Why We Get Sick

by Randolph M. Nesse

  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.

  MECHANISMS OF SENESCENCE

  What 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.

  Blood levels of uric acid, another antioxidant, are also correlated closely with a species’ life span. We humans have lost the ability, possessed by most other mammals, to break down uric acid. Because uric acid crystals precipitate in the joint fluid and cause gout, this loss is often cited in medical books as a deficiency in human biochemistry, but, as noted in this extract from a biochemistry text, it may also be an advantage that facilitates our long life:

  What is the selective advantage of a urate level so high that it teeters on the brink of gout in many people? It turns out that urate has a markedly beneficial action. Urate is a very efficient scavenger of highly reactive and harmful oxygen species—namely hydroxyl radical, Superoxide anión, singlet oxygen, and oxygenated heme intermediates in high Fe valence states (+4 and +5). Indeed urate is about as effective as ascorbate as an antioxidant. The increased level of urate in humans compared with prosimians and other lower primates may contribute significantly to the longer life span of humans and to the lower incidence of human cancer.

  The flaming painful gouty toe is a cost of a gene that may have been selected because it helps to delay senescence. This gene has effects that are the opposite of those already described, in that the gene gives benefits late in life by slowing aging while exacting its costs throughout adult life. It would be most interesting to see if aging is slower in people with gout.

  The levels of an enzyme that repairs abnormal DNA are also higher in longer-lived species. This demonstrates that damage to DNA is a force of selection, and, as with SOD and uric acid, it also demonstrates that nature has found a solution to the problem. If one sees natural selection as a weak force, one sees free radicals and DNA damage as causes of senescence. Appreciation of the strength of natural selection, however, makes one much more inclined to expect that damage from oxygen radicals and defective DNA is limited by evolved mechanisms that are as effective as they need to be to maximize reproductive success.

  As Austad points out, the mechanisms of senescence are likely to differ from species to species. Rats and mice, the subjects of most senescence research, are distant from humans, not only phylogenetically but also in their patterns of senescence. Austad therefore proposed extensive cross-species studies of senescence to uncover common patterns. He began his research on an island off the coast of Georgia where opossums had been living without predators for several thousand years and predicted that they would have evolved longer life spans. The field work—catching opossums on both the island and the mainland and determining their ages—took several years. (The task was much easier with the island opossums, because they sleep on the ground in plain view, having lost the defense, essential on the mainland, of hiding all day in deep burrows.) The results of the study? Not only do the island opossums live longer than their landlocked distant cousins, they also age more slowly on a variety of indicators. The cost of these changes, however, is smaller litters at all ages and delayed age at first reproduction. It is clear that the rate of senescence, like other life-history characteristics, is shaped by natural selection.

  SEX DIFFERENCES IN RATES OF SENESCENCE

  Back to humans. Boys born in the United States in 1985 are expected to live seven years less, on average, than girls, and comparable differences have been found in other countries and in earlier times. Why do women have this advantage over men? The most important evidence for why males age sooner in so many species comes from a cross-species comparison. Males that must compete for mates have shorter lives than females. Part of the increased mortality results from males fighting over females, but even males living alone in cages die sooner than females.

  Why are males the vulnerable sex? Male reproductive success is so dependent on competitive ability that male physiology is devoted more to this competition and proportionately less to preservation of the body. Their game of life is played for higher stakes. If unusually fit males can sire large numbers of offspring while mediocre males usually have none, heavy sacrifices must be made in the effort to reach high fitness. Among the processes sacrificed may be those that contribute to longevity.

  MEDICAL IMPLICATIONS

  Research on senescence seems to be disc
overing the value of an evolutionary point of view. Gerontologists are realizing that the mechanisms that cause senescence may not be mistakes but compromises carefully wrought by natural selection. An evolutionary view suggests that more than a few genes are involved in senescence and that some of them have functions crucial to life. These genes express their various effects in a seemingly coordinated cluster of escalating signs, because any gene whose deleterious effects occur earlier than those of other genes will be selected against the most strongly. Selection will act on it and other genes to delay its effects until they are in synchrony with those of other genes that cause senescence. This process explains the one-hoss shay effect, the concordance of many signs of senescence even though there is no internal clock that coordinates senescence.

  This view discourages the hopes of that lady on the plane, the hope that senescence is a disease that may someday be cured. Hopeful talk about a life-extending research breakthrough is just hopeful talk. What gerontological research does offer, and what justifies considerable investment in studying the mechanisms of senescence, is the likelihood that many diseases of senescence can be postponed or prevented so we can live more fully and vigorously throughout adult life. Despite our pessimism about substantially extending the life span, we concede that the history of science is full of confident theoreticians proving something impossible just a few years before it is accomplished. And we are well aware that natural selection has greatly increased our life span in just a few million years. So we ask not that gerontologists give up their efforts to extend the life span, only that they conduct them in the light of evolution.

  We should also note that pessimistic assessments of what science can accomplish often have substantial utility. They provide what philosopher E. T. Whittaker called postulates of impotence. Because of such pessimism, engineers no longer try to design perpetual-motion machines and chemists no longer try to turn lead into gold. If gerontologists stop trying to find the fountain of youth in some single, controllable cause of senescence, their efforts may prove more fruitful for human well-being.

  The clinician has more immediate concerns. The proportion of people over the age of eighty-five is growing six times faster than the population as a whole. In just the past three decades, the average life expectancy in the United States has gone from 69.7 to 75.2 years. More than a quarter of every health care dollar is now spent on patients in the last year of life, and the need for nursing home beds is expected to quadruple in the next twenty years. Medicine has changed its focus from acute diseases of children and younger adults to chronic diseases of the elderly. Doctors who imagined spending their careers giving antibiotics to stop pneumonia and doing heroic curative surgery now find themselves monitoring high blood pressure, evaluating memory problems, and relieving the symptoms of chronic heart disease. Many of these physicians and their patients still think of senescence as a disease. We expect that knowledge about the evolutionary origins of senescence will have profound effects that are difficult to predict.

  This perspective may also change how we see our own lives. Some may find it a consolation to know that senescence is the price we pay for vigor in youth. There is also relief as well as disappointment in knowing that no medical advance is ever likely to extend our lives to any dramatic extent. The search for some pill or exercise or diet that can save us from senescence may be replaced by an appreciation of life as it is, of vigorous function at whatever age. The preoccupation with living forever is likely to be supplanted by a desire to live as fully as possible, while it is possible.

  9

  LEGACIES OF EVOLUTIONARY HISTORY

  The past! the past! the past!

  The past—the dark unfathom’d retrospect!

  The teeming gulf—the sleepers and the shadows!

  The past—the infinite greatness of the past!

  For what is the present after all but a growth out of the past?

  —“Passage to India” by Walt Whitman

  Phil, the unfortunate television weatherman who lives one day over and over again in the movie Groundhog Day, enters a restaurant just as a diner begins to choke on a bite of food. Phil, having observed this scene many times before, calmly steps behind the gasping man, wraps his arms around the man’s upper abdomen, and suddenly squeezes hard. The food is expelled from the diner’s windpipe and he can breathe again, his life saved by Phil and the Heimlich maneuver.

  About one person in a hundred thousand chokes to death each year. While this death rate is small compared to that from automobile accidents, choking has been a persistent cause of death not only throughout human evolution but throughout vertebrate evolution because all vertebrates share the same design flaw: our mouth is below and in front of our nose, but our food-conveying esophagus is behind the air-conveying trachea in our chest, so the tubes must cross in the throat. If food blocks this intersection, air cannot reach our lungs. When we swallow, reflex mechanisms seal off the opening to the trachea so that food does not enter it. Unfortunately, no real-life machinery is perfect. Sometimes the reflex falters and “something goes down the wrong pipe.” For this contingency we have a defense, the choking reflex, a precisely coordinated pattern of muscular contractions and tracheal constriction that creates a burst of exhaled air to forcibly expel misdirected food. If this backup mechanism fails and an obstruction blocking the trachea is not dislodged, we die—unless, that is, Phil or someone like him happens to be nearby.

  But why do we need the protective mechanisms of traffic control and a backup choking reflex? It would be so much safer and easier if our air and food pathways were completely separate. What functional reason is there for this crisscross? The answer is simple—none at all. The explanation is historical, not functional. Vertebrates from fish to mammals are all saddled with an intersection of the two passages. Other animal groups, such as insects and mollusks, have the more sensible arrangement of complete separation of respiratory and digestive systems.

  Our air-food traffic problem got started by a remote ancestor, a minute wormlike animal that fed on microorganisms strained from the water through a sievelike region just behind the mouth. The animal was too small to need a respiratory system. Passive diffusion of dissolved gases between its innermost parts and the surrounding water easily supplied its respiratory needs. Later, as it evolved a larger size, passive diffusion was ever less adequate, and a respiratory system evolved.

  If evolution proceeded by implementing sensible plans, the new respiratory system would have been just that, a new system designed from scratch, but evolution does no sensible planning. It always proceeds by just slightly modifying what it already has. The food sieve at the forward end of the digestive system already exposed a large surface area to a flowing current. With no special modifications, it was already serving as a set of gills by providing a large proportion of the needed gaseous exchanges between internal tissues and environment. Additional respiratory capacity was created by slow modifications of this food sieve. Rare minor mutations that made it slightly more effective in respiration were gradually accumulated over evolutionary time. Part of our digestive system was thereby coopted to serve a new function—respiration—and there was no way to anticipate that this would later cause great distress in a Pennsylvania restaurant on Groundhog Day. Today, the food-sieving worm stage in our evolution is still found in the closest invertebrate relatives of modern vertebrates, which have combined respiratory and digestive passages, as shown in Figure 9-1.

  Much later, the evolution of air breathing caused some other evolutionary changes that we now have cause to regret. When part of the respiratory region was modified to form a lung, it branched off the lower side of the esophagus that led to the stomach. Accessory openings for air breathing at the surface of the water evolved, understandably, from the already available olfactory organs (nostrils) on the upper surface of the snout, not on the chin or throat. So the air passage opened above the mouth opening and led into the forward part of the digestive tract. Air then passed bac
k through the mouth and larynx to where the trachea branched off and went through this passage to the lungs. This is the lungfish stage (see Figure 9-2).

  Subsequent evolution moved the connection from the nostrils back into the throat so that the air passage was as completely separate from the digestive system as it could become without redesigning the structure of the head and throat. Thus a long dual-function passage was gradually shortened until only the crisscross remained, but we and all higher vertebrates are still stuck with it. Vertebrates have the unenviable capacity to be asphyxiated by their food. Darwin pointed out, in 1859, how difficult it is, from a purely functional perspective, to

  understand the strange fact that every particle of food and drink which we swallow has to pass over the orifice of the trachea, with some risk of falling into the lungs, notwithstanding the beautiful contrivance by which the glottis is closed.