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, H2O2, 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.