Long For This World_ The Strange Science Of Immortality Part 6

If you look at populations of animals on islands, as Darwin did, you see again and again that when birds or lizards or tortoises get marooned on an island where they are suddenly without predators, they begin to live longer and longer lives. Their descendants are Methuselahs.

This is likewise true of animals that evolve some other kind of protection from their enemies: the sh.e.l.ls of tortoises, the wings of birds and bats. All these creatures have evolved adaptations by which they can lift themselves out of the usual rut of danger. With those adaptations they can escape from a thousand ancestral enemies as surely as if they had drifted onto islands. And they too tend to live much longer than sibling species that failed to evolve such a route to safety.

If evolutionary theory is correct about the origin of aging, then life span should tend to lengthen whenever a species escapes a danger that had weighed on it for a long time. Bats make a test case. It turns out that many species of bats are Methuselahs. There are more than a thousand species of bats in the world. They live on every continent but Antarctica and they range in size from the b.u.mblebee bat of Burma, which has a body not much more than an inch long, to the Giant Golden-Crowned Flying Fox of Maitum, Sarangani, in the Philippines, which has a wingspan of five feet. They fit the pattern that present thinking about aging would predict. A greater horseshoe bat weighs about as much as a white-footed mouse, but the mouse lives at most eight years, and the bat lives more than thirty. A big brown bat weighs less than a house mouse, but the house mouse lives at best four years and the bat, nineteen. An Egyptian fruit bat weighs less than half as much as a Norway rat. The rat lives at most five years, while one Egyptian fruit bat is known to have attained the ripe old age of almost twenty-three. The little brown bat, which is the most common bat in the United States, is the size of a little brown mouse; the mouse can live three or four years and the bat as long as thirty-four.

Because they soar so high above their enemies, and can live such a long time, it makes perfect sense in evolutionary terms for bats to invest in expensive maintenance plans-unlike the house mouse or the brown rat, which sprout and die like weeds. It is the same with flying squirrels, flying opossums, and the flying lemur of the Philippines. Strictly speaking, they glide rather than fly, but as gliders they've evolved much longer life spans than mammals of about the same size that can't take to the air. The same principle holds again and again. Naked mole rats are safer than rats and mice because they spend their lives in burrows and tunnels. They can live almost thirty years. There are even parasitic worms that have found their niche in the safety of long-lived human guts. They live a hundred times longer than their cousins in the soil.

Presumably those Methuselahs evolved their long life spans gradually, over many generations. There are also conditions in nature that can induce an individual animal to slow down, grow carefully, and postpone reproduction during its own lifetime. Take calorie restriction. In principle, evolutionary biologists can understand why calorie restriction might lead animals in the lab to slow their rate of aging. It would be adaptive to be able to do that in the wild. During a famine, you don't want to breed; you don't want to bring a new litter of pups into the world to starve. You'd rather slow or suspend your growth, enter something almost like hibernation. You'd want to conserve fuel and energy, riding out the bad times, waiting for better times when it will make sense to reproduce. Calorie restriction probably triggers an adaptation that evolved over many millions of years to help animals cope with drought, famine, and deprivation in the natural world.

Now molecular biologists are finding and exploring some of the mechanisms by which our bodies respond to calorie restriction. In the laboratory, they are studying the genes and cellular tricks that come into play. Many of these genes turn out to be the very same ones that were transformed in the Methuselah mutants.

The quest to find Methuselah mutants has led to a whole bestiary of genes and their products. There is Sir2 (Silent Information Regulator 2), which was discovered in a yeast Methuselah. There is Indy (I'm Not Dead Yet), which was discovered in a fruit fly Methuselah. And on and on: chico, InR, daf-2, fos. Although the field is still tangled and confused, virtually all of these genes seem to be involved in the workings of calorie restriction and the regulation of metabolism. In other words, they connect the work of the skin-outs and the skin-ins; they link the evolutionary theory of aging with the calorie-restriction research of the last sixty years or so.

So far the study of Sir2 has been the most exciting. Sir2 was discovered by the molecular biologist Leonard P. Guarente, at MIT. Building on that discovery, Guarente and his students and former students began exploring a whole cla.s.s of proteins called sirtuins (named for Sir2), which are found everywhere in the tree of life, from yeast to mice to people. Work on sirtuins led them to the discovery of resveratrol, which is found in the skins of grapes. Resveratrol switches on sirtuins and prolongs the lives of laboratory mice.

One of Guarente's former students, David Sinclair, now at Harvard Medical School, has helped found a company called Sirtris to exploit the possibilities of resveratrol and find its active ingredients. Sinclair suspects that Sir2 may turn out to have two roles in the cell. First, it works hard to keep the genome stable, to prevent mutations from taking place-a kind of preventive medicine. Second, when DNA does get damaged, it makes repairs: surgical medicine. As our bodies age and we acc.u.mulate more and more DNA damage, Sir2 may get so busy doing emergency surgery that it can no longer keep up with its normal, calmer role of preventive medicine. Sinclair thinks that may be the origin of the Error Catastrophe. Although these are still very early days, Sirtris is now testing sirtuin activators in four clinical trials; and Sinclair himself has begun taking daily doses of resveratrol. As he is the first to admit, it is still too soon to say if he is young for his age.

In 2009, a paper published in Nature Nature announced another promising drug that slows aging in mammals. This work began with a good idea at the U.S. National Inst.i.tute on Aging (NIA). The NIH set up the program to allow investigators to test compounds that might intervene in the aging process and extend healthy life span. Scientists anywhere are encouraged to nominate compounds if they can make a case based on our current state of knowledge that they have a chance of making a difference. A series of compounds have now been tested. The first two did not do much for the mice, but the results of the third compound are remarkable. announced another promising drug that slows aging in mammals. This work began with a good idea at the U.S. National Inst.i.tute on Aging (NIA). The NIH set up the program to allow investigators to test compounds that might intervene in the aging process and extend healthy life span. Scientists anywhere are encouraged to nominate compounds if they can make a case based on our current state of knowledge that they have a chance of making a difference. A series of compounds have now been tested. The first two did not do much for the mice, but the results of the third compound are remarkable.

That compound is rapamycin, an antibiotic that was discovered in microbes found in soil samples from Easter Island. The compound's name is derived from Rapa Nui, which is what Pacific islanders called the place. It targets a piece of cellular machinery that is known simply as TOR (Target of Rapamycin). TOR became a target of interest to gerontologists when work in the laboratory of the molecular biologist Seymour Benzer, at Caltech, linked it to both longevity and caloric restriction. TOR not only helps to shape the life span in flies, worms, and yeast; it is also influential in what is known as the "insulin-like signaling pathway" by which a cell learns if there are nutrients around it.

TOR, like the sirtuins, plays a central role in metabolism. It helps promote the manufacture of proteins; it also inhibits the self-devouring behavior of autophagy. There, TOR seems to be part of an ingenious feedback loop. It enhances autophagy when the cell needs it, and then cranks it down when the housekeeping work is done. When the cell floor gets dusty, it helps draw the broom out of the closet and gets it sweeping. When most of the dust is gone, the broom goes back in the closet. In other words, TOR plays a role in both faces of metabolism: in the creative side, anabolism, and the destructive side, catabolism.

So it made sense to test rapamycin on mammals-on mice.

Testing began simultaneously in three laboratories: the Jackson Laboratory in Bar Harbor, Maine; the University of Michigan; and the University of Texas Health Science Center. Giving the mice the drug proved to be more complicated than the experimenters expected, and that turned out to be a lucky thing. Near the start of the experiment, when researchers added rapamycin to the mouse pellets, they found that the mice digested it quickly, so that the drug didn't build up to high levels in their bloodstreams. (Human patients have the same problem with rapamycin. They digest most of it in their guts and not much of it gets into circulation. A recent study suggests that taking the drug with grapefruit juice can help.) The researchers were forced to develop a special feed that delivered the antibiotic in capsules for timed release. Developing that special feed took them more than a year. By the time they had it ready the mice in the first cohort of the experiment were already six hundred days old. That put the mice in late middle age. A mouse of six hundred days is about as old as a man of sixty years.

The researchers decided to proceed anyway and the results were more interesting for the delay. Of the female mice in that first cohort, those that did not get the rapamycin had a maximum life span of about 1,100 days. The female mice that got the drug had a maximum life span of about 1,250 days. The maximum life span of male mice was also increased, from about 1,080 days to 1,180 days. If you look at the life expectancy of those middle-aged mice at the time they began to get the drug, the females' life expectancy was raised by 38 percent and the males by 28 percent. (Maximum life span is defined here as the average life span of the longest-lived 10 percent of the cohort. This is a more informative index of maximum life span than the age of the single very oldest mouse in the cohort. In fact, when the researchers a.n.a.lyzed the data, on the first of February 2009, 2 percent of the mice-38 out of 1,901-were still alive.)

We seem to be reaching a kind of hub here. Both the work on calorie restriction and the work on autophagy lead to TOR. And it makes sense that these two lines of research should intersect, because one of the adaptive responses of the body during a famine is to increase the rate of recycling of its own proteins. We start to tear ourselves down faster than we build ourselves up. We get thinner.

Molecular biologists are now studying rapamycin closely and trying to figure out how the experiment worked and why. They want to know why these middle-aged mice did not get thinner on their rapamycin diets. They also want to know whether rapamycin will help to postpone a wide array of late-onset diseases, from cardiovascular and neurological problems to diabetes to cancer. Since rapamycin has serious side effects, they will look for more benign and sophisticated drugs that target TOR, just as they are looking for ever more sophisticated drugs to target sirtuins.

It's intriguing that these new drugs play important roles in pathways that influence so many diseases. With sirtuins, the list includes diabetes, osteoporosis, and cancer, as well as neurodegenerative, cardiovascular, inflammatory, and mitochondrial diseases. With rapamycin, the list is also long, and one particularly promising line of research involves Huntington's disease.

With Huntington's the junk forms because one gene has a sort of stutter in its genetic code. It repeats the letters CAG more than thirty-five times. That unfortunate string of extra letters of code means that the protein is defective; the cell manufactures it with an extra piece or f.l.a.n.g.e sticking out of it and that extra piece seems to make it clump inside the cell.

Recently a team led by David C. Rubinsztein, a biochemist at the University of Cambridge, tried treating these cells in a petri dish by giving them rapamycin, on the theory that boosting the body's ability to take out the garbage in this way might help. It did. Rubinsztein's team also tried rapamycin on a strain of mice that had been engineered as models of Huntington's disease. To test its grip, they let a mouse hold a metal grid with its forelimbs, lifted it by the tail so that its hind limbs were off the grid, and gently pulled backward by the tail until the mouse finally let go. The antibiotic helped sick mice do better on this grip test, and it reduced their tremors.

Most people don't show symptoms of Huntington's until they are at least forty years old, and in almost every case they know the disease runs in the family. These days the mutation is easy to test for. Someday it might be possible to postpone the onset of symptoms and give people more healthy years. In the best scenario, you could delay the onset of Huntington's so long that they would never get the disease because something else would get them first.

The same kind of strategy might work with Parkinson's and other neurodegenerative diseases in which garbage piles up in or around our nerve cells. It may be the same kind of story will be found with the molecular trash known as Lewy bodies, which acc.u.mulate in the nerve cells of people who develop Parkinson's, as well as with the trash that piles up in the nerve cells of people with amyotrophic lateral sclerosis (ALS) and other diseases that are rarer and less well known but just as deadly. Typically the damage starts to pile up at least five or ten years before the first symptoms. If the problem could be diagnosed and treated that early, for instance with a drug like rapamycin, which hastened the cells' own brooms, then we might postpone some of the worst diseases of old age, in the best case indefinitely. Two neurologists at Harvard Medical School, Peter T. Lansbury and Hilal Lashuel, note in a review of the problem that this approach has a few strong medical advantages. You don't have to know exactly why the crud is building up and you don't have to know exactly what harm it is doing. All you have to do is encourage the cells' brooms to sweep it up. This is exactly the point that Aubrey de Grey has been making in his arguments about the Seven Deadly Things.

Because most of these nerve cells have to last us our entire lives, they are particularly vulnerable to junk piling up. They can't dilute it by dividing and dividing, like cells in the bone marrow or the gut or the skin. But it is possible that this basic problem of garbage piling up in cells will turn out to be the cause of many diseases of the human body; and early treatment, as here, may turn out to be a way of helping the body stay healthy for longer and longer amounts of time.

Again, the point is that evolution has already given us the broom. Evolution gave us the tools we need for keeping house; evolution gave us the whole house. But evolution did not give us the means to keep house for as long as we would like. Now that we live longer and longer, we wear out the brooms.

The cell's brooms include not only autophagy and lysosomes, but a parallel system involving a molecule called ubiquitin, which tags misfolded proteins in the part of the cell where they are manufactured, the endoplasmic reticulum. Proteins that are misfolded as they come out of the endoplasmic reticulum are carried right back into the body of the cell, into the fluid called the cytosol, where they are dumped into barrel-shaped garbage-disposal units called proteasomes. This particular garbage-disposal process is known as endoplasmic reticulum-a.s.sociated degradation, which has the acronym ERAD. Here we're getting drawn into the cellular machinery at a very fine and grungy level. The garbage barrel known as the proteasome has a narrow mouth. That limits the size of the junk that can pa.s.s into it and the recycled bits that can pa.s.s out of it. The autophagosomes that carry trash to the lysosomes are often much smaller than the piles of Huntington's trash they are trying to dispose of. They're like boa constrictors trying to swallow elephants. They may or may not be able to do the job on their own.

G.o.d speed the broom. Again, rapamycin has unpleasant side effects when taken long-term. But there may be other drugs that can help the brooms and enhance autophagy. Rubinsztein reported recently that lithium, valproate, and carbamazepine seem to help induce autophagy, too. Combinations of those drugs may do as well as rapamycin with fewer side effects. Of course, as he notes, keeping the housekeeping crews cranked up this way may cause problems of its own. The sorcerers' apprentices may do damage we can't imagine with each extra whisk of the brooms. Or not. Even if autophagy speeds up so much that a brain cell throws out many of its mitochondria, Rubinsztein thinks the cell will still manufacture enough of its energy compounds, its ATP, to function. So you might be able to get the brain cells to stay cleaner and run cleaner with fewer factories and less energy; and the result might be less cellular pollution and longer life.

Huntington's is the disease that first led biologists to the evolutionary view of aging: the view that our bodies are powerless against declines that begin once we have pa.s.sed the age of reproduction, because evolution is blind to them. That idea was first expressed by J.B.S. Haldane, one of the most brilliant and eccentric British biologists of the twentieth century. Aubrey de Grey likes to quote Haldane's maxim about the acceptance of controversial scientific ideas. There are four stages of acceptance, said Haldane: "One: This is worthless nonsense. Two: This is an interesting, but perverse, point of view. Three: This is true, but quite unimportant. Four: I always said so."

Chapter 9.

THE WEAKEST LINK.

Toward the end of my summer in London, I went on a day trip with Aubrey. I wanted to visit the site of the very wildest of Aubrey's eureka moments, the place where he had solved the hardest problem of all.

In his program Strategies for the Engineering of Negligible Senescence (SENS), he'd called for mending seven weak links in the chain of life. And in his first flush of enthusiasm for SENS, he'd come up with proposals for mending six of these seven. But even Aubrey had despaired of fixing the seventh link, the weakest link, which is the problem known as cancer. Cancer is caused by mutations in the DNA in the cell's nucleus, and Aubrey didn't see what could be done about that. Our bodies already have huge troops of DNA proofreaders and DNA repairers. The proofreaders evolved long ago to keep cells in multicellular bodies from running amok. They do an extremely good job. But since there are many trillions of cells in a human body, and every one of them is subject to daily mutations, errors do eventually slip through. All you need is one nasty typo in one errant cell among the trillions, and you start building a tumor, and the great chain of your mortal life is broken. A few prophets of regenerative medicine do talk about engineering even better proofreaders than evolution has produced thus far. Aubrey did not believe that this was the answer. He could not see how we could ever do much better at proofreading than nature already does. If we are going to live indefinitely, our proofreaders would have to be absolutely perfect. They would have to catch every single mutation indefinitely, and that seemed like too tall an order.

And then, once a tumor grows it is very hard to kill. Many tumors evolve swiftly because they have escaped the body's proofreaders. They mutate wildly. As Aubrey has written, "Each cell in a tumor is a furnace of inventive potential." Because they evolve so swiftly, these cancers are apt to find ways to resist any attack we mount against them. Some tumors invent ways to eat and digest anticancer medicine. Others invent ways to coat themselves so that the medicine won't get inside them. Then, one day-"one dark spring," as Aubrey writes-the cancer blossoms again. The power of evolution is the secret of the secret of life, the spring of life's creativity. It has brought forth the fruitful tree of life; and in each generation it cuts us down in the most horrible of deaths.

Aubrey was satisfied with the first six proposals in his SENS program. He had demonstrated to his own satisfaction that with work we could fix six of the seven weak links in our mortal chain. For junk inside cells, we could stimulate the cell's garbage-disposal system to do a better cleanup job. In principle, that would cure Parkinson's disease, Alzheimer's disease, and so on. So that was one link mended. For junk outside cells, we could stimulate the body's immune system. That would cure heart disease and prevent strokes. That's two links. For trouble in the mitochondria, we could inject a healthy set of mitochondrial genes into the cell's nucleus and thus keep aging cells from losing energy and winding down. That's three. For our cross-linked, snarled, tangled proteins, we could find medicines that snip the links. Human bodies would no longer wrinkle or crumple, inside or out. That's four. Some of our cells slow down and become dormant as we grow older, but we can train our immune system to clear those away. That's five. Some cells die, and their corpses pollute their neighborhoods with toxins; the immune system can clean that up, too. That's six.

Those Strategies for Engineering Negligible Senescence were fine and good; but Aubrey could not conquer aging without a cure for cancer. Without that, SENS would do very little to extend human life. Eliminate every other disease of old age and millions of people would live just a few years longer, only to die of cancers of the colon, brain, breast, lung, or skin. Aubrey's first broadside about SENS had left out cancer, but he knew he could not avoid it forever. "If you read that paper closely," Aubrey says, "you'll see I knew d.a.m.n well the whole business of curing cancer was a ma.s.sive hole in the scheme." He knew that he had to cure all seven of the deadly ills of aging. The better we do with any six, the worse we will suffer from the seventh. In fact, this trouble is already upon us, in the form of cancer, thanks to the successes of modern medicine. The longer we live, the more likely we are to get it; the younger we die, the more likely we are to escape it. "It's very easy to cure cancer," as Aubrey puts the problem, sarcastically. "All you do is fire all the heart surgeons and so on. It's very cheap as well."

To stay young for centuries, we have to learn to cure every kind of cancer. And we have to eliminate for all eternity, or at least for a thousand years, the chance of developing cancer. Yet the longer we live, the more likely we will be to develop it. As one oncologist has put it, "Advancing age is the most potent of all carcinogens."

"So it all seems a bit sad, really. It all seems a bit of a lost cause," said Aubrey. "How could we ever cure cancer?"

This problem had begun to worry him as soon as the glow faded from his eureka moment in California, the night he'd resolved to fight his "seven deadly things." As Aubrey confesses in his book Ending Aging Ending Aging, he feared "that mutations would act as s.h.i.+p-smas.h.i.+ng cliffs to any ark that we might build to survive the deluge of metabolism and emerge into an ageless future."

He was so close. His gla.s.s was almost full. In principle, he had already cured six of the seven deadly troubles of age.

On your left, the dream of the Phoenix, the bird of immortality. On your right, the nightmare of the Hydra, the metastasizing demon. These are the dreams that have surrounded us from the beginning-life, immortal life; and death, inevitable, inescapable death-and they haunted Aubrey in the starkest possible form.

Aubrey worried about cancer until early in the spring of 2002, when he went to a scientific meeting in Ravenna. He was abstracted during the meeting; in his mind, he kept returning to the problem of cancer. Afterward his hosts organized a tour of the ancient city, and along with the other biologists, Aubrey, still distracted and far away, trooped through the churches, beneath the legendary golden mosaics. He did not know it-he does not care much about history-but Ravenna has inspired leaps into immortality for thousands of years. Julius Caesar collected his army there before crossing the Rubicon. Dante finished the Divine Comedy there in the last years of his life; the mosaics inspired some of his visions of eternity, like candles lighting candles. Yeats made a pilgrimage to Ravenna. Years afterward, when the poet felt repulsively old, "a tattered coat upon a stick," he remembered the place; he implored all the saints and sages of the past to help him write immortal verse; he saw them standing before him "in G.o.d's holy fire / As in the gold mosaic of a wall," and he begged them to gather him "into the artifice of eternity."

After the tour, Aubrey set out for home. He took a bus alone to nearby Forl and got out in the center of town. Forl is one of those small Italian towns where you can walk from the bus station to the airstrip. It was a warm day, for March, and when Aubrey had almost reached the airport he stopped at a cafe to drink and think.

He was sitting alone at his table, when suddenly it dawned on him what to do about cancer. As he lifted his gla.s.s of beer, he hit upon what he called a proper cure. He saw a way to fix the weakest link in our mortal chain.

Aubrey thought of the tips of the cell's chromosomes, the telomeres. Everyone in the field of gerontology knows that the telomeres wear away a bit each time a cell divides. According to present thinking, that is why our cells cannot divide indefinitely. We do have an enzyme for repairing the telomeres, called telomerase, but cells run out of it as they age. Then their chromosomes fray, and they come to the end of their tether.

For years, gerontologists have wondered how we could supply our aging cells with more telomerase, and live longer. At the same time, many cancer researchers have wondered about the opposite problem. They would like to find ways to eliminate telomerase from tumors, so that cancer cells would cease to multiply. Cancer cells carry mutations that allow them to make plentiful supplies of telomerase, and that is one of the reasons they have become immortal.

In his first thoughts about SENS, Aubrey too had hoped to eliminate telomerase from cancer cells. But there is a problem with that approach, as there is with every attack on tumors. As long as our bodies carry the gene for telomerase, a cancer cell can always find a way to make more of it. Somewhere in the course of the innumerable random mutations that take place in our trillions of cells, there will always be one rebel that chances upon the trick, makes itself immortal, and multiplies out of control.

Aubrey's insight was this. If we were to eliminate just one gene from the body-the gene for telomerase-then every cell in the body would be unable to repair its telomeres. No renegade cell could rediscover and re-create telomerase. "Creation of a new gene out of nothing does of course occur on evolutionary timescales," as Aubrey has written; "but that takes many, many generations." Even if our bodies lasted thousands of years, we would not have enough cells or enough time to achieve it. The secret of regeneration would be lost. No cell could ever build a tumor, because it could not divide often enough to get out of control. Eliminate that single gene from a human being, and not even our stem cells would have telomerase. Stem cells normally have plenty of it; they need it to replenish our bodies with young cells as our old cells wear out. Without telomerase, even stem cells would reach their limit early. That way they could not run wild with cancer. In a sense, every cell in the human body would be sterilized.

We could maintain tissues like blood, gut, and skin by periodically reintroducing new stem cells. None of them them would have telomerase, either. We would reseed the body with them, and repeat the operation again ten years later. "Then we'd have to do it again, indefinitely," Aubrey says. "But the point is, we'd never introduce a cell that had the capacity to mutate into a cancer." would have telomerase, either. We would reseed the body with them, and repeat the operation again ten years later. "Then we'd have to do it again, indefinitely," Aubrey says. "But the point is, we'd never introduce a cell that had the capacity to mutate into a cancer."

That was his eureka in Forl: take the telomerase gene out of the body!

In many ways this is a desolating vision, a disastrous idea, because without telomerase the body could no longer regenerate itself in the places that need regeneration most. Our skin and the lining of our gut, our outer and inner linings, are always repairing and replacing themselves because they get the most wear. At regular intervals we would introduce stem cells into the body to rebuild those outer and inner linings. We would insert stem cells that we had genetically engineered, cells with abnormally long telomeres. And before those stem cells began to wind down, we would just top up our tissues with more of them. That might not be an easy procedure. No one knows how to do it now. But eventually it would be just one more medical routine for the young, healthy immortals of our boundless future. When cells escape into cancer, they become immortal. We would prevent the birth of those cells and become immortal ourselves.

Aubrey calls this plan, his cure for the "seventh deadly thing," Whole-Body Interdiction of Lengthening of Telomeres (WILT). It is an ugly idea, as Aubrey himself is the first to admit. Not everyone will find it attractive. He writes, "The idea of eliminating from the body a function known to be essential for survival is a conceptual leap that takes substantial justification even to contemplate, let alone implement." He believes most of us will not see its appeal until medicine has managed to cure the other diseases of old age-until we have figured out how to prevent heart attacks, strokes, Alzheimer's disease, Parkinson's disease, and diabetes. At that point, however, so many people will be living long enough to get cancer that we will be willing to undergo something even this traumatic.

In the WILT procedure, patients would undergo periodic bouts of chemotherapy to kill all the cells in the bone marrow. Then they would receive injections of bone marrow in which the cells had no telomerase. Aubrey estimates that they might need new bone marrow transplants every ten years or so. They would need replacements of their skin stem cells every ten years or so, too. The same is true of the innermost layer of the lung; but "there is no reason to think that we won't make quick and relatively painless progress on this front once we put our mind to it," Aubrey writes in Ending Aging Ending Aging. Getting fresh stem cells into the gut might be more difficult but could be accomplished by the same general tools and techniques that people endure when they get a colonoscopy.

By adding fresh stem cells wherever and whenever they were needed, we would keep reseeding the body.

Of course, we would have to denude the body of native stem cells first. That would require high doses of chemotherapy. The treatment would get rid of the cancer and clear the body of all its fertility, which we would then continue under new management. It would be a far more brutal treatment than a radical mastectomy. But, then, think of the painful and expensive procedures that many people are willing to go through just to look young, Aubrey argues; many people pay for chemical or laser "peels" of skin even if the benefit is merely cosmetic. His denuding of native stem cells would allow people to continue to be be young, not just look young. Since we have no way of curing cancer now, and can't imagine a way that would be foolproof, or evolution-proof, and since the better we do at living longer, the more cancer will attack us, Aubrey thinks we should start working on WILT. young, not just look young. Since we have no way of curing cancer now, and can't imagine a way that would be foolproof, or evolution-proof, and since the better we do at living longer, the more cancer will attack us, Aubrey thinks we should start working on WILT.

Might cancer cells find some surprising way to escape even this attack? Cells seem to be able to lengthen their telomeres with enzymes other than telomerase. But if that happens, Aubrey says, we will figure out what those enzymes are, and delete them, too.

The transformation of the human body to a totally WILTed state would have to be performed gradually. We would have to endure the rigors and horrors of all that chemo. Men might become permanently sterile and might want to set aside sperm first, to be frozen and stored in fertility clinics. But our risk of cancer would no longer rise with age; it would actually decline.

Not long after he got home from Italy, Aubrey convened a panel of experts to consider WILT. One of the partic.i.p.ants in his WILT summit, Nicola Royle, a senior lecturer in the Department of Genetics at the University of Leicester, refused to have her name attached to the paper that resulted. But Aubrey puts a positive spin on that. It wasn't that Royle didn't think his idea would work. She was bothered only by the goal itself, the creation of nearly immortal human beings.

Aubrey had now gone from his starting point to the very limit. He'd begun by imagining that we might keep aging bodies alive by clearing away debris. With WILT, he was envisioning an overhaul of the body. To do what he was describing would be to remove from the body its own powers of rejuvenation and to a.s.sume this power and responsibility, entirely and permanently, for ourselves.

"Now, it's critical to remember, we're talking about a proper cure proper cure," Aubrey said. "Not just to postpone cancer by ten years. We've got lucky here, with evolution having given us this window of simplicity in the middle of a highly complicated cause of events. Cancer is compositionally simple and we have that window to get rid of it." All we have to do is kill one gene-the gene for telomerase.

People have never thought in these terms before, he said, because people have always thought of the body as requiring its own powers of rejuvenation. "The epidermis does constantly renew," said Aubrey. "And it renews from stem cells at the bottom. And those cells do express this gene telomerase. If they didn't have it they'd conk out, and we'd end with no skin. The same is true of the blood, and the same is true of the gut. The same is true of quite a lot of tissues that we rather rely on.

"So this seems like a bit of a showstopper on the face of it." But really, again, all it would take is the subtraction of one gene.

"Why cure cancer that well that well?" Aubrey asked me, when he first laid out his vision of WILT. "Because if you can cure cancer-I mean really cure it-then you've actually done the hardest thing there is in curing aging."

And how soon did he think we could take over the body's powers of rejuvenation?

"It could take ten years; it could take twenty years; but it's not a century away."

From the moment Aubrey told me about WILT, I knew that I would have to see the place where he had his vision. I thought it would make a wonderful story that he had found his path toward eternal life after wandering in Ravenna. For his part, Aubrey was perfectly happy to lead me to the place where he'd had his eureka moment. He was pleased that I was willing to take WILT so seriously, because most of his colleagues in gerontology thought the idea was crazy. In fact, they thought WILT was by far the weakest link in his scheme. Their objections were numerous. How would you eliminate the gene? How would you deal with the side effects? How would you carry out the necessary procedures: reseeding the bone marrow, the gut, the skin, the lungs? It would be far, far worse than conventional chemotherapy. Cure the disease and kill the patient Cure the disease and kill the patient. Biologists who hear Aubrey's idea for the first time often become furious. "WILT is clearly nonsense and the main reason why so few scientists take him seriously," says Jan Vijg, the cancer specialist and gerontologist at the Albert Einstein College of Medicine, who is one of Aubrey's strongest supporters among established gerontologists. "This has nothing to do with disliking Aubrey or seeing him as a compet.i.tor or whatever. WILT is just sheer nonsense."

But this is the point at which Aubrey feels that conventional scientists reveal their fatal lack of imagination. What they don't understand, what they don't factor in, is the way medicine will begin to accelerate once we achieve our first modest successes in the war against aging. Once we realize that Aubrey is right in broad principle, and aging can be cured, there will be no stopping us. There will be no obstacle we can't leap over. That is why he has no patience with the pessimism of the gerontologists or the modest optimism of the demographers. When demographers say that during the next century we may gain another decade or two or three in life expectancy, they merely extrapolate from the history of human health in the nineteenth and twentieth centuries. Aubrey calls them "extrapoholics." If we move fast enough, with each researcher building on the work of the immediately preceding researchers, then we will achieve what Aubrey calls escape velocity. Escape velocity, he's written, is "the point when improvements to the comprehensiveness and safety of human life-extension treatments are being made faster than people are aging: that is, when the remaining average life span of those who are receiving the latest therapies, and who are of the age that derives the most benefit from those therapies, begins to increase with time even though they are getting chronologically older." In other words, we achieve escape velocity when science is adding to our life expectancy faster than we are living it-or, in Aubrey's metaphor, when the engines of biomedicine are lifting us upward faster than the forces of decline and decay are dragging us down.

"Escape velocity," Aubrey says, with satisfaction: "it's a bit of a glib phrase but I think it does the job as well as any other pair of words."

His faith in the coming of a new millennium pushes Aubrey even farther out into the dark-or into the boggy fringes of his field, where the footing is treacherous. It puts him at odds with all the conventional gerontologists who talk about adding just a few more comfortable years to our lives. This conservatism of theirs is what he rails against, above the babble of voices in the Eagle. Most gerontologists are so timid! They're happy to trumpet such a modest research program. They're happy to agree with the a.s.sumption that we can't live forever. "Most other people are using this as a funding strategy funding strategy!" he cries indignantly. "So it means that we have repulsively repulsively political phrases like, 'Our goal is adding life to years, rather than years to life.' I mean, I throw up when I hear that! I have no words to describe my disgust for that." His delivery is astonis.h.i.+ngly quick, as if he were das.h.i.+ng madly upstream with water sheathing and coating the rocks. "They think it's going to be what politicians want to hear-what purse-string holders want to hear. And that political phrases like, 'Our goal is adding life to years, rather than years to life.' I mean, I throw up when I hear that! I have no words to describe my disgust for that." His delivery is astonis.h.i.+ngly quick, as if he were das.h.i.+ng madly upstream with water sheathing and coating the rocks. "They think it's going to be what politicians want to hear-what purse-string holders want to hear. And that is is what they want to hear. But the fact is, it's a what they want to hear. But the fact is, it's a lie lie!"

And he gives his listeners a cosmic look that says: The victory is infinitely great and just ahead. Follow me!

So, early one summer morning I took a train from London, and Aubrey took a train from Cambridge, and we met at Stansted Airport for a flight to Forl.

The ticket line was moving slowly, and while we waited I studied the posters overhead. In an ad for Luxury Hilton holidays, a young woman stands at the beach in a red bikini-laughing. And in an ad for Vodaphone, two young men stand at the beach, laughing, with two young women on their backs, also laughing. The women are talking to each other on their cell phones. And the caption is: "How are you?" Another ad, aimed at a more staid crowd, is for Science and Health Science and Health by Mary Baker Eddy: "Fuel for your Spiritual Journey." There is a testimonial from a middle-aged man, L. Rodriguez, business entrepreneur: "I felt so unsure about the future...until I read this book." by Mary Baker Eddy: "Fuel for your Spiritual Journey." There is a testimonial from a middle-aged man, L. Rodriguez, business entrepreneur: "I felt so unsure about the future...until I read this book."

Aubrey had arrived at the airport before me, and he'd already bought his ticket. He looked a bit testy as he waited for me to get mine. "The trouble is, you're costing me valuable drinking time," he said at last. We arranged to meet in the airport bar.

When I found him again, the sight of him there at the bar gave me pause. Most of the time, I marveled at and was amused by his drinking. He carried it off with so much dash that I rarely questioned it. When Aubrey first told me about his work in Pennsylvania we'd talked for a day and a half. On the second day there was already a powerful yeasty smell in the room from the day before. My study smelled as sour as an old pub. I couldn't help counting when I cleaned up: eighteen bottles of beer.

Now Aubrey glanced up from his little round table at the airport bar and smiled. His mood had improved. "It's days like this that I feel particularly gratified that I don't need breakfast," he said.

On the plane to Forl, Aubrey showed me the latest issue of Fortune Fortune. It included a profile of Aubrey, with photos. "The Fortune Fortune photographer had a business card with a list of the famous people he's photographed," he said cheerfully. "So my ambition is to get on that list." photographer had a business card with a list of the famous people he's photographed," he said cheerfully. "So my ambition is to get on that list."

We landed in Forl and set off to find the bar where he'd had his idea. To pa.s.s the time as we walked through the streets, Aubrey asked me riddles. How many three-letter words could I think of for parts of the human body? The sun was so much brighter in Italy than in England that the black asphalt looked white. A woman on a motorbike whizzed past us, smiling and saying into a cell phone: "p.r.o.nto. p.r.o.nto. "p.r.o.nto. p.r.o.nto."-"h.e.l.lo. h.e.l.lo." We pa.s.sed alleys and shuttered stone buildings that looked blind. Pigeons in a dry fountain, on the corso della Repubblica. The long lane was like the long straight shot from birth to death that people can see from here, in the old Italian sun. The churches and stone walls seemed to be exerting gravity, as if they would pull you down, as certainly as falling. Apparently Aubrey was not susceptible to these suggestions. The novelist s.h.i.+rley Hazzard has written, "In Italy we learn...that the ability to rise to the moment, to the human occasion, is linked to a sense of mortality" but in Italy Aubrey had drawn the opposite conclusion, that we might escape from death's gravitational pull once and for all.

The scene of Aubrey's vision, when we found it, was nondescript: just a coffee shop with a few sc.r.a.ppy tables outside. Potted plants in concrete marked out a small s.p.a.ce on the asphalt for the tables. But the place was closed for the month of August. The windows of the shop were papered up with local newspaper. A cupboard the owners were throwing out or trying to give away stood by the door. Aubrey leaned against it in the shade. An old man pa.s.sed on a bicycle. Across the street there was a newsstand, and a joint called Blue's Bar. The life-giving, carcinogenic suns.h.i.+ne was intense now: steep noon Mediterranean sun. Roosters crowed from an overgrown backyard.

Aubrey explained that he'd sat outside that day, facing the street. He'd ordered a Tuborg. It came in a very large bottle-which must have been a liter bottle. "A young woman served me. I can say 'Birra.'" There was only one type of beer. The place was basically a coffee shop. "It was pretty deserted-I was the only person here. The temperature was warm, but not uncomfortable. I was grateful for the beer.

"I was on my second one when I had my critical idea. I didn't need another one after that, because I knew it was an important idea, and I was pretty happy. I just exclaimed to myself, then got up and walked in a jaunty manner in the direction of the airport."

I told Aubrey I found it interesting that he had arrived at his secular vision of paradise in the place where Dante wrote his own-a fabled place in the history of human yearnings toward immortality. But to Aubrey, the setting seemed to be a matter of complete indifference. Nothing in Tuscany seemed to have impressed him on his pa.s.sage through the first time, either. When I asked him what he remembered, he said, "It was really a rather uneventful meeting. Perhaps that's what cleared my brain afterward."

At my suggestion, we had planned to visit some of the great mosaic-lined churches of Ravenna after our stop in Forl. We found a bus in the center of town. I pressed Aubrey again about events surrounding the meeting. He did vaguely remember an opera singer. "I just could not believe so much noise could come out of two lungs! Obviously impossible. And she was a little girl as well. Adelaide's size, if that." When I pressed him some more, he grew impatient. "There were a couple of interesting places, certainly. Old palaces."

He doesn't like to travel; he doesn't like to eat; he doesn't have time for anything but drink and work, although his immortality project forces him to trot around the globe. He looked lanky, even skeletal, loping along through the streets of Ravenna. He got a lot of long, frank, solemn stares from children under five, but he did not seem to notice. "That's right," he said, in one square, "we ate most of our meals here. I'd completely forgotten that till I saw that repulsive tablecloth."

Aubrey isn't particularly interested in children himself. In any case, there are fewer children on the streets in Italy and in much of Europe than there used to be. As people around the world live longer, many of them decide to have fewer children. At the turn of the third millennium, seventeen countries in Europe recorded more deaths than births, notes the demographer Paul Demeny: Belarus, Bulgaria, Croatia, the Czech Republic, Estonia, Germany, Greece, Hungary, Italy, Latvia, Lithuania, Moldova, Romania, Russia, Slovenia, Sweden, and Ukraine. Around the world, birthrates have dropped from six per family in 1972 to a bit less than half that now, and some of the lowest birthrates anywhere on Earth are to be found in the cities of Italy. In some Italian towns, the rate is less than one.

"A lot of people point out overpopulation," Aubrey likes to say, when anyone brings up that objection to his immortality project. This will matter in principle, he says-but we woudn't have a big problem with too many children for a hundred years. In fact, people might wise up and not bother with them for an indefinite number of years. "Another way of looking at it-who cares? This is the way I like to look at it," Aubrey says. "We've got a chance of saving people's lives-and we have to do that. Letting people die is bad in the same way killing people is bad. So we've got to do it. Even if we needed severe birth-control measures. So we have have to do it. And people are very shocked when I say that. Especially when it goes further-when it means we'll end up in a world with more or less no children. Get over it! And people are not happy with that. But I don't know. Maybe it's just my personality, but I prefer to cut the c.r.a.p and get to the chase." to do it. And people are very shocked when I say that. Especially when it goes further-when it means we'll end up in a world with more or less no children. Get over it! And people are not happy with that. But I don't know. Maybe it's just my personality, but I prefer to cut the c.r.a.p and get to the chase."

We walked to Ravenna's Museo n.a.z.ionale. The cobblestones were gritty with gravel, and the marble steps were worn as smooth as stones on a beach. "My mother's so good to me," Aubrey said, stopping at the museum gift shop. She didn't ask him to visit often. "Her one condition is that I send her a postcard from wherever I go. And I'm enormously religious about it."

I flipped over his postcard and read the caption aloud to him: "Vault and Lunette with Good Shepherd."

"I don't spend much time choosing which postcard to send," said Aubrey.

Headless marble torsos loomed over us, attached to marble pedestals by hooks of steel, and then a life-size Christ, crucified: a great wooden Y. I asked Aubrey if he had gone to church as a boy. He said his mother had raised him as an Anglican. "She used to send me to church once a month. She gradually started going less and less. By the time I was ten, we went just at Christmas and Easter." At the time of his confirmation, he was a student at Harrow, a school in northwest London that has been educating boys since the year 1243. "It was a complete nonevent as I recall. I don't go as an adult. Churches are emptying out, to a large extent."

I asked him if he ever wondered why that might be.

"Not my area of expertise, your honor." He snorted and blew air out through his lips.