Science: Hungry for a longer life?

It is well known that rodents live longer if fed a reduced-calorie diet. If it worked for humans, would any of us prefer longevity to a cream cake? By Tom Kirkwood
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If you told a farmer in a drought-stricken part of Africa that going hungry might make him live longer, the kindest reply you might receive would be a pitying shake of the head. And yet, since the mid-Thirties it has been known that feeding laboratory mice and rats the bare minimum needed for survival lengthens their lives by as much as a year.

A year may not seem much to you and me, but if your lifespan is just three years to start with, a year's extension is a lot. Recent research shows that severe calorie restriction in short-lived animals may activate a "time-out" strategy to cope with periods of hunger. Supposing it works for humans, too - something we don't know as yet - could we hack all those hungry days and nights for the sake of 30 more years of the same? But even if it doesn't - or if we can't - we can look to calorie restriction to tell us how the rate of ageing is controlled.

Under-feeding in human beings is bad news. Famine stunts growth and shortens lives. If you are a woman, hunger harms the babies you carry. It even harms the next generation if your baby is a daughter. A woman's egg supply is formed when she herself is an embryo. If a mother is starved, her daughter's fertility may be affected.

Calorie restriction, however, is not malnutrition. Described as "under- nutrition without malnutrition", calorie restriction provides essential nutrients, but with a much reduced total energy intake. In mice and rats, reducing energy intake by 30-50 per cent increases lifespan by around a third. Unsurprisingly, the calorie-restricted rodent is lighter and smaller. It also tends to shut down its fertility. But, apart from these obvious differences, calorie-restricted animals are in many respects healthier. They perform better in tests of stamina and endurance, they have reduced rates of developing cancer, and, in keeping with their longer lifespans, they appear to age more slowly. Internally, they are better at repairing damaged molecules, such as DNA and proteins attacked by free radicals.

How does calorie restriction do all this? Could it just be that it is not the calorie-restricted diet that is abnormal, but the diet that offers continuous access to an unlimited food supply? The typical laboratory rat lives all its life in the rodent equivalent of a fast-food restaurant. Alert to this criticism, researchers have shown that calorie restriction still works when the animals are compared with others fed a controlled diet, which avoids any tendency towards becoming overweight.

Another idea is that calorie restriction simply reduces metabolism, slowing the production of toxic by-products such as free radicals. This harks back to an early notion called the "rate-of-living" theory, according to which organisms with a high metabolic rate live shorter lives. This has since been shown to be false - eg birds have higher metabolic rates than mammals, yet on the whole they live longer. In fact, the metabolic rate per gram of body mass is, if anything, increased in calorie-restricted mice.

At first sight, it seems paradoxical that a mouse or a rat puts more effort into its metabolism when food is scarce, but there is a way to explain it. Animals in the wild need to cope with a variable food supply. Good times are interspersed with bad. Hibernating animals deal with the regular lean times of winter by entering a state of torpor. An alternative, when interruptions in food supply are less predictable, is to be flexible about how energy resources are used. Making the best use of available energy is critically important in the harsh struggle for existence. In particular, an animal needs to pay special attention to how it allocates energy between maintenance and reproduction. Getting the balance right is, literally, a matter of life and death. It may explain why we age.

Some years ago, I suggested that the reason we age is that, under the imperative of natural selection, our genes evolved a strategy whereby, in effect, they treat the body, or soma, as disposable. The highest priority of the genes, from a Darwinian point of view, is to invest in offspring. Investing in a long life is of secondary importance - hence the "disposable" soma. We invest enough in maintenance to keep the body in good shape through what would have been the normal life expectancy of our ancestors - when life was nasty, brutish and short - but no more than that.

If the energy supply fluctuates unpredictably - a problem that is particularly acute for small animals with limited fat deposits - a key question is just how much should be invested in maintenance when the going gets tough. Should the animal neglect the maintenance of its soma and put all its energy into a last-ditch effort at reproduction? Or should it suspend reproduction until its prospects of successfully raising a litter are brighter? If it chooses the second option, it may even want to increase its maintenance and keep its soma in prime condition for making babies in the future.

The UK Treasury has powerful computer models to help explore the best options for deploying its fiscal budget, and it was to a computer that my colleague Daryl Shanley and I turned to investigate the best strategy for a mouse with its budget of calories. We developed, in effect, a "virtual" wild mouse. We challenged the virtual mouse with periodic bouts of "food shortage" and allowed it to evolve its optimal strategy. What we found was deeply interesting. When there was lots of food available, the virtual mouse did just what the real mouse does - it reproduced, and tuned its investment in maintenance to give a lifespan of around three years. But when the food supply fell, and the mouse could no longer manage both to maintain itself and to reproduce, it abandoned reproduction, it increased the effort it put into maintenance, and it lived longer. In other words, the computer model confirmed that the life-extending properties of calorie restriction make evolutionary sense.

No one knows whether calorie restriction works in humans, but let us suppose for a moment that it can. What would we have to do to gain our longer lives?

Mice and rats show the greatest gain when food is restricted early in life, soon after weaning. Such practice would be ill-advised in humans because it stunts growth and interferes with learning. The eating disorder anorexia nervosa, when it occurs in adolescents, delays or blocks reproductive maturation and bone development. Nevertheless, even when started only in adult animals, calorie restriction has a significant, though lesser, effect on lifespan. For humans, 18 might be a good age to begin.

A reasonable target for a calorie-restricted human might be 70 per cent of the normal diet. Herein lies the obvious difficulty. A typical maintenance diet for an office worker is 2,000 calories a day for a man and 1,800 for a woman. Reducing this to just 1,400 or 1,260 calories a day is an unappealing prospect. We will need to find ways to trick our bodies into feeling sated, even though our energy intake is so low that it would have most of us ducking into the nearest cafe for a hefty snack. Goodness knows, most of us eat far too much. We continue to do this - and to eat the wrong things - even though we know full well that it is bad for us.

In spite of being hooked on what for many of us are unattainable ideals of slender bodily perfection, we are tempted by high-calorie products such as chocolate bars, cream cakes and chips. The real difficulty with going hungry is that the benefits of a healthy old age, and maybe even of some extra years of life, seem pretty remote when you are tempted by immediate gratification.

Let's not be too gloomy if we can't match up to those sleek but hungry little mice. Calorie restriction is telling us a lot about the processes that affect the rate of ageing. No doubt, as we learn more, we will find other ways to use these insights to combat the diseases of ageing and to enhance our quality of life in old age.

Tom Kirkwood is professor of biological gerontology at Manchester University. His latest book, `Time of Our Lives', is published by Weidenfeld & Nicolson, price pounds 20. He will be giving the keynote speech at an ICA forum on Science, Ageing and Immortality, on 4 February at 7.30pm, at the Royal Institution, London (0171-930 3647)