Mutants (35 page)

This is a fascinating result. Not only is it consistent with the results of the fruit fly experiments, it suggests that had Alexander Graham Bell’s dreams ever come to fruition, his gerontocrats would have had an ever dwindling fertility. A more sobering thought is that many, though surely not all, aspects of the senescent decline of our later years may be difficult to meliorate without damping down the physiological and sexual excesses of youth. In the future, humans may well be able to engineer themselves, be it by better drugs or better genes, to live as long as they please, but the cost may be twenty-year-olds with all the vigour, appetites and charm of the middle aged.

LA VITA SOBRIA

Is there a recipe for long life? Luigi Cornaro thought there was. In 1550, the Venetian nobleman published a tract called
Discorsi della vita sobria
(Discourses on the sober life) in which he outlined the regime that had ensured his own longevity. He was probably eighty-three at the time, and lived until ninety-eight or 103 – there is some dispute about his birth date, though all agree that he reached a great age. By his own account he had, until the age of forty, lived a life of sensual dissipation. The consequences were pains in the stomach and side, gout, fever, and an unquenchable thirst. His physicians warned him that he must reform or die. He took their advice to heart and thenceforth devoted himself to a temperate and orderly way of life.

The chief ingredient of his new regime was simple: eating less, and then only what he found agreeable. ‘Not to satiate oneself with food is the science of health,’ he wrote. He is vague on specifics, but at the one point at which he reveals what his actual diet was, it does not sound too arduous. A typical meal would begin with bread, then a light broth, perhaps with an egg. But, he said, ‘I also eat veal, kid and mutton; I eat fowls of all kinds, as well as partridges and birds like the thrush. I also partake of salt-water fish as the goldney and the like; and, among the ovarious fresh-water kinds, the pike and others.’ A modest diet by sixteenth-century Italian standards then. Yet at one point he grew so thin that his friends urged him to eat more. Cornaro’s oracular reply was that whosoever wished to eat long must eat little.

This is a little smug, but the
Vita sobria
charms – Cornaro is so clearly delighted by his longevity. A portrait by Tintoretto shows him in his splendid dotage, a grave and fine-featured patrician with skin made translucent by age. Cornaro spent his
last years at his Paduan palazzo with its decorations by Raphael and at his villa in the Euganean Hills by the River Brenta with its exquisite gardens and fountains. ‘I did not know,’ he writes, ‘that the world could be so beautiful until I was old.’

The
Vita sobria
was a huge success. As he grew older, Cornaro added material to its successive editions: two, three, and finally four
discorsi
. A product of the Italian Renaissance, the book’s style was classical (Jacob Burckhardt cited it for its perfection), its physiology Aristotelian (much about moisture loss), and its sentiments Ciceronian (old age is a thing to be welcomed, a time of wisdom when passions have been burnt away). Its influence was long-lasting and can be found, for example, in the writings of the German physician Christian Hufeland, whose
Makrobiotik
(1796) outlines the theory from which every modern health-food fad ultimately derives.

The worst of it is that there is an element of truth in Cornaro’s claim that the route to great longevity is eating less. By this I do not simply mean the sort of diet that will stave off gross obesity or even middle-age spread, but serious dieting of a sort that few people could sustain voluntarily. The only reliable way to extend the general physiological life of a mammal is to give it no more than two thirds of the daily calories that it wants. Dozens of studies have shown that ‘caloric-restricted’
mice live anywhere between 10 and 50 per cent longer than those which are allowed to eat as much as they want. Age for age, they are friskier, glossier and healthier than their controls. And they are slimmer: about half the weight of controls. Caloric-restricted mice do, of course, eventually die, but the ages at which they get diabetes, infections, renal malfunctions, autoimmune attacks, musculoskeletal degeneration, cardiomyopathy, neural degeneration and, most amazing of all, cancer are all delayed. Studies on rhesus monkeys are now under way to see if caloric restriction extends life in primates, but it will be another decade before we know the answer.

Uncertainty has not stopped many neo-Cornarists from committing themselves to lives of rigorous dieting. Caloric restriction has become a health fad like any other, with its own books and gurus. The diet usually consists of about a thousand calories per day, which is necessarily supplemented with a battery of vitamins and minerals. A thousand calories is about the minimum number needed to sustain the life of an average-sized man, though not enough to sustain his sex drive (or, to judge by pictures, his sex appeal). Whether these ultra-puritans will reap their reward is an open question. The severe caloric restriction experienced by the Dutch population during the
Hongerwinter
of 1944–45 certainly had no detectable beneficial effect on the long-term mortality rates of the survivors, but it could be argued that it takes decades of near-starvation for its virtues to become apparent.

Caloric restriction works in rats, mice, fruit flies and nematode worms. Why it does so remains mysterious. One explanation goes back to the deleterious effects of reproduction. Caloric-restricted animals have fewer offspring than those allowed to eat all they want; perhaps the energy savings that come with not reproducing are enough to ensure longevity. But there is probably more to it than this. In caloric-restricted fruit flies
not only are the genes involved in reproduction largely switched off, but those involved in resistance to infection (the fly’s immune system) are turned on, so that immunity proteins are produced at higher levels than they would be normally. This result suggests at least two reasons for the longevity of caloric-restricted animals. There may be many others besides. About two thousand of the fifteen thousand genes in the fly’s genome show a response to caloric restriction. It is quite possible that caloric restriction works its magic by the cumulative benefits of dozens of different molecular pathways.

This should hardly come as a surprise. Evolutionary theory predicts that ageing is caused by the independent destruction of many different systems; if caloric restriction has such pervasive effects on health, then it too must work by maintaining the body in many different ways. Even so, many gerontologists still seek a single explanation for all the diverse manifestations of ageing and the way in which caloric restriction delays them. One idea is that ageing is caused by a kind of insidious poison that is a consequence of the very condition of being alive.

THE BREATH OF DEATH

‘We term sleep a death and yet it is waking that kills us,’ observed Thomas Browne in his
Religio medici
. That living itself is the cause of our decline – either by exhausting some vital substance or else by gradual self-poisoning – is one of the oldest ideas in the history of ageing science. In its most recent version, ageing is caused by small, pernicious molecules capable of
oxidising DNA, proteins, lipids, indeed almost anything they come into contact with. In the course of normal respiration, oxygen is reduced to water. But this is an imperfect process, and several other molecular species called ‘free radicals’ are produced as by-products. These molecules, which have chemical formulas such as •OH (the • signifying an unpaired electron), are especially abundant in mitochondria, the sub-cellular structures in which respiration takes place. From there they leak into the rest of the cell, attacking other structures as they go.

The free radical theory postulates that ageing is caused by the accumulated damage that these molecules inflict upon cells over the course of years. An abundance of correlative evidence supports this. Free radicals certainly damage cells, and the kind of damage they do becomes more common in old age. Most disturbingly, they cause mutations. The DNA of each human cell receives ten thousand oxidative hits per day. While many of these are repaired, many are not. Old rats have about two million mutations per cell, about twice as many as young rats do. Most of these mutations will have no effect on the health of a given cell. But should the radical hit a gene vital for the survival of a cell it might well kill it. Should it hit a proliferation-control gene in a stem cell it might initiate a cancer. Should it hit a gene in the cells that give rise to rise to sperm and eggs, it may be transmitted to future generations.

Free radicals are clearly pernicious. But do they cause some or all of ageing? Perhaps. Long-lived animals – be they innately so or else calorie-restricted – seem to be exceptionally resistant to toxins such as paraquat, a weed-killer that works
by inducing the production of free radicals. More direct evidence comes from genetic manipulations in a variety of animals. Animal cells contain a battery of defences against free radicals, among them a group of enzymes devoted to scavenging free radicals, the superoxide dismutases. Several different kinds of evidence suggest that they protect against some of ageing’s effects.

An especially active form of superoxide dismutase seems to contribute to the longevities of the fruit flies, alluded to previously, that were the result of generations of gerontocratic reproduction. The founding population of these flies was polymorphic for two varieties of superoxide dismutase. Selection changed the frequencies of these variants so that the more active form became much more common in the populations of long-lived flies than in the short-lived ones. This wasn’t just a matter of chance: the experiment was replicated five times, and the same result was found each time. In an even more direct demonstration of the benefits of this enzyme, flies were engineered to express human superoxide dismutase – apparently more potent than the fly’s own – in their motor neurons. They lived 40 per cent longer than un-engineered controls, a particularly interesting result for it implies that superoxide dismutase can protect the nervous system. Finally, in the last few years many mutants have been found in nematode worms and fruit flies that seem to confer extraordinary longevity (one of them has even been named
Methuselah
after the patriarch who, Genesis assures us, lived to the age of 969). These mutants do not alter the sequences of superoxide dismutase genes themselves but rather affect
genes that control when and how superoxide dismutase is activated. It is, it seems, hard to make a long-lived fly or worm without boosting superoxide dismutase by one means or another.

All these results suggest the following chain of argument: extra superoxide dismutase postpones ageing (at least in worms and flies); superoxide dismutase protects against free radicals; hence free radicals cause ageing. Does this imply that the means for postponing ageing in humans are at hand? Might we not simply engineer ourselves with a more effective superoxide dismutase and so gain years of life? The short answer seems to be no. Moreover, the reason that this won’t work casts some doubt upon one of the premises of the foregoing argument.

Our genomes contain three genes that encode superoxide dismutases. Mutations in one of these, SOD1, have been known for years. These mutations are gain-of-function and dominant: they give a hyperactive protein. It may be thought that this is precisely the sort of mutation that, by analogy with fruit flies and worms, might give a human lifespan of 120 years. In fact, they kill by the age of fifty or so. SOD1 mutations cause amytrophic lateral sclerosis (ALS), a particularly ferocious neurological disease in which the motor neurons of the spinal cord, brain stem and motor cortex are progressively destroyed, leading to paralysis and death. In America the disorder is known as Lou Gehrig disease after the baseball player who suffered and died from it. Nowhere is the issue of physician-assisted suicide as pressing as it is in ALS.

These mutations pose a paradox. They suggest that superoxide
dismutase kills motor neurons in humans, even as it protects them in flies. Why? For the last ten years this paradox has been resolved along the following lines. Superoxide dismutase is only the first step in an enzymatic pathway that neutralises free radicals. It converts the free radical oxygen anion, O•2, to another molecule, H
₂
O
₂
, more commonly known as hydrogen peroxide, whose destructive effects upon biological tissue can be gauged by its fame as the active ingredient in chemical drain-cleaners and the classic suicide blonde. It takes another enzyme, catalase, to neutralise hydrogen peroxide by converting it to water. Perhaps an imbalance in the activity of these two enzymes in humans, but not flies, leads to a build-up of hydrogen peroxide in neurons and kills them.

It is a reasonable explanation, but it appears to be quite wrong. The reason that SOD1 mutations kill motor neurons has nothing to do with free radicals or hydrogen peroxide poisoning. Rather, their deleterious effects seem to be related to some other, slightly mysterious, role that superoxide dismutase has in the brain. Neurons are strange cells. They are large, have long protrusions called axons, and a whole special cellular architecture that goes with this. Besides scavenging free radicals, superoxide dismutase appears to have some role in this architecture. Biologists have adopted a lovely phrase to describe such multitasking proteins – they call them ‘moonlighters’. Moonlighting SOD1 may also contribute to another neurological disorder, Down’s syndrome. Children with Down’s syndrome have three copies of chromosome 21 – the chromosome on which the SOD1 gene resides – instead of the usual two. Hundreds of different
genes reside on this chromosome, and any or all of them might contribute to the distinctive features of Down’s (mental retardation, the facial abnormalities, heart problems to name but a few), but the extra copy of SOD1 has long been fingered as one of the more destructive.