Long for This World: The Strange Science of Immortality - Jonathan Weiner (2010)
Part II. THE HYDRA
Chapter 7. THE SEVEN DEADLY THINGS
In the summer of 2000, Aubrey de Grey was invited to give a talk at a meeting in Los Angeles focusing on what to do about aging and how to bring all these lines of work together into a single research program. At the Marriott Hotel in Manhattan Beach, speaker after speaker presented hourlong talks reviewing one aspect of the aging problem or another. Each speaker analyzed one line of work without much reference to the others. As he listened, Aubrey felt demoralized. This really is a public-relations problem for the science of aging, he thought: how scattered and incoherent it all is. Aging is so chaotic, so Hydra-like. No wonder the world despairs of a cure. So many monstrous jaws agape, so many terrors gnashing their teeth at us all at once. And each gerontologist fights one set of jaws and ignores the rest.
Aubrey went to sleep in his hotel room feeling exasperated. Because of his frustration and his jetlag, he woke up after only a few hours. It was four o’clock in the morning—or noon, back home in England. Aubrey remembers sitting up in bed, tugging at his beard, and seething about the day. Suddenly a thought came to him: Why not just clean up all of the junk? If aging has no program, no plan, if we just fall apart in slow random motion, then there’s always going to be chaos in each body’s decline and fall. The evolutionary theory of aging predicts chaos. And chaos is just what you see at the cellular and molecular level, and what you will always see. But what these troubles all have in common is that they fill the aging body with junk. Maybe we can just clean up all the scree and rubble that gathers in our aging bodies. That is what came to him in the hotel room in California at four in the morning.
Aubrey told me all this a few years later. He was passing through the United States on a lecture tour in 2002, and I invited him to stop by for a day or two to explain what he was about. It was our first meeting. I picked him up at the airport in Philadelphia and as he huddled in the death seat of my car, enduring the curves of our country roads (we were winding our way toward my house in Bucks County, Pennsylvania, where I lived at the time), the poor man’s face looked pale to the roots of his hair and beard, corpse-gray in the cheeks. His head tilted toward the window as if toward martyrdom. He’d never learned to drive, he told me, when I asked him if he was all right. He couldn’t help feeling frightened in cars. That’s how everyone will feel, he said, when they realize that they may have hundreds or even thousands of years ahead of them. Once that truth sinks in, it will be hard to find anyone on Earth who is willing to ride in an automobile, much less a police car or a fire truck. Too much life ahead. Too much time to lose.
We stopped at a country tavern, the Pineville, and Aubrey relaxed with a beer or two. Once we were settled in my study and Aubrey was relaxing with another beer, I asked him about metabolism. To have any chance at engineering longer lives, didn’t we have to understand the intricacies of metabolism—all the ins and outs of our building up and our tearing down, all the invisible labors of the Phoenix, for which we burn away each day at 98.6 degrees?
Aubrey explained the thesis he’d been developing for the past few years. “We don’t have to understand metabolism, because we don’t have to clean up metabolism,” he told me, triumphantly. “All we have to clean up is the detritus that metabolism lays down. And the critical point is, the detritus is not complicated at all. There are only seven types of detritus, more or less. This is the key insight that underpins everything I say. It hasn’t been thought about by gerontologists. They’re scientists, not engineers.”
I had spent enough time in pathology labs, staring through microscopes at damaged tissues that reeked of formaldehyde, to know that our mortal detritus is incredibly complicated. But I’d promised to listen with an open mind.
Aubrey asked me to recall the theory of the disposable soma. After the age of reproduction, the whole body is disposable; so the garbage piles up. It is all very simply a problem of garbage disposal. Our bodies were not designed to last as long as we would like them to last. So why not keep them in good repair, as you would keep a treasured antique car in repair, scraping away the rust, replacing broken parts, and so on? We maintain our houses, too. If we want them to stay leakproof we have to caulk the sills, replace the roof every ten years. We have to repaint. We have to replant, reseed the gardens, clean the gutters, repoint the bricks with fresh mortar. It’s a lot of work, of course, but there’s nothing very mysterious or surprising about it. If we do all that and keep after it, the house will last a long time. So why not do the same thing for our bodies?
The beauty of this view of aging, Aubrey said, the beauty of the disposable soma, and the garbage catastrophe, is that curing aging requires no great knowledge of design. You don’t have to be able to design a car in order to maintain a car, or to build a house to maintain it, either. “Most people want to clean up metabolism—and metabolism is so crazily complicated. It won’t happen,” he says. “It’ll be decades before we understand the cell like a nuclear power station. So my radical idea is, don’t try to prevent damage. Let it take place.” And just keep cleaning up after ourselves—keep clearing away the nuclear debris. Although metabolism is complicated, the nasty by-products are not. It’s like the difference between a car and the rust and gunk in the engine. The mess may be hard to clean, but cleaning it out is a lot simpler than designing and building a new engine. Rust and gunk have no working parts. They just sit there and get in the way, he said.
Aubrey laid out this argument that day with prodigious intensity, leaning or half-lunging out of my office chair, bottle in hand, the beard pooling in his lap. Behind him stood my wall of books about biology. By this time I had quite a collection, after two decades of following the science of life, a long tall wall that ran the length of the room. I enjoyed Aubrey’s enthusiasm and I thought he was a great character, but I wasn’t hearing the kind of trumpet blast that would bring that wall of books tumbling down. Probably I was giving Aubrey the hairy eyeball now and then as I listened to him; but he was used to that, and that’s why he talked like an overeager salesman. With his larger-than-life beard and intensity he reminded me of a prisoner in a cell in an old New Yorker cartoon. Two men hang chained to opposite walls of a medieval dungeon. Nothing in the cell but tall stone walls, one tiny thick-barred window. Each wretch is chained about ten feet up on the wall, spread-eagled by shackles on both wrists and both ankles, each man with a beard of years hanging down past his waist. And the first prisoner is saying to the other, “Now, here’s my plan…”
With that kind of confidence, which struck me as slightly ludicrous, in the face of our mortal situation, Aubrey told me the story he has told a thousand times since: how sitting in his hotel room in the small hours that night, he made a list of the kinds of junk that builds up and what we might do to clear it away. When he was finished with his list he was greatly encouraged to see that it was short. Once you think of our body’s decline in terms of clearing away just a few types of damage, you’ve demystified the problem of the ages. You’ve reduced the greatest prisoner’s dilemma of human experience to nothing more than a list of puzzles. With our big brains, we are wonderful at solving puzzles and brain-teasers. There’s nothing that a little can-do spirit can’t do if we all pull together. I listened to Aubrey and I thought: There it is again, the voice of immortalists down through the ages. It was the same ageless voice I first heard in the Reading Room of the great public library on Fifth Avenue, up the flight of stone stairs between the lions Patience and Fortitude, when I met Ko Hung, Roger Bacon, and Paracelsus (born Theophrastus Phillippus Aureolus Bombastus von Hohenheim).
The list had changed a bit over time. He’d started out with nine deadly things, in his first paper on the subject. Since then he’d been adding and subtracting, lumping and splitting, until he had seven. All seven are well known, even notorious. In fact, Aubrey’s seven deadly things are to gerontologists what the seven deadly sins are to doctors of the soul. Here is one deadly thing: many of our molecules grow tangled and stiff with age; they get stuck together in more and more places, as if demons were dashing through our bodies daily with molecular staple guns. Biochemists call those staples cross-links. Here is a second deadly thing: the cells’ mitochondria fail with age. A third: junk collects inside our cells. A fourth: more junk collects in the spaces between our cells. A fifth: some of our cells get old and hang around in the body without doing their jobs—making a nuisance of themselves. A sixth: some cells die and poison the cells around them. And here is a seventh deadly thing. The very worst citizens among our cells accumulate dangerous mutations in the genes of the nucleus. Those cells’ descendants build tumors.
Aubrey explained that if we approach these seven deadly things methodically, the conquest of aging might turn out to be a very simple matter, at bottom. Start with the most basic kind of damage, the cross-links that stiffen our collagen and make our skin wrinkle those dismal things that chemists call the advanced glycation endproducts, the AGEs. These cross-links are nothing but junk that the body has not learned to get rid of. So, said Aubrey, all we have to do is break the cross-links. We can repair the damage of the AGEs. Chemists already know what they’re made of. Chemically, they are sugars. All we need is a solvent that can snap off those extra sugars without breaking or fraying the ropes. In other words, we need a solvent that is very highly selective. It has to be selective because most of our proteins, most of our molecular machines, contain cross-links made of sugars. They’re not confined to old ropes of collagen. They’re everywhere. We want a compound that breaks only the cross-links that have formed by accident without breaking all of the other cross-linked machinery that we need to stay alive. In the ideal situation, said Aubrey, the particular links we need to break would turn out to be the ones that are easiest to break; whereas the links we want to preserve would be harder to break; and with just the right set of chemicals and solvents we will be able to snip the feeble cross-links as fast as they form.
Researchers in big pharma are already at work on this kind of problem. After all, the first antiwrinkling cream that actually erases wrinkles will be worth more money than Viagra. Almost every human hide gets less elastic with age, a condition known as elastosis. Aubrey told me about a chemical that was being promoted at the time by a small biotech called Alteon. Alteon’s chemical of interest was purported to break one particular class of cross-links, called dicarbonyl linkages. The interesting thing about the drug was that it was supposed to work catalytically. That is, it broke one cross-link and then was released in its original form to break another.
I followed Aubrey’s rap about AGEs with the same polite interest and skepticism that I would have shown a sales rep from Alteon. It’s not a bad idea to try to prevent or fix those cross-links. That’s a perfectly reasonable goal for medical researchers to work on, since cross-links do so much damage to our aging bodies, inside and out. And, as Aubrey was saying, many researchers have been working on it for years. In fact, I recognized one of them when Aubrey mentioned his name. I’d met him back in the early 1980s, at about the time I met Maria Rudzinska. He was already working on the cross-links problem back then. It was interesting to hear that his ideas were finally being put to the test by a biotech company. I made a mental note: that might be worth checking out. But the specificity problem isn’t something to brush away lightly, with wrinkle treatments or anything else. The specificity problem is basic to medicine and always will be. If specificity weren’t a problem, you could cure any headache on Earth with a simple surgical tool called a sledgehammer. That procedure would work, but it would have side-effects. If specificity weren’t a problem, the historical model for Doctor Faustus wouldn’t have gone to jail; his facial-hair remover wouldn’t have taken off the patient’s face along with the hair. In medicine, you might almost say, specificity isthe problem. Without it, you’ve got no one left at the end of the day to pay your fee. “Cure the disease and kill the patient,” as Francis Bacon was the first to say. Medicines used to be called “specifics.”
Cross-links are one of the simpler items on Aubrey’s list of Seven Deadly Things. But as Aubrey laid them out for me, I thought some of his proposals did sound surprising and clever. He told me about his own special interest, the aging of our cells’ factories, the mitochondria. He reminded me that because of the low-grade chemical fires that burn day and night in the mitochondria, sparks are always flying around (metaphorically speaking), and some of those sparks singe the mitochondrial DNA. The ancient slaves inside our cells give us our energy, but they burn themselves in the fires of their own furnaces. That damage, the corruption of our mitochondrial DNA, is the second of Aubrey’s Seven Deadly Things.
Aubrey told me that he had thought of a way to deal with that damage. The DNA in the nucleus of each human cell contains about twenty thousand genes. But the DNA in our mitochondria is much simpler. It contains only thirty-seven genes and encodes only thirteen proteins.
People who are born with mutations in those thirteen mitochondrial genes are in serious trouble. Because the work of the mitochondria is vital, mutations there can cause rare and horrible diseases of the brain, the heart, the muscles, the liver, the kidneys.
Those precious thirteen are in the hot zone. The DNA that encodes them is subject to as much as one hundred times more cooking than the DNA that is ensconced in relative safety in the nucleus, farther away from the furnaces. If only those thirteen genes were inside the nucleus, they would be safer, Aubrey said. Then they would not be baking day and night in the fury of our molecular furnaces, the mitochondria. According to present theory, in fact, most of the mitochondrial genes have already made just that move. The ancestors of our mitochondria had about a thousand genes. All but those last thirteen genes have migrated to the nucleus.
“So the question is, why haven’t these genes moved?” Aubrey asked.
That startled me. I’d never heard the question asked before, or thought to ask it. What Aubrey was describing is, in fact, a fairly common phenomenon: when two living things become closely intertwined, they move genes around to achieve the best, most optimum, fit. Biologists discovered a similar story recently with aphids and the bacteria in their guts. It’s a little like the exchanges between cultures—when one tribe conquers and engulfs another (think jazz and blues in America). Gains and losses, as in a marriage. An article in the journal Science, describing the shifts of genes from the bacteria to their hosts, the aphids, summed it up neatly: “Any successful relationship demands sacrifices.” So Aubrey’s question was interesting. If the mitochondria have given up virtually all of their genes and shifted them to the relative safety of the nucleus, then why haven’t they shifted the last thirteen?
“There are lots of ideas,” said Aubrey. “All but one is complete piffle. The reason is hydrophobicity.” For complicated reasons, some of the cell’s machinery has to be so constructed that it is hydrophobic: that is, so that its molecules do not like contact with water. The word “hydrophobic” means, literally, afraid of water. And this question of hydrophobicity is vital throughout the cell because most of the fluid inside there, the cytosol, is water. All of the molecular machines that float, swim, hammer, and saw inside the cell have to work underwater. If they are hydrophobic, afraid of water, they may clump and ball up so tightly that they are unable to function. It’s the difference between, on the one hand, dropping spaghetti noodles into a pot of boiling water and, on the other hand, pouring in a splash of olive oil. The noodles will swirl around in the water, as long as you stir them once in a while, because pasta is not hydrophobic. But no matter how much you stir, the oil will just clump on the surface, because it is.
Aubrey took a swig from his beer bottle and discovered that it was empty. He said, “Another good thing about drinking all the time is that I keep my voice.”
I gave him a look. “Well, water will do that, Aubrey.”
Aubrey laughed his most charming and disarming laugh.
When he got back from my kitchen with another bottle of beer, he explained a bit more about hydrophobicity. Each and every one of the thirteen genes in the mitochondria encodes molecular machinery that is highly hydrophobic, he said. That may be why those thirteen genes never moved to the nucleus. So, he said, why don’t we move them ourselves? We should do what evolution has failed to do and inject good copies of those thirteen genes into the nuclei of human cells, using the procedures of gene therapy.
Here I gave Aubrey another skeptical look. But he was prepared for it. Gene therapists are already able to inject genes into multicellular organisms like flies and mice, and they are growing more capable and sophisticated every year.
“Totally straightforward,” Aubrey concluded. “With less than ten million dollars and within five years—or certainly ten years—I could make mice that did not have any mitochondrial DNA.”
I asked him how long those genetically-engineered mice would be likely to live.
“No idea,” Aubrey said. “If we did that and nothing else, it could be they’d live just a bit longer. But I don’t care. It’s a candidate mechanism, so let’s fix it! If we can fix it, we should. If there’s only seven things to fix, then we damn well should. Let’s not waste our time arguing that one or two of them might not matter.”
That is one of the logical necessities of Aubrey’s argument. You need to solve all seven problems at once if you want to extend our lives dramatically. Solving just one or two won’t do the trick. We’re looking at the sad, familiar truth that if one thing doesn’t get you, then another thing will. If you don’t get cancer you are likely to die of atherosclerosis. If you don’t get atherosclerosis then you are likely to die of Alzheimer’s. And so on. To extend human lives indefinitely, to engineer our bodies into a state of perpetual health, we would have to dodge every single one of those diseases, the late-onset diseases. We’d have to figure out how to cure them all or prevent them all, or at least to postpone their onset indefinitely. We’d have to cauterize every head of the Hydra. William James makes this point in another connection in “The Sick Soul,” a chapter in The Varieties of Religious Experience. “A chain is no stronger than its weakest link,” he writes, “and life is after all a chain.” In that same chapter, James calls death “the worm at the core” of all human happiness. “Let sanguine healthy-mindedness do its best with its strange power of living in the moment and ignoring and forgetting, still the evil background is really there to be thought of, and the skull will grin in at the banquet.”
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 accumulate in our mitochondria. Third, we have junk that accumulates 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 balls of nasty protein.
These clumps and balls 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; 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 accumulates 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 accumulate. 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. I read aloud the passage 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 quantity, 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 passed 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 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 Japan, 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. Accumulating damage drives our cells more or less crazy, Aubrey writes in 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 have a better chance than you, and you have a better chance than 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 teleportation. “Beam me up.” The beam from the spaceship 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, identity? 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 identity 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 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 piss 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 sex 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, 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 refreshing 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. The conquest of aging was impossible. The point that bothered me most in Aubrey’s spiel was his assumption 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 illustrate 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.” 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 glass 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 GOD.”
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 eyeballs. 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,” he said, “then we’re done!”