This Man Would Have You Live A Really, Really, Really, Really Long Time. If a mouse can survive the equivalent of 180 years, why not us? Or our kids? Scientific provocateur Aubrey de Grey has a plan.
(FORTUNE Magazine) – Absent-mindedly stroking his Rip Van Winkle beard, Aubrey de Grey recalls when he first realized how humans might halt the process of growing old. His "Eureka!" came at a research meeting in California four years ago. Jet-lagged and wide awake at 4 A.M., the British scientist posed himself a simple question: "What would it take to bioengineer a nonaging human?" The light dawned as he scribbled a list--it seemed that only seven things had to be prevented, mainly toxic byproducts of metabolism that accumulate in the body over time. "I realized that we could bloody well fix them all," he says. "We could go in and periodically clean up the seven deadly things before they cause problems."
Wishful thinking, perhaps. But de Grey has emerged as one of the boldest thinkers and organizers in the science of aging, whose ideas have begun to influence a whole generation of biologists, even as they make rapid strides toward understanding that universal curse. De Grey's vision is arguably no wilder than, say, predicting in 1950 that some decades thence we'd create goats that make spider silk. (In case you hadn't heard, goats implanted with spider genes secrete the stuff of the stronger-than-steel fiber in their milk.) As spider-goats show, biology is becoming ever more like engineering--a field whose problems yield to methodical attacks with known tools. Run that trend forward a few decades, argues de Grey, and you could see medical engineers sprucing up our bodies much as handymen replace dislodged roof shingles to prevent minor leaks from leading to collapsed ceilings. That means some people alive today may still be that way centuries from now, says de Grey.
What makes de Grey truly arresting, however, isn't how far out he goes but how he gets there--he builds close-knit arguments that aren't easy to rip apart. The edgy 41-year-old plays the provocateur to a "T." Last year he helped launch the Methuselah Mouse Prize for the world's longest-lived mouse. The inaugural award went to a scientist in Illinois whose lab mouse, a slow-aging mutant dwarf breed kept on a low-calorie diet, lived almost five years--the equivalent to 180 human years.
The prize is designed to spur anti-aging researchers toward the goal declared in a controversial report de Grey spearheaded in 2002. The "indefinite postponement of aging ... may be within sight," it proclaimed. The paper appeared in the Annals of the New York Academy of Sciences and was co-authored by a bevy of distinguished scientists, including Bruce Ames, originator of a widely used test for identifying substances that can cause cancer. It spells out how existing lines of research are paving the way to therapies capable of reversing tissue damage that accumulates with age.
Many gerontologists dismiss de Grey as a wild optimist who lacks grounding in the hard lessons of experimental biology. Grandson of a corn merchant and son of a single-parent artist mom, de Grey grew up in London and earned a Ph.D in computer science from the University of Cambridge. He works at the university as the "computer associate" of a team probing the fruit-fly genome--"my day job," he calls this. De Grey, whose wife is a geneticist, is also a world-class player of a nerdy, Go-like game called Othello and loves punting--propelling a small flat-bottomed boat along Cambridge's River Cam by pushing with a long pole against the river bed. Despite his eccentricities, he has earned respect even among the critics, who say that unlike most brash seers, de Grey is very knowledgeable and often worth listening to. "My conversations with Aubrey are invariably like the ones I have with colleagues after we've spent four hours in a pub," says University of Idaho gerontologist Steven Austad. "But with him you don't have to go to a pub for four hours--you just start from that point."
Take De Grey's list of aging's seven deadly aspects (see box). It represents a remarkably succinct precis of what science now knows about aging. Scanning the list brings home the fact that over the years we become our own garbage pits. We are wrinkled by worn-out skin cells that spit tissue-damaging enzymes, endangered by frayed DNA molecules that can cause cancer, and mentally degraded by tangled proteins that gum up our neurons. Meanwhile, needed cells in the brain, muscles, and other organs have a bad habit of withering away.
Some of de Grey's proposed fixes are already in the works, such as infusing so-called stem cells, which possess youthful powers of regeneration, to beef up withered tissues. But his most intriguing contribution has been to dream up radically new approaches, including a kind of ongoing, bodywide bioremediation program. It entails implanting in people genes from soil bacteria that give the bugs the ability to metabolize insoluble gunk. Gene therapy would provide the means--it involves injecting people with tame, bioengineered viruses that spread through their cells, inserting desired new genes into their DNA. The goal would be to enable our cells to get rid of detritus before it builds up in them and causes problems.
De Grey also wants anti-aging therapists of the future to correct a cellular design flaw that abets damage from highly reactive molecules called free radicals. (Free radicals are the baddies that supposedly can be neutralized with "antioxidants" such as vitamins E and C.) That vulnerability stems from the way our DNA is positioned in our cells. Most of our DNA nestles safely within the cell nucleus. But a small fraction of it (13 genes, to be exact) is found outside the nucleus in cellular structures called mitochondria, which serve as our bodies' energy generators. Trouble is, mitochondria churn out free radicals that can clobber their small parcels of DNA. Over time, such damage may dim our cells' power supplies. To prevent it, de Grey proposes putting functioning copies of the damage-prone mitochondrial DNA into the protective confines of the cell nucleus. Studies dating from the mid-1980s have already shown that this is perfectly feasible, he adds. The method of choice, once again, would be gene therapy.
The hardest aging problem to deal with, de Grey says, will be cancer. That's mainly because the DNA of tumor cells can quickly mutate and evolve resistance to virtually any drug. To remedy that, he has devised a radical gambit that entails knocking out key genes that all cells need in order to divide more than a few score times. The main gene in question is the code for telomerase, an enzyme that maintains telomeres, special DNA that sits at the ends of chromosomes (tightly coiled packets of DNA in our cells) like the protective aglets on shoelaces. Each time a cell divides, its telomeres get shorter. Once they're whittled down, the cell generally can't divide any more--unless, that is, telomerase is activated to elongate the shortened telomeres. Tumor cells find ways to abnormally switch on this mechanism and keep it on. Thus, totally shutting down the machinery--by using drugs to knock out the genes that encode its proteins--should keep tumors from growing wildly. (This blockade arguably would trump all cell-proliferation signals that are turned on in cancer.)
Even if it were to work, this futuristic therapy probably wouldn't be feasible for decades. For one thing, selectively knocking out particular genes in the trillions of cells throughout the body would be very tricky. De Grey believes that advances in gene therapy will eventually make it possible. An even bigger stumbling block may be side effects--eliminating genes involved in the rejuvenation of blood, skin, and other cells is likely to speed, not stop, decrepitude. But de Grey has an answer to that objection too: "reseeding" high-turnover tissues with periodic infusions of stem cells.
That may sound farfetched, but a limited form of the procedure, bone marrow transplantation, is routinely used in cancer therapy to regenerate red and white blood cells destroyed by high doses of chemotherapy drugs. De Grey predicts that the reseedings might be needed only about once a decade. At the periodic tune-ups, you'd check into a clinic for an intravenous infusion of blood stem cells, an endoscopic implantation of intestinal stem cells, and perhaps a procedure resembling a bodywide hair-follicle transplant to renovate your skin. To keep you cancer-free, the implanted cells would be genetically tweaked so that they were capable of dividing only a limited number of times.
De Grey thinks many of us could see all these solutions in our lifetime. Some of the therapies he writes about, such as drugs to eliminate brain gook thought to cause Alzheimer's, have already reached human clinical tests. As to the other needed therapies, given adequate funding, early versions have a "good chance of success in mice within ten years," he and the other scientists wrote in the New York Academy of Sciences paper; the therapies could be available to people within a few decades thereafter.
At that point de Grey thinks we may reach "escape velocity"--the happy state in which ongoing medical advances will be able to add years of life faster than they're subtracted by the passage of time, letting us elude the Reaper indefinitely. Or at least until we're killed by accidents, which de Grey figures will limit life expectancy to about 5,000 years. (The risk of fatal accidents has loomed large to him since he concluded that anti-aging therapies might let him live a very long time: "I now check the brakes on my bike more carefully, wear a seat belt when riding in the back seat of a car, and don't accept invitations to meetings in dangerous countries," he says.)
Even if he's right, de Grey is well aware that scientific feasibility doesn't equal political will. In fact, he says his own starting point in gerontology was his recognition in the mid-1990s of an institutional "fatalism logjam." Since there have been few signs of progress in the quest for anti-aging therapies, funding agencies generally dismiss such work as a waste of resources, or worse, as attempts to brew up snake oil. They won't pay for research, so no progress is made--which, in turn, keeps the impression of intractability in place. Thus, serious scientists have long avoided the pursuit of anti-aging therapies for fear of being labeled flaky dreamers or aspiring charlatans. The closest approach to such work is the relatively modest quest for medicines that prolong good health during old age. This entrenched timidity "just makes me spit," says de Grey. Many researchers on aging privately agree, he adds, but can't afford to be as outspoken as he is because it might hurt their chances to get grants. (A problem he doesn't have, thanks to his genetics job.) Breaking the vicious circle, he adds, will require a big, bold stroke.
That's where the mice come in. De Grey speculates that solving the remaining scientific puzzles to achieve "robust mouse rejuvenation" would require $100 million per year of focused research funding over the next decade. That sounds like a massive amount of money, but it isn't compared with the National Institutes of Health's annual budget of about $28 billion. And the bang-per-buck would dwarf that of other research pursuits. Says de Grey: "You can save more lives by helping to cure aging than in any other way."
De Grey believes that mounting a high-profile campaign to arrest aging in mice would rivet public attention on the huge promise of anti-aging research, making it politically tenable to put in serious money. The Methuselah Mouse Prize is the first step. The inaugural winner received only about $500, but later record-setters will get more; donors have given or pledged nearly $400,000 to bulk up the purse, says de Grey.
But is the world really ready for an aging cure? What about exploding retirement costs, or rancor in the workplace as people refuse to retire? What about overpopulation? What about the ultimate argument, that brevity gives life meaning?
De Grey's blanket reply to such objections is: Yes, that may be a problem, but how can you argue it's ethical to accept the deaths of tens of thousands of people a day from aging-driven diseases? Besides, he says, we'll find ways to cope. On the question of overpopulation, for instance, he offers this analogy of how we've handled it in the past: "Suppose you're a scientist 200 years ago who has figured out how to drastically lower infant mortality with better hygiene," he says. "You give a talk on this, and someone stands up in back and says, 'Hang on, if we do that we're going to have a population explosion!' If you reply, 'No, everything will be fine because we'll all wear these absurd rubber things when we have sex,' nobody would have taken you seriously. Yet that's just what happened--barrier contraception was widely adopted" about the time that infant mortality began dropping.
As to the question of life becoming so long that it loses its meaning, De Grey has a response that's truly guaranteed to silence critics: If you don't want to try it, you can simply reject rejuvenation therapy and fade away.