Long for This World

by Jonathan Weiner

  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 er
rors 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.