Long For This World_ The Strange Science Of Immortality Part 5

Then we have that mournful scholar dreaming of his lost Lenore, and the bird that croaks from the bust of Pallas just above his chamber door: "Take thy beak from out my heart, and take thy form from off my door!"Quoth the Raven, "Nevermore."

In any case, it's a simple point. If life is a chain with seven weak links, then you have to fix each and every one of those weak links to strengthen the chain.

Aubrey's suggestion about moving those vulnerable thirteen genes out of the mitochondria was intriguing. I've since talked about it with a number of biologists. All of them thought it was ridiculously complicated and risky, but a few found it interesting, even so. One famous molecular biologist, Seymour Benzer, at Cal Tech, who had taken up the study of mortality in his old age, told me that he and a student had tried to make the repairs that Aubrey was suggesting, in fruit flies, one summer. They ran into a few technical difficulties and he set the experiment aside.

Aubrey went on with his list. First, we have the cross-links that wrinkle our skins and stiffen our veins and arteries and do all kinds of visible and invisible damage to our bodies as we get older. Second, we have the mutations that acc.u.mulate in our mitochondria. Third, we have junk that acc.u.mulates inside the nerve cells of our brains. Whenever pathologists autopsy the brains of people who have died of Parkinson's, they find Lewy bodies, for instance, which are tiny b.a.l.l.s of nasty protein.

These clumps and b.a.l.l.s are hydrophobic; so we talked a little more about hydrophobicity, and its importance in the life of the cell. All of our molecular machinery in the cell is made of proteins, and when the cell manufactures proteins, they extrude from the cells' manufacturing sites like long straight noodles of pasta. After these long spaghetti noodles are extruded they fold up almost instantly into complicated and intricate shapes. Their shapes, if they were entered into contests, would win every prize on Earth for architectural, industrial, and sculptural design. It's as if you dropped the noodles into the pot and they did not just cook until they were al dente al dente; one of them folded up, in a time much less than the blink of an eye, into a machine that dices, and another into a machine that chops, and another into a machine that blends. And the tiniest differences in these designs can become matters of life and death as we get older. For instance, in some families, people tend to develop Alzheimer's disease very early, in their forties and fifties. They have the bad luck to carry mutations in their genes for beta-amyloid. The mutations make their beta-amyloid more hydrophobic. So it's more likely to clump in their cells. According to present thinking, if beta-amyloid clumps in your skin cells, it may not do much harm. But if it clumps in the nerve cells in your brains, it can do terrible harm, because those cells are so delicate, complicated, and crucial to our functioning as human beings. Michael Hecht, a chemist at Princeton University, is in the middle of a series of experiments in which he inserts various versions of beta-amyloid into bacteria to see if they clump and aggregate. He rigs the experiments so that if the beta-amyloid folds up properly, it lights up and fluoresces a bright green. But if the stuff clumps and aggregates in the cells, it doesn't light up. Again, it's all just simple cooking combined with simple engineering, but at the level of molecules instead of noodles and oil in a pot. Hecht makes random changes in the beta-amyloid and finds that those changes that make it more hydrophobic do make it tend to clump more. The fatal differences are subtle. A basic protein is shaped like a noodle with lots of little attachments called "side chains." If you have all those side chains in the right place, you may live past the age of one hundred with all your wits and memories. But if just one side chain is in the wrong place, your whole family is in danger of developing Alzheimer's in early middle age.

Sitting in my study, Aubrey reviewed the issue of the junk in the brain cells. No one knows how much damage this debris does to the brain and to the life of the mind. No one knows if or how they cause Alzheimer's and other dementias. We really don't know much about dementia, which is not surprising, because we don't know much about how brains produce consciousness. If we knew how the brain makes the mind, it might be easier to figure out why the brain stops making the mind. If we knew how the body makes the mind, we might be able to figure out how a sick body makes a sick mind. Meanwhile the study of Alzheimer's and other dementias is a huge, growing field, and the various schools of thought clash like ignorant armies. Some neurologists think the worst kind of junk in there is the beta-amyloid protein, or BAP; other neurologists blame the tangles, which are made of a protein called tau. These two camps call themselves the Baptists and the Tauists. Battles are fought between the Baptists and the Tauists. It's a small war; but even so, feelings run high.

While Aubrey was telling me his plans to clear away the junk from old brain cells, I heard my wife's steps hurrying up the stairs to my study. She poked her head in the door to tell me some news about a friend of ours. By a strange coincidence, the news had to do with Alzheimer's. Our friend's elderly mother had just been found wandering in a town half an hour from ours. Our friend was at work far away, and she had gotten a call from the police. She needed my wife to go fetch her mother from the station.

After my wife drove off, Aubrey returned to the battles of the Baptists and the Tauists. Each side had its points. "But I don't need to care about that," Aubrey said. "I take the view, no matter what the change is between young and old, if you fix everything, then-"

Just fix every weak link in the chain.

It had taken us a few hours to talk through just three of Aubrey's Seven Deadly Things: cross-links, mitochondrial mutations, and the junk that builds up between nerve cells. Three down, four to go. Aubrey seemed to feel more encouraged than discouraged as he laid all this out. Part of the beauty of his plan in his view was that you didn't need to settle the war between the Baptists and the Tauists, or any other controversy in science and medicine. The thing for us to do is to get rid of all the junk that acc.u.mulates in aging bodies. "I just want to fix everything unless I'm completely convinced it's not in the killer camp."

So that famous night before dawn in his motel room in California, Aubrey had scribbled them all down on a sheet of paper, the basic kinds of detritus that acc.u.mulate. The list itself was a bit confusing back then. In no particular order, here is one tidy way to sum it up: There's junk inside cells; and there's junk outside cells. There are mutations inside the nucleus; and there are mutations outside the nucleus. There are too few cells; there are too many cells. And there are the cross-links, which stiffen up our working parts everywhere throughout the body at the finest scale. Aubrey had to come up with strategies to fix each one of these Seven Deadly Things. These are the plans that he soon came to call his Strategies for the Engineering of Negligible Senescence, or SENS.

It's a provisional list, of course. Again, the manifold damage we call aging is like the Hydra. If we lop and burn off one head of the monster, the others remain our mortal enemies, and they will bring us down. Most doctors and medical researchers have made their peace with this. They'd be content to solve just a piece of the problem of mortality. If they succeed in treating arthritis or curing Alzheimer's they will slow aging by some small amount. Like inventors and innovators throughout modern history, they will give us the gift of a few more minutes, hours, days, a few years at the most. But immortalists like Aubrey de Grey don't want to slow aging, they want to kill it. To do that, they have to win a war on every front at once. They have to lop off every last head of the Hydra. It would be a labor of Hercules to lop them all off. But we could do it, Aubrey says. And he would be willing to add another to the list if it reared its ugly head.

After half a day of talking with Aubrey, I wasn't sure what to make of him. He did seem enormously well-informed. And he had credentials. He'd hosted an international meeting of gerontologists in Cambridge under the banner of SENS. "They gave me a standing ovation at the end of the meeting," Aubrey told me. "And I'll have to do it again, which suits me fine." And he'd arranged special, smaller meetings of experts to talk about some of his ideas for fixing the Seven Deadly Things.

On the other hand, it all did sound a little crazy. Darwin's mentor, the geologist Charles Lyell, advised him to avoid controversy it's a terrible waste of time. When you follow the edges and frontiers of science, you try to watch where you step. It's only too easy to waste years in controversy, or step right over the edge. A man with a bottomless bottle of beer, and a beard halfway down to the floor, who claims we can live a thousand years, presents a picture that more or less defines the realms beyond the edge of science, like those sea serpents in the old maps with the legend "Here be dragons."

From my bookshelf, I took down my copy of Bacon's History of Life and Death History of Life and Death. I read aloud the pa.s.sage where Bacon explains why we should in theory be able to live forever: "for all things in living creatures are in their youth repaired entirely; nay, they are for a time increased in quant.i.ty, bettered in quality." So much so that "the matter of reparation might be eternal, if the manner of reparation did not fail."

I thought Aubrey would agree with Bacon, but he shook his head. "That can no longer be sustained," he said. "It is true if you don't get down into too much microscopic detail. We see no decline in function of tissues until middle age. But the things that cause decline started in conception-or even before, you could argue, in the unfertilized egg. Certainly in prenatal life." Even in the tissues in an embryo, or the cells in a single tissue, slight errors are being made from one reproductive cycle to the next. When cells divide, the changes get pa.s.sed down. That is one reason that identical twins are never really identical. You could say that junk is already building up in the first moments of the life of the fertilized egg.

"What's going on during early life is a gradual laying down of damage," Aubrey said. "All the same things I've been talking about happen all through life. I'll try to say it concisely," he said, rapping his palms on his thighs. "A forty-year-old is different in composition from a twenty-year-old. In what way way is that person different? There are no easy answers. The differences are very subtle, very slight. But you know they're significant because the forty-year-old has a life expectancy that's twenty years shorter than the twenty-year-old." Whatever your age, and wherever on Earth you live, your mortality rate doubles every eight years or so, from birth to death. And it doubles because of the buildup of damage and garbage. is that person different? There are no easy answers. The differences are very subtle, very slight. But you know they're significant because the forty-year-old has a life expectancy that's twenty years shorter than the twenty-year-old." Whatever your age, and wherever on Earth you live, your mortality rate doubles every eight years or so, from birth to death. And it doubles because of the buildup of damage and garbage.

Every gerontologist knows about this doubling of mortality rates. This is one way to measure aging: the likelihood of dying at each age. Actuaries call it the "law of mortality." The mortality rate of a man of fifty is many times greater than the mortality rate of a boy at fifteen. In fact, our mortality rates-over most of the world-double every eight years or so. This is a puzzle: Why should the doubling rate be the same around the world when local populations have such different risks-for instance, low risk of breast cancer in j.a.pan, a tenth what it is in the United States? As a proponent of the theory of the Garbage Catastrophe, Aubrey argues that the rates are so uniform around the world because so many different kinds of junk build up in our bodies wherever we live on the planet.

"So what's going on during early life is a gradual laying down of damage," Aubrey said. We already have the start of atherosclerotic plaques in our major arteries and cross-links in our skin as toddlers.

"All the things I've been talking about happen all through life. The only reason it looked to Bacon as just described is that those types of damage, until they reach a threshold, a certain level of abundance-" Until we are thirty or forty, Aubrey said, the damage is too insignificant to matter. "Until then it looks like there's no aging going on."

That really is a sensible description of aging, according to present thinking. Unfortunately, I thought, Aubrey's prescriptions were carefully posed to sound more sensible and plausible than they might to skeptics who are aware of the trade-offs involved. Stimulating the immune system can be dangerous, for instance. The body develops inflammation to try to disperse a foreign body or kill it. And it is usually very effective; but the downside is that cells do it by releasing oxidants, and that's bad. So acute inflammation can be healthy, but chronic inflammation is not. That is why Caleb Finch, of the Andrus Gerontology Center at the University of Southern California, Los Angeles, argues that inflammation may be a crucial problem in aging itself.

But Aubrey had his stump speech about the Seven Deadly Things and he stayed right on that stump. Acc.u.mulating damage drives our cells more or less crazy, Aubrey writes in Ending Aging: The Rejuvenation Breakthroughs That Could Reverse Human Aging in Our Lifetime Ending Aging: The Rejuvenation Breakthroughs That Could Reverse Human Aging in Our Lifetime, by Aubrey de Grey, Ph.D., with Michael Rae. (On the back jacket, in big capital letters: "PEOPLE ALIVE TODAY COULD LIVE TO BE A THOUSAND YEARS OLD. A LEADING RESEARCHER SKETCHES THE REAL 'FOUNTAIN OF YOUTH.'") The damage, he writes, "forces our cells to flail about in increasingly desperate, disorderly, and panicked attempts to keep their heads above the waters of the aging process." The way to keep the forty-year-old's life expectancy the same as the twenty-year-old's is to keep cleaning up all of that detritus, by stimulating the immune system, etcetera. And we don't have to clean up everything that will ever matter to the aging body; only those insults that matter within our life spans now-only those things that slow us down in threescore years and ten. "Once this is accomplished," Aubrey writes, "our bodies will remain youthful during the years in which they are now undergoing a slow descent into decrepitude." So we will try to stay young and fit while we wait for more help from science, the way other generations strove to stay virtuous while they waited for the Messiah.

Once we did it, once we fixed all seven weak links, eliminated all of Aubrey's Seven Deadly Things, we would live long enough at last to achieve "escape velocity." We would live virtually forever. We would have achieved negligible senescence. At that point human life would be completely transformed, of course. Among other things, virtually everyone on this planet would feel as Aubrey did, that there was little point in having children, because there was so much to do. Each of us would feel that we had so much life ahead to enjoy just for ourselves.

"We'd have no one under the age of fifty soon enough," he said cheerfully.

I went down to the refrigerator with Aubrey to get him another bottle of beer, and we ran into my two boys. They were fourteen and seventeen years old, and they were curious about him. You don't meet many characters like Aubrey de Grey in small-town Pennsylvania.

Aubrey was wound or overwound, singing his long saga of the Seven Deadly Things, and he went straight back to the top when he saw my boys.

"Suppose we fix aging," Aubrey told them in the kitchen. "So your risk of death is postponed indefinitely. You'd live in the region of a thousand years. You You have a better chance than have a better chance than you you, and you you have a better chance than have a better chance than you you," Aubrey said, pointing with his right hand to each one of us in order of age, from the youngest to the oldest (me), while he squirreled his left hand deep into his beard.

"But once we have learned to postpone senescence indefinitely, our life span will become limited only by accidents, and that will give us an average life expectancy of one thousand years. So people are likely to live a long, long time," he said. "It seems extremely plausible to me that by then you'd live long enough to live essentially indefinitely."

My boys, both of them science-fiction fans, seemed comfortable with Aubrey's confidence that they would live indefinitely. One of them mentioned Star Trek Star Trek teleportation. "Beam me up." The beam from the s.p.a.ces.h.i.+p lifts the astronaut from here to there, sometimes thousands of miles away, or more-but maintains the same person. teleportation. "Beam me up." The beam from the s.p.a.ces.h.i.+p lifts the astronaut from here to there, sometimes thousands of miles away, or more-but maintains the same person.

"Yes," said Aubrey. "That is fast teleportation. This is slow teleportation. You'd be maintaining the same person from century to century by medical means. And if you suffered an accident, eventually we'd know enough to put you back together again no matter what happened."

I protested. We don't know how the brain works. What about the brain, the mind, ident.i.ty? Aubrey replied that there was no way of knowing what exactly the doctors would have to transfer into the reconstructed brain to make sure that ident.i.ty is carried over. But in practice he was sure the doctors of the future would be able to do it.

I gave Aubrey another look.

We can't do anything like that now, he conceded. "But it's not implausible for, say, one hundred years from now." To make a map of your patient you'd scan the brain. Then you'd have all the information you'd need to re-create your patient in case of an accident. "Not obvious you could not not do it." He found such scans perfectly easy to imagine. You'd get one every month. Then if you came to some sticky end, your doctor would use the last scan to reconstruct you. Beam you up. Restore you, and restore your memory files. You wouldn't lose one bit. do it." He found such scans perfectly easy to imagine. You'd get one every month. Then if you came to some sticky end, your doctor would use the last scan to reconstruct you. Beam you up. Restore you, and restore your memory files. You wouldn't lose one bit.

Aubrey went on, with the same sort of pleasure with which he'd just been talking about clearing away the junk from aging brains. "Well," he said, "would you really be the same person that went under the truck? I've tried to think subjectively: What is my emotional attachment to the body that went to sleep in O'Hare last night?" He said he was perfectly able to reestablish a sense of continuity after sleep. Why not after a scan? "I think it's very likely."

All this is far in the future, I cautioned my boys. We don't know how to begin to do this now.

Aubrey agreed. But we don't have to worry about any of that today, he said. We are still very attached to our bodies. He used the phrase "meat puppets." We want to keep our meat puppets. If we achieve immortality by uploading our minds into supercomputers, then we will have to say goodbye to our bodies, our meat puppets, forever. "So, not uploading," Aubrey said. "I'll stick with the meat-puppet approach. Of course, if you live a thousand years, driving will be outlawed! It could be a highly risk-averse world." Here he returned to his theme in my car on the way from the airport. If you hope to live a thousand years and you are struck by a cab at twenty-five, you lose an awful lot. "That would p.i.s.s people off. So there will be an incentive to improve medical care-traditional medical care. And there will be all kinds of safety precautions. Climb a mountain, they'll catch you before you hit the ground if you fall. Automated cosseting. But of course there's only so far you can go. Like how many people you could have s.e.x with without catching something." My boys looked impressed that Aubrey was talking so freely in front of them.

I asked him how long he thought it might be before we arrive at this automated, cosseted world.

"I wouldn't be surprised if it's here in a hundred years," he replied. "I plan to be around. I will warn you that I was surer of that ten years ago than I am now. I feel it's all very well to take this view selfishly. But ultimately if I can do something to add even one day to the human life span..."

Here he went into his statistical rap. Already this was the third or fourth time I'd heard it. He was beginning to remind me of a wound-up clock that chimes on the hour, or a salesman who makes the same speeches so often that he forgets what he's just said to you and lives in mortal danger of repeating the same anecdotes two or three times in one pitch. He explained about escape velocity, and saving one hundred thousand lives a day.

While Aubrey talked, I tried to read my boys' faces. No, they did not seem shocked by his confidence that they would live forever. They took their immortality for granted. If anything, I thought they seemed happy to meet an adult who was willing to acknowledge the truth. They told me later on that they thought Aubrey's argument was sensible. He seemed very full of himself, but his premise was only common sense. One of them told me, "I think he is knurd. He is excessively sober." My son had gotten the word from Sourcery Sourcery, a science-fiction novel by Terry Pratchett. "Knurd" is "drunk" spelled backward. Pratchett writes, "Knurdness strips away all illusion, all the comforting pink fog in which people normally spend their lives, and lets them see and think clearly for the first time ever. Then, after they've screamed a bit, they make sure that they never get knurd again."

For his part, when we were back in my study over the garage, Aubrey told me that he found it refres.h.i.+ng to talk about immortality with teenagers. They are people who are positive and adventurous about the future. He feels frustrated when he talks with those who are less adventurous. "That means nearly everybody in influence and power," he says. "Middle-aged and older. They find it so shocking that we might create a world so different from the world they're used to. They're very resistant to even thinking about the desirability of it-that it might be a good thing. People are like that. There's only so much change they can think about. I'm guilty of this myself. Young people talk about uploading. One of your sons brought this up. I just can't see it-can't see it being useful. It seems in no way desirable. But that may be a danger of being over thirty."

Of course, we were getting ahead of ourselves. There were really two enormous questions to discuss: feasibility and desirability. As philosophers say, "can" is not the same as "ought." Aubrey and I agreed that we would save "ought" for another conversation.

I felt sure that the answer to the first question was no no. The conquest of aging was impossible. The point that bothered me most in Aubrey's spiel was his a.s.sumption that we could understand the machinery of our bodies well enough to clean them up. "But we don't have to understand metabolism," he insisted, once again. "I say, go in early enough but also late enough. Early enough to help, but late enough so that you are out of the way of the really complicated stuff."

He saw himself as working in the tradition of the theoretical biologists. "Theoretical biology has an incredibly bad name," he said. "And the reason it's got a bad name is well understood. Since we deal with such complicated systems, biology is a big big subject, and it's very easy if you're an amateur to read a bunch of literature and come up with a nice hypothesis to explain all this data; and if you're careless, you tend to rush into print without checking to see if your idea is consistent with the other 99 percent of data that you haven't got around to reading. This has happened a lot. That's how theoretical biology got into the fix it's in today.

"But the other side of it is that if you have any decent ideas, and the biologists can't see any gaping holes-you do it once and people take you seriously. Twice or three times and you're a phenomenon. So I basically kept my foot out of my mouth for two or three years and everyone was very happy to treat me as a proper scientist, even though I had no idea how to work a pipette." He took a swig of beer and wriggled his fingers together to ill.u.s.trate his pleasure.

In fact, after his moment of revelation at the Marriott in California, Aubrey had done a huge amount of work with established scientists. He'd kept his job as a computer programmer in the Department of Genetics at the University of Cambridge. It was only in his spare time that he worked on the conquest of immortality, or "the engineering of negligible senescence," the creation of human bodies that hardly age. He was an amateur-but an extraordinary one. He'd published a paper about mitochondrial diseases with one of the world's leading authorities on the subject. Papers with famous gerontologists; venerated epidemiologists; legendary cell biologists.

He was the most accomplished amateur scientist I'd ever met. He was also the most arrogant. "At the moment," Aubrey told me, "probably I'm the only person in the world who has reasonably in-depth knowledge of all the related fields of life extension. That's not going to remain the case for very long. People are going to start putting two and two together. People will start realizing the reason for their pessimism is they haven't been paying enough attention to the facts facts." He railed against gerontologists. "It would be very hard to find anybody to debate me and make a good fight of it without my making a fool of them. Because they are fools. Not in the sense of their intelligence but in terms of what they know. They just haven't done their homework. They're not fools in terms of intellect. But they just haven't had the time or inclination to get the right constellation of knowledge." When Aubrey was explaining one of his most daring and disturbing ideas about longevity, he told me, "In two or three years the whole area will be two or three times bigger than it is now. Due almost entirely to my own efforts."

That evening in Bucks County, my wife and I took Aubrey to a dinner party honoring a friend of ours, a painter. We were celebrating his retrospective at the local art museum. Because Aubrey would not know anyone, we worried that he might feel lost and out of place. He'd had a long day. Besides, I'd gotten the impression from Aubrey's nervous spell in my car on the way to my house from the airport, and from his rapid, thick speech in my study, that he might be shy. A guru needs tremendous force of personality. All in all, I didn't think much of his prospects. At moments as I'd listened to him unspool his spiel I thought he might have something. At other moments, I thought his Seven Deadly Things was nothing more than a list of seven of the hardest problems in medicine. The field of longevity was already full of larger-than-life personalities, dreaming dreams no mortal ever dared to dream before. I doubted that he would find a place at the table of the great world. I was afraid he might have trouble just finding a place at the dinner party.

But I did not know Aubrey. He strode into the party like a conqueror. "Since I've been drinking beer all day I think I'll stick to that," he told our host briskly, when she offered him a gla.s.s of wine. Then he seated himself at the center of a long table in our host's living room and took over. Lifting his beer, he began explaining his mission, and the Seven Deadly Things, to our friends up and down the table.

I don't remember every word he said at that dinner. In ten years, the feasibility of his plan would be clear, he said. Within ten years, people would realize that they have been sleepwalking for the last six millennia, "or whatever it is." Soon the explosion of interest in life extension would be a more or less catastrophic phenomenon around the world, instead of the slow steady buildup we're seeing now. Pandemonium! "What will also change is the amount of trouble I'm making," he said. He did have force of personality. He seemed to feed on the stares of our friends. He grew larger and larger in his chair, there at the center of the long table, until he looked like Jesus at the Last Supper. (Since Aubrey predicts the coming of the kingdom of eternal life not in Heaven but right here on Earth, maybe I should call it the First Breakfast.) My wife borrowed my notebook and wrote to me in block letters: "HE IS MORE SURE OF HIMSELF THAN G.o.d."

After that first meeting, I tried to catch up with Aubrey now and then when he was in the States. When he's in New York on one of his lecture tours he sometimes drops in on Janet Sparrow's lab at Columbia's medical school to see how she is doing with the junk that builds up in the retinas of elderly eyeb.a.l.l.s. I joined him there recently. Listening to them talk gave me a glimpse of the different perspectives of a careful specialist like Sparrow and a theatrical figure like Aubrey, who is a general and impresario in the War on Aging. There's a great difference in temperament and tempo between the bench scientists in laboratories, scientists who take things one half-step at a time, and the planners of millennial campaigns. In Aubrey's presence I asked Sparrow what she thought of his idea of attacking and clearing away the lipofuscin from aging retinas.

"Yes, people ask-what about breaking it down?" Sparrow said, speaking very, very carefully. "But then you've got to worry about the health of the cell." Breaking down trash inside living cells might cause new problems, she said.

"We're lucky in the location of the lysosome," Aubrey countered. Because the junk is already packed into the lysosome, the cell's garbage-disposal and recycling unit, it is sequestered from the rest of the cell. "So that sidesteps our ignorance," Aubrey said. Nothing in our lysosome is intended to get out. If through our ignorance we break the junk into toxic by-products, those poisons will still be locked away safely in the lysosomes.

Sparrow did not quite agree. Molecules of lipofuscin do fragment and diffuse out of the lysosomes, she said quietly. Those fragments may be damaging. The garbage disposal is always breaking down and self-repairing, so stuff is always getting out of there and drifting around in the cell, like the dustlike floaters and motes in aging eyes.

In Sparrow's field, as in many specialized areas of medicine, there are debates over whether junk like this does harm or is merely benign, a by-product of the disease process, whatever that may be. For instance, in the study of Alzheimer's, there are those debates between the Baptists and the Tauists. The Baptists think beta-amyloid is what makes us sick and the Tauists think it's tau. Then there are experts who think that neither compound is toxic. They are just innocent by-products. Something else, something that is bad for us, is going wrong in our brain cells. So I asked Sparrow if the same debate applied in the retinas, which are, in fact, derived from our brain cells-our retinas are the only parts of our brains that are not enclosed in our skulls. Are there squabbles about lipofuscin too-with some people arguing that it hurts our eyes and others arguing that it's harmless?

Sparrow explained, very cautiously and carefully, that my question about lipofuscin had indeed been debated for years in her field. Because the lipofuscin in the retina glows in the dark, most specialists now do believe that in macular degeneration, at least part of the problem might be these molecules of lipofuscin. "We're trying to understand if they're negative," said Sparrow. "We think it's increasingly apparent they are."

Aubrey nodded. "The case isn't closed. But it sure ain't gonna do any harm, getting rid of them!" I had a strong feeling that he wasn't speaking to Sparrow or to me. He was speaking to my notebook and pen, and through them to the world. "And if we restore everything everything," he said, "then we're done done!"

Chapter 8.

THE METHUSELAH WARS.

"Vermiculate questions," Francis Bacon called them, "fierce with dark keeping."

Controversies-niggly, bookwormy controversies-bedevil scholars in every age. Every field of study has battlegrounds that burn up scholars' time and energy. To the casual bystander it's all academic squabbling and logic-chopping. To the scholars themselves it is almost life-or-death. Aubrey's work is contentious at least in part because it keeps him darting around in the no-man's-land between battlefields. And yet if you take a long view of the Methuselah wars, you can see that they may be winding down, and you can see that Aubrey, or certain key positions of Aubrey's, may just survive.

In the science of life today, the biggest battlefield lies between biologists who study life whole and those who a.n.a.lyze its working parts. They're the "skin-out" people and the "skin-in" people. In the skin-out camp you have the naturalists, the ecologists, the field biologists, the evolutionary biologists. In the skin-in camp you have the cell biologists and the molecular biologists, experts on gadgets and widgets that are too small to see through a microscope.

Those who study nature whole and those who study it at the level of molecules rarely see eye to eye. Skin-out people look at the big picture and skin-in people look at the microscopic or submicroscopic picture. Skin-out people tend to think about the panorama of history, and skin-in people tend to think about the mes.h.i.+ng of molecular gears. Francis Crick once scolded Stephen Jay Gould: "The trouble with you evolutionary biologists is that you are always asking 'why' before you understand 'how.'" Meanwhile the evolutionary biologists blame the molecular biologists for asking how and never why.

The evolutionary biologists are tied to Darwin and nineteenth-century natural history. The molecular biologists are tied to Watson and Crick and twentieth-century physics and chemistry. Darwin was the greatest life scientist of the nineteenth century; Watson and Crick made the greatest breakthrough of the twentieth century, and from the beginning they've seen themselves as ringing out the old and ringing in the new. They see the skin-out biologists as describers, anecdotalists, stamp collectors. In universities, molecular biologists get most of the grant money, the new buildings, and the power. They've relegated the evolutionary biologists, ecologists, and naturalists to the corners of the old buildings and the natural history museums. The dustbins.

It has been an epic rift. The skin-in people tend to be excited about the engineering projects they can do. They study the body's works and wonder how much of their new knowledge they can translate into how much power to improve or save human lives. The skin-out people, the evolutionary biologists and ecologists, tend to worry about what we're doing to the rest of the planet, and what we can do to save the other ten or twenty million species that live on it.

In the early years of the molecular revolution, the skin-in people weren't very interested in the problem of aging, because they didn't think there was much they could do about it. One of the young revolutionaries, Leslie Orgel, a collaborator of Francis Crick's, argued that aging is probably caused by damage to DNA. Our DNA is continually jostled and shaken by cosmic radiation from outer s.p.a.ce, and by the agitation of the living molecules around it in our own bodies, and these collisions-along with a thousand and one other accidents-can cause mutations. If mutations occur in the egg and sperm cells, they can cause problems for the next generation. If the mutations occur in other cells, they can cause problems for our own bodies, because DNA contains information that is crucial for the cell in all of its manufacturing processes. When the wrong genes get the wrong mutations, you could say that a cell no longer knows how to live. Orgel argued that cells with mutations would make defective molecular machinery, and the defective machinery would then behave badly around the genes, and eventually the cell's production lines would get hopelessly, viciously snarled. Errors would pile on errors. Orgel called this the Error Catastrophe.

Many skin-in biologists found this hypothesis intriguing. After all, DNA is precious. Genes can't be repaired as simply as the rest of the cell's apparatus. When genes are corrupted or destroyed, the cell has lost priceless information. It's bad to lose a cake; it's worse to lose the recipe. If mutations in cells can lead to cancer, maybe they also cause the many kinds of deterioration that we call aging. So the skin-in people were drawn to Orgel's idea; but few of them worked on it. The Error Catastrophe is a difficult hypothesis to test. Each cell contains six feet of DNA, tightly spooled, with about three billion letters of genetic code on the spool. As the cell ages, it gets typos in unique, random places along those six feet of DNA, as well as typos in the elaborate machinery that reads the DNA. How would you keep track of all those typos and prove that they're aging the cell? We all do have days when aging feels like an Error Catastrophe. But it is an ugly hypothesis to study. It would be very messy to prove; and even if you could prove it, what could you do about it?

By and large, then, the skin-in people left the problem to the skin-out people and their arguments about the evolution of aging. To skin-in people, those arguments were not really science at all. If you couldn't understand a problem at the level of molecules, you weren't a biologist; you were just a philosopher.

Then, in the 1980s and 1990s, both camps began to realize that aging might be malleable. Naturally, each camp a.s.sumed that the other side's work had to be wrong. But each camp figured out how to make Methuselahs: creatures that live much longer than the rest of their kind.

The molecular work was started by a researcher named Michael R. Kla.s.s at the University of Houston. Kla.s.s reasoned that at least some of the sources of our longevity have to be in the genes. So he decided to go looking to see if he could find a longevity gene by making mutants in the laboratory and looking for Methuselahs. For his search he used the tiny round nematode worm Caenorhabditis elegans Caenorhabditis elegans. He bred lots of mutant worms by feeding them a toxic compound called ethyl methanesulfonate. Then he grew them in petri dishes, where he let them graze like sheep or cows on lawns of bacteria. Every day he would collect the worms, put them on a nice fresh bacterial lawn, and see how many were still alive. Through the microscope he zoomed in on the worms' throats, one by one, to see if they were still alive, still swallowing bacteria.

Kla.s.s created one thousand different strains of mutant worms. Out of that thousand he found just one strain that he considered to be Methuselah mutants. But he noticed that if he put those worms on a little lawn of bacteria in the center of a petri dish, they would wander off the lawn and try to graze on the bare gla.s.s. Apparently that strain seemed to have trouble smelling its food. So those worms were hungry. Probably those wandering worms weren't getting enough food, he decided, and that was why they lived a long time. If they lived a long time because they were half-starved, that was not news-they'd be living longer because of calorie restriction. He was looking for a worm that lived longer purely because a mutation had extended its life span. He decided that he had failed. And after doing so much work, Kla.s.s concluded, reasonably enough, that aging genes must be very, very rare, if they exist at all. So Kla.s.s abandoned the experiment.

Not long afterward, a biologist named Tom Johnson asked Kla.s.s if he could look at that last mutant more closely. Johnson looked at the worms through the microscope. He thought they ate fine. Their calorie intake was not restricted. So after a great deal of work Johnson traced the gene that had mutated and made that mutant strain live so long. He named the gene age-1 age-1. Johnson found that when he raised age-1 age-1 worms in petri dishes at the warm, humid, Floridian temperature of 25 degrees C (77 degrees F), their maximum life span was more than doubled: it increased by 110 percent. A few strains did even better. Their average life spans increased by 120 percent. worms in petri dishes at the warm, humid, Floridian temperature of 25 degrees C (77 degrees F), their maximum life span was more than doubled: it increased by 110 percent. A few strains did even better. Their average life spans increased by 120 percent.

At that time, most experts on the biology of aging mistrusted this work. They were evolutionary biologists. They thought it was impossible that a single gene could do very much for life span. According to the line of argument that ran from Darwin to Medawar to Williams to Kirkwood, when bodies age they just fall apart. The disintegration is not programmed. It is not written in our genes. So how could a single gene make so much difference? Something must be wrong with the experiments.

A few years later, a third molecular biologist, Cynthia Kenyon, decided to take up the search for longevity mutants. There was still so little interest in the subject of aging, and the study was thought to be such a backwater, that she had trouble finding a student she could persuade to work on it. When she did, at last, she found a mutant worm that she thought was perfectly beautiful. Under the microscope, ordinary old C. elegans C. elegans worms look granular and ugly, as if they were made of cottage cheese. But these mutants stayed smooth and elegant almost to the end of their lives. Cynthia Kenyon published her first studies of Methuselah mutants in 1993, ten years after the first paper by Kla.s.s. worms look granular and ugly, as if they were made of cottage cheese. But these mutants stayed smooth and elegant almost to the end of their lives. Cynthia Kenyon published her first studies of Methuselah mutants in 1993, ten years after the first paper by Kla.s.s.

Kenyon's mutants caused a sensation among molecular biologists. The science that grew out of Watson and Crick's "secret of life" had now found the secret of the fountain of youth. If they could make a Methuselah worm, soon they'd be able to genetically engineer a human Methuselah. Whether or not that was true, the link between the gene and the long life of the worms was very clear, news of Kenyon's mutants traveled fast, and here and there other molecular biologists began to enter the field of gerontology. I happened to be present one afternoon at the lab of a grand old man of molecular biology when a young scientist gave a seminar about longevity mutants. Seymour Benzer, one of the founders of the field with Watson and Crick, was fascinated. He seemed astonished to think that we really might be able to understand aging at the level of the genes. He began looking for longevity genes in fruit flies the way Kla.s.s, Johnson, and Kenyon had in worms. When he was eighty years old, Benzer discovered a Methuselah fly. He used to talk about that fly in an almost shady way, lowering his voice, making it thin and quiet, as if he and his listeners were convicts in neighboring cells, as if he had to drop his voice and turn it edgewise to slip a scribbled message between prison bars.

The evolutionary biologists remained skeptical about the molecular biologists' Methuselah mutants. To the skin-outs it still seemed impossible that a single gene could matter that much to the life span. Disposable soma theory predicted that there should be many genes that go wrong with age. Aging was a Hydra with at least nine heads. You couldn't kill it with just a single kick. According to disposable soma theory, the Methuselah mutants should not exist. I once talked about them with John Maynard Smith, a grand old man of British evolutionary biology, who worked out some of the mathematical theory that flows from present thinking about aging. He and I met on one of the upper floors of New York's American Museum of Natural History. Maynard Smith was a brilliant scientist who had started out as an aeronautics engineer. He'd helped improve the fighters and bombers of World War Two, the planes that the young airmen of the RAF flew over London and Berlin after burning their initials into the ceiling of the Eagle. After the war, Maynard Smith had done both theoretical and experimental work on the science of longevity. Now he was nearing the end of his life. When I asked him about the biologists who thought it might be possible to engineer a human Methuselah, he shook his head. He said that something seemed to happen when serious people approached the problem of aging and death. They just seemed to go mad.

As a software engineer with a wide range of interests in biology, Aubrey de Grey is in the camp of the molecular types, the genetic engineers, and also in the camp the evolutionary biologists. Still, he's a proud engineer at heart. When I told Aubrey what Maynard Smith had said, he smiled. "John Maynard Smith? I have the greatest respect for his intelligence. But he's an evolutionary biologist. He finds it hard to think in an engineering-type way."

That's the way the two camps flame each other. They fire off those killing salvoes again and again. Once I was talking with a famous biologist-a molecular biologist-who had just joined Rockefeller University, and I asked him if he had ever heard of Maria Rudzinska. He looked blank. I described her work to him, how she had been trying to understand death and dying without looking at genes and molecules, just by watching aging cells through a microscope.

"There used to be a lot of deadwood around this place," he said.

In the 1980s, while the skin-in people were making Methuselah mutants, the skin-out people made their own Methuselahs. They did it the old-fas.h.i.+oned way: not through genetic engineering but through Darwinian breeding experiments. At about the same time that Kla.s.s engineered the first Methuselah worm, a young evolutionary biologist named Michael Rose bred Methuselah flies. Typically fruit flies breed at the age of a week and a half. Rose watched carefully and selected only the flies that kept breeding in old age, and he bred those. It was work that could have been done in the nineteenth century just as well as in the twentieth. And it didn't violate the disposable soma theory, because Rose a.s.sumed that many, many genes would be involved in making a Methuselah.

It was very hard work. Rose bred millions of fruit flies, and each experiment took between thirty and fifty fly generations. But he found that it was possible to play with a fly's length of days. When he allowed only older flies to breed, generation after generation, they evolved longer life spans; when he allowed only the younger flies to breed, they evolved shorter life spans. Rose and his thesis adviser, Brian Charlesworth, announced the creation of the first of these evolutionary Methuselahs in 1983.

Again, unlike the Methuselahs of the molecular biologists, Rose's were acceptable to the evolutionary biologists. These populations of fruit flies represented the same miracle that has happened again and again in the wild. See, for instance, the bats, the flying squirrels, the flying lemur of the Philippines, all of which are Methuselahs. Any population of living things that finds itself in conditions in which it is able to breed at later ages will begin to evolve longer life spans. Since Rose could replicate that miracle again and again quickly in the laboratory, he argued that adding years of vigorous healthy life must be comprehensible at the level of the genes. He didn't know which genes had changed; evolutionary theory predicted that the change must have been produced by a constellation (or cl.u.s.ter or galaxy) of genes. Evolutionary biologists thought they understood the why of aging, and according to evolutionary theory the existence of a single powerful Methuselah gene was impossible. Even so, changes in life span could not happen so quickly and so repeatedly, both in the wild and at his laboratory bench, unless it was a relatively simple trick to bring off.

Rose championed the evolutionary Methuselahs and tended to brush aside the molecular Methuselahs. He dismissed those Methuselahs as Johnny-come-latelies. In his memoir, The Long Tomorrow The Long Tomorrow, Rose writes, "It is always entertaining when molecular biologists rediscover findings from evolutionary biology. They have such an appealing naivete, like the moment when my son Darius gleefully discovered at the age of one that gravity would help him knock over a gla.s.s of milk."

To the outside world, of course, the battlefields of biologists weren't very interesting. What was interesting was the creation of all these Methuselahs. Cynthia Kenyon, who put the Methuselah worms on the map for molecular biologists in the 1990s, was not only a gifted scientist but young, photogenic, buoyant, and articulate on camera. She was invited on dozens of television shows and news shows to talk about them. When people asked her, Wouldn't it be weird to have adult grandchildren? she would shoot back a snappy answer to the interviewer's questions. "I think every grandparent wants to live to see the grandchildren grow up." She made the study of mutant worms sound s.e.xy. "They are like eighty-year-olds who look forty." And, "I can make your dog live forever!"

Michael Rose also got a lot of press. A generation before, at mid-century, Peter Medawar had dared to imagine that the total span of human life might be lengthened by "stretching out the whole life span symmetrically, as if the seven ages of man were marked out on a piece of rubber and then stretched." Rose declared that ambition too modest. What if we could stretch out the time we spend young without stretching the time we spend withered and decrepit? If we learn to control the genes that govern life span, we could do that. Who knows? We could make youth last threescore and ten years, and age last only one or two years. Certainly we could prolong youth without prolonging age. We could open that door with a few twists of the skeleton key.

These twin victories on either side of the trenches in the Methuselah wars helped revive the field of gerontology. The skin-ins and the skin-outs still don't get along. Skin-out biologists still doubt that you can kill aging with a single gene. Skin-in biologists are still playing with single genes to make more Methuselahs. ("My rule of thumb is to ignore the evolutionary biologists-they're constantly telling you what you can't think," Gary Ruvkun of the Ma.s.sachusetts General Hospital told a reporter from the New York Times New York Times not long ago.) Even so, more people on both sides are entering the field, and a resolution of the paradox is beginning to emerge. This battle is beginning to die down. not long ago.) Even so, more people on both sides are entering the field, and a resolution of the paradox is beginning to emerge. This battle is beginning to die down.

Evolutionary biologists can see why tinkering with genes might extend the lives of worms, or flies, or mice. It's true that Darwinian evolution does not design bodies to be long-lived. And yet, there are conditions in nature that permit a population of animals to grow up relatively slowly and reproduce at later ages, just as the flies do in Michael Rose's laboratory breeding experiments. Suppose a pair of mice drift out to sea on a log and arrive on an island where there are no cats, hawks, or owls. Suddenly they are safer. Generation after generation, their descendants can flourish if they invest in slow, careful growth, in the kind of cellular quality controls that biologists call "longevity a.s.surance systems." The mice on that island will live long and prosper. Their descendants will inherit their good genes and live longer yet. So aging is in some ways under the control of the genes, even though aging itself is not designed by evolution.