Kenyon's Ageless Quest

A San Francisco scientist's genetic research renews the ancient hope for a way to slow aging

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At Cambridge, she trained as a developmental biologist under Sydney Brenner, who received a share of the 2002 Nobel Prize in Physiology or Medicine for work showing how genes dictate the development of organs and tell some cells when to die, as though they’d been preprogrammed to self-destruct at a particular time. Brenner had long championed the virtues of experiments with the nematode C. elegans. The translucent smooth worms, barely the size of the comma at the end of this phrase, are in constant motion; viewed under a microscope, they carve sinuous arabesques across the gel on which they’re grown in the lab. To scientists, the worm provides a remarkably revealing model of genetics in action. C. elegans has a three-day cycle from birth to laying eggs and lives a little more than two weeks. It possesses a relatively modest 19,000 genes, and has the added benefit that its body’s 959 cells are virtually transparent when viewed through a microscope—enabling scientists to literally peer into the worm’s parts as it develops, whether naturally or in response to an experiment. Soon Kenyon became part of an army of researchers who, through sophisticated experiments, could show genes being activated in distinct patterns. Those tests yielded important clues about which genes controlled specific steps in the worm’s growth, development and aging.

She learned not only the exquisitely sensitive genetic choreography of developing organisms, but also that when it comes to genes, evolution keeps going back to the same well: the genes that control the development of nematodes and frogs and mice also tend to control human development (albeit in slightly more complicated ways). Similarly, Kenyon theorized that aging in nematodes and people might also be controlled by comparable genes. Moving to the University of California at San Francisco in 1986, and aware of the work of Tom Johnson, a University of Colorado biologist who had studied a nematode that lived longer than usual, Kenyon and her co-workers looked for genes that, when altered in particular worms, made those worms live longer than others. She found that changing one specific gene, called daf-2, dou- bled the animal’s life span and also prolonged its youthful activity. Another scientist, Gary Ruvkun of Harvard Medical School, discovered that the genes in question regulated a hormone-signaling system in the worm that is surprisingly similar to the way the human body signals the need for both the hormone insulin, which spurs the breakdown of sugar, and an insulin-like growth factor (IGF-1), which affects physical growth. Flouting the scientific tradition of understating one’s findings, Kenyon began to talk about the “fountain of youth gene,” an idea, as she recalls it, that people thought was “kind of cute.”

As Kenyon and co-workers delved into the problem, they learned more about the insulin-signaling pathway, showing that when certain worm hormones were suppressed, it activated a host of other genes that appeared to play a role in extending the animal’s life. So the question became: Did evolution favor this mechanism and pass it along to other organisms? “Is it in humans?” Kenyon asks. “We don’t know.” Still, she and other scientists have what they believe are promising leads—thus the work at Elixir and other biotech firms to identify human versions of the same life-extending genes found in simpler creatures.

One of Kenyon’s buddies from her Cambridge, Massachusetts, days was Guarente, a meticulous and somewhat reticent molecular biologist. He has studied important but esoteric aspects of gene regulation for 20 years. In the mid- 1990s, his research group discovered a family of specialized genes that influence the life span of yeast cells. Called silencing genes, their job is to make proteins that smother, or silence, other genes, usually in response to changing environmental conditions. When the MIT biologists genetically engineered yeast to have an extra copy of one such gene, called sir-2, the yeast cells lived longer. As important as the function of the sir-2 gene—it directs the making of an enzyme—is that the gene is activated when food intake and metabolism are reduced. In short, the silencing gene linked the high-tech molecular manipulations of life extension in yeast to a low-tech life-extension strategy that had been known for decades in rats: a starvation diet.

In a classic set of experiments in the 1930s by Clive McCay at CornellUniversity, rats fed just enough food to fulfill the animals’ nutritional needs but not enough to maintain their usual weight lived about 20 to 40 percent longer than rats raised on a normal amount of food; some lived twice as long. More than half a century later, caloric restriction remains the only proven strategy of life extension other than gene engineering. It has been demonstrated to work not only in rodents but also in yeast, fruit flies, spiders and fish, and, in continuing studies sponsored by the National Institute on Aging, it appears to have a similar effect in monkeys.

The link between diet and longevity has intrigued fanatics as well as researchers. Aprofessor emeritus of pathology at UCLA and a member of the 1991-1993 Biosphere 2 experiment, Roy Walford, 79, has undertaken a much-publicized experiment on himself—for years he has eaten a nutrientrich diet of just 1,600 calories a day in the hopes of extending his life. (His research is now complicated by his own amyotrophic lateral sclerosis, or Lou Gehrig’s disease.) Likewise, according to the Wall Street Journal, hundreds of Walford disciples are restricting themselves to as few as 1,500 calories a day in hopes of living longer.

Guarente, following up on his group’s discovery of a lifeextending sir-2 gene in yeast, a single-celled organism, has more recently shown that the more complex nematodes possess an analogous gene that can also prolong life. In fact, the researchers showed that endowing nematodes with an extra copy of that gene prompted the worms to live nearly 50 percent longer than usual. In any event, human beings possess versions of both the daf-2 and sir-2 genes, which is what tantalizes researchers, biotech investors—and consumers.

Around 1996, Kenyon began showing, to venture capitalists, a five-minute film dramatizing the difference between geezer and genetically rejuvenated nematodes. “I show them the movie, of worms that are normal that are about to die after two weeks, and the altered worms that are still moving,” Kenyon said. “They see it with their eyes, you know? . . . And that’s really all you have to do. It speaks for itself.” In December 2000, Kenyon and Guarente started Elixir with the ultimate hope of selling a product—ideally, a small molecule that could be packaged as a pill—that would extend life span and prolong youthfulness by affecting the sir-2 gene, among other parts of the insulin-signaling system. Last year, Elixir merged with Centagenetix, another Cambridge-based biotech firm, which has been scouring the chromosomes of centenarians and other very old people for genes that may have contributed to their long lives.

Even before the yeast and nematode research, scientists suspected that genes play a role in determining life span. More than 50 gene mutations affecting it have been identified in various animals. Agroup headed by Thomas Perls, of the Boston University School of Medicine and one of the cofounders of Centagenetix, has investigated many centenarians in New England and beyond, and this past November he reported that a gene on chromosome 4 appears related to life span. (People who lived to 100 were more likely to have a particular version of the gene that produces a protein that plays a role in processing fat.)

Such findings dovetail with Kenyon and Guarente’s approach. “When single genes are changed, animals that should be old stay young,” they wrote recently. “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.”


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