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The New Age of Man

by Malcolm Gladwell

Michael R. Rose began his quest to solve the problem of human aging in 1976 with 200 garden-variety, fertilized 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 aging, 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 kinds of flies which survive are those which reproduce the fastest, and these were no exception. They were, in Roses 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 would have continued to reproduce at the same breakneck pace. But Rose wasnt 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, Roses operations occupy about 4,500 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 flys 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 aging 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 isnt 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 ten-year time lag before my colleagues start to realize what it is all about, and he is unsparing in his scorn for some of his fellow researchers on aging. 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 doesnt need them. Im known for being clear partly because Im 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 aging at the University of Southern California, has put it, If someone says something stupid, hell 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 aging 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. Theyre 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 Kenyons nematode research didnt yield any useful insight into how human beings age, I dont 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 analyze 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.

Were 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. Well run them through a variety of tests to see whats 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. Hes 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: Its going to be like the deployment of electricity. Its going to take a long time because its going to be a big, complicated technology. Youll 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 Roses 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 fifteen years ago, scientists didnt talk like this. The traditional scientific approach to the problem of aging 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 Centers 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 aging process were treated with skepticism.

Even the idea of treating aging 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 aging 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 color 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 Schools 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 on 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 tumors.

The new field of aging 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. Last year, two researchers at Montreals 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 8 weeks as a normal worm moves at 2 weeks. Over the past 5 years, too, an entirely separate field has arisen that analyzes aging at the cellular level and looks to treat and possibly cure many of the conditions and diseases of old age by focussing 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 aging 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 Roses flies and seeing them buzz about energetically in their plastic cages weeks after normal flies would be dead. Its 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. Roses 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 2 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 Swifts 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 realizes 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 aging. 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 gray day in late June, 23 children from around the world gathered for a picnic lunch at a campground in South Dakota. The youngest was 2-1/2 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 40 pounds. 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 4 or 5 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 wouldnt 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 backs 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 didnt have any candles on it.

How can teenagers be as old as octogenarians? This question has bedeviled 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 aging and extending human life.

Consider the skin of progerics the most obvious and most puzzling manifestation of their disease. Childrens 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 aging 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 aging 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. Its not that skin cells die; rather, its as if they had become senile.

The cell seems to undergo a kind of derangement, says Judith Campisi, an expert on aging 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 away at the healthy collagen, and almost stop pumping out collagen altogether. Campisi has done experiments in which she has pinpointed senescent cells with a blue stain and then taken comparative photographs of young and old skin under a microscope. The pictures are striking. In the first case, there are healthy fibroblasts encased in rich, red-stained collagen. In the second, the slide is spotted with blue senescent cells, and in the matrix around them the collagen has been reduced to a thin, wavy swirl.

How long your skin stays healthy, in other words, depends in part on how long fibroblasts stay in their healthy, dividing state or, as scientists now speculate, on how long your telomeres are. That could be why a 50 year-old person who has spent every summer in the sun looks a lot older than one who has spent every summer in the shade: the fibroblasts of the sun worshipper have had to divide many more times to repair damage from ultraviolet rays. In this sense, the length of your telomeres may be a better indicator of how old you are than is the number of years you have lived a point neatly captured by a handmade poster I saw in the office of a telomere researcher I visited. Beneath a photograph of a grinning baby the child of one of the researchers someone had written, Ha! My telomeres are longer than yours. This is also why progerics seem so old: by late childhood they have the telomeres of someone in a nursing home. At an age when other children still have thick, smooth skin, progerics fibroblasts have already started to stop producing collagen. Progerics get heart disease, on this theory, because the cells that line their arteries start running out of telomeres and the arterial walls start to harden. Their movements get creaky because the cartilage that lines their joints begins to break down.

My Danny died in March, Bill Purcell, a friendly, white-haired Englishman I talked to at the picnic, told me, speaking of his son. He was adopted. He came to us when he was 11. About 6 months later, he had a massive stroke that left his left side paralyzed. We thought we were going to lose him. He was like a rag doll. He came back, although he was never as active after that. Three years ago, he lost the sight in one eye due to hypertension. He handled it well. That was in October. Then, in August of 1994, another eye went and that left him totally blind. His world was black. He was very frail. His features had caved in, and his movements were slow and painful. He had all the problems associated with a very, very old man. Purcell added, Danny died of old age. He was 22.

At this point, the idea that telomeres regulate the aging of cells is only a theory. Although there is plenty of highly suggestive evidence in its favor, it hasnt 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 aging was essentially defeatist: it suggested that aging 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 bodys machinery we can substantially prolong life, for if there are genetic changes capable of shortening telomeres in progerics, then shouldnt 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 Harbor 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 80s she did ground-breaking 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 wasnt 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.

I like to think of Cal and myself as like that old television commercial for Reeses peanut-butter cups, where the chocolate and the peanut butter run into each other, Greider told me. She didnt specify who was which ingredient, but she didnt really have to. When I met her, she was 8 months pregnant but was still charging around her laboratory, a petite and dynamic woman with frizzy brown hair and a beautiful smile. Shes the chocolate. And Harley 40ish, trim, and with thinning hair, soft-spoken and precise is the peanut butter.

Harley, a Canadian, studied science at the University of Waterloo in Ontario a fact not without sociological significance. Waterloo is a school for science nerds, much like MIT, which is to say that, like MIT, it attracts and nurtures a certain kind of stubborn and prickly intellectual idiosyncrasy. But it is a Canadian nerd school, and so all those stubborn and prickly idiosyncrasies appear only through the filter of Canadian conformity and self-effacement. Had Albert Einstein taught at Waterloo, he would have had a brush cut and worn Haggar slacks, and that is the impression Harley gives as well, that his bland demeanor is less a matter of character than of presentation.

Harley came to Geron in 1993, and works out of a small office in the firms 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 countrys 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 aging. 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 Harleys 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 buildup 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 telomeres. 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 stabilize telomeres, automatically replacing every bit of telomere lost during cell division. Normal cells know how to make the enzyme, but they dont: 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 didnt grasp its significance until almost 8 years later, when she and Harley began finding telomerase in human tumor cells. Then they realized they might have stumbled on a beautiful and straightforward strategy for fighting cancer to find the telomerase switch in tumor 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 six hundred million years, Its 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 dont do a good job of finding and killing cancer cells that have escaped to other parts of the body those metastatic tumor 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 sidestep that problem. With a few, minor exceptions, tumor 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 tumors would simply divide themselves out of existence.

Two years ago, at the American Association for Cancer Research, which is the major yearly meeting on cancer, there were two posters which advertise research papers on this topic, Jerry Shay, a cell biologist at the University of Texas Southwestern Medical Center in Dallas told me. A year ago, there was one symposium and maybe 12 posters. This year, there were two symposiums and about 70 posters. My guess is that next year the numbers will be even higher.

The theory has one important limitation. Telomere shortening seems to be involved in the aging 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 dont solve every one of a cells 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, dont divide at all, dont lose their telomeres, and dont 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 aging but is not a solution to the overall problem of aging. In the future, Geron may be able to treat arteriosclerosis and make our skin beautiful again. But telomere therapy wont 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 its usually not until middle age that the body becomes vulnerable to cancerous mutations, and consequently for most people ending cancer isnt going to buy them a great deal more time. On average, eliminating cancer gives the average American only about 3 extra years of life expectancy. And thats only half of it. Because most people who get cancer are already sick with a number of other diseases, those 3 extra years of life may leave them even sicker. If you make some great stride in preventing cancer, well, then were 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 orthopedic 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 nonfatal diseases are going to move in. Curing cancer would be an example of the expansion of morbidity, not the compression of morbidity.

In a fascinating recent paper, three demographers Mark Hayward of Penn State; Eileen Crimmins of the University of Southern California; and Yasuhiko Saito of Nihon University in Japan showed how changes in cause of death would affect morbidity. The three researchers broke down the life expectancy of men and women at the ages of 70, 80 and 90 into two categories: active years, which are the years when people can still take care of themselves, and inactive years, which are the years when those people need assistance in everyday living or are bedridden. By this measure, the average 70 year-old American woman can today expect to live until she is almost 85, of which 12 of those remaining 15 years are active, and 3 years are inactive. Now, assume that we cure cancer. By the groups estimate, that woman will now live until shes 86. But of those extra 14 months of life only about half will be active. For the rest of that time, the woman will be battling the problems that she might otherwise have avoided by dying sooner diabetes, arthritis, Alzheimers, Parkinsons, and osteoporosis, for instance. I suppose that there are some 70 year-old women who might still want those extra 14 months, even if the last half of them were spent in a nursing home. But I think it fair to say that most 70 year-old women would gladly give up the extra 14 months if there were some way of shrinking the 3 years of inactive life they now face to 2 years or 1 year or, best of all, zero. In other words, in old age we really dont want to get rid of the diseases that kill us before weve gotten rid of the diseases that slow us down, that rob us of our independence, that put us at the mercy of someone else.

Another way to look at this matter is from the standpoint of cost. If we were to cure cancer, and give 6 months of inactive life to the average 70 year-old woman, thats 6 months with a nurse or in a home that society is going to have to pay for. The financial implications of this are huge. Joshua Wiener of the Urban Institute in Washington, estimates that under assumptions of low disability that is, if changes in medical care and in the health of the elderly have the effect of compressing morbidity in the 4-year period between 2016 and 2020 America will spend $134 billion (in constant dollars) on long-term care of the elderly. Under assumptions of high disability, however that is, if we do something like cure cancer and give several months of inactive life to the elderly that same figure will nearly double, to $215 billion. Even if every 70 year-old woman wants those extra 14 months, can society afford to give them to her?

This is not to say, of course, that Grieder and Harley and everyone else studying the telomere questions should abandon the effort. Thirty-five percent 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 doesnt 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 aging 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 Roses fruit flies? Do they have a Struldbruggian problem? The answer seems at first glance to be no. They dont 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 Roses sprawling laboratory, we walked by a giant refrigerator where Roses Methuselah flies meet their maker, marked in the sarcastic manner of graduate students, Fruit Fly Heaven. In the fly world, Roses 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 Roses 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 6 times as fecund as welfare-state flies. They reproduce so quickly that in the real world their offspring would quickly overwhelm the offspring of Roses 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 aging and death soon after reproduction. Some researchers have hypothesized 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 institutionalized mental patients at the turn of the century found that castrated men lived longer than uncastrated ones. To live longer involves a tradeoff, and that means that if Rose ever develops his line of anti-aging products it is quite possible that they would require us to make the same kind of sacrifice that Methuselah flies do. Ill tell you what the tradeoff will be, Rose told me. No question. Randy teenagers will be a thing of the past. James Dean, Kurt Cobain. All those people. Well lose that. He snapped his fingers. Well 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 vigor 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 endeavors. 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 Im not sure that all of us feel the same way. Isnt the surge of insanity of youth part of what makes the rest of life livable? 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 hed read on this question was Robert Heinleins Methuselahs Children, a science-fiction novel from the 50s. 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 Roses 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 Methuselahs 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. Heinleins 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 havent thought of that in centuries instead of I havent thought for that in years. Here is the books 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 dont want to die. But what is the purpose of our long lives? We dont 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 dont know, said Lazarus, and I dont have any way to find out and Im 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 arent for us at all, ever. Either way, Im satisfied to be living and enjoying it. Mary my sweet, carpe that old diem! its the only game in town.

Carpe that old diem?

When Jonathan Swift wrote Gullivers 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 Cornaros 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 medicines 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 9 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 satirizing when he had Gulliver, upon first hearing of the Struldbruggs, rhapsodize over the possibility of immortality. Swifts 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 recognized 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 aging 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 aging is characterized 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.

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