These results provide at best mixed support for the idea that a want of telomeres causes ageing. Sufficiently short telomeres can clearly cause premature ageing; but since this happens only after six generations of attrition, they cannot be the cause of normal ageing in mice. While it is tempting to dismiss the whittling away of telomeres as an explanation of ageing in humans, it is probably too soon to do so. Laboratory mice have extraordinarily long telomeres – far longer than ours. If our telomeres are rather short at the start of our lives and must, by virtue of our greater size and longevity, undergo far more attrition than a mouse’s, it remains quite possible that they matter to us.
One way to prove the point would be to clone a human. Clones should start life with abnormally short telomeres, for they are produced without the aid of germ cells and so their telomeres are never renewed. Successive generations of clones should have shorter and shorter telomeres and age with increasing rapidity – all the more so if the clone-donors are elderly. What with the global ban on human cloning this experiment is not likely to be carried out soon – unless by UFO cultists or renegade Italian obstetricians. But, of course, it has been done in animals. Sheep 6LL3, a.k.a ‘Dolly’, got her chromosomes from the udder-cells of a six-year-old Finn Dorset. She therefore began life with substantially worn-down telomeres. Many thought that she would age fast. Some arthritis aside, however, she was quite healthy; there was nothing exotic about the viral disease that prompted her euthanasia at the age of six. Clones of other animals such as cattle and mice often suffer from a variety of health problems such as obesity, but none have been reported to be progeric. Still, these are early days.
Telomerase-mutant humans would be informative too. There is another progeria, rarer than Werner’s but even more severe, in which catastrophic ageing begins in childhood. The victims of this disorder usually die by the age of twelve or so, again from heart attacks, by which time they are to all appearances very small octogenarians. Their symptoms suggest defective telomeres. Even if this grim disease can be explained by too-rapid cellular senescence, we will have penetrated only a small way into ageing’s mysteries. For while the progerias hasten some aspects of physical decline, they leave the minds of their victims untouched.
MAKING A CENTURY
In the last ten years there has been a revolution in the study of ageing. Much of it has come from the study of the nematode worm Caenorhabditis elegans. This worm is only about 1 millimetre long, and it is possible to grow thousands of them in petri-dishes. They are perfectly transparent. Under a powerful microscope it is possible to see every single one of the 959 cells in their living bodies. For whatever reason, it has been especially easy to identify worm mutants that are extraordinarily long-lived. Some of these mutant worms live twice as long as normal worms do: forty-two days – in human terms, about 150 years.
So far, at least a hundred genes have been identified in worms that, when mutated, cause them to live longer. Many of these mutations disable the worm’s insulin-like growth-factor-signalling pathway. As a consequence of doing so, the whole physiology of the worm changes. Mutant worms that are defective for IGF signalling reproduce less, store large amounts of fat and sugars, and activate a whole battery of genes that encode for stress-resistance proteins, among them superoxide dismutase. The result is worms that radiate health even as their normal contemporaries wither in their petri-dishes.
We have come across insulin-like growth factor before. It is the lack of this hormone that makes pygmies small and its excess that makes Great Danes large. It is also one of the hormones that, when inactivated in mice, cause them to be dwarf and long-lived. In worms, IGF does not seem to control body size (something of a surprise since it does so in so many other creatures, including fruit flies). Even so, taking these findings from worms together with what is known about IGF in mice, flies and many other creatures, it is possible to sketch an account of a mechanism, perhaps universal to all animal life, that allows animals to live longer when they need to.
Worms are not frightfully bright. The nervous system of any one worm, including what passes for its brain, contains only 302 neurons; a human brain has around a billion-fold more. Even so, a worm has nous enough to know how much food it has. When a worm perceives that it is about to starve, neuronal signals from sense organs in its head signal the rest of the body and IGF signalling is shut off. A change in environment mimics what many mutants do, and the result is the same: the worm lives longer.
This should sound familiar. It is, in effect, what happens in caloric restriction in mice and rats. And it suggests an interpretation for how and why la vita sobria has its beneficial effects. Far from being an odd laboratory phenomenon of interest only to gerontologists and diet gurus pursuing dreams of immortality, the caloric restriction response is probably a device that has evolved to allow animals to cope with the vicissitudes of life. Perceiving that it is in for hard times, a young animal alters its mode of life. Instead of investing resources in growing large and reproducing soon, it switches to survival mode. It remains small and ceases to reproduce, in effect gambling that sooner or later better times will come. If this view of caloric restriction is correct, then its enthusiasts are attempting nothing less than the revival of devices evolved to cope with the deprivation that was surely our lot for millennia of prehistory (and surely a lot of history too). Though they do not know it, when they calculate their foods to the last calorie, surround themselves with bottled vitamins, and monitor, as they must, their bone density by the month, they are playing the part of civilisation’s most dedicated discontents.
Can longevity genes be found in humans? Many scientists think so. In France, Britain, Holland, Japan, Finland and the United States gerontologists are busily compiling lists of centenarians and analysing their DNA in order to find out why they live so long. They do so not in the expectation that there is any one mutation or polymorphism that all these centenarians have in common – and they fully accept that some centenarians will have made their century by a combination of good luck and virtuous living. Rather, the approach is to scan many genes which, for one reason or another, are believed to contribute to the diseases of old age and to search for those variants that are more common in geriatric survivors relative to the rest of the population.
One of the first longevity genes to be identified in this way was apolipoprotein E (APOE). The protein encoded by this gene comes in several polymorphic variants called ?2, ?3 and ?4. About 11 per cent of Frenchmen and women under the age of seventy carry at least one copy of the ?4 variant, but in French centenarians this number drops to 5 per cent, the difference being made up by the ?2 variant, which becomes more common. This implies that should you wish to see your hundredth birthday, you should hope to have at least one copy of ε2 but none of ε4.
This is because the APOE gene, which encodes a protein involved in cholesterol transport, has been implicated in Alzheimer’s disease. About one in ten people aged sixty-five or over will contract Alzheimer’s, but the odds are skewed drastically if you are an ?4 carrier. One copy of ?4 relative to none increases your risk of Alzheimer’s three-fold; two copies increases your risk eight-fold. Were this not enough, ?4 also predisposes to cardiovascular disease. With this sort of molecular double jeopardy it is easy to see why ?4 carriers rarely survive to a great age.