Longer lifespan hopeful

       It may be the ultimate free lunch - how to reap all the advantages of a calorically restricted diet, including freedom from disease and an extended healthy lifespan,without eating one fewer calorie. Just take a drug that tricks the body into thinking it's on a diet.
       It sounds too good to be true, and maybe it is.Yet, such drugs are now in clinical trials. Even if they should fail, as most candidate drugs do,their development represents a new optimism among research biologists that ageing is not immutable, that the body has resources that can be mobilised into resisting disease and averting the adversities of old age.
       This optimism, however, is not fully shared.Evolutionary biologists, the experts on the theory of ageing, have strong reasons to suppose that the human lifespan cannot be altered in any quick and easy way. But they have been confounded by experiments with small laboratory animals, including roundworms, fruit flies and mice. In all these species, the change of single genes has brought noticeable increases in lifespan.
       With theorists' and their gloomy predictions cast in the shade, at least for the time being,experimental biologists are pushing confidently into the tangle of linkages that evolution has woven among food intake, fertility and lifespan.
       "My rule of thumb is to ignore the evolutionary biologists - they're constantly telling you what you can't think," Gary Ruvkun of the Massachusetts General Hospital remarked in June after making an unusual discovery about longevity.
       Excitement among researchers on ageing has picked up in the last few years with the apparent convergence of two lines of inquiry: single gene changes and the diet known as caloric restriction.
       In caloric restriction, mice are kept on a diet that is healthy but has 30 percent fewer calories than a normal diet. The mice live 30 to 40 percent longer than usual with the only evident penalty being that they are less fertile.
       People find it almost impossible to maintain such a diet, so this recipe for longevity remained a scientific curiosity for many decades. Then came the discovery of the single gene changes,many of which are involved in the body's regulation of growth, energy metabolism and reproduction. The single gene changes thus, seem to be pointing to the same biochemical pathways through which caloric restriction extends lifespan.
       If biologists could only identify these pathways,it might be possible to develop drugs that would trigger them. Such drugs could in principle have far-reaching effects. Mice on caloric restriction seem protected from degenerative disease, which may be why they live longer. A single drug that protected against some or all the degenerative diseases of ageing would enable people to enjoy more healthy years, a great benefit in itself, even if it did not extend lifespan.
       The leading candidates for such a role are drugs called sirtuin activators, which may well be mimicking caloric restriction, in whole or in part. The chief drug is resveratrol, a minor ingredient of grapes and red wine. Sirtris Pharmaceuticals of Cambridge, Massachusetts, is now conducting clinical trials of resveratrol, in a special formulation, and of small-molecule drugs that also activate sirtuin but can be given in much lower doses. The resveratrol formulation and one of the small chemicals have passed safety tests and are now being tested against diabetes and other diseases. The Food and Drug Administration (FDA) does not approve drugs to delay ageing, because ageing in its view is not a disease.
       The resveratrol tests are still under way, but last month the results with another substance,the anti-fungal drug rapamycin, were published.Rapamycin was found to extend mice's lives significantly even though by accident the mice were already the equivalent of 60 years old when the experiment started.
       Rapamycin has nothing to do with caloric restriction, so far as is known, but the study provided striking proof that a chemical can extend human lifespan.
       Another result, directly related to the caloric restriction approach, emerged last month from a long-awaited study of rhesus monkeys kept on such a diet.
       The research was led by Richard Weindruch of the University of Wisconsin. As fellow primates,the monkeys are the best possible guide to whether the mouse results will apply in people. And the answer they gave was ambiguous.
       The monkeys who had spent 20 years on caloric restriction were in better health than their normally fed counterparts, and suffered less diabetes, cancer and heart disease, apparently confirming that caloric restriction holds off the degenerative diseases of ageing in primates as well as rodents.
       But as for lifespan, the diet extended life significantly only if the researchers excluded deaths that were apparently unrelated to ageing,such as under the anaesthesia necessary to take blood samples. When all deaths were counted,lifespan was not significantly extended.
       Some researchers think it is perfectly valid to ignore such deaths. Others note that in mouse studies one just counts the numbers of dead mice without asking what they died of, and the same procedure should be followed with monkeys,since one cannot be sure if a death under anaesthesia might have been age related.
       With the rapamycin and rhesus monkey results,David Sinclair said,"we have more weight on the side of people who think it's going to be possible". He emphasised the ability of both caloric restriction and sirtuin-activating drugs to postpone the many diseases of ageing, at least in mice. To have one drug that postponed many degenerative diseases in people would be a significant advance, he said, even without any increase in longevity.
       People may live so long already that no drug could make much of a difference. Probably because of reductions in infant mortality and other types of disease, human life expectancy in developed countries has been on a remarkable,unbroken upward trend for the last 160 years.Female life expectancy at birth rose from 45 years in 1840 to 85 years in 2000.
       An important difference among experts on ageing is whether there is an intrinsic rate of ageing. Supposing there were cures for all diseases,what would one die of, if one died at all? Vijg and Campisi believe there is a steady build-up of damage to DNA and to proteins such as collagen and elastin fibres that knit the body together.Damage to DNA means that the regulation of genes becomes less precise, and this regulatory drift disrupts the stem cells that repair each tissue. Even if all diseases could be treated, it is not clear that anything could overcome intrinsic ageing.
       Miller, on the other hand, said he believes that no clear distinction can be made between disease and other frailties of ageing."Anything a doctor can charge for we call disease, but wrinkled skin, white hair or not feeling good in the morning, these we don't call disease," he said.
       He said he thinks that the idea of intrinsic ageing is not well defined and that contrary to the theories of the evolutionary biologists, there may be simple ways to intervene in the ageing process.
       In the view of evolutionary biologists, the lifespan of each species is adapted to the nature of its environment. Mice live at most a year in the wild because owls, cats and freezing to death are such frequent hazards. Mice with genes that allow longer life can rarely be favoured by natural selection. Rather, the mice that leave the most progeny are those that devote resources to breeding at as early an age as possible.
       According to this theory, if mice had wings and could escape their usual predators, natural selection ought to favour longer life. And indeed the maximum lifespan of bats is three-and-ahalf times greater than flightless mammals of the same size, according to research by Gerald S.Wilkinson of the University of Maryland.
       In this view, cells are so robust that they do not limit lifespan. Instead the problem, especially for longer-lived species, is to keep them under control lest they cause cancer. Cells have not blocked the evolution of extremely long lifespans,for example, that of the bristlecone pine, which lives 5,000 years, or certain deep sea corals, whose age has been found to exceed 4,000 years.
       Some species seem to be imperishable. A tiny freshwater animal known as a hydra can regenerate itself from almost any part of its body,apparently because it makes no distinction between its germ cells and its ordinary body cells. In people the germ cells, the egg and sperm,do not age; babies are born equally young, whatever the age of their parents. The genesis of ageing was the division of labour in the first multicellular animals between the germ cells and the body cells.
       That division put the role of maintaining the species on the germ cells and left the body cells free to become specialised, similarly in neurons or skin cells. But in doing so the body cells made themselves disposable. The reason we die, in the view of Thomas Kirkwood, an expert on the theory of ageing, is that constant effort is required to keep the body cells going."This, in the long run, is unwarranted - in terms of natural selection, there are more important things to do," he writes.
       All that seems clear about lifespan is that it is not fixed. And if it is not fixed, there may indeed be ways to extend it.