The great choice for this generation is assisted suicide or experimental prolongevist science.
—DAVID GOBEL, PRESIDENT, THE METHUSELAH FOUNDATION
The assumption behind the cold and hot approaches to antiaging is simple. It’s this: By understanding the biology of aging, we can either intervene to slow or stop detrimental processes (via CR and CR-like drugs), or we can replenish certain factors that will help us feel, and, in some ways, actually be healthy longer (via hormones). But what if we were to say, simply, that we don’t care about that, that we don’t care why our car is getting rusty, or that it is running out of fuel, but that what really matters is keeping the car running by vigilantly repairing all damage? Like the vintage car buff whose Model T still looks and runs like the day it came off the Ford assembly line, we can view our body’s main enemy not as rust (free radicals) or insufficient fuel and oil (declining hormones) but, simply, as damage. Damage to our internal systems—regardless of its cause—will eventually kill us. Our priority should be to eliminate the damage and then replace or rejuvenate the worn-out parts. Period. Yes, free radicals may cause some of that damage, but if we wait until we can harness oxidative stress in just the right way, well, we’ll be pushing up daisies. Yes, lack of growth hormone might be bad, but replacing it for too long, who knows? If we can just get a lot better at repair—that might be the key to push out healthy life span, and, perhaps even more, push out maximum life span. This engineering approach—highly experimental, pragmatic, and controversial—constitutes the third wave of antiaging thought. Its practitioners have offered everything from new kidneys built with your own cells to thousand-year life spans. Much of what you believe about it will depend on how you understand your own body and the processes that make it what it is.
Consider an experiment that almost every American, at one time or another, likely declared as incredibly weird, bizarre, unfathomable, or downright unnatural. It concerns an ear, a human ear that was grown on the back of a mouse. From the first announcement of its creation by two Boston scientists in 1992, the mouse ear, inevitably paired with a mental graphic of a mad scientist holding a test tube, has served as a vehicle for every imaginable fear that the public holds of modern science, from genetic engineering (which it wasn’t) to infectious disease (ditto). One image it hasn’t been paired with is that of an aging man or woman, but that, if you think about it, is utterly appropriate. The body of practical medical science that the mouse ear was meant to symbolize—that of tissue engineering, or the making of new body tissues and organs—serves the purpose of life and health span extension perfectly. If it wears out, replace it. But unlike knee and hip replacement, which depends on mechanical additions to the body, or organ transplant, which replaces like with like but is highly dependent on organ donations, tissue engineering is about making new organs and tissue from one’s own cells, thereby removing the problems of limited supply and immunological rejection. It is a new science, although the idea has been around at least since the Renaissance, when many artists took to painting the memorable scene of Saints Cosmas and Damian attaching a new leg to a wounded soldier.
Because tissue engineering is such a new industry, it is possible to find and speak to its founders, who are not saints, but rather, a small cadre of Boston physicians and scientists. They are Dr. Joseph Vacanti, a Massachusetts General pediatric surgeon, his brother Dr. Charles Vacanti, and their friend Robert Langer at MIT. The Vacantis hailed from a large Nebraska family of ambitious Italian American stock—all of the brothers went into medicine. Joe Vacanti, a handsome, velvet-voiced man, recalls that “there was never a time I remember not knowing that I was going to be a surgeon.” After medical school at the University of Nebraska, he earned a surgical internship at Massachusetts General, working with the late Judah Folkman. Folkman made one of the most important medical discoveries of the twentieth century—that of angiogenesis, or how new blood vessels are born. Folkman had put his observations in the service of cancer research. His was a clear and fundamental mission: a tumor tissue—any tissue—could not grow without a blood supply. Hence, if one could find a way to selectively stop or inhibit the growth of blood vessels, one could stop the growth of a cancer. Such was the origin of what we now call anti-angiogenics. Young Vacanti, his mind expanded by what he had learned in Folkman’s lab, found that he was even more interested in pediatric surgery as a career. He had an inkling that some version of angiogenics might be valuable there, perhaps in service of organ replacement. Many of his little patients needed new livers, but demand constantly outstripped supply of donated organs. “I watched in agony and [was] completely helpless as several children faded into coma or hemorrhaged to death,” he says. “It occurred to me that if we could build liver tissue, we could transplant on demand.”
He and Langer began to experiment, eventually coming up with a polymer surface, or “scaffold,” upon which to seed living liver cells. When he stepped back and looked at the results under a microscope, he could see that the liver cells were growing in contact with the polymer, without any toxic effects. The next task was to grow a three-dimensional chunk of liver, and that was where Folkman’s work on blood vessels came into play. “The research question was in a way the inverse of what Dr. Folkman was concerned with—we had to find a way to encourage the growth of blood vessels. But we found we could use so much of what we had learned in his lab.” Every gram of human tissue has one billion cells, and every cell must be within five microns (or five 25,000ths of an inch) of a blood vessel. Certain proteins—complicated growth factors—had to be present in the right amount at the right time. How could they engineer such complexity?
What followed was a lengthy period of contemplation—one not unlike Clive McCay’s reveries by the trout pond or Denham Harman’s ruminations in the Berkeley labs—during the summer of 1986, when, while vacationing on Cape Cod, Vacanti saw the solution. It was waving gently at his feet in the form of seaweed. “The solution was staring me right in the face! Branching seaweed was nature’s way of providing a massive surface area for the plant to extract dissolved gas and nutrition from the sea.” He called Langer and the latter set to work designing and fabricating microscopic, ball-shaped clusters of branching, biodegradable polymer. They could now seed this with living cells and grow tiny chunks of tissue. Later they used similar principles to craft ear cartilage, seeding it with living cells, and, famously, implanting it on the back of a mouse to act as an incubator. It worked. “All of this we did, really, as engineers,” Vacanti says. “We were scientifically skipping steps—we didn’t know every single pathway, every single gene, involved in tissue growth. We were acting on some basic principles from our disciplines. Because the point was never just research—it was ‘what could this do for a real patient?’” What followed was a spate of innovation. The Vacantis and Langer built structural tissues for urinary repair, skin, cartilage, bone, and blood vessels. In 2000, the Vacantis and Langer figured out how to use silicon wafers and micromachining—inspired in part by the ways of computer chip makers—to produce delicately branched scaffolding materials. They have already done successful transplants, in animals, of partially engineered organs—heart valves in lambs, partial stomachs in rats, kidney structures in pigs. The ability to build a massive chunk of functioning tissue, like a liver, is still, says Vacanti, “a ways off. I can’t even speculate on when.”
Although the Holy Grail of whole organ generation for humans has remained elusive, the Vacanti-Langer team’s numerous partial victories have prompted others in the field to rethink the whole idea of organ replacement. Perhaps the most radical notion is that, in the future, our organs may not look at all like the organs we have now. If our kidney’s filtering system goes, we may simply replace it with an organ, built from our own cells, that only performs the organ’s waste-filtering functions, leaving the original organ to do things like process potassium. “Most organs are just a bunch of tubes,” says Gabor Forgacs, a tissue engineering renegade at the University of Missouri. “It does not have to look like the human kidney. The point is to be able to quickly manufacture a working organ out of the patient’s own cells that will do the job that the organ is no longer doing. We have to make these sort of leaps. Because, I mean, we know we can’t rely just on donated organs. Look at the huge demand we have even today that we cannot meet. If you want to live forever, we’ve got to do better.”
A compact, tousled-hair Hungarian with a charming Old World edge, Forgacs is a relative latecomer to tissue engineering. His original degree was in physics, but upon landing at the University of Missouri in the late 1990s, Forgacs found himself caught up in that university’s huge investment in tissue engineering, using pigs as the principal experimental model. There he met John Critser (no relation to the author), one of the country’s foremost porcine embryologists. Critser encouraged Forgacs to push some of the traditional thinking about tissue development. He was a perfect person to do so, Critser says, because Forgacs was not from the traditional farm belt-animal husbandry world, but, rather, from “a theoretical background.” I found out what Critser meant when I met up with Forgacs at the National Swine Research Conference in San Diego in 2008. There he was giving a presentation to his colleagues about his breakthrough idea— “organ printing,” the use of cell clusters and a printerlike device to literally build new organs from the ground up. The genesis of the idea, he said, came from the fact that he didn’t like the Vacantian insistence on using a collagen scaffold to guide the shaping of a new organ. “I’m not big on scaffolds for a lot of reasons,” Forgacs said. “What is the right scaffold for the right cell? What if it is not fully degradable?” Instead, he said, “I wanted to find a way to get the cells to guide themselves into a structure of their own.”
To do that, he had to go back to hard biophysical principles, specifically the well-observed phenomena of tissue self-assembly. In self-assembly, clusters of cells in the embryo sort themselves out into inner, middle, and outer tissue walls. “I was totally fascinated by this,” he told me later, “because, you know, I was educated in brrrrutally theoretical physics—everything had to have a reason, a place in the schema. What was the determining factor?” The answer was surface tension—the amount and distribution of surface tension guided cells to sort themselves into the correct configuration. Get the cells in the right configuration of surface tension, perhaps aided with various growth factors, he reasoned, and “the magic,” as he likes to call it, would happen. By using aggregates of cells as the “bio-ink,” a gel-like biopaper and a programmed printerlike device, Forgacs succeeded in creating transplantable mouse and pig arteries, in one case building the rudiments of a working mouse heart. The latter was the kind of big, signature piece that is required to attract government funding these days (which he has), but Forgacs doesn’t get really excited until he starts talking about the human kidney. Concluding his talk to the Swine Conference, he exclaimed, “I want to build a kidney! It is such a … stup-eed organ! So simple. What is stopping us?”
After his talk, another scientist collared him in the hotel lobby and pushed a little: “What is so stupid about the kidney?” he asked. “Which cells would you use first? Would you build its filtering function, or the structure that governs blood pressure regulation or what?” Forgacs had a comeback. “Yes, I have a dream, which is to build a kidney. But I would be happy with a simple workable filter. I would even be happy if, at the end, what I have made is a way to rapidly make branchable arteries out of your own cells. I would rest easy knowing I have done that. That would be a good life’s work.”
Cells remain the key to tissue regeneration—bone marrow cells, muscle tissue cells, liver and heart cells. But the Holy Grail of cells—stem cells, which can become any kind of tissue—were captive for years by strict limits imposed by conservative federal science policy. In the summers of 2006 and 2007, all of that changed, when scientists at two institutions invented their way around the policy. They discovered a way to take cells from the tail of an adult mouse and make them act like embryonic stem cells. Their technique, referred to as “induced pluripotency,” uses viruses to infect adult cells with genes that make them into stem cells, which can then be coaxed to become any kind of cell. The implications of their discovery are huge, and while much work remains to replicate it safely in human cells, the basic scientific principle has stood. In 2008, researchers at Harvard University succeeded in using a virus to reprogram mouse pancreas cells that normally only make digestive enzymes with genes that tell them to make insulin. This they did, importantly, in a live animal with diabetes; its diabetes went into remission. Most believe it is only matter of time until human adult cells can be similarly reprogrammed.
When that happens, Dr. Doris Taylor, a molecular biologist at the University of Minnesota, will be ready. Taylor has been studying stem cells for years, and for some time she has believed that aging is, fundamentally, a failure of such cells. “For most of our lives, endogenous—internal—repair of tissue is the norm, because we have stem cells all over our body,” she explains. “Yet we do not heal as well at seventy as we do at twenty. That’s because the number and quality of stem cells declines with time. Aging is a failure of those remaining stem cells to deal with disease and damage.” The insight—a twenty-first-century version of Cornaro and Galen’s notion about aging and the depletion of “radical moisture”—drove Taylor from her original specialty, pharmacology, into cell biology, with an emphasis on cell delivery and cell therapy. As she recalls, it is hard to work in that world, with the vast theoretical potential of cell manipulation constantly swirling about one’s mind, without also thinking of something practical, concrete. “We began to think, ‘can we use these ideas to make a whole organ?’”
To Taylor, the missing ingredient in such a venture was not cells, but the “3-D matrix” upon which to implant cells and build, say, a heart. In a kind of midwestern Frankenstein moment a few years back, she mused upon one obvious source of such matrixes—cadavers. Why not? If you could somehow drain, say, a heart of all the former owner’s cells and then implant a series of stem-cell-like heart cells from a living patient, you might get a working organ. She began to tinker with the idea, using, fortunately, rat hearts. First, how to drain, or decellularize, the old heart? After a number of failures, she and a lab associate tried infusing one with a fairly commonplace detergent solution. What they were left with was a clear, translucent scaffold in the shape of the original heart.
They then recellularized the heart matrix with new heart cells from a young rat. Then, instead of building a large medieval platform that could be raised to the castle roof by clanking gears and pulleys, where the heart would await repeated lightning strikes, they stimulated the heart with a small laboratory device, creating artificial circulation and even blood pressure. Now there was a weak pulse. Taylor then implanted the new heart into the abdomen of an unrelated rat. Not only was the new organ not rejected, but a blood supply began to develop as cells from the host began to populate the heart walls and vessels. Much work remains on certain fundamental questions— “Can stem cells be placed anywhere in the body and still produce a heart or a kidney? Or must that stem cell be placed in a certain anatomic position to do so?” But “it doesn’t seem unreasonable to me to use human cells and matrixes to meet this huge and growing pressure we have for new organs in transplants of all kinds.”
Perhaps what is most provocative about Taylor’s work is the challenge it poses to the status quo: What’s next? She has, in a sense, solved the cell biology question. Now the question is one of scale, of how to test the idea on more human-size organs. “The pig is perfect,” she says, “the scale and the physiology are right, and you can pump the right amount of blood.” Taylor’s hopes for the pig led me back to John Critser, at the University of Missouri’s Swine Research Center. Perhaps more than anyone else in the country, Critser, a longtime embryologist who has studied everything from mice to elephants, sees the big picture when it comes to tissue engineering. He is the classic out-of-the-box thinker in a traditional field; one of his more remarked-upon experiments, considered key in the arena of rare species preservation, was to implant ovarian tissue from an endangered elephant into a lab mouse to produce … an elephant oocyte, or egg. Because he is such a strategic thinker to specific ends, I asked him what he thought constituted the biggest barrier to progress for tissue engineering. After all, tissue engineering has commanded several billions in venture capital over the years, and the NIH itself has committed sizable resources as well. Where were the organs? I wanted to buy one. What was holding things up?
A thoughtful, soft-spoken man with an elegant head of silver hair and a neatly trimmed mustache, Critser at first demurred. I understood. The world of animal experimentation is a world fraught with public misunderstanding, extreme emotions, anthropomorphism— “selling the animal short,” as one animal lover once defined it—and just plain queasiness. We talked about the intermediary steps that must now happen to translate breakthroughs like Forgacs’s and Taylor’s into human reality. We also discussed how that process was so fundamentally linked to animal work, particularly xeno-transplantation—say, pig to nonhuman primate. We wondered if the public would ever be ready for that. How shocking, even for Critser, were the photos that appeared a few years ago on the front page of the New York Times, the ones that showed Chinese peasants hand-drying pig intestines for use in making the human heart drug heparin! Well, what about the Chinese? I asked. Critser raised his silver eyebrows a little and hesitated again. “China will overtake us with xeno-transplantation, I’m convinced,” he said finally. “For better or for worse, they seem to be ready to take the risks that go with it, maybe risks we are not ready to take yet.”
There are those, however, who are already thinking about how tissue engineering, rebranded as rejuvenation medicine, will come to the assembly line. Chris Mason, a British physician and a leading public intellectual on the subject at the University College London, says, “the real barrier is ‘what happens when a therapy is ready?’ How do you scale up production to meet the needs of a big patient population?” You can learn a lot about that gap if you look at how resources are apportioned in the few stem cell therapies already out there. Consider corneal adult stem cell therapy, in which cells are harvested from the patient’s good eye, incubated on a contact lens, and implanted over the bad eye. It works. But it takes a hundred lab workers, clad in bulky bunny suits and maneuvering slowly over big bioreactors, to come up with enough cells for one thousand patients. That’s fine for small age-related diseases, but not for bigger ones, like Parkinson’s or diabetes, he says. “You will solve the unemployment problem before you solve the patients’ problem if you continue that way.” Automation offers one path, with one company in California, Advanced Cell Technologies, taking the lead with a robotized assembly line for collecting stem cells.
All of that may go a long way toward treating specific diseases of aging, but in more than one way tissue engineering resembles the piecemeal approach of modern geriatric medicine. What about pushing out maximum healthy life span, or even reversing aging, the coveted prize of the modern biogerontologist? What if someone took the engineering approach pioneered by the Vacantis and, instead of applying it to specific organs, applied it to the body as a whole? Could one engineer a human to age slowly at the cellular level, and so not only extend maximum chronological age but also transform healthy middle age from a 30-year span into a 60-, 90-, or even a 120-year span? And by focusing biomedical resources this way, might one eventually engineer a series of interventions that allow one to live well into the 200-, 300-, and 400-year range?
For decades in the field of gerontology, one dared not even suggest such a notion, particularly if one lived within ambulance range of a state mental hospital. There were dogmas. First, aging was thought to be a universal—all organisms aged; they deteriorated over time. Period. Second, outside of CR in mice and rats, there was no evidence that maximum life span in any organism—yeast, fly, worm, rat, mouse, monkey, human—could be successfully expanded. Life expectancy, yes. Maximum life span, no. Third, aging was random and unregulated. How could you a reengineer a process that voluble? And who would do it? Gerontology and geriatrics were filled with pretty satisfied folk who seemed content playing scientist, not engineer. Yet … what if the dogma wasn’t true? What if aging was not universal? Or random? What if life span could be altered?
Beginning in the early 1990s, the dogma began to unravel, at least in the more freethinking realms of the academy. One salvo came from Caleb Finch, an evolutionary gerontologist at the University of Southern California. Although preeminent in his field, Finch—tall and Darwinesque in mien—was an intellectually restless fellow, constantly working across disciplines to come up with deeper ways to understand the phenomenon of aging. A collaborator with everyone from Walford to Hayflick, he had somehow avoided the intellectual ossification of his fellows in Big G and remained engaged with huge, open-ended inquiries, ranging from inflammation to evolutionary neurobiology to hormonal signaling. In the late 1980s, Finch began to wonder out loud—likely out of earshot of Hayflick et al.—if, indeed, age-related deterioration was universal at all. An inveterate naturalist and environmentalist, he began studying reports from marine biologists looking at fish populations and how they aged. One species, the rockfish, jumped out. One of its geni, the rougheye rockfish, could live as long as 140 years, while cousins of the same species lived only 12 years. Dissected, the old fish displayed almost no age-related deterioration. More: there was little if any decline in the rockfish’s ability to fight infections or reproduce, and they showed no age-related increase in cancerous lesions. The fish, of course, eventually died—usually from some form of predation—but the revolutionary point was that age-related decline was not inevitable. Finch dubbed the phenomenon “negligible senescence.” Later, writing in the Annals of Gerontology Biological Sciences, he expanded the idea: “The prospects for continued increase in human life expectancy are of course unknown, but examples from the natural world suggest that no firm limit is built into the human genome. The efforts to modify human aging via drugs, diet, and lifestyle interventions are entirely consistent with the observed plasticity in life histories in numerous other species.”
No firm limit is built into the human genome. If senescence—time-linked deterioration in a species—was not fixed by a hard genetic program, if it is not the inevitable cause of most death, could it be slowed down by the human hand? Michael Rose, an evolutionary biologist at the University of California, Irvine, set out to explore that question by breeding long-lived fruit flies. This he did, as he puts it, by “tricking evolution”: He forced the flies to wait until they were older to reproduce. “The ones who [eventually] do [breed] are those that have already proven they can live that long and have the physiological wherewithal to reproduce,” he explained. “Multiple generations of this procedure makes them live better than twice as long.” The significance of that, he says, is that “aging is in no sense any basic feature of cell biochemistry.” The rebellion against Hayflickism was now in full tilt. Asked by Discover magazine what his work meant for humans, Rose—inclined to sarcasm—let loose with a full gun: “There are all kinds of people who are opposed to us doing anything [about aging]. The Federal Government has this need for us to die on our due date, so you don’t bankrupt Social Security or Medicare. And I have on a number of occasions heard people give very moving addresses as to why we should die as soon as possible. I think the phrase that most stuck in my mind was ‘So that we can know God’s love sooner.’ And let me just say for the record, I am all for those people dying. They can go ahead. I just know other people who don’t want to die, and least of all by the horrible and unattractive process of aging, and I don’t see any reason why they shouldn’t be allowed to go on living.”
If deterioration isn’t universal, and aging doesn’t constitute a basic feature of cell biochemistry, what, then, controls it? Beginning in the late 1980s and early 1990s, a number of scientists, inspired by the growing influence of evolutionary biology and the patterns it revealed, took to working with simple organisms—yeast, the earthworm, the fruit fly—to see if there were links between genes and aging. Genes, after all, tell a body which proteins to make, and because yeast and earthworms were fairly easy to genetically manipulate, one could readily mutate specific genes and then measure life span consequences. In 1991, Cynthia Kenyon, a young evolutionary biologist at UC Berkeley, exploded on the scene by showing how two insulin receptor genes in the earthworm, daf 2 and daf 16, doubled the life span of the worm when those genes were mutated. Moreover, the mutations also doubled the health span of the worm. They were Cornaro worms. As Kenyon liked to say, sometimes in the presence of the press, “These animals are magical: they are like 90-year-olds who look and act 45.” More important, she broke the old dogma that aging was haphazard and random. If you knew enough about what controlled it, well, perhaps you could control aging. At MIT, Leonard Guarente, and, later, David Sinclair, following their own leads in yeast, worms, and mice, came to similar conclusions. They also focused their search on the insulin pathway and genes they called SIRT. SIRT, like Daf, and like CR, seemed to activate the ancient starvation response, pushing the organism into repair and maintenance mode.
The excitement in gerontology circles was infectious. By 2000, mainstream scientists were saying things—out loud—that only a few years before might have gotten them permanently assigned to teach freshman biology. In one notable Nature article, Kenyon and Guarente proclaimed, “The field of aging research has been completely transformed in the past decade…. When single genes are changed, animals that should be old stay young. In humans, these mutants would be analogous to a ninety-year-old who looks and feels forty-five. On this basis we begin to think of aging as a disease that can be cured, or at least postponed The field of aging is beginning to explode, because so many are so excited about the prospect of searching for—and finding—the causes of aging, and maybe even the fountain of youth itself.”
There was an almost overwhelming common theme, as well. More and more, control of a body’s energy use was directly linked to life span extension. Some called it energetics. Others call it “nutrient partitioning.” In all this one could hear echoes of Masoro, Walford, and even, when you thought about it, Cornaro. Twenty-first-century science had come all the way back to Cornaro. But would there be a Cornaro of antiaging engineering?
I had heard about Aubrey de Grey some time before I met him, briefly, at a CR conference in fun city, Tucson, Arizona. At the time, he was hanging around with Michael Rae and April Smith, and I assumed that he was a CR practitioner. He is lean to the extreme, and there was all about him the air of Alternative Man—long hair, a hermit beard, a blousy shirt. I knew that he was a Cambridge cell biologist who studied aging, and that he had appeared on numerous TV shows, where he had made a series of outrageous statements to the effect that humans could be made to live a thousand years. In gerontology circles, which I was beginning to frequent, everyone had an opinion about him. One opinion: he was an irresponsible opportunist, a fanatic, a fabulist.
De Grey had managed to acquire this reputation by purposely inflaming Big G. Perhaps the most offended was the CR-mouse science alliance, the modern-day version of Walford and Masoro represented by the University of Michigan’s Richard Miller, arguably the world’s leading thinker on mouse CR and aging, and his frequent collaborator David Harrison, a specialist in mouse stem cells at the Jackson Laboratory in Maine. Miller and other members of the American mouse mafia had sought a large grant from the National Institute on Aging (NIA) to test possible antiaging compounds in mice that mimic CR’s effects, and de Grey, no fan of CR, had made the mistake of publicly suggesting that, in his opinion, the most a human could expect from CR was two to three years, so why bother? In one famous remark, he noted that “the long-lived mammals that Miller describes are much smaller than normal members of the same species—not something most people would impose on their children even if long life resulted.” He even went so far as to compare the mouse mafia to the A4M. The NIA continued the mouse grant anyway, but the acrimony remained. When I spoke with Miller, a bearish Santa Claus of a man, four years after his original exchange with de Grey, he immediately brought the subject up, unprovoked. “You don’t really want to talk about my mice,” he said. “You want to talk about Aubrey de Grey—that’s all you journalists ever want to talk about! He’s … he’s … like catnip to you!” Harrison reacted almost identically, all the way down to the catnip—an odd metaphor for mouse scientists, but, as Einstein once probably remarked of creamed spinach, “Whatever.”
There was more to de Grey’s list of sins than mere infringements on professional turf and money. Over a period of about ten years, he pushed and packaged the tentative notions developing in mainstream laboratories and conference rooms—that life span is not fixed, that it might be engineered in mammals, and that senescence can be negligible—and then used them as a basis to argue against the standard way of moving such observations into medical science. If we know such things are true, de Grey would say, then we must stop treating aging as some interesting phenomenon that we can do nothing about. Aging is a disease. “It kills fucking 100,000 people worldwide every day, and I want to stop it,” he told a rapt audience at one of the popular TED intellectual forums. The way to do so, he said, involved nothing short of abandoning the old ways—of trying to find a natural, evolutionary pathway and then find a way to tweak it so that the organism would not deteriorate. Rather, the task should be either to eliminate the damage—be it plaques in arteries or amyloid proteins in the brain—or to make the damage benign. The way to do that was through engineering. This he dubbed, in a tip of the hat to Finch, “Strategically Engineered Negligible Senescence,” or SENS.
De Grey then went on to market every single theory of aging as an engineering theory. Consider free radicals. As de Grey saw it, the problem with that theory was not just that free radical damage to the cell might be a minor factor in aging, as Arlan Richardson had been saying, but that the most important damage done was to the mitochondria’s own DNA. In fact, he said, mitochondrial mutations were the engine of aging not because they hurt the cell, but because they turned the cell itself into a kind of traveling perfect storm, one that created huge flows of damaging free radicals, body-wide dysfunctional cell metabolism, and, ultimately, cell death. Instead of trying to stop free radical production, one instead should find a way to head off the whole process by reengineering the entire human cell. That could be done, he argued, by relocating all of the mitochondria’s DNA into the protective cell nucleus, where it would be much less likely to get fried and mutated. With a big enough investment, this, he argued, could be done through gene therapy techniques. If it worked, it would be transformative. If one was fond of describing the free radical theory as the rusting of the body, then, with reengineering, you would end up with a body that didn’t rust.
To say that the reaction in Big G was intense is like saying that the weather in Burma is sometimes warm. In a major quasi-consensus statement, some of modern gerontology’s biggest hitters pronounced the SENS agenda a “farrago” and a “fantasy.” De Grey, they went on to say, was guilty of “clever marketing” that allowed him to “short-circuit the traditional scientific channels of new ideas.” Personal attacks followed. In an article for Technology Review, the physician-writer Sherwin B. Nuland noted that de Grey drank a lot of beer and ate a lot of sweets, and that his wife (twenty years his senior) “lacks a full set of teeth” and smokes a lot of cigarettes. In the same issue, Jason Pontin, the editor, called de Grey a “troll,” noting that: “He dresses like a shabby graduate student and affects a Rip Van Winkle’s beard; he has no children; he has few interests outside the science of biogerontology; he drinks too much beer.”
Beer consumption—the new gauge of intellectual integrity?
There were those in Big G, however, who were not so quick to decry. Instructively, these were the same evolutionary biologists whose pioneering work, now conventional wisdom, fueled so much of de Grey’s repackaging of gerontology. Caleb Finch, whose 1990 paper on the rockfish originated the whole notion of negligible senescence, was now one of the world’s leading gerontology scholars and the author of the definitive Biology of Human Longevity. I asked him why he refused to join his brethren in their anti-SENS effort. “One reason,” he told me. “It is totally unproductive. Who is he hurting? I mean, look, Aubrey is a polemicist and monomaniac immortalist. That being said, he has stimulated a lot of new thought on extending the health span that could conceivably allow for unprecedented longevity, as well as deeper understanding of the mysteries of aging. What is wrong with that?”
One wet summer day in 2007, I took an express train out of London to see de Grey. He met me at the Cambridge station, looking a little bleary-eyed from a recent spate of travel. He had come via a very old bicycle, which he pushed as we walked up the cobbled streets to the Eagle Pub, the famous tavern where Watson and Crick first conjured the double helix. I asked de Grey if he wanted lunch, and when he said no, I asked if he practiced CR. “God no!” he said. “Why would I do that? I’ll just have a pint.”
Like all of today’s PowerPoint visionaries, de Grey has a diagram that he insists you consider. He drew it on a napkin for me as I snacked on fish and chips and he drank lots of beer. It looks like this:
Its simple lines depict what he sees as the basic architecture of modern aging research. The bottom line represents the key aging process—human metabolism. This constant burning of nutrients by the cell and its often poor processing of by-products causes cell damage. Leave that damage to accumulate and you get pathology, disease, and death. Fair enough, so far.
The top line shows where the main branches of aging sciences tend to focus—gerontologists study the processes in metabolism that lead to damage, and geriatricians treat the disease consequence of that damage. In the middle of that line sits de Grey’s conceptual time bomb: the as-yet-unrealized role for “a pure engineering approach,” as he likes to call it. “You see,” he said, “this is all about a repair and maintenance effort. It’s not about trying to understand all the possible variables of human metabolism. We don’t need to do that to live a lot longer. We just have to identify the key damage and … eliminate it.”
The analogy that comes closest, he says, is that of the perfectly preserved vintage car. It wasn’t designed to run for a hundred years, but it does so because of careful and constant repair and maintenance, using the best tools and materials available. The same with the human body. Focus on the rust that gathers on our fuel lines—the plaque that gathers on and around our arteries—and get rid of it. Forget about interfering or altering the basic process that leads the body to produce it in the first place, the fixation of modern pharmacological science.
To advance this paradigm buster, de Grey has identified seven domains of “cellular interventions” that, given the right scientific and economic support, will stop and even reverse the aging process in human beings. They all bear the imprint of his original thesis about mitochondrial DNA damage—the damage is the thing. His logical tack in describing such interventions, while often zigzaggy, sails a fairly consistent overall course. First, identify a form of cellular breakdown. Start with, say, lysosomal dysfunction, in which a cell’s waste-burning organelle, or component, becomes overwhelmed and unable to do its job. That job, as he describes it, is burning up lipofuscin, a nearly indissoluble after-product of metabolism. Now look for the wide-ranging disease possibilities inherent in that breakdown. In the case of lysosome dysfunction, he says, this can range from atherosclerosis (because the cells that attack inflamed arterial plaque can’t process the waste and instead rupture and blow up), to macular degeneration (because of lipofuscin-like buildup behind the lens), to Alzheimer’s (wherein cells can’t keep up the policing of errant plaques and proteins that build up and impair neuronal health). Then ask: what would that lysosome need to be able to break down all that damaging waste? The answer, he says, would be more of the enzyme that it usually uses to do so, but has now been depleted. Find a new source for that enzyme and reintroduce it into the cell. Voila! Clean veins and clear vision in the year 2500. “The goal is to wipe out the damage using any benign weapon available,” he says, “because it’s the damage that causes the disease.”
What about cancer, a disease of uncontrolled cell growth? Answer: use nanotechnology to design molecular “Swiss Army knives” to “unscrew” cancer-cell surface barriers to oncology drugs. Better still: delete the gene for telomerase, the enzyme that enables cellular division in the first place. How about diabetes-producing visceral fat cells? Answer: stimulate the immune system selectively to target and kill those cells. What about muscle, skin, and organ tissue loss? Replace them with stem cells that reproduce the lost tissue. Amyloid plaque production associated with Alzheimer’s? A vaccine that clears the plaque. And how about hardened arteries and weakened ligaments caused by so-called cross- 1 inking extracellular proteins? Answer: after discovering a hyphenation reducer, inject safe chemical agents that break apart the disease-causing links or use nanotechnology to design targeted “molecular buzzsaws.”
There are vast problems with all of these—in a sense, SENS is a farrago. But what seems to irk de Grey’s peers the most is not his approach, but his optimism. Where most scientists err on the side of assuming something will not work, de Grey believes we simply have to assume a 50 percent chance of success. His optimism can take over, sometimes to comic effect. Writing in his 2008 book, Ending Aging, about the side effects of deleting the gene for telomerase—his cancer cure—de Grey says: “One potential side effect of the loss of telomerase from our cells might be eventual sterility for men. If having children is still a priority in a post-rejuvenation world, then men may choose to freeze their sperm in advance.”
There is another huge difference between de Grey and his peers. Unlike other pioneers in aging, de Grey’s intellectual evolution did not include any level of enrapture with a member of the animal kingdom. There was no McCayian brook trout, no Masoroian rat, no Walfordian mouse. Yes, he knows all of those “models,” as he calls them, as well as yeast, worms, and flies. But he displays little sense of wonder at it all. As de Grey tells it, “I’ve never been able to not see through to the end result, and make a decision based on that.” He offered up an example. “When I was young, my mother insisted that I take piano lessons, but I soon got to the point where I started asking myself, you know, ‘what’s the point of this. To be a pianist?’ No! I wanted to do something bigger, to make a difference.” He was eight at the time.
He progressed through the elite Harrow, and then read computer science at Cambridge, where he was recruited by the software entrepreneur Clive Sinclair to work on artificial intelligence, or AI. De Grey proved himself a brilliant technological problem solver. Computer code—that was his mouse, fly, and brook trout, and he reveled in it. As Aaron Turner, de Grey’s programming partner from those days, recalls, “One fateful day as we had been alternately discussing matters both theoretical and practical while perusing the many ‘formal methods’ books I’d accumulated, Aubrey suddenly slapped the book he’d been reading closed and proclaimed, ‘I know how to do it!’ From all the pieces of the formal verification jigsaw puzzle assembled in his head, he’d been able to construct a path from problem to solution, which he could ‘see’ in his mind’s eye.” De Grey’s AI days came to an abrupt end when that ever-nascent enterprise tanked in the early 1990s. By then he had made contact with a number of scientists who needed computing power and expertise. Through his wife, the fruit fly scientist Adelaide Carpenter, he met the evolutionary biologist Michael Rose, who was in the midst of his life span extension work on fruit flies. Rose hired de Grey to help compile a computerized fruit fly gene index, and it was while immersed on the screen that he acquired the aging bug. What amazed, and later infuriated, him, about aging was “that no one was doing anything about it!” Why was that? “It was considered a career killer, and it was considered boring. I couldn’t believe it. Here was something that kills a hundred thousand people a day and it’s boring?” But it was also because of gerontology’s strange coming of age in the 1970s. Back then Robert Butler, the first head of the NIA, was fond of saying that calling aging a disease was tantamount to saying that all aged people were diseased. It was like blaming the victim. There also was the ascendency of Hayflick, who, as de Grey saw it, was constantly conflating his in vitro results with in vivo conclusions. Worse, to de Grey’s mind, were Hayflick’s endless tirades about how life span extension would be a bad, immoral thing. “The result, as far as I saw it, is that a lot of gerontologists who are in their seventies now were sort of stillborn intellectually and ground down by the Hayflick doctrine.”
By the mid-1990s, he was in full tilt rebellion against that doctrine, reviving the mitochondrial theory of aging while, at the same time, becoming a transhumanist, the movement founded by Ray Kurzweil that advocated a very de Greyian-style belief: that humans can and should seek a union with machines and technology to produce better, superior humans. Why not? De Grey ordered another pint and went on to explain how Kurzweil’s futurism had impacted him and a whole generation of students by “improving our appreciation of likely timeframes.”
As if on cue, two fresh-faced undergraduates came up to our table and insisted on talking to de Grey. “Er, sorry, Dr. de Grey?” one of them said. “I just wanted to say that I heard your lecture about antiaging medicine and that I thought it was brill—”
“Then what are you doing about it?” de Grey replied, a little testily.
“What?” his student admirer said, clearly puzzled.
“What are you doing about it?” de Grey repeated, tapping his knuckles on the table before him. “Look, go to my website at Mprize.com and look under ‘what you can do.’ There’s a list of six things you can do to help. Then if you have any more questions we can talk. All right?”
They scooted off, and naughty Dr. de Grey had another beer.
If you wanted to rejuvenate the brain using the engineering approach—focusing, say, on regrowing dead areas caused by stroke and other traumas—you would be hard-pressed to find a more impassioned pioneer than Rutledge Ellis-Behnke. An engaging, balding man with a cherubic countenance and a fondness for medical history—he often cites a three-thousand-year-old Egyptian papyrus on trauma treatment as an inspiration—Ellis-Behnke works as a researcher in brain surgery and neural regeneration at MIT and the University of Hong Kong. As he tells it, the latter provided him a firsthand look at something most academics never see: an epidemic of brain injuries. In China these were caused largely by the skyrocketing use of automobiles, and, later, by soaring rates of new building construction. “These are lifelong injuries, enormous trauma,” he says. “I mean, the number one reason for brain trauma in China for years was bus vs. pedestrian. Think of that. Bus. Pedestrian. That’s huge!”
When he would go home to Boston and MIT, he and Professor Gerald Schneider, a specialist in brain and cognitive science, began to tinker with various ways of regenerating neural connections. They faced huge obstacles. For one, if you introduce a foreign material to stimulate growth, you can cause a catastrophic immune response. “And remember, when you lose brain regions, it is not enough to simply replace cells,” Ellis-Behnke says. “The brain is like a nursery. You have to find a way to let it regrow the many different types of cells that it needs to do an extremely complex job.”
One of the materials he and Schneider played with was a liquid peptide, or biological building block, dubbed RADA16. RADA contained a series of amino acids sandwiched together using nanotechnology—very small scale molecular engineering. RADA was useful because of its unique structure. Its two most hydrophobic, or rejection-prone, amino acids were sandwiched in between the two most hydrophilic, or least rejection-prone, amino acids. Once applied to, say, a cut or wound, RADA did what all good nanoparticles do: it self-assembled. To test its medical utility, Behnke and Schneider turned to the ever-unlucky laboratory hamster. Cutting the key visual nerve systems in several of the animals, they then applied a solution of RADA, and waited. Within twenty-four hours, all of the treated hamsters displayed signs of healing, and within six weeks, vision was functionally restored to all of the adult animals, with more than 80 percent of the severed nerve tracts reconstituted. There was no immune response, no rejection.
What had happened? As Ellis-Behnke details it, the nanoparticles simply self-assembled into a kind of meshlike scaffold, one that perfectly mimics the body’s natural neuroknitting structures, and then, once new nerves have grown, dissolves into a substance that can nourish the newly knit and highly alliterative network. In a sense, RADA does what Vacanti, Forgacs, and Taylor all want to do, but from the ground up. “It is creating a permissive environment in which the body’s repair and growth mechanisms can flourish, but without adding new cells itself.” RADA, a breed of nanoparticles known as SAPNS, for self-assembling peptide nanofiber scaffolds, has also been tested in living rodent liver tissue, with similar success. Human application might come as soon as three years; faster, of course, with more money. But as Ellis-Behnke sees it, nano materials bring with them something else for future consumers of antiaging medicine. It is a different way of thinking about the body, he says, and, as he often does, he turns his thoughts to history. “With the pyramids, the Egyptians were building things beyond their comprehension with materials they didn’t understand. We are at the opposite end. We are building extremely small structures where we do not understand the normal rules and forces that hold these things together. We are just groping through the darkness about how to take molecules and build structures.”
What if you could design drugs that, instead of simply controlling hypertension, actually reversed the age-associated damage that causes it in the first place? For some time Pierre Moreau, the dean of the faculty of pharmacology at the University of Montreal, worked in the realm of arteriosclerosis, the vast complex of processes that leads to artery stiffening and, eventually, heart disease and death. He had his eye on one key and understudied form of damage, that known as medial elastocalcinosis, or MEC. MEC is happening to you as you read this. MEC is what happens in your aorta when the little proteins known as elastin, which make it possible for your artery to expand and contract as your heart pumps, come under attack. The invader is calcium, a mineral used by the body for many useful ends, but which, in this case, creates vast damage. Inside the middle of the artery lining, calcium binds to elastin and creates a stiff web of fibers, which turn the once-flexible aorta into a resistant tube. What follows is an increase in blood pressure, and, perhaps just as important, an increase in overall pulse pressure. Both are bad for the heart. No wonder that MEC is now considered a major cause of heart disease.
Moreau, puzzled by why calcium was so attracted to elastin, did what all good medical scientists do today. He created a rodent model of the disease, then subjected the animal to various drug treatments to see if he could affect the process. What he found was surprising. “At first we were just thinking of using this drug as a preventive against further damage,” he recalls. “And that is what we got. But then we were amazed. If you continued the rat on the drug, we found you could remove the calcification from the vessel wall.” Like any sober-minded scientist, he has since focused on the mechanisms behind the phenomenon; a human application is some ways off. But the point is right on the de Greyian money. You can remove age-associated damage in a mammal and renew the artery. Monkey with the process—not just to slow it down, but to eliminate age damage altogether.
If you want to eliminate damage to the body, and keep the proverbial human Model T in mint condition, one of the best targets would be excess fat, particularly fat that accumulates around the stomach. This is because we now know that fat cells, or adipocytes, are not simply passive, inert blobs of lipids that look unsightly, but, rather, active, microendocrine organs that, in and of themselves, can do a lot of damage. They spray out all kinds of inflammatory molecules that have been tightly linked to everything from heart disease to brain aging. They predispose us to diabetes. But controlling their accumulation over a lifetime has proven vexing; the human body, after all, was engineered by evolution to deal with food scarcity and infection. Until about five hundred years ago, it made perfect sense to have a body that was skewed to acquire and hold on to calories, and to use those cells to fight infection from unsanitary living conditions. That’s what a fat cell was selected to do. Today, in a hygienic, food-abundant world, we do not need it to perform those functions, but it does. Moreover, our entire body has evolved to make it easy to hold on to fat cells. As we get older, it even favors retention of fat cells over retention of muscle cells, something most aging men and women try to fight, with little success, by diet and exercise.
So, what if you could reverse-engineer the human body to fend off fat cell accumulation? Then you would get a body less aged. For the past ten years or so, Professor Kim Janda, a balding, amiable chemist with the jaunty countenance of an athlete, has been working on just such a scenario. Janda, who makes his home at the Scripps Research Institute in La Jolla, got the idea when he was working on another, equally vexing problem—drug addiction. In addiction, almost the same impasse obtained as with obesity. Medical science had come up with various ways to block the effect of various drugs, such as cocaine, but nothing seemed strong and safe enough to use for long periods of time. He began to ask: What if you could immunize the body against a drug molecule, say, cocaine? Using classic vaccine methods, he and his staff made a vaccine from cocaine antibodies, then injected it into lab rats that had been habituated to cocaine. The rats steadily reduced their cocaine use; they had become immune to its gratifying effects.
Janda then started thinking about obesity, and how traditional diets had failed because the body has such a deeply dedicated system of retaining weight. He zeroed in on a hormone produced in the stomach called grehlin. Grehlin’s role is to maintain energy balance, and its levels soar when someone diets, sending all kinds of signals through the brain: Decrease energy expenditure. Defend existing weight. Add new weight by stimulating appetite and depressing satiety, the feeling of fullness. Eat that Big Mac. Janda had already seen what would happen if you “knocked out” the gene for grehlin in lab mice; they stayed leaner, were more active, and tended to burn fat rather than store it. So, what if you made a vaccine that, essentially, immunized the brain from grehlin? Using the same system he used for the cocaine vaccine, he made a grehlin vaccine that targeted the same immune spots in a rat that humans have. The results: less weight gain, more lean mass, less fat mass. As might be expected, Janda attracted enormous interest from drug companies for human trials, although getting permission from a review board to, essentially, make someone immune to a natural body chemical, will likely be difficult and require a lot more money.
The vaccine approach permeates experiments in everything from cancer to Alzheimer’s, but to date the results have been, at best, mixed. In the case of cancer, it is possible to create a vaccine that prevents breast cancer, but its utility to the aged is limited, because the vaccine’s effectiveness depends upon the availability of immune cells, in which the elderly are chronically underfunded. In the realm of Alzheimer’s, researchers have been able to create antibodies to amyloid plaque, inject it into humans, and actually clear the plaque from brains. Unfortunately that clearance doesn’t translate into clinical benefits; it does not slow or halt dementia onset. Nevertheless, there is some hope that, by artificially modulating plaque-making processes, science will make the brain better able to maintain neural balance, or homeostasis, fending off degeneration and even rejuvenating neural circuitry.
Plaque—all kinds of plaque, from arterial to neural—is one of the great targets of de Grey’s “destroy the damage” approach to antiaging medicine, and so it is hardly surprising that one of his more ambitious, and outlandish, proposals takes aim at it not by standard biomedical tactics—reducing cholesterol formation, say, through statin drugs—but via the strange, germy world of environmental engineering. He wants to find a bacterium that eats the stuff.
As de Grey tells it, he got the idea the way he’s gotten others, by reconsidering older theories of aging, in this case, the theory of autophagy. Autophagy— “self-eating”—refers to the cell’s internal system of waste disposal. Like all cell functions, it is performed by substructures known as organelles; in the case of autophagy these are called lysosomes. For decades, cell biologists have argued about one critical aspect of the balloon-shaped lysosomes, namely, the fact that, with biological age, they become less and less able to completely clean up biological waste—left-behind plaque being the central concern. The debate turned on this: Was the lysosome’s declining capacity caused by aging, or was this decline the cause of cellular aging itself? No one could ever agree, and autophagy theory became one of Big G’s perennial debate topics, with only a few researchers pursuing it with the zeal of, say, free radical believers.
De Grey, typically, said: so effing what? Who cares if we don’t know its ultimate origins? What if we can reengineer or augment the cell so as to keep the lysosome up and running? If you could do that, he reasoned, you could clean up the arterial plaque that causes heart disease and stroke. The same, he reasoned, with certain proteins in the brain and Alzheimer’s; if you could restore the lysosome’s cleanup ability early in that disease process you could maintain neuronal balance, or homeostasis. Another kind of plaquelike substance known as A2e is a direct cause of macular degeneration. All three of these de Grey rebranded as “lysosomal storage disorders,” a term normally used for a handful of rare diseases. The goal, he argued, was to augment the lysosome and let it clean up the damage. As is his inclination, he asked a hugely unsettling question along the way: If you wanted to find a bacterial enzyme that degraded human cholesterol, where would you look for it? In a graveyard? In a medical waste dump? Where? He talked the National Institute of Aging into sponsoring a roundtable on the subject, and he invited not just the usual cast of biogerontologists, but also all kinds of people who normally did things like clean up oil spills and toxic waste sites.
The project, now dubbed LysoSENS, landed in the laboratory of Pedro J. Alvarez, the chair of Environmental Engineering at Rice University and perhaps one of the nation’s leading authorities on bioremediation—the use of soil microbes to clean up waste sites. I met the professor in his office, where we drank strong coffee and Alvarez, an elegant man with an easy Old World way, showed me a series of slides on what has become a lifelong passion—soil bacteria. The field of biore-mediation, Alvarez explained, grew out of one central insight by the British bacteriologist E. F. Gale in 1952. Gale, surveying the vast increases in industrial wastes generated during the postwar period, asked a simple question: Why aren’t these substances accruing more rapidly in the environment? His answer, after endless study of waste sites, was equally simple and even elegant: It was because soil microbes responded to any new energy-rich substance by evolving an ability to use them as a food source; in effect, any new substance created selective pressure on surrounding organisms to use them for food. This Gale’s followers named the “principle of microbial infallibility.” It is a theory that has stood the test of time, Alvarez says. “I mean, right now, in my lab, I have soil bacteria that cannot live without the presence of TCE, an incredible environmental toxin that did not exist 140 years ago. Think about that. Look how quickly evolution worked. Remarkable. Really remarkable.”
He picked up the thread and went on. “And it occurred to Aubrey, and then to some of us in bioremediation, that maybe it was not such an outlandish idea, that perhaps you could do a form of medical bioremediation.” He went on to talk about how the process worked, the endless bench science required to first isolate samples that degraded, say, 7-keto, then identifying the specific gene in that bacteria that coded for the degrading enzyme, and then the long task of figuring out how to get that gene into a mammal, how one might ensure that the gene carried no bad side effects, and how it might then be readied for clinical trials in humans. “Who knows when?” Alvarez said with a twinkle in his eye and a counterbalancing shrug of his slender shoulders. “But this whole endeavor suggests some remarkable things about humans.”
It was the second time in the conversation that Alvarez veered into the realm of the “remarkable,” so I asked him what he meant. He grew visibly animated. “I mean that maybe we are more plastic as a species than we thought. Remember, until about one billion years ago, horizontal gene transfer was the norm—not through heredity as we have come to think of it, or even through mutations, but from one gene from one organism transferring itself to another for survival reasons. It was how, for example, we got our adaptive immune system.” He noted the identification of specific proteins that bacteria use to cross-transfer DNA, the emergence of drug-resistant bacteria as an example, and then pointed to the recent work of several Rice colleagues, who have proven that the majority of DNA in the genomes of some plant and animal species—humans, mice, wheat, and corn—originated from horizontal gene transfer. “I mean, we can actually trace kingdom-to-kingdom gene exchanges.” So where does this take us as humans? I asked. “Well, I don’t know,” Alvarez said, the shrug now triumphant over the twinkle. “I can’t, eh, speculate on that.”
De Grey, of course, can. The last time I saw him we were in Westwood Village, just outside of UCLA, and he was in a good mood. One of his associates had just published a mind-bending paper on autophagy, and how, by improving a certain kind of lysosome process, one could not only prevent liver cell aging, but actually rejuvenate damaged liver cells. In rodents, of course. But there was the proof of principle, modern science’s chief fund-raising tool, and if you could just get enough of this kind of work into clinical trials for humans, he said, we might then find it possible to engineer our own “escape velocity.”
What was that? I asked. It sounded like some weird transhumanist thing to me. De Grey ordered the duck ragu ravioli and a beer and brushed his enormous beard to the side.
Longevity escape velocity, or LEV, he explained, is what will happen when improvements in “damage elimination” begin to come in regular intervals, each one further extending maximum life span, and each one giving science more time to improve previous treatments. The result, which he has carefully plotted against accepted mortality tables used by mainstream Big G, would produce life spans of 200, 300, and up to 1,000 years. In the foreseeable future, he sees gains of no less than thirty years. How would that happen? I asked. There would be a panel of state-of-the-art interventions, he said, “maybe every ten years. In hospital, almost certainly, because it’s so unprecedented to be doing lots of things at the same time—there would be a big requirement for detailed monitoring of the effects. As time goes on and the treatments become more mature, they will become less laborious; I can imagine them being self-administered in the end.”
That reminded me of Pedro Alvarez’s comment about horizontal evolution. Was de Grey essentially saying that we will engineer our own antisenescent evolution? “Human evolution will soon be greatly accelerated, despite the reduction in death rate, because of somatic gene therapy,” he wrote me later. “I suppose that counts as horizontal gene transfer in a way, but a lot of the changes being introduced will be changes to our existing genes, such as changing our apoE4 [Alzheimer’s-prone genes] to [less prone] apoE3.”
What would it require to get to the LEV launching pad? The first thing, of course, is money—a huge, war-on-cancer-type effort focused on aging, driven by a combination of enlightened government and private money. That would propel the science to obtain one of de Grey’s benchmarks, the expansion of mouse life span by two years, or what he calls RMR, for robust mouse rejuvenation. The second goal was perhaps the more difficult: changing the deeply held beliefs people have about aging. He’d gone on about this before, when we met in Cambridge. “People really go into a sort of pro-aging trance when you start talking about radically extending life. It’s as if they’d rather defend something they think they know—that life span is finite—than deal with aging itself as a disease and as something to be defeated.” He sipped his beer. “Isn’t that amazing? Can you believe it?” I mentioned that it can be troubling when a theory defines all disbelievers as semipathological, but he didn’t rise to it. De Grey has become almost too good as a debater.
Just as we were getting ready to go, I asked de Grey how a recent conference he’d organized at UCLA had gone. He looked nonplussed. “Stage three,” he said. Stage three? As it turns out, he was referring to Mohandas Gandhi’s famous dictum about social change—“First they ignore you, then they laugh at you, then they fight you, then you win.” De Grey took it up, not bitter at all. “I’ve been at Gandhi stage three for maybe a couple of years. If you’re trying to make waves, certainly in science, there’s a lot of people who are going to have insufficient vision to bother to understand what you’re trying to say.”
Gandhi? As in the Great Mahatma? I could accept all the talk about SENS, LEV, RMR, horizontal evolution, and the like. But Gandhi-ji? With a shave and a dhoti, he might pass. But, really, had de Grey checked out of the realm of reason, skipped class on reality 101? I mean, was his cookie somehow missing a few chocolate chips? Is beard length inversely correlated with reality? I began to feel a lot like I had in my last encounter with the CR people, or with Thierry Hertoghe. It made me wonder: Does antiaging science inevitably lead one to do a tap dance down the Meshugga Turnpike?
I’d had a chance to run de Grey’s vision past a group of highly educated, stylish Londoners gathered at a club to celebrate the birthday of an up-and-coming British comic. They didn’t think he was crazy at all, but rather, dangerous.
“It’s greed. Just another example of how baby boomers just can’t accept limits,” one young woman said.
“That’ll be good for the environment, won’t it?” said a marketing executive. “Just imagine another 50 million people a year on the planet and never fucking leaving! Fucking brilliant!”
“One thousand years! He’s got to be an American, right?”
No, de Grey’s not an American. But American scientists may be carving out the best middle path to the science of life span extension.
The mole, from Edward Topsell’s The History of Four-Footed Beasts and Serpents, 1607.
