Why We Get Sick (19 page)

Many people have thought that senescence must benefit the species. When one of us (Nesse) first became fascinated by senescence as a college sophomore, he investigated every explanation he could find and concluded that senescence was necessary to make room for new individuals so that evolution could keep a species abreast of ecological changes. This was just a step away from the position of the nineteenth-century Darwinian August Weismann, who wrote, in 1881, “Worn-out individuals are not only valueless to the species, but they are even harmful, for they take the place of those which are sound. Hence, by the operation of natural selection, the life of our hypothetically immortal individual, will be shortened by the amount which was useless to the species.”

Nagging misgivings about this theory grew after he learned that natural selection acts not for the benefit of the species but normally for the benefit of individuals. There had to be another explanation. When he revealed this preoccupation with the evolutionary explanation of senescence to colleagues in the Evolution and Human Behavior Program at the University of Michigan, they laughed and asked how anyone could possibly not know about the 1957 paper on senescence by a biologist named George Williams.

Williams’s paper draws on insights by biologists J. B. S. Haldane and Peter Medawar to show how natural selection can actually select for genes that cause senescence. In 1942, Haldane realized that there would be no selection against genes whose harmful effects occurred only after the oldest age of reproduction. This was a major advance but did not explain why reproduction should cease. In 1946, Medawar went further and showed that the force of selection decreases late in life, when many individuals have been killed by forces other than senescence:

Williams expanded these ideas into the pleiotropic theory of senescence. (Genes are called pleiotropic if they have more than one kind of effect.) Imagine that there is a gene that changes calcium metabolism so that bone heals faster, but the same gene also causes slow and steady calcium deposition in the arteries. Such a gene might well be selected for, because many individuals will benefit from its advantages in youth, while few will live long enough to experience the disadvantage of arterial disease in old age. Even if the gene caused everyone to die by age 100, it would still spread if it offered even minor benefits in youth. This argument does not depend on the prior existence of senescence. Other causes of death—accidents, pneumonia, and all the rest—are sufficient to reduce the population at older ages. Nor does the theory depend, like Haldane’s, on cessation of reproduction.

The existence of menopause is a related mystery. Why hasn’t it been eliminated by natural selection? Menopause is unlikely to be simply a result of senescence because most species continue to have reproductive cycles even into old age and because human menstrual cycles consistently stop within a few years of age fifty instead of gradually tapering off in parallel with other decreases in organ functions. In his 1957 article, Williams offered a possible explanation of menopause. A woman makes a substantial investment in each child, and this investment will pay off genetically only if the child survives to healthy adulthood. If the mother has more babies (with the associated dangers) even as the ravages of age become severe, she is having children she may not be able to care for, and she is risking the future
success
of her existing children. If, instead, she stops having additional children and devotes her effort to helping those she already has, she may have more total offspring who grow up to reproduce themselves. Recent papers by anthropologists Kim Hill and Alan Rogers challenge this explanation of menopause, but the hypothesis nonetheless offers a fine example of how kin selection might explain apparently useless traits.

Not all genes that cause senescence necessarily have early benefits. Some were simply never exposed to selection because too few people lived long enough in the ancestral environment for the gene to cause a disadvantage. This explanation was thought sufficient by Alex Comfort, the distinguished biologist who is equally well known, in somewhat overlapping circles, for his classic texts
The Biology of Senescence
and
The Joy of
Sex. If Comfort is right, senescence should almost never cause the death of wild animals. He observed that decrepit animals are rarely found in nature and concluded that senescence is not a factor in the mortality of wild populations. But don’t forget the sports records. If aging animals run just a little bit slower, they will be caught by predators sooner than their younger competitors are and will thus die from the effects of senescence long before we would notice any decrepitude.

One way to look into this situation is to calculate the force of selection acting on wild populations by comparing the survival curve for the actual population to a curve for an imaginary population that is identical except that its mortality rate does not increase with age. The ratio of the areas under the curves gives an estimate of how much senescence decreases fitness (
Figure 8-2
gives an example). In many wild mammals, senescence is a major negative selective force, and most genes that cause senescence are thus within the reach of natural selection. Their prevalence is probably explained by benefits early in life.

F
IGURE
8-3. World record marathon times for men, ages 10 to 79. (Data from
Runner’s World
, 1980.)

The astute reader will now want to see some examples of such senescence genes with early benefits. Many genes that have multiple effects are known: for instance, the gene that causes PKU causes fair hair in addition to mental retardation. Here, however, we are interested in genes that have one effect that gives a benefit in youth and another effect that imposes a cost with age. In a 1988 article, University of Michigan physician Roger Albin cited several diseases that may result from such genes. One candidate is hemochromatosis, a disease that causes excess absorption of iron and death in middle age, when the resulting iron deposits destroy the liver. Earlier in life the ability to absorb extra iron may give people with this disorder an advantage (avoiding iron-deficiency anemia) that outweighs the later disadvantage. Albin notes that the prevalence of this gene (about 10 percent of the population has it) can also be explained by heterozygote advantage. Or this may be a gene that is maintained by sexually antagonistic selection. It may benefit women, who need the iron to replace what they lose during menstruation, but harm middle-aged men, who simply accumulate excess iron.

In another example, Albin notes that some people have a gene that results in excess production of a gastric hormone called pepsinogen I. These people are more likely than others to get peptic ulcers and, as they grow older, to die from these ulcers. Throughout life, however, these people have high levels of stomach acid, which may provide extra protection against infection. Insofar as we are aware, no one has carried out the test Albin suggested, of looking to see if high levels of pepsinogen I protect people against gastrointestinal infections such as tuberculosis and cholera.

Paul Turke, an evolutionary anthropologist and senescence researcher who has gone to medical school to become a Darwinian physician, reminds us that the whole immune system is age biased. It releases damaging chemicals that protect us from infection, but these same chemicals inevitably damage tissues and may ultimately lead to senescence and cancer.

The genes that predispose to Alzheimer’s disease may also have been selected for because of earlier benefits. The most common cause of devastating mental deterioration, it affects 5 percent of people by age sixty-five and 20 percent by age eighty. It has long been known to be influenced by genetic factors, as shown by many familial cases and by its high frequency in people with three copies of chromosome 21.
In 1993, scientists from the Department of Neurology at Duke University discovered that a gene on chromosome 19 that makes a protein called apolipoprotein E4 is especially common in people who develop Alzheimer’s disease. People who are heterozygous for the gene have a 40 percent chance of developing the disease by age eighty. So far as we know, no one has looked for possible benefits early in life in those people who later develop Alzheimer’s disease. Now that this gene has been discovered, it should be possible to address the question. S. I. Rapoport at the National Institute on Aging has suggested a related explanation. He notes that Alzheimer’s disease is characterized by abnormalities in more recently evolved regions of the brain and that it does not occur in other primates. This led him to suggest that the genetic changes that led to the very rapid increase in human brain size over the past four million years either cause Alzheimer’s in some people or produce side effects that have not yet been mediated by other genetic changes. It would be very interesting to see if intelligence early in life is higher, or brain size larger, in people who have the gene that predisposes to Alzheimer’s disease.

Considerable laboratory evidence demonstrates that genes with early benefits contribute to senescence. Population biologist Robert Sokal bred flour beetles, those common kitchen pests, and selected for those that reproduced early in their life cycles. After forty generations, the beetles selected for early reproduction produced considerably more offspring sooner in life, but they also aged and died earlier, possibly an effect of genes selected because of their benefits early in the life span despite their costs later in life. Biologists Michael Rose and Brian Charlesworth went the other way, breeding fruit flies that reproduced late in their life cycle. These fruit flies not only had more offspring later in life, they also lived longer and had fewer total offspring, exactly what would be expected if the artificial selection had eliminated genes with early benefits and later costs.

Growing evidence suggests that such genes contribute to senescence in wild animals. For years, gerontologists accepted Alex Comfort’s erroneous conclusion that senescence does not occur in wild animals. In a classic example of seeing what they expected to see, many scientists who studied wild populations didn’t even bother to check to see if the oldest animals showed increased mortality rates, they just assumed that mortality rates remained constant throughout life. Now that gerontologists have begun looking, however, the evidence
is everywhere. For many species, senescence decreases reproductive success more than do all other forces of selection combined. This does not prove the role of pleiotropic genes in senescence, but it certainly challenges the theory that natural selection simply has not had a chance to eliminate the genes that cause senescence.

While evidence for senescence in wild animals supports our tradeoff theory of senescence, it has been challenged by evidence that the life span can be readily extended. Severely restricting the diets of rats and mice increases their life span by 30 percent or more. This seems mysterious, because a major increase in life span resulting from something as simple as caloric restriction is inconsistent with our belief that senescence results from many genes acting in concert. So why don’t mice and rats eat less and live longer? The first possibility is that they are normally overfed in the laboratory and thus age prematurely. Perhaps their bodies are designed for less lavish diets, so that the starvation experiments were not extending the life span but simply reducing the adverse effects of excess food. This does not seem to be correct. Rats and mice who can eat all they want to are not much heavier than their wild relatives, and poorly nourished rats live even longer than wild animals that are protected from predators and poisons.

Harvard biologist Steven Austad reviewed hundreds of studies of dietary restriction and found the key in a crucial fact mentioned in only a few studies. The food-deprived rats may live longer, but they don’t have offspring. In fact, they don’t even mate! They seem to remain at a prereproductive state of development, waiting for an adequate food supply. The mechanisms that explain diet-induced longevity remain of great interest, but to an evolutionist, dietary restriction that eliminates reproductive success is no boon but almost as bad as early death.

W
hat proximate mechanisms are responsible for senescence and limited longevity? Recent research has found several. Free radicals, for instance, are reactive molecules that damage whatever tissue they contact. Our bodies have developed a number of defenses, especially
a compound called
Superoxide dismutase
(SOD), that neutralizes free radicals before they can cause much damage. Lack of normal SOD may cause amyotrophic lateral sclerosis (also known as Lou Gehrig’s disease), a fatal disease of muscle wasting. The levels of SOD in various species are directly related to their life spans. On the one hand, this shows that damage by free radicals is indeed a proximate cause of senescence, but on the other it demonstrates how natural selection adjusts a defense to whatever level is needed.