So one day quite soon we'll live a helluva long life - maybe become immortal

1. Towards immortality
The growing power to change human nature
By Alun Anderson/The World

Science can be a little scary. Its potential to transform life itself has led to predictions that we might re-write our own genetic make-up or merge our minds with machines. But 2007 will show that it is not these sci-fi possibilities that are of immediate concern. Real possibilities of changing our human nature are creeping up from a less obvious direction. More and more drugs developed to treat disease are turning out also to offer the potential to “enhance” the cognitive powers of healthy people, and to push human life expectancy much further, perhaps to 115 years and beyond.

The potential to alter our nature and lifespans elicits strong reactions. The transhumanists—a loose coalition of scientists, technologists and thinkers who seek opportunities to enhance the human condition—see change as desirable. Human nature, says Nick Bostrom, an Oxford University philosopher and advocate of transhumanism, is “a work in progress, a half-baked beginning that we can learn to remould in desirable ways…we shall eventually manage to become posthuman, beings with vastly greater capacities than present human beings have.” Others argue that we will never have sufficient wisdom to make ourselves more than we are. Francis Fukuyama of Johns Hopkins University describes transhumanism as one of “the world’s most dangerous ideas”. But whatever you may think, the possibilities for changing your nature by direct biochemical intervention are arriving now.

There is no greater goal for transhumanism than the conquest of death. Some of the most controversial advocates of technological improvements to humans, including Ray Kurzweil, an American inventor and author, and Aubrey de Grey, a gerontologist and chairman of the Methuselah Foundation, argue optimistically that immortality may become achievable for people who are alive today. But even without the yet-to-be-invented technologies that they say will make this possible, there are good reasons why we can hope to live a lot longer.

Transhumanists question the conventional wisdom that the human lifespan is coming to a natural limit. History shows that every limit announced by experts is quickly overturned. Back in 1928, an American demographer, Louis Dublin, calculated that the upper limit on average life expectancy would be 64.8 years, a daring figure at the time, with American life expectancy then just 57 years. But now his figure looks timid, given that life expectancy for women in Okinawa, Japan, has passed 85.3 years, 20 years more than Dublin claimed possible. Also looking timid are the scientists who later predicted that life expectancy would nowhere pass 78 years (in 1952), 79 years (1980) and 82.5 years (1984).

Can this steady rise in life expectancy be replaced with a giant leap? Many transhumanists think so. We already know that cutting back severely on calories in the diet can give life expectancy a remarkable boost—between 30% and 50%—in a range of animals. Now evidence is emerging not only that this approach may work in humans but also that drugs may provide the benefits of calorie restriction without the pains of the diet.

Life-extension enthusiasts who have been eating just 1,800 calories a day for an average of six years (a healthy Western diet averages 2,700 calories a day) do indeed show signs that their bodily ageing is slowing. Eating far fewer calories does not simply slow metabolism, nor do the advantages come just from being thin, as aggressive calorie-burning exercise does not confer the same benefits. Rather, calorie restriction appears to trigger natural defences designed to boost the chances of survival during periods of food scarcity. As many of those defensive responses are co-ordinated by a set of genes called sirtuins, there is a chance that drugs can be used to trigger their action directly, without the diet. Chemicals that affect sirtuin activity have been found in plants and one, resveratrol, extends lifespan in test animals. In one species of fish, maximum lifespan increased by almost 60%. Humans will be pleased to know that resveratrol occurs naturally in red wine

Efforts to develop sirtuin-targeting drugs and test them for clinical safety are under way, but the companies working on them stress a goal of activating “health-promoting genes”, rather than life-extension itself. That is just too controversial.

The same is true of other drugs that may enhance human capabilities. Modafinil provides an interesting example. The drug was developed to treat narcolepsy and sleep problems but is a hit with healthy people who want to improve their concentration and skip sleep. Modafinil users dramatically improve their ability to solve classic tests of planning ability, like the Tower of London task where sets of coloured discs on pegs have to be moved from one pattern to another in the fewest moves. More than 40 other cognitive enhancement drugs are under study around the world.

Numerous drugs are also in development that may enhance or alter memory. In the brain, memories are coded in patterns of links between nerve cells and are laid down in two stages: the first when the strength of signals between cells is temporarily enhanced and the second when memory is consolidated through the synthesis of new proteins. Ampakine drugs target the first stage, boosting excitatory communication between nerve cells, as well as stimulating brain growth. Results are encouraging, at least for middle-aged rats. Recently scientists found that the drug turned back the clock for a key measure of decline in memory function.

Another drug, propranolol, has the quite different aim of weakening troubling memories. Memories are etched with particular strength in stressful situations, including wars, car accidents and rapes. Later these memories can return as a painful part of post-traumatic stress disorder. Propranolol blocks the impact of stress hormones on memory formation and, if taken very soon after the trauma, turns down the intensity of recall. More surprising is a new drug called ZIP (Zeta Inhibitor Peptide) that makes rats forget everything they learnt recently, without affecting their learning ability. ZIP has not been tested in humans but has the potential to wipe out all new memories.

Transhumanists have been quick to debate where such drugs might lead: not only might they lessen stress disorders, but they could also remove the feeling of guilt by lessening memories of wrongdoing, or dull the pains of love lost. Such possibilities highlight the problems of playing with human nature. We may be more efficient, but without the feelings of others around us.

That leaves us with the great unresolved debate in transhumanism: whether, if we choose to “enhance” ourselves, we can say we are the same person afterwards, and whether that matters. But one thing is certain: whatever ailment drugs may be developed to treat, if they can also be used to provide someone with a competitive advantage, or prolong life, people will take them.


2. Can ageing be stopped?
Gerontologists consider the maximum lifespan for humans to be about 120 years. But with rising evidence for a genetic "death programme," which in principle could be amended, some researchers are starting to believe the limit could be extended
By Philip Hunter/Prospect Magazine

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.)

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

Ageing science has been divided between optimists and pessimists ever since the first modern theories emerged in the mid-19th century. Pessimists argue that ageing, following the second law of thermodynamics, is caused by the same inevitable decay that afflicts machines and inanimate objects. They accept that biology has evolved repair mechanisms to mitigate the damage, but insist that these merely delay death long enough to ensure the reproductive survival of the organism.

The optimists point out that all animals have immortal reproductive cells ("germlines"), and argue that ageing and longevity are genetically determined through programmes that can in principle be amended. 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.

Right now the optimists are in the ascendant, bolstered 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 boosted 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 practised in some religions, might well extend human lifespan.)

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, or apoptosis, 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. Evolution has added disposable buffers called telomeres to the DNA to allow for some shortening. However, after a certain number of divisions, these buffers are spent, after which further copying eats into the active DNA sequence. 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.

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.

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—oxidise parts of nearby cellular components, in particular proteins and DNA. The process is akin to the rusting of metals upon exposure to air. Many of these toxic, oxidising substances are called free radicals because they are electrically neutral and therefore stable, but also highly reactive because they have an unpaired electron seeking a mate from any neighbouring molecule.

Methionine happens to be the amino acid most prone to losing electrons through oxidation, and so perhaps in some way restricting it within the diet persuades the organism to use another amino acid where possible, thus reducing its overall susceptibility to oxidation. Whether this is true or not, a recent Spanish study found that methionine restriction definitely decreases oxidative damage to crucial mitochondrial DNA and proteins.

Is there a death programme?

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 programme."

There is some evidence that free radicals are manipulated by death programmes in those animals where ageing kicks in suddenly. One of the best studied examples is the salmon, many varieties of which appear to age suddenly and die aged about three, after one glorious orgy of reproduction. Free radicals increase rapidly during this period, but the fact that they seem to be held at bay until the salmon has done its reproducing suggests that there is an underlying programme at work. Perhaps the effect of methionine restriction might be to "edit" such an ageing programme in mammals, postponing its instructions.

Not all gerontologists agree with the death programme 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 offspring 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.

But a finding in 2005 appears to have swung the argument decisively in favour of an ageing programme. A study at the Russian Academy 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 mop up free radicals.

The study more or less confirms the existence of some form of death programme. If there were no programme, the salmon's abrupt death after reproduction could only be the inevitable 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.

This raises the question of why the salmon has evolved this type of ageing programme. 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 cease competing for resources once their reproductive energies are spent. The dead parents may even provide food for the fish upon which their young feed.

Immortal animals

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. Immortal reproductive cells are kept separate from the body's somatic cells, which only need to survive one reproductive generation.

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 recognised signs of ageing. This is possible because their bodies are permeated by germ cells whose primary purpose is to form buds that break off to yield 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.

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.

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 favour of long-lived individuals. Instead, evolution selects those organisms that are highly reproductive during their short lives.

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.

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.

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 signalling in long-lived people.

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.

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

Ageing in humans, as in other mammals, appears to be a co-ordinated 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.

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.

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.