It was one year ago that Yoda died. While he was smaller than most, carrying a mutation that disabled the production of three hormones required for normal growth, he did not appear to be sick. At the time, there was no apparent cause of his death. He was four years and twelve days old, and apparently healthy.

But Yoda had lived his entire life in a cage, part of ongoing life span research at the University of Michigan Medical School. When he celebrated his fourth birthday there, guests included Richard Miller, a professor of pathology in the geriatrics center, and Princess Leia, a female mouse and Yoda’s constant companion. Yoda had already outlived three of his other playmates.

When he died, Yoda was the world’s oldest lab mouse, and over the course of his life, he had provided important clues as to how genes and hormones affect the aging process and postpone associated diseases. Mice with genetic mutations like Yoda’s seem to delay aging and develop diseases like cancer forty percent later than normal mice do, and researchers like Miller hope they will teach scientists something about how to slow these processes in humans. What scientists learn from rodents, they believe, will eventually be applied to human beings. This is the dream— no, the expectation—of Aubrey de Grey, a Cambridge University gerontologist and the founder of the Methuselah Mouse Prize, named for the 969-year-old patriarch whom de Grey, who is tall and lanky, with a beard tapering to a scraggly point at the middle of his chest, resembles.

The Methuselah Mouse Prize provides scientists the world over with a cash incentive—currently about $60,000— to produce the oldest mouse ever known to man. The “longevity prize” has a twofold objective: First, to encourage researchers to test genetic tweaks and drug interventions that could postpone aging in humans as well as mice; second, to generate public interest and enthusiasm for science that aims to extend life. Until the public takes the research seriously, de Grey believes, there will not be adequate funding or advocacy of anti-aging work by experts. “The whole point of the prize,” says de Grey, “is to encourage people to try things that might not be considered plausible by the gerontology establishment.”

It’s been fourteen years since de Grey, a trained computer scientist, married Cambridge University geneticist Adelaide Carpenter, who studied various developmental and metabolic processes in fruit flies. Through her, de Grey learned of the biological and chemical factors that promote aging, mainly toxic metabolic byproducts that build up in the body over years. He found himself fantasizing about halting these toxins, which can slow and impede essential cellular processes in their tracks, and “began to realize that if science really focused on the problem, aging might not be that hard to intervene in.”

So he attended conferences and meetings where a handful of scientists powwowed over beers, dreaming up ways to interest the public in anti-aging research. A prize for long-lived mice, they reasoned, would be ideal in several respects: Mice are among the easiest lab animals to work with; their “fur appeal” attracts the attention of journalists and the public; and they are, in many ways, our miniature biological counterparts. Since genome organization is very similar in mice and humans, there is often an analogous Homo sapiens gene for every Mus musculus gene targeted in an experiment. Mice previously have been used to identify and analyze genes that cause human conditions like deafness and sickle cell disease.

Gregory Stock, director of the Program on Medicine, Technology, and Society at the University of California, Los Angeles’ School of Public Health, was present during those early conversations. He had already attempted to start an antiaging research competition called the Prometheus Prize, and while it stalled for lack of funding, he still believed the idea of a prize would empower people who love to compete. Plus, it had another enormous advantage: With a prize for the accomplishment of a goal, there would be no payout for work that was not successful. “If you could actually alter the process of aging itself, that would be a fundamental transition in the human experience,” he says. “It would lead to a complete remaking of human society and the way we see ourselves and others.”

The real goal of any anti-aging competition, then, de Grey and Stock felt, would be to get people so excited about anti-aging science that more funding and innovative avenues of research would be generated. With just a few genetic manipulations, scientists had already extended the life spans of worms by a factor of seven. But “people don’t identify with worms very well,” de Grey points out. “Mice may be nearer to us emotionally—they’re more likely to make sense, enough to motivate the quest to develop good, reliable techniques and eventually translate them to humans.” Still, he did not know where the dream was headed until he met David Goebel, an entrepreneur involved in several science-publicizing ventures. Goebel had seen de Grey’s work referenced online and decided to contact him. It was 2002, and the pieces were starting to fall into place: De Grey now knew Goebel, and Goebel happened to know the architect of the X Prize.

The Ansari X Prize planners had offered $10 million to any team that could complete a private suborbital space flight, and had spurred research efforts from a variety of competitors. (They recently awarded the first prize to SpaceShipOne, which exceeded an altitude of 328,000 feet twice within a fourteenday period.) De Grey and Goebel aspired to follow in their footsteps. A contest similar to the X Prize, they had reason to believe, would galvanize anti-aging research both by directing scientists’ competitive drive toward a specific goal and attracting the attention of major media outlets.

As a way to kick off the contest and garner some press attention, the nonprofit Methuselah Foundation, of which Goebel is executive director and de Grey is chairman and CEO, awarded an inaugural Methuselah Mouse Prize to Southern Illinois University physiologist Andrzej Bartke in June 2003. Bartke had recently produced a mouse that lived for 1,819 days, one week shy of five years. A world record holder, thought de Grey, was something the public could understand and identify with.

Bartke had been experimenting with transgenic mice that overexpress growth hormone when he noticed that they were aging prematurely. Less than normal amounts of the growth hormone, he guessed, might promote longevity. So Bartke and his team developed a growth hormone “knockout” mouse that produced the hormone but could not respond to it. They set aside a group of these mice for study and got striking results: These mice outlived their normal siblings by fifty percent. The long life span of these mice, Bartke reasons, could be related to the complex connections between growth hormone resistance, insulin production, and the body’s metabolic processes. Mice that do not react to growth hormone also do not produce another hormone called “insulin-like growth factor,” which usually interacts with insulin to direct cells’ metabolic processes and stimulate their maturation and division. Alteration of this key metabolic pathway could therefore be what causes knockout mice to age more slowly. “The mice have a combination of low insulin levels and high sensitivity to insulin, probably resulting from the fact that they have no growth hormone,” says Bartke. “Some studies in human centenarians support the idea that there is a link between high insulin sensitivity and long life.”

Still, there are many hurdles to be cleared before a procedure like growth hormone knockout can be implemented in humans. Mice that cannot respond to growth hormone have some undesirable characteristics: They tend to be small, chubby, and sterile. Bartke is continuing to pursue the possibilities of modifying the chemical sequence of events that growth hormone controls, working toward a postponement of aging that is not only possible to replicate in humans, but also attractive. “When you talk about life extension, the public has an image of decrepit people being forced to exist in nursing homes,” he says. “But, if we are able to prolong life, what would happen is that the good and healthful period of life would be prolonged, and the period of sickness and decrepitude would be postponed.”

To date, no drugs or technologies have been developed that allow scientists to slow, prevent, or reverse the aging process in humans. Previous research has zeroed in on the biochemical factors that promote aging, such as cellular toxins and the oxidation reactions that occur during cellular respiration, but effective strategies to undo the damage these processes cause have yet to be developed. Even Hollywood stars—who may have the greatest stake in remaining young, and the means to do something about it—must resort to superficial fixes like face lifts, Botox injections, and “memory-enhancing” gingko supplements, for lack of any truly effective anti-aging therapy.

A number of potential therapies do show promise, however. Harvard University scientists, for example, are developing a pill that may increase activity of a gene that blocks the process of cell death, allowing organs to function longer—although its efficacy has not yet been proven in large-scale trials. With the continual incentive of the Methuselah Mouse Prize, scientists also have been actively pursuing research in other directions. Any scientist who can produce the verifiably oldest mouse will receive payment corresponding to the margin by which the existing longevity record is broken; if the mouse lives twice as long as Bartke’s, for instance, the payment will be half the existing prize fund. Yet they all see the forest through the giving tree: At stake are the questions that are becoming ever more crucial as the baby-boom generation edges toward senior citizenry. Will I grow old more slowly and gracefully than my parents did? Can I count on another few decades of life once I hit sixty? For how long can any of us be vital creatures? In a 2003 article published in the Journal of Applied Physiology, Christiaan Leeuwenburgh proved that rats kept on a calorie-restricted diet throughout their lives maintained higher levels of muscle mass in old age than rats that ate normally. (Loss of muscle mass is considered a major indication that the aging process is in full swing; this, more than any other factor, restricts the mobility and independence of elderly people.) Leeuwenburgh and his team at the Biochemistry of Aging Laboratory at the University of Florida put a group of male rats on caloric restriction from infancy, feeding them meals ten percent smaller than the normal meals fed to a control group and then progressively decreasing portion size until they were eating forty percent less than normal.

The results were startling. In old age, the deprived rats had a higher strength to body mass ratio than old rats on a normal diet—a ratio, in fact, similar to that of most young rats. This indicated that their muscle cells were almost unaffected by the metabolic byproducts that ordinarily accumulate in tissues with age and impede their function. Caloric restriction would have the same anti-aging effect on mice that it does on rats, Leeuwenburgh believes, since the genetic makeups of the two rodents are very similar.

“Calorie restriction blocks and slows down chemical processes so cells are healthier at an older age,” he says, although the exact biological sequence of events that prevents harmful substances from building up in tissues when food intake is low remains unclear. “It has effects on gene expression. Certain proteins that prevent cells from dying, called ‘apoptotic proteins,’ are increased.”

Why on earth would caloric restriction, of all things, have these effects? Leeuwenburgh explains that “when animals and humans evolved, there wasn’t much food, and we really had to work for what we were getting. We were always trying to get to a source of food, and, probably, our cells were at a starvation-type level.” In other words, since we evolved under restrictive circumstances, our bodies may be best suited to exist within them.

As the body’s normal metabolic processes turn food and oxygen into energy, they constantly yield free radicals— molecules that contain highly reactive, unpaired electrons—as a side effect. Because of their unstable nature, these molecules can wreak havoc on the body, often referred to as “oxidative damage.” It’s speculated that because dwarf mice like Yoda have lower core temperatures and slower metabolisms, they produce less of the reactive oxygen that damages genes and leads to aging.

In a normal body, free radicals steal electrons from other molecules and become unstable, merging with surrounding molecules to produce compounds that can damage proteins, membranes, and nucleic acids. Over time, the accumulating damage manifests itself in visible symptoms: skin that has lost its elasticity, deteriorating organ function, and cancerous growths. It’s possible that negating the harmful effects of free-radical molecules would slow the course of aging.

To counter free-radical damage, Doctor Richard Cutler and his team at the Kronos Longevity Research Institute in Phoenix are investigating ways to strengthen the expression of many genes that naturally keep the oxidation process in check. These genes regulate the production of enzymes and proteins that react in beneficial ways with free-radical molecules, negating their potential to damage cells, organelles, and genetic material. In testing an assortment of genetic interventions in mice, Cutler hopes to find effective ways of decreasing the amount of oxidative stress that cells are exposed to. Once he develops a strain of mice that naturally produces high levels of antioxidants, he will monitor and care for the animals fastidiously in hope of producing one that could break Bartke’s record.

Some detractors use Cutler’s strategy—perform a genetic intervention, then wait to see whether any of the mice happen to survive to very old age—as proof that the scientific merit of the Methuselah Mouse Prize is dubious. It is misguided, they say, to be interested only in the age of the oldest mouse, which may be an anomaly. One super-aged mouse could simply be a fluke, whereas producing multiple old mice provides more concrete evidence that an anti-aging technique works reliably.

There are also scientists who quibble with the very idea of focusing on longevity above all else. “It’s true that going out of existence is a very scary thought,” concedes Neil Charness, an expert in the psychology of aging at Florida State University. “The real prize, though, is not necessarily to live the longest, but to live well the longest.”

To those ends, the Methuselah Foundation has recruited competitors for an additional award, the “rejuvenation prize,” which rewards successful interventions started late in a mouse’s life span. Researchers must average the ages of the oldest ten percent of mice used in a given experiment, and groups of at least twenty mice must show rejuvenation in at least five different markers of aging. The older the mice when the experiment starts, the more credit given at its conclusion. Late last year, Stephen Spindler, a professor of biochemistry at the University of California at Riverside, was presented with the first such prize during the Gerontological Society of America Conference in Washington, D.C. Spindler had started a group of mice on a calorie-restricted diet at nineteen months—middle age for a species that is considered elderly once the age of two is reached.

The mice were rejuvenated: DNA microarray analysis, a technique for examining the activity of genes, revealed they had become physiologically and biologically younger. They lived, on average, fifteen percent longer than those on a normal diet, and fewer of them died from cancer. The most surprising implication of his experiments, Spindler says, is that “calorie restriction acts quickly to extend life; it’s not a slow-acting effect over the lifetime of the animal.”

When the mice receive smaller amounts of food, their bodies make use of existing tissues for energy—an effect that would be deadly if carried to the extreme of starvation, but which, in moderation, encourages the rebuilding and rejuvenation of tissues that are torn down. “During caloric restriction, your body turns itself over more,” says Spindler.

While he concedes that the fruits of his research—in the form of drugs and other biological interventions that could slow aging in the human population—are not likely to appear for several years, Spindler sees tremendous promise in the burgeoning field of anti-aging research. Ventures like the Methuselah Mouse Prize and the research it spurs will help turn skeptics into believers, erasing the public perception that his line of work involves a hopelessly quixotic search for some bogus fountain of youth. “People just aren’t used to the idea that we should be able to live more slowly,” Spindler says. “But, from our experiments, we know that humans are nowhere near their maximum life span yet.”