Let us return to the test tube analogy and modify the scenario in a lifelike direction. Suppose a laboratory manager replaces each broken test tube by the purchase of a new young one, and marks the date of replacement on the new tube. When the population of unbroken test tubes is examined twenty years later, many newer test tubes will populate the laboratory simply because the older ones had a greater cumulative opportunity to break. Imagine now that a manufacturing defect makes test tubes of a particular age extremely fragile. The lab manager would hardly notice if the fragility were confined to old test-tubes, because few would reach the affected age anyway. However, a manufacturing defect that made young test tubes fragile would be apparent quickly, and the lab manager probably would contact the supplier for free replacements. The evolutionary point is that natural selection is more likely to eliminate harmful mutations in young individuals than in old ones.

Similarly, senescence and death in real organisms are features that evolved as logical consequences of the declining force of natural selection through successive age classes in a population. The strength of selection on genes in eighty-year-olds inevitably is less than the strength of selection on the same genes in teenagers. Natural selection is more indifferent to the problems of somatic deterioration in old age because these problems are trivial on gene representation in successive generations compared to any difficulties that appear earlier in life. Thus, aging and death exist not because they violate some rule of evolution, but rather because natural selection simply fails to pay sufficient attention to the matter.

Much like the vision of the Nup peoples of Nigeria described earlier, evolutionary geneticists view senescence and death as virtually inevitable repercussions of organismal reproduction. To look at it another way, consider a large, nonsenescent population with individuals of various ages, as depicted in the box at the top of Figure 5.3. Because the population initially is not aging, the probabilities (p) of survival from one age class to the next by definition are equal (i.e., p1 = p2 = p3 . . .). If accidental deaths occur and if the population is to survive, individuals must reproduce, thereby generating new members of the age zero cohort (see Figure 5.3, bottom). However, with procreation come age-specific selection pressures favoring reproduction earlier rather than later in life. These selective forces arise because individuals with proclivities for late as opposed to early reproduction have a greater exposure to

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a) mutation accumulation b) antagonistic pleiotropy

Figure 5.3 Diagrammatic view of natural selection's influence on the evolution of aging. Above: mean probabilities (p) of organismal survival through successive age classes within an age-structured population. If the population shows accidental deaths only and no aging, then pi = p2 = . . . pn 0. Below: two alternative hypotheses for how diminishing selective pressures through successive age classes in a population of reproducing individuals can lead to age-specific negative (—) and positive (+) genetic features characteristic of senescence. In all diagrams, circle sizes are proportional to the numbers of individuals in each age class, and arrows pointing right and left indicate population impacts via relative survival and fecundity, respectively.

accidental deaths and, thus, are likely to leave fewer immediate offspring; and early propagators benefit further when some of their descendants themselves survive to reproduce.

Such reasoning has been formalized mathematically into a population genetics theory that appears to have solved the evolutionary paradox of aging.46 This theory has received support from laboratory experiments on fruit flies in which researchers forced natural selection to pay greater attention to individuals of old age. In population cages, all eggs produced by flies less than three weeks old were discarded such that only eggs laid late in a fruit fly's life survived to beget the next generation. Under this selective regime, any genes favoring longer survival and age-delayed reproduction were much more advantageous than before, and conversely, any genes promoting early reproduction were selected against. After a mere twelve generations, late-reproducing flies had evolved a 10 percent longer lifespan. The experiments were continued, and flies with life expectancy twice that of the originals recently have been produced! These results are consistent with predictions of the evolutionary theory of aging, and also demonstrate that selectable genetic variation for longevity does exist (at least in fruit flies).

At the penultimate level of explanation for senescence are two conventional evolutionary hypotheses regarding how diminishing selective pressures with age may be translated into "hard-wired" properties of the genome (see Figure 5.3, bottom). The first of these is the "mutation-accumulation" hypothesis,47 the idea that later age classes become genetic garbage bins where alleles with age-delayed deleterious somatic effects accumulate in evolution because of weak selection pressure there against their loss. As a further aspect of this hypothesis, modifier genes are favored by natural selection that serve to delay the consequences of deleterious alleles to the individual, with the net effect that negative genetic expressions are shoved into older age.

Huntington disease, described in Chapter 3, provides a good example. This genetic disorder of middle and late life is far more common than can be accounted for by a balance between recurrent mutation and negative selection alone. Instead, its prevalence reflects the fact that the gene's horrible effects typically are delayed beyond reproductive age and, hence, are practically invisible to natural selection. Although devastating to the individual, the actions of the Huntington gene are nearly neutral from the standpoint of genetic fitness. By contrast, progeria (a genetic disorder that gives children the symptoms and appearance of old age) affects reproductive fitness profoundly and, thus, is strongly selected against. As expected, the incidence of progeria is vastly lower (one in several million births) than that of Huntington disease.

The second evolutionary hypothesis of aging is "antagonistic pleiotropy,"48 the idea that alleles for aging are favored by natural selection because their beneficial effects at early stages of life out weigh antagonistic deleterious effects later on. For example, genes predisposing for the calcification of bones in adolescents might improve an individual's mean genetic fitness by strengthening limbs, and hence would increase in population frequency despite promoting atherosclerosis (calcification of artery walls) in older age. Any gene or combination of genes that promotes this state of affairs will tend to spread through a population simply because younger individuals make a disproportionate contribution to the ancestry of future generations. As stated by Peter Medawar, "A relatively small advantage conferred early in the life of an individual may outweigh a catastrophic disadvantage withheld until later."49 Or, as George Williams states, "Natural selection may be said to be biased in favor of youth over old age whenever a conflict of interests arises."50 Overall, both antagonistic pleiotropy and mutation accumulation probably contribute to the aging phenomenon; the hypotheses are not mutually exclusive.

At more immediate levels of physiological mechanism, the conventional kinds of medical explanations for aging finally come into play. If we are not killed first by a plane crash or food poisoning, we nonetheless senesce and eventually die from cancer, heart disease, stroke, Huntington disease, or any of a host of other endogenous disorders. The genetic underpinnings of these age-related pathologies have evolved to a ubiquitous status because natural selection simply doesn't care whether older individuals survive and reproduce.

One ramification is that death is far more inevitable, in fact, genetically predisposed, than the medical community might lead us to believe. Although mean life expectancy has nearly doubled in the United States in this century, virtually all of the improvement can be attributed to better hygiene, antibiotics that combat infectious diseases, better food and water supplies, and other public health measures that make our environments less hostile. There is little evidence that our genetic pace of aging has been altered even one iota. Rather, we seem backed against a wall of longevity that appears nearly insurmountable. A sobering realization is that if the two current leading causes of death in the United States—cancer and heart disease—were totally eliminated, only about six years would be added to mean life expectancy in this country. The marginal dividends to be expected from beating back other genetic disorders of old age will be far lower. If real breakthroughs in gene-based longevity are to be achieved, they will have to come from insights and treatments into the underlying nature of the aging process itself, rather than from combatting individual disorders.

One such general mechanistic possibility for aging returns us to the topic of DNA repair. Recall that in the Bernsteins' view, the inevitable DNA damages that have selected for recombinational repair also contribute to the gradual deterioration of the body's cells.51 Although refined mechanisms for DNA repair exist in somatic cells, damage control is incomplete and cellular functions are compromised as the molecular insults accumulate.52 If cells somehow could be insulated against mutational damage, or improved with respect to DNA damage recognition and repair, might the proverbial fountain of youth be tapped? We don't yet know. For the moment, let us look backward at nature's pathways to immortality.

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