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Wake-Up Call

A software engineer is the last person you'd expect to see dissecting the biology of aging. But Aubrey de Grey's radical views have stirred up debate in the field of gerontology.

In a gaggle of gerontologists, Aubrey de Grey sticks out. It isn't just his strikingly long and voluminous brown beard that sets him apart, nor the fact that the tall, slender Brit often talks at such a fast and fervent clip that he leaves listeners in the dust. In the world of biologists who study aging, de Grey makes his mark by thinking and acting like the software engineer he originally trained to be.

A scion of the computer programming culture, the 39-year-old typically works from noon to midnight. He gets up at 11 a.m. for his "day" job at the University of Cambridge: maintaining FlyBase, an international database of information about the Drosophila genome. But his night job--and true passion--is pondering ways to turn back the clock of human aging.

De Grey's interest in the science of senescence began as a hobby, but it soon led him to reprogram himself as a theoretical biologist. In recent years, as an armchair gerontologist imbued with the let's-fix-it attitude of an engineer, he has advanced a number of provocative concepts that have won him increasing recognition--as well as some skepticism--from researchers in the discipline.

In October 2000, de Grey helped instigate a small roundtable discussion on "strategies for engineered negligible senescence" (SENS). Hosted by biochemist Bruce Ames of Children's Hospital Oakland Research Institute in California, the daylong confab of eight scientists--including other well-established biologists in the field of aging--concluded with a startlingly optimistic outlook: A combination of already-existing or foreseeable biotechnologies, such as stem cell transplants, might enable researchers to reverse aging in mice within 10 years. The roundtable's participants further concluded that similar accomplishments might follow "rapidly thereafter" in humans, within another few decades.

For de Grey, the conference was a major coup. He wants to wake up a community that he views as excessively cautious and prod gerontology researchers to acknowledge the possibility that retarding aging or rejuvenating decrepit bodies is within reach. "I'm trying to dispel what you might call the apathy or despondency or complacency ... [regarding] the feasibility of doing something serious about aging in the foreseeable future," he says. In addition to galvanizing the scientists, he's calling for an open public discussion on the biological, social, and political upheavals that the mere anticipation of successful life-lengthening remedies would inevitably provoke.

Other scientists are listening. "I like some of his papers. I don't agree with them all, but I like the fact that somebody is writing them and that they're written intelligently," says demographer S. Jay Olshansky of the University of Illinois, Chicago. "It's a healthy part of this debate and discussion of aging."

De Grey came to gerontology almost by accident. A London native, he fell in love with computers as a teen after playing around with a programmable calculator that his mother bought for him. He got a degree in computer science from the University of Cambridge in 1985 and embarked on a career in software engineering, writing programs designed to detect mistakes in other programs. His detour into biology began with a walk down the wedding aisle. "It was all my wife's fault," says de Grey, who in 1991 married Adelaide Carpenter, a Drosophila geneticist at the University of Cambridge. "It wasn't even intentional, but I ended up learning a great deal of biology over the next couple of years just by saying, 'What did you do today, dear?'"

This knowledge fed de Grey's natural curiosity about aging. His interest, he says, stemmed from the same self-preserving instincts that most people have: "I'm seriously not in favor of aging; I would really like to do something about it," he says wryly. He became puzzled as to why more biologists weren't studying what he views as "the major unsolved problem" in their arena.

In 1992, de Grey joined the FlyBase project at Cambridge. After a hectic 2 years helping to set up the resource, he began working on his own software research project on the side, but that endeavor "wasn't exactly catching fire," he says. He reconsidered his options and, at the end of 1995, he decided instead to pursue his fascination with aging. After immersing himself in the gerontology literature, he soon perceived a gap in the underlying science: "There weren't enough people drawing ideas together from different parts of the field and trying to synthesize things. It was more monopolized by experimentalists working rather in isolation from each other. And so I thought I might be able to make a contribution," he recalls.

In about a month of intensive study, de Grey devoured all the information he could find about mitochondrial DNA (mtDNA) mutations, potential mediators of the oxidative damage that many researchers believe drives senescence (see "The Two Faces of Oxygen"). In February 1996, he came up with an idea about how such mutations might accrue in cells--a novel mechanism, it turns out, that other investigators had not considered. De Grey submitted a write-up of his theory to the editor of Bioessays, who was an acquaintance, and the journal published it in 1997. The hypothesis drew the attention of some researchers who study mtDNA and generated new ideas for experimental studies. "It was a real case of beginner's luck," says de Grey of his first publication.

Rounding out his transition into gerontology, de Grey subsequently obtained a Ph.D. in biology from his alma mater, although not by the traditional route. Alumni of the University of Cambridge can apply for a doctoral degree by submitting a body of research--a book or a series of papers--and defending it before a panel of examiners. De Grey did so and received his doctorate in late 2000.

He has come up with new concepts about how to not just delay or prevent, but actually undo, aging-related changes (see de Grey Viewpoint). For example, the buildup of damaged lipids and proteins inside or outside cells is a suspect in neurodegenerative disorders and other diseases--take amyloid deposits in Alzheimer's disease (see "Detangling Alzheimer's Disease") or oxidized cholesterol in atherosclerosis (see Praticò Review). De Grey's proposed solution: Using gene therapy, supply lysosomes--the cells' garbage disposals--with extra enzymes to degrade the junk. Such enzymes might be found in soil bacteria, some of which can even chew through recalcitrant pollutants such as PCBs.

And because no successful attempt to combat aging can ignore that most wily disease of old age--cancer--de Grey has an even more radical idea for outfoxing it. Malignant cells can't proliferate without a way to replenish their telomeres, so he suggests deleting the genes that encode telomerase and other enzymes that perform this task from all dividing cells in the body. Because normal cells in the blood, skin, and other tissues need telomerase to survive, stem cell transplants could periodically replenish them. Such interventions were among the technologies that the SENS roundtable group identified in 2000 as holding potential for reversing the frailties of aging. "These technologies may be hard to develop and may be ambitious, ... but they're not hard enough to be called science fiction," says de Grey.

De Grey has no interest in doing benchwork, figuring that plenty of expert experimentalists already populate the field. And because he doesn't have to run gels, grow yeast cultures, or apply for grants, he says he has time to scrutinize the literature more widely than almost any lab scientist--about 10 hours per week browsing PubMed and reading papers. "Ultimately, a successful theoretician has to be able to bring ideas together from far corners of the field and generate new ideas from the different data," he says. "Most of my ideas ... are pretty damned obvious. But I was the only person in a position to have the ideas, because other people just haven't read the right combination of literature."

Mind games. De Grey relishes a good intellectual challenge. He has been playing Othello for 20 years and is chair of the British Othello Federation. [Credit: Thierry Bousch]

De Grey is a "very good scholar," says Olshansky, adding that anybody can become an expert in gerontology--by carefully reading the literature, acquiring solid knowledge of the field, and talking and debating with researchers. "But it takes a lot of time. And he has taken that time and effort."

De Grey's bold interpretations can put him out on a limb, and some scientists view his optimism about antiaging treatments as premature and naive. Olshansky, for instance, says that it's too soon for the term "reversing aging" to be used in scientific discourse given that no one knows whether the aging process can even be slowed (see Olshansky Viewpoint and Olshansky Perspective).

De Grey's reputation is "different with different people," says friend Konstantin Khrapko, a geneticist at Harvard Medical School in Boston. "I've heard [critics say] many times, 'He doesn't do experiments, he doesn't really understand.'" Although de Grey might not have the same type of knowledge as an experimentalist does, Khrapko says, the field needs voices like his. De Grey ties different ideas together and "stimulates the whole process" of scientific discourse, Khrapko adds.

"He really pushes the edge," says Gregory Stock, director of the Program on Medicine, Technology, and Society at the University of California, Los Angeles, who helped organize the 2000 SENS roundtable. "[But] nobody thinks that he's nutty. He's clearly a very smart guy. He's very well read and very knowledgeable. ... I think he's a very good influence on the field."

Despite his contrary perspectives, de Grey maintains friendly relations with those who don't see eye to eye with him. His cordial standing is evident in the fact that he's in the midst of organizing a major biogerontology meeting, with a lineup of prominent speakers such as Michael West, CEO of Advanced Cell Technology in Worcester, Massachusetts, and gerontologist Tom Kirkwood of the University of Newcastle upon Tyne, U.K. De Grey is "very easy to get along with," says Olshansky. "What I like is that he will disagree agreeably. There are plenty of people out there ... who disagree disagreeably."

Olshansky recalls one particularly agreeable occasion of disagreement. Once, when he traveled to London for business, de Grey invited him to Cambridge and took him boating in a punt, a small, flat-bottomed craft that's navigated with a long pole. "It's actually one of my fondest memories," says Olshansky. "We were punting on the river at Cambridge and debating issues associated with aging. It was really delightful."

Another of de Grey's favorite backdrops for talking science is the nearest pub. "His intellectual work starts with a beer," Khrapko jokes. "He says that's what nourishes his brain." But what really fuels de Grey's work is far more basic. At the end of the day, his interest in gerontology isn't merely academic. He considers aging "a barbaric, uncivilized phenomenon that shouldn't really be tolerated in polite society." If, by playing the role of rabble-rouser, he can help speed the arrival of successful antiaging therapies, he might someday help prolong hundreds of millions of lives, perhaps even his own. Says de Grey, "I want to make a difference."

* Ingfei Chen, a contributing editor in Santa Cruz, California, would like to hang on to all of the telomerase in her cells, thank you very much.

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