The Fountain of Health -- Part 1
Monday, April 3, 2006
Antiaging research could provide a powerful approach to treating the many diseases of old age.
By David Rotman
This article -- a feature story in Technology Review's March/April 2006 print issue -- has been divided into two parts for presentation online. This is part 1; part 2 will appear on Tuesday, April 4.
For the better part of two decades, Richard Weindruch, a professor of medicine at the University of Wisconsin-Madison, has fed half of a colony of 78 rhesus monkeys a diet adequate in nutrition but severely limited in calories -- 30 percent fewer calories than are fed to the control group. Scientists have known for nearly 70 years that such calorie restriction extends the life span of rodents, and Weindruch is determined to find out whether it can extend the life span of one of man's closest relatives, too.
It's too early to know the answer for certain. The monkeys in Weindruch's lab are only now growing elderly. And with 80 percent of them still alive, "there are too few deaths" to indicate whether the animals on the restricted diet will live longer, says Weindruch. But one thing is already clear: the monkeys on the restricted diet are healthier. Roughly twice as many of the monkeys in the control group have died from age-related diseases, and perhaps most dramatically, none of the animals on the restricted diet have developed diabetes, a leading cause of death in rhesus monkeys.
These encouraging, albeit preliminary, results are sure to cheer those few who have adopted severe calorie-restricted diets in hopes of living longer. But their real significance is the further evidence they provide that calorie restriction affects the molecular and genetic events that govern aging and the diseases of aging. Indeed, while calorie restriction remains impractical for all but the most determined dieters, it is providing an invaluable window on the molecular and cellular biology of disease resistance and the aging process.
Up until a decade or so ago, most biologists believed that the aging process was not only immensely complex but also inevitable. People aged, they assumed, much the way an old car does: eventually, everything just falls apart. Then in the early 1990s, Cynthia Kenyon, a young molecular biologist at the University of California, San Francisco, found that mutating a single gene, called daf-2, in worms doubled their life spans. Before the discovery, says Kenyon, "everyone thought aging just happened. To control aging, you had to fix everything, so it was impossible." Kenyon's research suggested a compelling alternative: that a relatively simple genetic network controlled the rate of aging.
The race to find the genetic fountain of youth was on. Within a few years, Leonard Guarente, a biologist at MIT, found that in yeast, another gene produced a similar dramatic increase in life span. Soon after, Guarente and his MIT coworkers made another startling discovery: the yeast antiaging gene, called sir2, required for its activity a common molecule that is involved in numerous metabolic reactions. Guarente, it seemed, had found a possible connection between an antiaging gene and diet. The gene, Guarente thought, might be responsible for the health benefits of calorie restriction; and indeed, the lab soon confirmed that calorie restriction in yeast had life-extending effects only when sir2 was present.
Since the discovery of these and other antiaging genes in lower organisms, the scientific search for live-longer genes in people has, not surprisingly, garnered much publicity. Often lost in the excitement about the prospect of triple-digit birthdays, however, is a far more realistic and immediate implication of the research. While learning how to extend the life span of humans could take many decades, if it's even possible, researchers are already using insights gained from studies of aging and the effects of calorie restriction to search for new drugs to treat the numerous diseases tied to getting old.
The incidences of many illnesses, including cardiovascular disease, Alzheimer's, and cancer, rise nearly exponentially with age. And while we still don't know exactly why, we do know that calorie restriction -- at least in test animals -- delays the onset of a broad swath of these age-related diseases. "It's something people are surprised to hear, because it really begs the question, how is that possible? There must be some common metabolic component. But no one really knows how all those diseases can be tied together," says Guarente. Nevertheless, some biologists hope that a drug that mimics the molecular effects of calorie restriction might also delay the onset of some or all of these diseases.
At least one company, Sirtris, a small but heavily funded startup in Cambridge, MA, believes it is close to finding such drugs. The company, which boasts an impressive group of prominent molecular biologists and geneticists on its scientific board, was cofounded by David Sinclair, a former postdoctoral researcher in Guarente's lab and now an associate professor at Harvard Medical School. Sirtris has come up with hundreds of molecules that activate the SIRT1 enzyme, which is produced by the mammalian homologue of sir2. (Seven different SIRT genes have been found in humans; these and their homologues in other species are collectively known as sirtuins.) If the company is on the right track -- and Sirtris says potential drug candidates for treating diabetes and neurodegenerative diseases are expected to begin preliminary human tests over the next several years -- the molecules could mimic the genetic effects of calorie restriction, offering its apparent health benefits without its drawbacks.
"It's known that calorie restriction greatly enhances the body's natural ability to fight diseases," says Sinclair. The vital questions, he says, are what controls that process and whether we can develop drugs to target it. "We don't assume we know everything about it, but we do strongly believe that sirtuins are a major component in what could be a master regulatory system for human health."
Old Yeast
The identification of the life-extending effects of sir2 in yeasts was no accident: Lenny Guarente had been searching for the causes of yeast aging for almost a decade when he and his MIT graduate students methodically zeroed in on the gene in 1999. It was an important finding, but its real significance became more apparent over the next year and a half.
First, Guarente and his students found the sir2 gene in round worms. Since yeast and worms diverged evolutionarily billions of years ago, the presence of the same gene in both organisms suggested that it might be shared by other animals, including humans. Then came the bombshell. The expression of the sir2 gene required the presence of another molecule, called NAD; as any biologist knew, NAD is involved in numerous metabolic reactions in many organisms. "This finding that sir2 was NAD dependent meant to us that sir2 could connect aging to metabolism and therefore to diet," says Guarente. "Once you see this activity, a child could point out, Maybe this would connect to caloric restriction."
Perhaps not most children, but other molecular biologists certainly saw the connection, and labs around the world soon began to puzzle out the effects of sir2. Scientists knew that calorie restriction could have an impact on disease. And now there was evidence of a strong link between sir2 and calorie restriction. "If you put those together," says Guarente, "you can formulate a hypothesis that sir2 genes will impact diseases of aging."
Amidst this flurry of research, however, it was a 2003 paper in the journal Nature by Sinclair and his collaborators that really caught the attention of those hoping to turn the science of sirtuins into drugs. Sinclair identified a class of common chemicals, called polyphenols, that activate sirtuins. The findings suggested it might be possible to develop small-molecule drugs that could interact with sirtuins and turn on their apparent beneficial effects.
Six months after the Nature paper, Sinclair cofounded Sirtris with Christoph Westphal, then a partner at Polaris Venture Partners, a Waltham, MA-based venture capital firm. [Disclosure: Polaris general partner Robert Metcalfe is on Technology Review's board of directors.] Less than two years later, the startup has $45 million in venture financing and a series of drug candidates that activate SIRT1 and other sirtuins in mammals. Within a few years, says Westphal, now Sirtris's CEO, the company hopes to begin testing the safety of the sirtuin activators in humans. "We're aiming to mimic calorie restriction with small molecules," says Westphal. "The great break for us was to find those small molecules."
Meanwhile, members of Sinclair's Harvard lab are busy conducting experiments on thousands of mice to prove the benefits of sirtuins in treating disease and aging. The mice are stacked in endless rows of small, clean cages packed into a series of locked rooms. Some of the mice, partly bald and stiff jointed, have been genetically engineered to age prematurely. Other cages hold animals genetically destined to get colon or prostate cancers, while yet other mice will develop neurological impairments of a kind associated with Alzheimer's disease. The researchers crossbreed these mice with animals genetically engineered to overexpress one of the sirtuin genes, then monitor how the offspring fare -- whether the sirtuins fight off the diseases or prevent premature aging. Taken together, it is a massive effort to understand the role of sirtuins in mammals, with thousands of mice providing different pieces of the puzzle.
Given that the mice experiments are just a year old, and mice typically live for around three years, results are still preliminary. There is not yet any conclusive evidence, for one thing, that activating or overexpressing sirtuins increases the life span of the mice. But Sinclair says that the studies completed so far all show "that the diseases in the mice have been ameliorated."
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