Leonard Guarente: Unlocking the Secrets of Long Life
For someone with a passion for prolonging life, Leonard Guarente has flirted with cutting it short. As a third grader in Revere, Mass., the gritty town where he grew up, Guarente smoked about five cigarettes a day. "I was doing it to be cool," explains the 48-year-old grandson of Italian immigrants. "I quit after the ringleader kid moved away."
Now Guarente is leading efforts to solve one of the most intriguing mysteries of aging: why eating much less makes life last longer. Research has shown that severe caloric restriction can prolong life. In one study, lab mice that were fed 60 percent of their normal allotment of food lived up to 16 months longer than their expected 40-month lifetime. Researchers in aging are intensely interested in finding out why, and whether it's possible to reap the longevity benefits of caloric restriction without suffering the hunger pangs. So is the public.
Guarente, a molecular biologist at the Massachusetts Institute of Technology, is trying to answer that "why" by finding genes that account for the extra-long lives of skinny lab rats. That's not a simple task. It is difficult to pinpoint the genes that cause any disease, and particularly genes of aging, which clearly has multiple causes. So Guarente started looking for the aging genes in yeast, a fungus that is in the same family of cells as humans but has only 6,200 genes, compared with people, who have up to 100,000. After nine years of effort, Guarente announced in September that he had identified both a yeast gene and a metabolic enzyme that help explain the antiaging effect of caloric restriction. It's the closest yet that any scientist has gotten to identifying a genetic key to the aging process.
Guarente hadn't set out to study aging. The subject was considered unfashionable in the 1980s, when he was an untenured professor of genetics at MIT. With tenure, however, came a ticket to explore a pioneering avenue of study. Cancer, he decided, was too well staked out. Learning and memory were too complicated. But by the early 1990s, aging was becoming increasingly acceptable as a topic of serious research. In 1991, two graduate students convinced him they should look for aging genes in yeast. A year passed, and "we had nothing," Guarente says. But by then the professor was intrigued, so he decided to keep going.
Armoring DNA. It took four more years of unrewarded toil, seeking genetic mutations in long-lived yeast, before the group identified a link between aging and genes called silencing information regulators. They zeroed in on the SIR2 gene in particular as the key longevity factor. SIR2 "silences" misfiring genes by keeping the cell's DNA tightly coiled. This slows down the development of genetic waste in the nucleus, which ultimately leads to the cell's death.
The researchers knew that SIR2 worked by removing clusters of clingy chemicals called acetyl groups, which loosen the coiled DNA. But they weren't sure how. In an experiment to elicit a chemical reaction, Guarente and post-graduate student Shinichiro Imai combined SIR2 with the coiled yeast genes and NAD, a chemical important in metabolic processes. What they found was surprising. The mixture simply cleaned the acetyl groups away. "It was serendipitous," Guarente says.
And it was important. The fact that NAD and SIR2 work together to slow aging suggested Guarente had found a molecular link between caloric restriction and longevity. His theory is this: If an animal eats less, it needs less NAD to metabolize food, and there will be more NAD to activate SIR2. The more SIR2 can silence other genes in the cell, the longer the cell will live. Last September, Guarente published his findings in Science.
"The results are really intriguing," says Cynthia Kenyon, who researches aging in roundworms at the University of California-San Francisco. "One wants to know if it is operating in other animals and if so, how." Guarente has already begun studies in mice, but results will take three to four years.
If Guarente is right, sometime in the distant future there could be a SIR2 pill that would provide the longevity benefits of caloric restriction, which Guarente says is too difficult. "You become rail thin, you're cold, it kills your sex drive, and you can't socialize with friends over meals." As someone who loves his pasta and seafood, he says, it's no way to live.
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Born: June 6, 1952; Chelsea, Mass. Education: B.A., MIT; Ph.D., molecular biology, Harvard. Goal: Find fountain of youth. Role model: Leonardo da Vinci. Favorite movie: It's a Wonderful Life, "because it shows the importance and dignity of each individual." True confession: Listens to alternative rock, including Green Day and Smashing Pumpkins.
With Andrew Curry
This story appears in the December 25, 2000 print edition of U.S. News & World Report.