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Q&A: Leonard Guarente

The skinny on the fountain of youth
December 1, 2005

Lenny Guarente has spent much of the last two decades patiently chipping away at the genetic and biochemical underpinnings of the aging process, an area of research often plagued by extreme hyperbole and extravagant claims.

The MIT biologist is particularly focused on one tantalizing clue: for about 70 years, researchers have known that rats tend to live longer when fed a diet that is adequate in nutrition but very low in calories. While biologists are still unsure whether severe calorie restriction will have the same antiaging effect on humans, Guarente believes he and his fellow researchers have found the genes and a mechanism responsible for delaying the aging process – at least in lower organisms.

Technology Review: If all goes well with antiaging research, what might be possible in five to 10 years?

Leonard Guarente: I hope in 10 years that we are way down the road of drug discovery in finding compounds that will deliver at least some of the benefits of calorie restriction. And I think SIR2 is going to be one of the important targets that we want to go after with drugs.

TR: That’s a gene you have identified as being involved in aging, isn’t it?

LG: We definitely think it is involved in the aging process. In particular, it seems to be involved in sensing caloric intake and asserting effects on cells to adjust life span. We think calorie restriction is a tremendous opportunity for us to intervene pharmacologically and have a positive impact on human health.

TR: So people won’t be going on a special diet to get the effects of calorie restriction, they’ll take a drug?

LG: I think so, because the amount of calories you would be taking in to get the benefits is rather a severe diet, about 1,000 to 1,200 calories a day. And most people who have tried this diet find it unpleasant. It makes them cold, it makes them hungry, they’re irritable, and I think compliance would be very difficult. So, the idea is to understand what this diet does in an effort to develop drugs that would hit at least some of the targets and deliver at least some of the benefits.

TR: You’re talking about treating specific diseases, not the aging process.

LG: The big idea here is that there is a close connection between aging itself and diseases of aging. If one had a favorable impact on the underlying aging process, diseases of aging would also be forestalled. And those diseases would include cancer, diabetes, cardiovascular disease, and neurodegenerative diseases – really major diseases.

TR: How did you find this antiaging gene?

LG: This gene came out of studies of aging in yeast. We started those studies in 1991, and the question we wanted to answer was, Do yeast cells age? And if they do, are there one or a small number of genes that are particularly important in dictating the life span of these cells? For four or five years we published nothing because we were just banging away at the problem. It took eight years before we could come to the conclusion that this one gene, SIR2, influenced the life span.

TR: The gene also promotes longevity in worms and fruit flies. What seems to be its common role?

LG: The idea would be that when food is scarce it is an advantage to be able to recognize the scarcity and slow down aging and reproduction, to postpone reproduction for when food becomes available again. And now there is some evidence that this is in fact the case.

TR: Is this also true in humans?

LG: It is a good hypothesis that something like this will be true in mammals. And there are hints. But I would say there is no conclusive evidence yet. But we know that the mammalian version of SIR2, which is a gene call SIRT1, has at least some of the activity in cells that one would anticipate for a life-extending function. What needs to be tested is whether it affects aging in the whole organism.

TR: How large is this effect of calorie restriction on aging in rodents?

LG: Studies show this diet could extend life up to 50 percent. So, it is pretty substantial. But there are people out there claiming science will allow people to live thousands of years. I tend to believe that is a lot of bunk. But the opportunity we do have is nothing to sneeze at. I think it is the major opportunity that Mother Nature has given us to intervene in the aging process. And by intervene I mean not just to promote longevity but to fight diseases.

TR: Other researchers are testing the antiaging effects of calorie restriction in monkeys, aren’t they?

LG: Those studies have been going on for some 15 years now. I know of two studies, and both are reporting that the diet induces the same physiological changes as in rodents, which is a very good indicator. There’s no report yet on whether it makes the monkey live longer, because that data takes a long time to be available. But I think we’ll know quite soon.

TR: Is all the hype a good or bad thing for antiaging research?

LG: It cuts both ways. The good part is where there is public interest, there is funding available for the research. The bad thing is that if the work does get overhyped in the media it raises false expectations. I get asked a lot, “What is taking so long?”

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