Mutants (34 page)

The evolutionary explanation for why we, and most other creatures, age rests upon two ideas, both implicit in Haldane’s explanation for the frequency of Huntington disease. The first is that the ill-effects of some mutations are felt only late in life. Most obviously a mutation might cause a slow-progressing disease. The Huntington mutation is just such a time-bomb. So is the SOST mutation that causes sclerosteosis in Afrikaaners; children are relatively unaffected but the excess bone growth kills in middle age. So are mutations in BRCA1, the familial breast-cancer gene whose ill-effects are usually felt only by women in their thirties and forties. And so is a variant of the APOE gene called ?-4 that predisposes elderly people to heart attacks and Alzheimer’s.

Such examples could be multiplied, yet it must be conceded that not a great deal is known about the time-bombs with the
longest fuses, those that detonate past middle age and that cause senescence. For the moment, let us simply suppose that they exist. To do so, however, is not sufficient to explain ageing. It is also necessary to understand how it is that time-bomb mutations have come to be such an inescapable part of human life. Haldane alluded to the explanation for this when he argued that the Huntington mutation is not seen by natural selection. The same logic can be applied more generally. Imagine a dominant mutation that renders a twenty-year-old man impotent for the rest of his life. In twenty-first-century Britain at least, relatively few men have fathered children by the age of twenty, and after age twenty, the victim of such a mutation will never do so. Whatever he may accomplish in the course of the rest of his life, as far as genetic posterity is concerned he may as well never have been born. The same mutation may occur many times in many men but it will, adolescent fathers aside, never be transmitted to future generations and so will always remain rare. Imagine now another dominant mutation, one that also renders its carrier impotent, but does so only at the age of ninety. For such a man, the odds are excellent that he will be quite oblivious to his loss for the simple reason that he will be dead, having been previously claimed by cancer, a cardiac infarction, influenza, or a failure to notice the approach of the Clapham omnibus. Six feet under, the cost of Viagra is not an issue. Alive and virile he will, however, have sired any number of children, some of whom will bear the mutation, as will some of their children, and so on. Indeed, it is quite possible that the mutation will, simply by chance, spread throughout the population so that, after many
generations, all men will be impotent at age ninety – essentially the case today.

This argument is just a restatement of Haldane’s: that the force of natural selection against deleterious mutations declines over the course of life. But it was another British scientist, Sir Peter Medawar, who first generalised this to explain the diversity of ways in which our bodies break down while ageing. Late in life, some mutations impair our cardiovascular fitness, others our resistance to cancers or pathogens, others virility, yet others our wits. Such long-fuse mutations have afflicted us forever and, unimpeded by natural selection, they have spread and become universal.

Medawar’s explanation of the ultimate causes of ageing surely has a great deal of truth to it, but it has one weakness, and that is its appeal to chance. It is easy to see why mutations that cause some grievous error in old age are not selected against, but is that absence of impediment enough to account for their spread throughout humanity? Perhaps. There are probably thousands of different mutations that have ill-effects late in life, and each of these must have occurred incalculably many times in human history. It is certainly plausible that some spread by chance, particularly at times when population sizes were small.

But an appeal to chance is never satisfying; we would prefer a deterministic theory. In 1957, an American evolutionary biologist, George Williams, proposed one. He argued that the mutations that cause ageing spread not by chance but because they confer some benefit, albeit only to the young. Imagine, once again, a mutation that causes impotence at age ninety, but that
also confers unusual virility at age twenty. The carrier of such a mutation might well sire more children than other men, and so the gene would spread. In the calculus of natural selection, small benefits reaped early often outweigh severe costs paid later on. Old age, in this view, is the price we pay for the lavish beauty and exuberant excess of youth.

Some geneticists have used this logic to explain why Huntington disease is so common. They argue that women with the disorder are, in the first stages of their disease, unusually promiscuous, or feckless, or at least unusually fecund. One study has shown that women with Huntington disease have more illegitimate children than their unaffected siblings. Perhaps, the argument goes, the disorder causes unusually high levels of gonadotropin, a hormone that influences sexual behaviour. There is little evidence to support any of this.

More generally, so little is known about the genes that cause human ageing that it is difficult to know whether Medawar’s or Williams’s view is the more accurate. In a way, the difference between the two theories does not matter; they may both be right, for they are similar in their causes and their consequences. Both propose that ageing is not
for
anything, but is, instead, just an epiphenomenon of evolution. It is ultimately due to the inability of natural selection to act against the mutations that cause disease in the old. Neither theory says much about the mechanical or molecular causes of ageing. They do not point to any one molecular device that we can fix and so ensure our immortality. Rather, both suggest that no such device will be found, and imply that ageing is the collective consequence of
many different mutations that gradually wear down and then destroy our bodies.

Perhaps this is why, despite much effort, the mechanistic causes of ageing remain so elusive. The root of ageing’s evil has been claimed, at one time or another, to lie in any one of a dozen aspects of human biology. Some have claimed that it is caused by the fermentation of bacteria in our guts; others by a slow-down in the rate at which the body’s cells divide; yet others have pointed to the exhausting effects of bearing and raising children. Others again have proposed that ageing is caused by the exhaustion of some vital substance, or else that chemicals produced by our own cells gradually poison us. Many of these ideas are probably absurd, but some probably contain at least an element of truth. What follows is a survey of some of the most plausible ones: a brief history of decay.

GERONTOCRATS

In his declining years, flush with cash and fame from having invented the telephone, Alexander Graham Bell turned his attention to genetics. His first efforts were modest. He bred a variety of sheep with four nipples instead of the usual two. Then, combining his interests in sound and heredity, he studied the genetics of deafness. But his passion was the genetics of human longevity. He began with the family of one of America’s Pilgrim Fathers, a William Hyde (settled Norwich, Connecticut, in 1660), whose descendants, all 8797 of them, had been traced by genealogists. Analysing their records, Bell concluded that
longevity was mostly inherited. Neither his data nor his statistics justified this conclusion. But he wasn’t far wrong – modern estimates put the heritability of European longevity between 20 and 50 per cent. In the event, it was enough to set him off on far grander plans.

Like many early-twentieth-century scientific men, Bell was an enthusiast of eugenics. Not ‘negative’ eugenics – the state-enforced sterilisation of the mentally disabled and the antisocial – that were vogueish in the 1920s, for this he found repugnant. Bell was a humane man; it is not for nothing that America’s premier organisation for the deaf bears his name. His view of eugenics was more ‘positive’, liberal, indeed entrepreneurial: he saw it as an instrument in the marketplace of human affections. Bell proposed, and then began, the compilation of vast numbers of longevity records from Washington, DC, area schools. His idea was to ask children how old their parents and grandparents were, and then publish the results along with their names and addresses in a volume that he called, without equivocation, a ‘human stud-book’. People, he thought, would be sure to consult his stud-book; the descendants of long-lived individuals would search each other out, fall in love, and breed. What of the descendants of short-lived people? Perhaps they would simply remain unmarried. Or perhaps long-lived and short-lived people would separate into distinct races; there would be true gerontocracy. Genetic progress, like economic progress, requires efficient markets, and efficient markets need information; it was all very clear.

* * *

Alexander Graham Bell’s scheme was visionary and only slightly mad. (Who among us would choose the object of our desires on the basis of mean grandparental longevity?) Unsurprisingly, it foundered with his death in 1922. Yet had the scheme become universal, and had people behaved as Bell hoped they would, the results would surely have been spectacular. There is no doubt that the careful breeding of long-lived families would, with time, have resulted in a strain of long-lived people. Perhaps not patriarchially long-lived, but a good deal longer than the seventy-something years that is all we can reasonably hope for. We can guess this, because experimental schemes, not too different from Bell’s, work in other creatures.

In the 1980s the evolutionary account of ageing given by Williams and Medawar inspired researchers to attempt the creation of a breed of long-lived fruit flies. If the ultimate cause of ageing lay in the absence of natural selection late in life, they reasoned, perhaps long-lived flies could be produced by forcing natural selection upon old flies. A fruit fly can breed at two weeks of age, almost as soon as it emerges from its pupa, but by ten weeks it is quite old, perhaps as old as an octogenarian human. Male fruit flies never survive to this age, and the few females that do, the hardy survivors, have depleted metabolic reserves, tattered wings and feeble legs.

They can, however, lay at least a few eggs. And so populations of fruit flies were bred, generation after generation, only from the eggs of the oldest flies. The effect of this was to favour genetic polymorphisms that promoted survival and fertility at old age. As these increased in frequency, the flies evolved ever-longer
lifespans. The speed at which this happened was remarkable. Ten generations of selective breeding were enough to increase the average longevity by 30 per cent – in human terms the equivalent of raising life expectancy from seventy-eight to just over a hundred. Fifty generations of selection, and life expectancy doubled.

Closer examination of these long-lived fruit flies showed that they were amazingly hardy. Deprived of food or water or subjected to noxious chemicals, they survived where shorter-lived flies expired. But glory in old age exacted a cost. As the flies’ longevity evolved ever upwards, fertility in early life declined. Females laid fewer eggs, males were less inclined to mate. Eschewing profligacy, long-lived fruit flies hoarded their resources and established reserves of fats and sugars instead. They became sluggards, moving, breathing and metabolising slower than normal flies.

This result was just as predicted by George Williams’s theory. If ageing is the genetic price of early-life reproductive success, then, conversely, increased longevity must be bought at the cost of a vigorous and fertile youth. This implies a simple economic relationship between fertility and longevity. A fly has only so many resources; it may use them to live to an old age or it may expend them on its progeny, but it cannot do both. It’s a line of argument that goes back to Aristotle. In his account of animal physiology he supposed that animals need ‘moisture’ to live, and that they had a limited amount of it: life is warm and wet, and death is cold and dry. ‘This is why,’ he writes, ‘animals that copulate frequently and those abounding in seed age quickly; the
seed is a residue, and further, by being lost, it produces dryness.’

Since Aristode, numerous studies have confirmed that reproduction exacts survival costs in a variety of creatures. The severity of these costs at the limit is shown by
Antechinus stuarti
, an Australian marsupial mouse. For the males of these mice, existence is little more than sex. Their brief adult lives consist of fighting other males, wandering about in search of females and, when they find them, engaging in exhausting twelve-hour-long copulations repeated daily for nearly two weeks. Perhaps unsurprisingly, after a single mating season they are dead, their tissues showing all the signs of catastrophic senescence. By the time they are done, they are devoid of sperm, their prostate glands have shrivelled up, their testes have become invaded by connective tissue, their adrenal glands are hypertrophied, their livers necrotic, their gastric tracts are haemorrhaging, and their penises are quite flaccid.

Marsupial mice are an especially blatant illustration of the idea that ageing is the consequence of youth’s excesses. But there is evidence that the same economic principle affects humans, albeit to a more modest degree. The British have, of course, no Pilgrim Fathers to genealogise. Instead they have an aristocracy, mostly dating from Norman times, whose singular, indeed defining, virtue is an obsession with their own line of descent. Traditionally, the genealogies of Britain’s noble houses have been recorded in the volumes of
Burke’s peerage
, but these days a handier account of the pedigrees of most British peers, from the Dukes and Earls of Abercorn to the Barons of Willoughby de Broke, is available on CD-ROM. This database, which stretches back to 740 AD, contains, in so far as they are known, the birth
dates, marriages, and progeny of the British nobility, and has been used to test the idea, evident to the parents of any newly born infant, that having children takes years off your life.

Before the Industrial Revolution, the wife of a British peer could expect to live to the age of forty-five. She could also expect to bear two or three children. These averages, however, conceal much variety in the chances of life. Some women died young, and so had very few children. Some died in the decade or two after menopause (fifty to sixty): on average they had 2.4 children. But some – albeit rather few – survived past age ninety. These elderly women had had, on average, only 1.8 children, and nearly half of them were childless.