Can ageing be stopped?

by Philip Hunter

Gerontologists consider the maximum lifespan for humans to be about 120 years. But with rising evidence for a genetic "death program," which in principle could be amended, some researchers are starting to believe the limit could be extended

  1. Old age hardly exists in wild animals. Accident, illness or predation usually kill long before the potential lifespan has been reached. Humans, though, especially in the developed world, are pushing in ever larger numbers towards the maximum lifespan, thought by most gerontologists to be around 120. (The world longevity record is held by the Frenchwoman Jeanne Calment, who died in 1997 aged 122 years and 164 days.)
  2. In Britain in 1901, life expectancy at birth was 49 for women and 45 for men. By 2002, this had risen to 81 and 76 respectively. This rapid increase in longevity has created hopes among gerontologists not just of an extended "quality of lifespan" well into the nineties, but of lifting the 120-year limit.
    Optimists and pessimists on ageing
  3. Ageing science has been divided between optimists and pessimists ever since the first modern theories emerged in the mid-19th century. Pessimists argue that ageingis caused by the same inevitable decay that affects machines and inanimate objects. They accept that biology has evolved repair mechanisms to minimize the damage, but insist that these merely delay death long enough to ensure the reproductive survival of the organism.
  4. The optimists point out that all animals have immortal reproductive cells ("germlines"), and argue that ageing and longevity are genetically determined through programs that can in principle be changed. They argue that biology has the tools to cope with wear and tear almost indefinitely, if only there were an evolutionary route to get there.
  5. Right now the optimists are in the ascendant, encouraged by recent experiments that have extended the life expectancy of mice from around two years to three, with some reports of up to five. Such progress is unlikely in humans, for whom evolution has already raised maximum lifespan well beyond comparably sized mammals—including great apes—but the work sheds valuable light on some of the mechanisms involved. The recent progress in mice was made by the application of the discovery, dating back to the 1930s, that lifespan could be increased dramatically in almost all animals by a diet low in calories but comprising all vital nutrients. This remains the one proven strategy for boosting life expectancy and slowing down ageing across a wide range of species. (On this basis, occasional fasting, as practiced in some religions, might well extend human lifespan.)
  6. Ageing is also closely linked to growth. Small members of mammalian species tend to live longer, as has been observed in dogs, mice and horses. It seems that retarded growth is associated with an overall slowdown in the processes that lead to ageing. It should certainly delay the process of cellular senescence, the point at which cells stop dividing. Each time a cell divides, the DNA of the daughter cells is usually slightly shorter than the DNA of the parent, as a result of deficiencies in the copying process. Put simply, some cells can only divide a certain number of times before they die, and so if the time intervals between divisions are increased by slower growth, this aspect of ageing will be delayed.
  7. It turns out that a low-calorie diet is not the only way to extend the lifespan of a mouse. The same effect can be obtained on a diet with normal calories but reduced protein. Moreover, it seems that it is not the protein that matters, but one specific component: the amino acid methionine. The finding is surprising because methionine is one of the nine essential amino acids. A diet totally deficient in methionine would kill a mouse in a few weeks. Yet the optimum level for longevity seems to be lower than is taken in a normal diet.
  8. It is not known exactly how methionine restriction extends lifespan, but the answer could be linked to the oxidative or free radical theory of ageing. This states that the primary cause of ageing lies in the toxic by-products of energy metabolism within our mitochondria (the sub-units of the cell that produce energy). These by-products—chemicals such as hydrogen peroxide—oxidize parts of nearby cellular components, in particular proteins and DNA. The process can be compared to the rusting of metals when they are exposed to air. Many of these toxic, oxidising substances are known as free radicals.
    Is there a death program?
  9. But even this may not be the final answer to the methionine riddle, for some researchers argue that free radicals are merely mediators of ageing rather than the underlying cause, with their role ultimately controlled by genes orchestrating a "death program."
  10. There is some evidence that free radicals are manipulated by death programs in those animals where ageing starts suddenly. One of the best studied examples is the salmon, a fish which appears to age suddenly and die aged about three, after one season of reproduction. Free radicals increase rapidly during this period, but the fact that they seem to be stable until the salmon has finished reproducing suggests that there is an underlying program at work.
  11. Not all gerontologists agree with the death program theory. Tom Kirkwood, one of the leading figures in the field, argues that the sudden post-reproductive death of the Atlantic salmon is not evidence of programmed ageing but the natural consequence of an extreme evolutionary phenomenon called "semelparity," meaning having all your children at once. The argument is that semelparous organisms invest all their life energy in a single reproductive event, after which there is no point being able to resist ageing.
  12. But a finding in 2005 appears to have swung the argument decisively in favor of an ageing program. A study at the RussianAcademy of Sciences found that salmon can live much longer and continue reproducing when infected by pearl mussel larvae. In some cases, infection by this parasite extends life fourfold, to 13 years. It seems that the parasite has evolved a mechanism to avert the salmon's abrupt death so it can continue providing shelter and food for the parasite's development and reproduction. For a parasite dependent on the survival of its host, this is a sensible strategy. While the mechanism for this effect is not yet fully understood, it seems that the larvae produce a small protein that helps to neutralize free radicals.
  13. The study more or less confirms the existence of some form of death program. If there were no program, the salmon's sudden death after reproduction could only be the result of wear and tear, in which case there would be limited scope for the mussel larvae to intervene. The fact that the larvae can increase the salmon's lifespan by such a huge factor by release of particular compounds indicates that there must normally be some mechanism hastening the ageing process.
  14. This raises the question of why the salmon has evolved this type of ageing program. One explanation is that it reproduces in rivers where food is scarce, and that therefore it is in the interests of the species for individuals to die and stop competing for resources once their reproductive energies are finished. The dead parents may even provide food for the fish upon which their young feed.
    Immortal animals
  15. But other questions remain. Although ageing is kept slow in the salmon until reproduction occurs, it still takes place. As in many animals, including humans, the ageing process starts at birth, but is kept in check until reproductive life is over. So can ageing ever be stopped altogether? At first sight this might seem unlikely, but all animals have immortal germlines—sequences of sex cells, like the sperm or ova—and we do not pass on the artefacts of ageing to our offspring. Evolution brought this about because any animal whose offspring were born old would soon become extinct.
  16. So the question arises: has any animal exploited the immortality of its germline to resist ageing indefinitely? The answer is yes. A few examples have been found among simpler organisms, one of the best studied being the hydra, a small freshwater animal up to 20mm long. Hydra appear to be able to regenerate endlessly with none of the recognized signs of ageing. This is possible because their bodies are full of germ cells whose primary purpose is to form buds that break off to produce offspring. These germ cells also create new tissue within the body, which in effect is the offspring of itself, constantly forming new cells to replace old ones. The line between reproduction and regeneration is blurred.
  17. Although higher animals lack such regenerative powers, there are plenty of examples of individual organs being replaced in this way. Some sharks replace their teeth several times over their lifespan in order to continue feeding and to prolong their reproductive lives.
  18. So why has evolution not used regeneration more ambitiously to extend reproductive lifespan? The answer lies in the high risk of death by accident or predation. In an animal such as the mouse, death by misadventure becomes almost inevitable after a few years, so there is little selective pressure in favor of long-lived individuals. Instead, evolution selects those organisms that are highly reproductive during their short lives.
  19. But the equation changes abruptly for animals that have evolved the power of flight. When predators can be left on the ground, it becomes reproductively advantageous to live significantly longer. This is almost certainly why flying birds and bats live between four and ten times longer than non-flying mammals and birds of the same size. Flight itself, with its huge energy demands, may also have led to the development of efficient respiration and metabolism that, as a side-effect, reduces the production of damaging free radicals.
  20. Research on birds and bats is shedding light on the genes involved in extending maximum lifespan as well as the biochemical mechanisms that bring it about. Along with research in non-flying mammals such as mice, this is helping to identify candidates for intervening in the ageing process. In particular, there is growing hope that aspects of ageing can be tackled by targeting specific metabolic pathways with therapies that mediate hormonal or other factors known to be involved. Work in mice over the last three years has also shown that lifespan can be extended by directing antioxidants specifically at mitochondria.
  21. It has also been shown, in some animals, that the effects of calorie or protein restriction can be obtained via drugs without actually dieting. The effects of diet on ageing appear to operate particularly through the production of insulin and related enzymes with their role in growth and maintenance of correct blood glucose levels. The primary metabolic pathway involved, IGF-1, is known to be involved in ageing, and decreasing the activity of the protein receptor involved in IGF-1 has been shown to extend lifespan in mice. The case is still unproven for humans, but a number of studies are assessing whether there is reduced insulin signaling in long-lived people.
  22. Human ageing has a separate dimension that becomes ever more relevant as people live longer. In animals, the various ageing processes seem to progress in tandem. For humans, there is evidence that ageing of the brain is partly uncoupled from the other organs. The evidence for this comes from observations of people suffering from premature ageing conditions, such as Werner's syndrome.
  23. The implication is that if it becomes possible to extend human lifespan, it cannot be assumed that mental deterioration will automatically be postponed. So it is important to continue the distinct study of brain ageing, including factors such as accumulation of tangled protein, or plaques, associated with some forms of dementia, including Alzheimer's.
    Extending lifespan and quality of life
  24. Ageing in humans, as in other mammals, appears to be a coordinated process orchestrated by a relatively small number of genes. If this is the case, then it makes sense to tackle many age-related diseases through this genetic core rather than treating each one as a separate case—with the possible exception of some brain conditions.
  25. There is potential for humans to mimic the biologically immortal hydra, by exploiting our stem cells in the regeneration of organs damaged by age-related diseases. The ability of adult stem cells, which remain in the body throughout life, to regenerate heart muscle cells has already been demonstrated in mice. Organs regenerated this way would in effect be brand new, and "younger" than all the other tissues and organs. Such regeneration might not immediately boost life's span, but should greatly improve its quality in old age.
  26. Indeed, for humans the principal target should be quality of lifespan rather than absolute longevity. For now at least, few of us want to live beyond 120, but we would like to continue enjoying the good life for as long as possible within that ultimate span.