Nevertheless, both Adelaide and Aaron indulged Aubrey’s hopes of the Cure-All of Cure-Alls. They admired him. Someday it might be Aubrey’s turn to have his words on display in the Eagle, like James Watson and Francis Crick, when he had found the secret of eternal life. Someday it might be Aubrey’s turn, like the young pilots of the Battle of Britain, to place a chair on a table, stand on the chair, and sign or singe his extraordinary name across the ceiling. Justify your existence!
John Archer told me that he found Aubrey’s idea provocative enough to be worth taking up in an experiment in his laboratory—not as a major experiment, but a Friday experiment, as he put it. It seemed to me that Archer was almost as uncertain about Aubrey’s ideas as I was, although he spoke about him with great warmth and enthusiasm. “Now, Aubrey has phenomenal energy,” Archer said, “and the trouble with science is—” He plunged into a colorful tirade about the faults and conservatisms of scientists, who can’t see past their own noses, and who eat their young. Here you have a bright young man of spirit, a newcomer whose views are just a wee bit novel, and what do his elders choose to do but gather round and devour the poor lad alive. “In reality we need more Aubreys, God help us. Chaps like him who can see over the hedges. What we’ve got here is a Renaissance man. Missed his century by a few hundred years.”
Since then, by dint of persistence and propaganda, Aubrey has managed to get some high-level scientists to take up his graveyard idea, the microbial remediation of the aging body. There is a bioremediation program exploring Aubrey’s idea at Rice University; and another at Arizona State University, led by Bruce Rittmann, one of the world’s leaders in bioengineering and bioremediation. Rittmann is an authority on breeding bacteria to clean up Superfund sites. On the side he’s now trying to clean up aging cells.
The field as a whole—the study of good housekeeping as the key to good aging—has grown a great deal in the years since Aubrey began championing it. When old cells begin to fumble with their molecules, whether in the course of construction or destruction, creation or demolition, they can accidentally make junk that is bad for them. A certain protein that most cells manufacture daily for use in their membranes, a protein as commonplace and crucial in the membranes as plywood sheeting in the walls of construction sites (although nobody knows what it is for) can get accidentally misfolded to form the junk called beta-amyloid that accumulates between the brain cells of people with Alzheimer’s disease. Beta-amyloid is badly handled by those garbage-disposal units the lysosomes. It builds up in the brain in deposits like drifts and junk heaps. Trouble with lysosomes may be a cause of the buildup. Failing lysosomes may also help hasten late-onset diseases like diabetes, thyroid problems, and the weakening of the immune system. And of course the aging pigment lipofuscin also builds up in old retinas and causes macular degeneration.
Confusing things can happen in lysosomes, as in the fog of war. Cells can use them to devour invading parasites like the bacteria streptococcus. On the other hand, a cell that has been hurt or poisoned may devour a good part of its own substance and die. Nobody knows whether the cell is trying to kill itself or heal itself. Apparently the very same mechanism can promote survival and promote death. Perhaps when the cell devours itself too fast to rebuild, it dies.
It may be that our ability to maintain a healthy balance between the creation and destruction of molecules is what makes the difference, at the very finest scale of mortality, where we are examining life and death virtually one molecule at a time. Specialists in the lysosome, along with another cellular disposal unit, a stout, barrel-shaped structure called the proteasome, like to argue that housekeeping may turn out to be at the heart of it all. Many gerontologists think the Good Housekeeping people are a bit too enthusiastic; they think the self-cleaning, self-devouring work of autophagy is only a part of the problem of mortality. But it is certainly true that autophagy plays a role during the body’s time of growth, from embryo through youth to maturity. It is one of the ways the body sculptures itself to produce its final form, carving away webs between the fingers of the young embryo to produce the hand, or whittling away excess neurons from the brain of the infant to produce and refine each working mind. The machinery of autophagy is also important when aliens invade; when bacteria and viruses intrude on the body, some of the defensive work of demolition is done by autophagy. And autophagy is crucial at every moment of our lives in the nest of the Phoenix, where we are continually consumed and reborn. But our bodies are not designed to do it perfectly forever because our whole bodies are, in the last analysis, disposable.
It is easy to see how trouble in lysosomes might spiral out of control as we get older. For instance, free radical damage may interfere with the lysosome’s ability to digest big bites of the cell—macroautophagy. Then, because the lysosome can’t handle those big bites of the cell, more free radical damage builds up around it. When a cell is young, these bites really are gigantic. A healthy young lysosome can swallow a mitochondrion—it can take in a whole factory in one gulp. Because an aged lysosome can’t do that, more mitochondria that need scrapping may sit around unscrapped. And because the cell can’t swallow large chunks of itself at one go, billions of smaller molecular machines inside the cell have a longer “dwell time.” They sit around longer, increasing the chances that they will get bunged up and malfunction and make other stuff badly, which will then sit around, too, mucking things up.
In Sweden, Ulf Brunk and Alexei Terman, a colleague of Brunk’s at the University of Linköping, have coined a name for the hypothesis that it is junk that gets us, trash that brings us down. In their hypothesis, the more garbage there is in the cell, the less efficient its metabolism. As all good housekeepers know, each bit of junk you leave lying around makes it more likely that there will be more junk lying on top of it or to the side of it, crap piling on crap. At last you get an explosion of junk, according to Brunk and Terman.
They call this the Garbage Catastrophe.
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 l
ived 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 is the 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.”
Long for This World Page 13