Independent Perspective News

The way evolution works makes it impossible for us to have genes that control how long we live - or does it? It may be time for a major rethink, says Garry Hamilton

"AT ITS most extreme, we were accused of fraud," recalls biologist Tom Johnson. Fifteen years ago, he and colleague David Friedman, both then at the University of California, Irvine, announced a result that contradicted everything biologists thought they knew about ageing and lifespan. They showed that a change in a single gene was responsible for making nematode worms live up to 65 per cent longer than normal.

The finding was greeted with intense scepticism. Critics were vehement: a creature's lifespan couldn't possibly be manipulated so easily because ageing was not controlled by genes. Rather, it was simply a product of random, uncontrolled degeneration. To suggest otherwise was to imply that evolutionary theorists were completely wrong in what they believed about ageing.

But since then, critics have had to eat their words as a growing body of results threatens to demolish long-standing theories of how and why we age. Scientists have come to accept that simple organisms such as flies and worms possess a simple switch that dictates lifespan. Some are even convinced that this switch works through a handful of molecular signals that affect the rate of ageing.

In January this year came an even more surprising result. French researchers revealed that mammals possess a similar switch. They unveiled a single-gene mutation that extends longevity in mice via a molecular pathway similar to the one in the worm. This surprise finding is being hailed as powerful evidence that all animals have a genetic switch that can alter normal lifespan.

The idea that lifespan has an inbuilt, genetically controlled flexibility has sparked a spirited debate. Some researchers believe such results fit nicely with existing theories of how and why we age but others argue it will force a major rethink. "It's quite clear that this pathway is regulating the rate of ageing," says Cynthia Kenyon, a geneticist at the University of California, San Francisco, and one of the leaders in the study of the genetics of ageing. What's more, she adds, human intervention could alter this pathway.

The main bone of contention is that if genes do control the rate of ageing, they must have somehow evolved for this purpose by natural selection. And for decades, evolutionary biologists were convinced that genes specifically for ageing couldn't have evolved, because the process starts after an organism has successfully reproduced and should therefore lie beyond the reach of natural selection. Leonard Hayflick, a gerontologist at the University of California, San Francisco - famous for his discovery that human cells cannot divide indefinitely - is firmly in this camp. Last year, he released a letter signed by 51 scientists warning the public against the notion of an ageing program that could be manipulated. "Ageing is not, as some might think, a genetically programmed process, playing itself out on a rigidly predetermined schedule," wrote Hayflick and his co-authors. "The way evolution works makes it impossible for us to possess genes that are specifically designed to cause physiological decline with age, or to control how long we live."

The idea that ageing and death are evolved traits was first mooted after Darwin outlined his theory of evolution in 1859. Alfred Russel Wallace, who came up with the idea of natural selection at around the same time, suggested that individuals are programmed to die so as not to compete with their offspring, an argument expanded by influential German biologist August Weismann. But students of evolution later concluded this made little sense. For one thing, animals consistently live much longer in captivity. How could they have evolved a genetic program that never gets used in the wild? Secondly, if a death program did exist, selection would likely favour individuals who acquired genetic mutations that allowed them to escape that program, live longer and so have the chance of producing more offspring. By the time of his death in 1914, Weismann had largely changed his mind. In the 1920s, programmed ageing was dismissed as a "perverse extension of the theory of natural selection".

Current explanations for why ageing occurs first emerged in the late 1940s when Peter Medawar began formulating his "mutation accumulation" theory. According to Medawar, genes that have a negative impact on health only late in life will tend to accumulate in the genome due to the absence of selective pressure to remove them. Take Huntington's disease, for example. This genetic disorder is deadly, but since its effects usually only begin to occur when carriers are in their 30s or 40s, the gene has already been passed on to the next generation. In 1957 noted American evolutionary biologist George Williams added a twist to this theory. According to Williams, ageing results from natural selection favouring mutations that bestow advantage to an individual early in life - regardless of the negative effects these same genes may have after reproduction is over. For example, Williams suggested that selection would favour a gene that helped calcify bones to make them stronger early in life, even if it meant calcification in arteries later on in life.

Balancing act

In the late 1970s, gerontologist Tom Kirkwood, now at the University of Newcastle upon Tyne, built on Williams's notion that ageing is the result of a trade-off. According to Kirkwood, an organism has only a limited budget of energy to divide between reproduction and maintaining its own tissues. The result is a trade-off, with the organism diverting energy to reproduction and neglecting maintenance, resulting in ageing. The extent and pattern of this energy diversion will be dictated by a species' ecological circumstances. Mice, for example, live in harsh conditions and are the favourite meal of many a predator. Their need to invest in early and frequent reproduction helps explain their short lifespan.

By the 1980s, as the revolution in molecular biology was helping researchers unravel the genetic pathways underlying complex processes such as embryonic development and growth, gerontologists were being told not to bother. Johnson's discovery that a single gene named age-1 altered the longevity of worms was not only doubted, it was downright ignored. But then, in 1993, Kenyon described a second longevity gene in worms, daf-2.

This finding turned heads, partly because daf-2 had an even more dramatic impact on lifespan than age-1 - mutant worms lived on average twice as long as normal - and partly because the gene was known to be involved in sending worms into a weird physiological state called a dauer larva. Prior to adulthood, juvenile worms can enter this state in response to starvation. They stop growing and developing, and store extra fat and seal themselves up at both ends. This delay in their development can extend their normal two-week lifespan by months. Kenyon found that by altering the expression of daf-2 just a little, worms lived longer without becoming dauers. This raised the possibility that the extended lifespan was independent of the other changes associated with the dauer state.

This finding took on greater significance in 1997 when scientists at Harvard Medical School in Boston cloned daf-2 and discovered that it codes for a worm version of the human insulin receptor, a molecule used for transporting insulin into cells that is key to regulating energy metabolism. For longevity researchers, this was an intriguing development. Since the 1930s researchers have known that lab animals will live much longer when their calorie intake is restricted - 50 per cent longer in the case of rats. The same has been seen in species ranging from yeast to dogs. The parallels between long-lived daf-2 worm mutants and calorie-restricted animals suggested that Kenyon had found part of a molecular pathway that affects lifespan in most, if not all, animals.

These discoveries in worms were followed by others showing that alterations to genes with similar functions in yeast and fruit flies also extended lifespan. January's big news, from a research team led by Yves Le Bouc at the Institute of Health and Medical Research in Paris, came from experiments on mice in which another insulin-related signalling pathway had been disabled. In this instance it was the insulin-like growth factor-1 (IGF-1) pathway, which regulates many functions including energy metabolism. In the mouse experiments, knocking out the pathway extended average longevity by 33 per cent in females and 16 per cent in males. It looked as though insulin-related pathways were involved in ageing in a mammals, too. "This finding is the most definitive evidence yet that this really is an evolutionarily conserved pathway," says Johnson.

Assuming that this system exists in most animals, how might it work? How could just a few genes affect the duration of life? The mutant animals created by researchers such as Kenyon seem to be more resistant to cellular damage, and accumulated damage is believed to be the main cause of ageing. Numerous studies show that virtually every one of these long-lived animals is better at avoiding the kind of cellular damage normally caused by exposure to chemicals, extreme temperature and UV radiation. Could these signalling pathways damp down the activity of cellular repair machinery, and so promote ageing?

Evidence to support this idea comes from the finding that worms with a mutant daf-2 gene lose their life-extension if they also lack parts of their damage repair machinery. Cells have a range of proteins and molecules that protect them from damage - such as the antioxidant enzyme superoxide dismutase They also come equipped with repair mechanisms to undo damage after the fact (New Scientist, 15 March, p 40). Worms without daf-2 will lose their extra longevity if they are also missing daf-16, a gene needed for the production of two key enzymes that prevent cell damage - cytosolic catalase and manganese superoxide dismutase.

But how does the daf-2 pathway actually work? At the moment it's not clear, but there are some clues. From investigations done in Kenyon's lab and elsewhere it appears, in worms at least, to involve neurons releasing insulin-like hormones. These trigger the release of a second hormone that travels to cells throughout the body. No one knows what this hormone does, but researchers speculate that it somehow acts as a general inhibitor of the damage limitation and repair systems.

Slowly does it

For Kenyon, this all adds up to one thing: animals lacking genes such as daf-2 live longer because they age more slowly. But Hayflick and others disagree. They say there is at least one other feasible explanation. What if longevity is being increased because such gene mutations make individuals more resistant to one particular cause of death - say heart disease?

To address this question, researchers are now attempting to define and measure ageing in worms at the cellular level, so they can see if the process is actually slower in long-lived mutants. In one recent set of experiments, Delia Garigan, working with Kenyon, identified several age-related changes in worm cells. These included a gradual blurring of the boundary of the cell nucleus and a change in the texture of cytoplasm from smooth to curdled. Garigan also noted a correlation between these changes and the loss of mobility that also strikes aged worms. Next, Garigan looked at cells from daf-2 mutant worms and saw a delay in the signs of ageing. Nuclear boundaries, for instance, remained visible for approximately 20 days, whereas in normal worms they disappeared after only five days.

The researchers who accept that a single genetic pathway can affect ageing, are now arguing over whether such a process evolved specifically to cause ageing. Those who think it did not argue that the ageing pathway is compatible with existing evolutionary theories that see ageing as the price paid for successful reproduction. According to this idea, animals faced with food shortages undergo changes that include storing more fat, delayed reproduction and a ramping up of the mechanisms that maintain, repair and protect cells from molecular damage. Proponents of this view see delayed reproduction as the primary effect of the survival mechanism, and added longevity as a secondary effect.

Evidence for this view comes from experiments showing that when large numbers of flies are selectively bred to lay eggs when young, their lifespans shorten over the generations, while those bred to lay eggs when they are older live longer. What's more, the price of the trade-off is evident in the extreme side-effects experienced by most long-lived mutant organisms. These range from complete or partial disruption in fertility, to dwarfism. "I really don't believe there is a set of genes that are designed to make you age," says Monica Driscoll, a geneticist at Rutgers University in Piscataway, New Jersey. "There are certain genes that contribute to how you age. But the idea of a program analogous to what you have for development is probably not right."

But another recent set of experiments from Kenyon's lab seems to support the idea that this genetic pathway evolved, at least partly, to promote ageing. Andrew Dillin turned down daf-2 activity in normal worms until they reached young adulthood, when he returned it to normal. He discovered that these animals experienced the same reduced fertility as in daf-2 mutants, but failed to live longer. But when he disrupted daf-2 after the normal worms reached adulthood, the animals lived as long as daf-2 mutants but without the accompanying reduction in fertility. This suggests that the daf-2 signalling pathway's control over longevity is separate from its effect on reproduction. Kenyon thinks this points to a separate genetically determined ageing program. Perhaps Wallace was right after all. "Why does daf-2 remain active during adulthood, if the only apparent effect of its action is to speed up ageing?" says Kenyon. "I'm starting to like the idea that it prevents animals from competing with their young."

There is also growing doubt over whether a trade-off is always a necessary condition of added longevity. The long-lived IGF-1 mice seemed normal in almost every way: normal body temperature, normal circadian rhythms, normal metabolism, normal litter sizes, normal number of pregnancies, normal onset of infertility. The only difference was a slight reduction in size. In females, this size reduction was eight per cent, not a bad swap for a lifespan extended by a third. While this debate remains up in the air, there are researchers from both sides who are now prepared to say it's wrong to view ageing as a process that can't be altered. The powerful effects that genes appear to have on the body's ability to withstand the ravages of time, whether or not they actually evolved for that purpose, suggest that a fountain of youth may be out there after all. The trick is to find it.