Cover story: Heaven can wait

Michael R. Rose began his quest to solve the problem of human ageing in 1976, with 200 garden-variety, fertilised female fruit flies. He was then a graduate student in genetics at the University of Sussex, testing a new idea known as the evolutionary theory of ageing, and he started out by putting his flies in milk bottles with nutrients in the bottom. In the uncertain world of the fruit fly drosophila, where predators and natural hazards abound, the kind of flies which survive are those which reproduce the fastest, and these were no exception. They were, in Rose's words, "trailer-park flies": quick to reach sexual maturity, capable of laying a thousand eggs in their five-week period of fertility, and for a few hours, just after they reach maturation, possessed of almost dizzying sexual prowess. Left to their own devices, they continued to reproduce at the same breakneck pace. But Rose wasn't interested in the normal rules of fruit-fly life. He wanted to reward not the flies that reproduced the fastest but the ones that lived the longest; and so, once his female flies came of age, he would wash away their eggs and larvae every other day, destroying all the progeny of his most precocious flies. The only eggs he saved were those laid near the very end of the fruit flies' five-week fertility cycle - in other words, those eggs born to the parent flies who were healthy and sexually active latest in life. Then, with these eggs in hand, he repeated the process. He bred those specially selected fruit flies, and kept only those offspring produced at the very end of the fruit-fly fertility period, once more rewarding the hardiest and longest-lived flies. He stayed in the lab sometimes for 21 hours at a stretch, and when he went home he would see flies in his sleep. He bred generation after generation, eventually conducting his experiment on a scale that no other fruit-fly researcher had ever attempted, and each time he measured the life span of a new round he found that his drosophila offspring lived a little longer than their forebears.

After getting his PhD from Sussex, in 1979, Rose moved to the University of Wisconsin, and then, two years later, to Dalhousie University, in Canada, shipping his flies with him each time by express mail. In 1987, he and his flies moved again, this time to the University of California at Irvine, and there he expanded his research to more and more strains of flies, painstakingly monitoring how his selected flies differed from normal flies and, in the process, learning perhaps as much as anyone has ever known about what it means to extend life dramatically. Today, Rose's operations occupy about forty-five hundred square feet of laboratory space on the Irvine campus. He has more than 50 people working for him. He has 170 separate populations of drosophila, comprising somewhere between half a million and a million flies, and on long benches in his laboratory, dozens of plastic fly cages are stacked up five and six high. In the past 20 years, he has bred 500 successive generations of flies, and in doing so he has doubled the fruit fly's maximum life span from about 60 days to about 120 days and counting. He has created a race of fruit fly Methuselahs.

Rose is a dark-haired man of 41, handsome in a boyish way, with slow, deliberate movements. When he describes his flies, he does not wave his hands or raise his voice excitedly. He speaks in a steady, affectless monotone, and projects an air of complete self-confidence. Among his peers, Rose is considered a brilliantly innovative scientist, who has almost single-handedly brought the evolutionary theory of ageing from an abstract notion to one of the more exciting topics in science. When Rose started using evolutionary techniques to extend the life of drosophila, no one else was trying it. Now that he has proved that the method works, the field is growing, and Rose isn't shy about stating - and defending - his accomplishments. He is, in his own words, "brash, blunt, and in-your-face". He says things like: "In all my work, there is an eight- to 10-year time lag before my colleagues start to realise what it is all about." And he is unsparing in his scorn for some of his fellow-researchers on ageing. The son of a Canadian Army officer, he estimates that by the time he was 12 he had lived in 20 different places, and he still has the air of the "new boy" about him - the defensive aloofness of one who has never had the opportunity to make friends and so has decided he doesn't need them. "I'm known for being clear partly because I'm not diplomatic," he says, contrasting himself with many of his peers, who, in his words, communicate with "a great deal of Peter Lorre-shuffling of the feet". As Caleb Finch, who studies ageing at the University of Southern California, has put it: "If someone says something stupid, he'll hit them between the eyes with it."

Before I met Rose, I spent an afternoon in the laboratory of Cynthia Kenyon, a young professor of biology at the University of California at San Francisco, who is doing ageing research with the microscopic worms known as soil nematodes. Kenyon says she works with nematodes in part because they have an aesthetic appeal for her. "The first time I saw them, I was a graduate student at MIT, and another graduate student showed me what they looked like," she said. "They're transparent, and I watched them eat. I watched the food move into the intestines, and all the cells and the nuclei, and it was really beautiful."

When I asked Rose whether he finds his flies beautiful, he looked at me sharply and said: "Am I one of those people obsessed with flies? No." The difference between Rose and Kenyon is not that Kenyon cares about her work and Rose does not. It is that, like many biologists, Kenyon brings to research a trace of romanticism. This is the reason many researchers can spend a lifetime behind a laboratory bench: they are able to imagine a certain dignity and meaning in the narrow, microscopic worlds they study. In the event that Kenyon's nematode research didn't yield any useful insight into how human beings age, I don't think she would consider her work a failure. She has, in some sense, made a beautiful organism more beautiful. Rose, on the other hand, seems to view his work without any sentiment. Everything he does seems contingent on a much more ambitious - even audacious - conviction: that what he has learned about extending life with drosophila can be applied to extending life in human beings.

Rose wants his experiments to be repeated in mice, which are close enough to human beings genetically to make them a useful model. He hopes researchers will take those long-lived mice and analyse them, in an attempt to identify all the ways in which they differ genetically from normal mice. They may, for example, make much more or much less use of certain hormones or proteins. Certain genes may be more active in long-lived mice than in normal mice, or vice versa. Living organisms are like pianos, each of which has a different melody played out on its genetic keys. Rose believes that if researchers can find out what tune is being played by long-lived mice, they can come up with a method of playing an equivalent tune in human beings.

"We're talking about thousands of mice," says Rose, who is a consultant for a company preparing to perform these experiments. "Once we have those mice, we can get the basic knowledge we need in order to tweak mammals to make them live longer. We'll run them through a variety of tests to see what's being up-regulated or down-regulated, then find some way to mimic that in humans. That can be done through several interventions, from supplying substances in a pill to IV infusion."

Rose is not by nature a dreamer, and as he spoke, in his patient, matter- of-fact manner, a Coke untouched in front of him, he made it clear that none of what he proposed would be simple or quick. He's not talking about one pill but many, he said, and not something you would take once but something you would probably take day in and day out for years: "It's going to be like the deployment of electricity. It's going to take a long time because it's going to be a big, complicated technology. You'll have a big, elaborate industry, like General Electric, which will involve companies that turn out many products for a considerable amount of money, so that people are going to have to spend a very significant fraction of their disposable income every year on products that will keep them young and robust."

But Rose makes it clear that he expects those efforts to result in fundamental increases in life span. At one point when we were talking, he walked into the hallway outside his office, where a research paper posted on the wall showed, in a bar graph, how long Rose's Methuselah flies were now living. "Look here," he said, pointing to the graph. "This would correspond to a human life span of 200 years."

Ten or 15 years ago, scientists didn't talk like this. The traditional scientific approach to the problem of ageing has been to accept our biological limits and try to rearrange the lives and the care of the elderly to make old age more manageable. Our efforts have been largely palliative - to put elevators in buildings, to make public spaces accessible to wheelchairs, to devise better treatments for cataracts, to perform coronary-bypass operations to cut down on chest pain, and even, in the case of one of the more imaginative projects sponsored by the Centres for Disease Control, to try to make fluid-filled pads for elderly hips and thus protect against the fractures that are such a common form of disability in the old. The motto of the Gerontological Society of America has been "Add life to years, not years to life", which is a statement not just of intention but of apparent fact. For a long time, no one thought you could add years to life. Mice were thought to live about two years, dogs about 15 years, and human beings at most 100 years - all according to some immutable genetic clock - and any scientists who made spectacular claims of reversing the ageing process were treated with scepticism.

Even the idea of treating ageing with hormones like testosterone, melatonin, and DHEA - currently being celebrated as the fountain of youth in one breathless magazine article after another - does not represent a dramatic departure from this way of thinking. Hormone-replacement therapy is meant to give the ageing body a tune-up, to delay or lessen certain problems associated with old age. Yet even that modest goal comes with certain caveats. DHEA, for example, changes the colour of rodent livers from pink to brown; when 16 rats were fed DHEA for a year and a half, in a recent study at Northwestern University, 14 developed liver cancer. Nor is melatonin likely to be any better. Writing in the journal Cell late last year, Steven Reppert and David Weaver, of Harvard Medical School's Laboratory of Developmental Chronobiology, pointed out that the animal experiments that triggered the melatonin craze were conducted on strains of mice with a genetic defect that made it impossible for them to produce melatonin of their own. When the experiments were done in mice that, like human beings, make the hormone naturally, the authors noted dryly, "The treatment actually shortened survival by inducing reproductive tract tumours."

The new field of ageing is quite different. It is not a tune-up so much as an engine overhaul. There is Rose, with his Methuselah flies, and behind him, in just the past decade, there has arisen a whole field of scientists using evolutionary and genetic techniques to create entirely new long- lived strains of lower organisms. Earlier this year, two researchers at Montreal's McGill University published a paper in the journal Science showing how they genetically altered worms to live almost seven times as long as is normal. Kenyon showed me one of her mutant worms moving across a microscope slide as gracefully and vigorously at eight weeks as a normal worm moves at two weeks. Over the past five years, too, an entirely separate field has arisen that analyses ageing at the cellular level and looks to treat and possibly cure many of the conditions and diseases of old age by focusing on the mysterious role played by the strips of DNA that cap the ends of our chromosomes. There are now serious researchers - not just science fiction writers or crackpots - who think that we are close to curing cancer and other diseases of old age, and there are some who are convinced that the day is not far off when science may be able to extend the human life span by 20 or 50, or even 100 years. To this new crop of researchers on ageing - those who look at the extension of life at a cellular or evolutionary level - growing old now seems less an immutable fact of human existence than a chronic disease that can be delayed and treated and manipulated as if it were diabetes or high cholesterol. This is what is so extraordinary about looking at Rose's flies and seeing them buzz about energetically in their plastic cages weeks after normal flies would be dead. It's not that they are imposing and impressive and bear the marks of some dramatic scientific intervention. Quite the opposite: they look just like normal flies and act like normal flies. Rose's flies, by their very ordinariness, make longer life seem eminently possible.

But such research also raises all kinds of hard questions, some of which may not be obvious at first. So far, extended life has proven to be a healthier life, because better health in itself prolongs life. Such is the case, certainly, with most of the medical advances of the 20th century which have so dramatically improved life expectancy. Because of modern obstetrics, many fewer die in childbirth, and that, along with the development of antibiotics and the effective eradication of infectious diseases like tuberculosis, smallpox, and cholera, means that people who used to die at 25 or 30 have been given an extra few decades of healthy adulthood. More recently, the push to exercise more and eat healthier foods seems to have had a similar effect, because people who take care of themselves suffer fewer problems in old age. Epidemiologists call the idea that improvements in health will shrink illness and disability the "compression of morbidity" hypothesis, and it is what we all want. In fact, it is what we immediately assume will happen when scientists talk about prolonging life.

There is another possibility, however: that advances in medicine will lead people to live longer but without commensurate improvements in health. In other words, science may succeed in pushing the average life expectancy from 75 years to 95, but the diseases that used to leave us sick and disabled at 82 or 83 may still hit at 82 or 83 - the result being that we would live in a nursing home for the last 12 years of our lives instead of the last two years. Epidemiologists call this possibility the "expansion of morbidity", and it has commanded more and more attention in recent years. Today, many kinds of medical improvements that we have devised are, after all, no longer aimed at saving people from dying at 25 or 30 of tuberculosis or smallpox, and so enabling them to enjoy another 40 or 50 years of healthy life. Those diseases have been cured. Most attempts to improve longevity today focus on the diseases that primarily afflict the old - cancer, heart disease, stroke, arthritis - which means it is now much more likely that saving people from one disease may only result in their getting sicker and sicker with another.

Jonathan Swift's Gulliver, on the third of his famous voyages, learns of a strange group of immortals known as the Struldbruggs. The news fills Gulliver with "inexpressible Delight", for he imagines lives rich with wisdom and experience. He automatically assumes, as most of us do, that longer life means better life. When he meets the Struldbruggs, however, Gulliver realises his error. What he is faced with instead is the expansion of morbidity:

At Ninety they lose their Teeth and Hair; they have at that Age no Distinction of Taste, but eat and drink whatever they can get, without Relish or Appetite. The Diseases they were subject to, still continue without Encreasing or diminishing. In talking they forget the common Appellation of Things, and the Names of Persons, even of those who are their nearest Friends and Relations. For the same Reason they never can amuse themselves with reading, because their Memory will not serve to carry them from the Beginning of a Sentence to the End; and by this Defect they are deprived of the only Entertainment whereof they might otherwise be capable.

This is the difficult question raised by the new optimism about fighting ageing. If we are now on the verge of adding new years to human life, what kind of years will we be adding? Will we be compressing morbidity, or are we about to turn ourselves into a race of Struldbruggs?

On a grey day in late June, 23 children from around the world gathered for a picnic lunch at a campground in South Dakota. The youngest was two and a half and the oldest 15, and they all ate hot dogs and wore baseball caps and ran around excitedly on the grass. It looked at first like a standard summer picnic, but then, on second glance, what had looked like running was actually a kind of determined hobbling, and in almost every instance the heads covered by those baseball caps were completely bald.

The 23 children at the picnic had, in almost every case, neither eyebrows nor eyelashes. Their eyes and ears stood out, because their heads seemed to have shrunk. Few of the children were much more than three feet tall or could have weighed more than about 40lb. Their skin was thin and crinkly, like old newsprint, and when one of the little boys took off his cap I could see the veins bulging out from his scalp. Most seemed to have hip problems and stiff joints - this is what gave them their wide-legged, shuffling gait - and many had heart problems so serious that they were taking four or five different drugs every day, in combinations usually reserved for the most enfeebled of 70 and 80 year olds. These were children who think and feel and talk like other young children, but they had the frail and wizened appearance of the very old. In fact, depending on your definition of what old is, they really were old. One of the strange things about the genetic mutation they share is that if you took a sample of their cells and put it under a microscope side by side with cells from an 80 year old, you wouldn't be able to tell the difference.

The children at the picnic were what are known as progerics - or, more technically, victims of Hutchinson-Gilford syndrome, a rare, probably genetic, disease that causes the interval between childhood and old age to shrink from the normal 50 or 60 years to just over a decade. There are fewer than 30 children with progeria around the world, and every summer a Philadelphia-based charity - the Sunshine Foundation - invites all of them, free of charge, to a week-long reunion somewhere in the United States.

Last year, the reunion was near Lake Wales, Florida, and this year it was just down the road from Mt Rushmore, on the western edge of South Dakota, where the flat prairie of the east turns into rolling meadows and rocky peaks. The main attraction of the picnic was two local motorcycle clubs, whose members began driving the children around the campground on the back of their Harley-Davidsons - wizened 11 and 12 year olds clinging happily to beefy, leather-clad bikers. Later, a cake was brought out to celebrate the birthday of one of the children, a 15-year-old girl from Mexico. But, since most progerics die of a heart attack or a stroke by their late teens, birthdays at progeria gatherings are rather like birthdays in nursing homes - less about the anticipation of the upcoming year than a moment of thanks for the year that has passed. The cake didn't have any candles on it.

How can teenagers be as old as octogenarians? This question has bedevilled scientists ever since progeria was first identified, in the 19th century. Over the past few years, however, at least a partial answer may have been found, and it goes a long way toward explaining why some researchers are now so optimistic about attacking the diseases of ageing and extending human life.

Consider the skin of progerics - the most obvious and most puzzling manifestation of their disease. Children's skin is normally thick and smooth and resilient, and when, by the age of 60 or 70, the skin becomes crinkly and thin we attribute the change to a lifetime of sun damage, injury, and general wear and tear. This is the way we think about ageing in general - that after you walk enough miles, and your heart pumps enough blood, and your brain performs enough work, your body starts to break down, just as a car does when the odometer reaches 75,000 or 100,000 miles. But this analogy seems less apt if at the age of 11 or 12 progerics already have skin every bit as thin and papery as that of 80-year-old adults. What the progeric children suggest is that, whatever processes make our skin sag - or, for that matter, make our joints go bad or our arteries harden - they run independently of the chronological clocks we use to count the passing years. The progeric children suggest that ageing has its own mechanism, and here something known as telomere theory offers an elegant and fascinating explanation.

Among the cells that make up human skin are the fibroblasts, which float in a sea of collagen, the substance that makes skin thick and resilient. Each fibroblast is a tiny repair kit, which works to keep skin healthy. If you suffer sun damage or a cut, your fibroblasts will make a substance called collagenase, which breaks down the damaged collagen and clears it away. If necessary, your fibroblasts will divide, to replace the damaged cells, and then they will pump out new collagen, so that what is known as the matrix can return to normal. This is a remarkably efficient operation. But it comes with one limitation. Inside a fibroblast, on the end of each of its chromosomes, there is a telomere, which researchers propose is a sort of timing device. Every time a fibroblast divides and the chromosomes inside the cell split up in order to form two new cells, the telomere gets a little shorter. The telomeres of a 10 year old, for example, are, on average, longer than those of a 20 year old, which, in turn, are longer than those of a 40 year old. After a fibroblast has divided about 50 times - which will take the average person into middle age - the telomere is shortened to a "critical length", and the timer goes off. A cell with a critically shortened telomere cannot divide any further, and so the whole repair operation that is used to keep skin thick and healthy is thrown out of whack. It's not that skin cells die; rather, it's as if they had become senile.

"The cell seems to undergo a kind of derangement," says Judith Campisi, an expert on ageing at the Berkeley National Labs, in California. Instead of using collagenase selectively, to clear away damage, and spending most of their time pumping out collagen, the senescent cells start to pump out a large amount of collagenase, which eats at the healthy collagen, and almost stop pumping out collagen altogether.

At this point, the idea that telomeres regulate the ageing of cells is only a theory. Although there is plenty of highly suggestive evidence in its favour, it hasn't been definitively proved. If - or once - it is, however, it is not hard to see how revolutionary it will be.

The original wear-and-tear idea of ageing was essentially defeatist: it suggested that ageing was inevitable, because it seemed so clearly linked to the passage of time. But telomeres suggest quite the opposite. In fact, telomeres make it much easier to believe people like Michael Rose when they say that by tinkering with the body's machinery we can substantially prolong life, for if there are genetic changes capable of shortening telomeres in progerics, then shouldn't there also be changes capable of making them longer in the rest of us?

Two of the principal architects of telomere theory are Carol Greider, a molecular biologist at the Cold Spring Harbour Laboratory, on Long Island, and Calvin Harley, who is chief scientific officer at the Geron Corporation, a California-based biotechnology firm primarily devoted to applications of telomere theory. When Greider was in graduate school at Berkeley, in the early Eighties, she did groundbreaking work with telomeres, but it did not occur to her at the time that they might play a role in cell senescence. Harley, then at McMaster University, in Canada, was interested in cell senescence but wasn't yet a telomere expert. Their fields were so distinct that ordinarily the two might never have met. But in one of those serendipitous events that often lead to scientific breakthroughs, Greider began dating a biologist who shared lab space with Harley at McMaster. "I would go and chat with Cal when I was visiting," she recalls. "It was basically just a pleasant, scientific interaction." They kicked around the idea that their fields might somehow be related. By the end of the decade, they were collaborating - sending research materials back and forth through the mail. In 1990, and again in 1992, they jointly published landmark papers laying out the idea of telomeres as cellular clocks - papers that spawned what is today one of the hottest fields in molecular biology.

Harley came to Geron in 1993, and works out of a small office in the firm's cluttered, maze like headquarters in Menlo Park. Over the past few years, he has been steadily exploring the implications of telomere theory, gathering many of the country's leading telomere experts and setting up collaborations with others - like Greider - who remain in academe. As a result, Geron is at this point exploring projects in an astonishing number of fields.

The telomere hypothesis suggests, for one thing, that Aids is a disease - at least in part - of cellular ageing. According to the theory, the Aids virus does its damage by taking on and eventually defeating the human immune system. Among other things, it overwhelms the white blood cells known as CD8s, which the body uses to fight HIV. Why are CD8s overwhelmed? Well, it turns out that the telomeres of certain CD8 cells in Aids patients are, in Harley's words, "as short as the telomeres we saw in centenarians". The cells are so busy trying to fight HIV, dividing and redividing in order to keep the virus in check, that in a decade or so they run through telomeres that would otherwise last them a normal lifetime. "What we want to do," Harley says, after stressing that this idea is only in the earliest of stages, "is to find some way of increasing the life span of those cells." For example, it might be possible to remove the CD8 cells of someone in the earliest phase of HIV infection, lengthen their telomeres in a test tube and put them back in, giving the patient a rejuvenated immune system.

The same thing could be done - again, in theory - for heart disease. According to this idea, arteries clog because as the cells that line arterial walls get injured by high blood pressure and cholesterol and smoking, they have to divide and redivide much more than they would normally, and thus run through their telomeres early. Once senescent, the cells that line the arterial walls start to misbehave just as senescent fibroblasts do: they stop producing critical factors that keep blood vessels healthy, and instead hasten the process of hardening, the build-up of cholesterol that foreshadows heart disease. The theoretical solution is the same as for CD8 cells: find some way to lengthen their telomeres, so they can withstand the onslaught of cholesterol and high blood pressure much longer.

Perhaps the most important potential application of telomere theory - and the subject most telomere researchers are concentrating their energies on - is in the treatment of cancer, and it is a concept of such extraordinary elegance that when Greider (who must have explained telomere theory hundreds of times) described it to me it was almost as if she were talking about a painting she had just seen in the Louvre. The idea starts with the most puzzling of the many questions raised by cancer: how is it that a cell escapes its normal growth limits? A cancerous cell, after all, is a cell that will not stop dividing. There are, in fact, cancer cells that have been grown continuously in laboratories for decades filling petri dish after petri dish. The puzzle is that this kind of immortality would seem to be impossible, since any cell that keeps dividing will eventually run out of telomere. So how do cancer cells get around the telomere problem? The answer is thought to be the presence of an enzyme known as telomerase, which, for reasons that no one quite knows, is present in cancer cells but not in most normal cells. Telomerase has the extraordinary ability to stabilise telomeres, automatically replacing every bit of telomere lost during cell division. Normal cells know how to make the enzyme, but they don't: in a normal cell, the telomerase switch is turned off. One of the ways in which a cell becomes cancerous, however, is that through some random mutation or mistake it finds a way to turn the telomerase switch on, so that the cell has the ability to divide indefinitely without ever tripping the telomere timer.

Greider discovered telomerase in the winter of 1984, when she was working with a single-cell pond-dwelling organism known as tetrahymena. But she didn't grasp its significance until almost eight years later, when she and Harley began finding telomerase in human tumour cells. Then they realised they might have stumbled on a beautiful and straightforward strategy for fighting cancer - to find the telomerase switch in tumour cells and turn it off.

Blocking telomerase is actually much easier than the reverse - trying to lengthen telomeres. Harley says of the suppression of telomerase in normal cells: "You have something that has evolved for a specific function over millions of years - roughly 600 million years. It's harder to turn that on than to turn it off, just as there are many more ways to make a car stop running than to make it run better." Suppressing telomerase is also, at least in theory, a hugely attractive way of fighting cancer. Right now, standard cancer fighting techniques don't do a good job of finding and killing cancer cells that have escaped to other parts of the body - those metastatic tumour cells which lodge in the lungs or the liver and usually end up killing the patient. Standard cancer drugs also have the problem of being unable to distinguish between healthy cells and cancerous cells. They attack every dividing cell they meet, and therefore the treatment of cancer is sometimes as dangerous as the disease itself. But if Geron develops - as it hopes to do - a pill that turns off telomerase, it should side-step that problem. With a few, minor exceptions, tumour cells are the only cells in the body that produce telomerase, and therefore the therapy should be able to zero in, like a guided missile, on cancer cells, wherever they might be, blocking the enzyme that makes them immortal. The idea is that, with a few months, or perhaps a year, of continuous telomerase therapy, cancer tumours would simply divide themselves out of existence.

The theory has one important limitation. Telomere shortening seems to be involved in the ageing of a whole range of cells throughout the body, from skin to arteries and to various organs, but telomere shortening is not the only factor that causes cells to age. In the course of a human lifetime, cells are also frequently damaged by the task of breaking down oxygen, and, as we get older, they often fail to correct mistakes in DNA, which means that if you extend telomeres you don't solve every one of a cell's problems. Perhaps more important, there are vast numbers of human cells that don't run through their telomeres in the way that skin cells and the cells of our livers and lungs do. Neurons, the electrical wires of the brain, for example, don't divide at all, don't lose their telomeres, and don't undergo senescence. Neither, for that matter, does heart tissue. For this reason, Harley and Greider make a point of saying that telomere theory is a useful way of attacking certain diseases of ageing but is not a solution to the overall problem of ageing. In the future, Geron may be able to treat arteriosclerosis and make our skin beautiful again. But telomere therapy won't be able to prevent us from losing our memory or to stop our hearts from wearing out.

Perhaps the best way to think about this is to imagine what would happen if telomere therapy ends up being the cure for cancer, which is likely to be the first disease that Geron would address. Curing cancer would represent an incalculable contribution to modern society. But would taking out just one disease - even a disease that ranks as the second leading cause of death in America, behind heart disease - really make that much difference? For one thing, most types of cancer are diagnosed in patients over the age of 50, since it's usually not until middle age that the body becomes vulnerable to cancerous mutations, and consequently for most people ending cancer isn't going to buy them a great deal more time. On average, eliminating cancer gives the average American only about three extra years of life expectancy. And that's only half of it. Because most people who get cancer are already sick with a number of other diseases, those three extra years of life may leave them even sicker. "If you make some great stride in preventing cancer, well, then we're left with all the illnesses that have not had much attention - varicose veins, migraines, arthritis, sensory impairments, hearing and vision impairments, and a variety of orthopaedic impairments," Lois Verbrugge, a social demographer at the University of Michigan and WESTAT, Inc, says. "You will have people creaking around for a lot longer, and all these other diseases are going to ascend. If the fatal diseases move out, then the non-fatal diseases are going to move in."

This is not to say, of course, that Greider and Harley and everyone else studying the telomere questions should abandon the effort. Thirty-five per cent of all American cancer patients are under 65, and any remedy for this disease would represent an incalculable medical advance. Nor is it to say that telomere theory doesn't represent a critical contribution to our understanding of why certain cells in our bodies age, and why certain diseases arise as a result. It is simply to say that a partial solution to the ageing problem is in some ways worse than no solution at all. We might only be creating a new race of Struldbruggs.

What then, about Michael Rose's fruit flies? Do they have a Struldbruggian problem? The answer seems at first glance to be no. They don't crawl around the cages in their dotage. They are stronger and fly as much as five times as long as the average fly. Because they are fertile for a much longer time, they have not 1,000 offspring, like normal flies, but up to 2,000. They can weather hardship and deprivation and other conditions that would make other flies drop dead. "We have created flies that can survive for 10 days under conditions of starvation," Rose told me. "A normal fly dies after a day or two." As we were talking in Rose's sprawling laboratory, we walked past a giant refrigerator where Rose's Methuselah flies meet their maker, marked, in the sarcastic manner of graduate students, "Fruit Fly Heaven". In the fly world, Rose's drosophila are the blessed.

They are not, however, superior to normal flies in every way. Trailer- park flies may live only 50 days, but they are very good at producing lots of offspring very quickly under adverse circumstances. That trait is critical in the wild. In fact, for all the alleged superiority of Rose's Methuselah flies - which he calls "welfare-state flies" - they could never compete with trailer-park flies, outside the friendly confines of their plastic cages. In the period of peak fruit-fly fertility - the few giddy hours after puberty that Rose calls "prom night" - trailer-park flies are something like six times as fecund as welfare-state flies. They reproduce so quickly that in the real world their offspring would quickly overwhelm the offspring of Rose's Methuselah flies. In other words, you cannot have it all. Many of the same genetic traits that make a trailer-park fly a sexual juggernaut also serve to shorten its life. This is true not only of flies, in fact, but for a wide range of organisms. The surge of hormones that accompanies the mating season of marsupial mice and Pacific salmon also seems to be the reason that those species undergo ageing and death soon after reproduction. Some researchers have hypothesised that prostate cancer in human beings is a consequence of genes that are involved with the production of seminal fluid - in other words, with fertility - earlier in life. A study of institutionalised mental patients at the turn of the century found that castrated men lived longer than uncastrated ones. To live longer involves a trade-off, and that means that if Rose ever develops his line of anti-ageing products it is quite possible that they would require us to make the same kind of sacrifice that Methuselah flies do. "I'll tell you what the trade-off will be," Rose told me. "No question. Randy teenagers will be a thing of the past. James Dean, Kurt Cobain. All those people. We'll lose that." He snapped his fingers. "We'll lose the high testosterone surge of insanity that so much of American culture is based on."

This is a critical point. When most of us think about the meaning of immortality, or, at least, a radical extension of life - we think about endless youth, about being 20 forever. And under those circumstances - being given an opportunity to experience the thrill and vigour and "insanity" of youth over and over again - the idea of immortality is highly seductive. But immortality and youth are not necessarily the same thing, and Rose is talking about endless middle age - about always being 50 and never being 20, which is a very different prospect. The idea appeals to Rose, because he is a scientist, a man consumed by his own thoughts and intellectual endeavours. The one moment I saw Rose lose his customary detachment and grow passionate was when he spoke of what he felt was "one of the most poignant tragedies of human existence", which is that "you spend all your life learning how to do things, learning what it all means, and then you die". Rose, immersed in the life of the mind, may not object to the idea of trading in his callow 20-year-old self for a permanent authoritative middle age. But I'm not sure that all of us feel the same way. Isn't the "surge of insanity" of youth part of what makes the rest of life liveable? To put it more bluntly, there is a real possibility that for many of us a life undifferentiated by the contrasts of young and old - a life removed from the variety and novelty that physical change brings - might well be boring, which is surely as serious a Struldbruggian problem as physical impairment.

At the end of our discussion of the implications of longer life, Rose told me that the "best thing" he'd read on this question was Robert Heinlein's Methuselah's Children, a science-fiction novel from the Fifties. The book is about a group of human beings who have been selected because of a family history of longevity and induced to marry among themselves, producing, in the course of several hundred years, descendants capable of living two and three times the normal human life span. It is the human equivalent of Rose's work with fruit flies, and that may be why it appeals to him so much. "It deals with the social questions," Rose told me. But Methuselah's Children deals with the social questions raised by longevity in a way that could seem satisfactory only to people who were not actually interested in the social questions to begin with. Heinlein's approach to the questions raised by radically extending life is simply to have his very old people act exactly like normal people, with the one exception that they say things like: "I haven't thought of that in centuries," instead of: "I haven't thought of that in years." Here is the book's sole moment of philosophical reflection, a conversation between its 183-year-old heroine, Mary Sperling, and its 213-year-old hero, Lazarus Long:

There was silence. At last she said, "Lazarus, I don't want to die. But what is the purpose of our long lives? We don't seem to grow wiser as we grow older. Are we simply hanging on after our time has passed? Loitering in the kindergarten when we should be moving on? Must we die and be born again?"

"I don't know," said Lazarus, "and I don't have any way to find out... and I'm damned if I see any sense in my worrying about it. Or you either. I propose to hang onto this life as long as I can and learn as much as I can. Maybe wisdom and understanding are reserved for a later existence and maybe they aren't for us at all, ever. Either way, I'm satisfied to be living and enjoying it. Mary my sweet, carpe that old diem! - it's the only game in town."

"Carpe that old diem"?

When Jonathan Swift wrote Gulliver's Travels, in the early 18th century, a series of apparent scientific and medical breakthroughs had created a new optimism about the prospects of extending life. The Venetian architect Luigi Cornaro's work on how to live long, Discourses on the Temperate Life, was reprinted in 50 editions in England through the 18th and 19th centuries. The English philosopher Francis Bacon laid out, to great acclaim, his theories for improving longevity, calling it medicine's "most noble" objective. The pioneering British doctor William Harvey autopsied a poor farmer named Thomas Parr in 1635 and announced that he was 152 years and nine months old at death - a finding (later discredited) that lent Parr such celebrity that he was buried in Westminster Abbey, close to where Charles Darwin was later buried. This was the attitude that Swift was satirising when he had Gulliver, upon first hearing of the Struldbruggs, rhapsodise over the possibility of immortality. Swift's concern was not just that people seemed to want to live forever; it was that they still desired to live longer, even in the face of evidence that longer life only brought increased infirmity. What Swift recognised was that this desire was basically irrational: that men were so afraid of death that they constructed an "unreasonable" fantasy of what living longer would mean - unreasonable because it supposed a "perpetuity of Youth, Health and Vigour" when the real question was "not whether a Man would chuse to be always in the Prime of Youth, attended with Prosperity and Health, but how he would pass a perpetual Life under all the usual Disadvantages which old Age brings along with it".

There are ways around the problem that Swift outlined, of course. Telomere therapy combined with medical interventions that address some of the other mechanisms of ageing might be a good start toward extending life without extending disability. In the case of the evolutionary approach, Rose says that people who wanted to take his pill regime later in life might still be able to achieve an appreciable - if much less dramatic - increase in life span without giving up their youth. But this is all very speculative and all very far off. For the moment, the battle against ageing is characterised by an unrestrained enthusiasm that sounds an awful lot like Gulliver when he first heard about the Struldbruggs. Then he actually met the Struldbruggs, the living exemplars of what longer life really was, and his fantasies about defeating death were laid to rest. He looked immortality in the eye and turned away: "They were the most mortifying sight I had ever beheld".

Copyright 1996 Malcolm Gladwell. All rights reserved. Originally published in a slightly different version in The New Yorker Magazine, Inc