2008-07-23

BOSTON, Mass. — One day last month, clad in white plastic garments from head to toe, Dr. David Sinclair showed a visitor around his germ-free mouse room here at Harvard Medical School.

The mice, subjects in studies of health and longevity, are kept in wire baskets under intensive nursing care. A mouse gym holds a miniature exercise machine that tests the rodents’ ability to balance on a rotating bar. In a nearby water maze, mice must recall visual cues to swim to safety on a hidden platform, a test of their powers of memory. Those that forget their lessons are rescued as they start to submerge and humanely dried out under a heat lamp, Dr. Sinclair assured his visitor.

Dr. Sinclair is a co-founder of Sirtris, a company that itself has been swimming in uncharted waters as it works to develop drugs that may extend the human life span. But it seemed to have found a safe platform last month when it was bought last month by the pharmaceutical giant GlaxoSmithKline for $720 million.

Sirtris has two drugs in clinical trials. One is being tested against Type 2 diabetes, one of the many diseases of aging that the company’s scientists hope the drugs will avert. With success against just one such disease, the impact on health “could be possibly transformational,” said Dr. Patrick Vallance, head of drug discovery at GlaxoSmithKline.

The new drugs are called sirtuin activators, meaning that they activate an enzyme called sirtuin. The basic theory is that all or most species have an ancient strategy for riding out famines: switch resources from reproduction to tissue maintenance. A healthy diet but with 30 percent fewer calories than usual triggers this reaction in mice and is the one intervention that reliably increases their life span. The mice seem to live longer because they are somehow protected from the usual diseases that kill them.

But most people cannot keep to a diet with a 30 percent cut in calories, so a drug that could activate the famine reflex might be highly desirable. Dr. Leonard Guarente, an M.I.T. biologist who founded the field of sirtuin biology, thinks the famine reflex is mediated through the sirtuin enzymes. Dr. Sinclair, his former student, discovered that sirtuins could be activated by drugs. The most potent activator that emerged from his screens was resveratrol, a natural substance found in red wine, though in amounts probably too low to be significant for health.

The Sirtris drug being tested in diabetic patients is a special formulation of resveratrol that delivers a bloodstream dose five times as high as the chemical alone. This drug, called SRT501, has passed safety tests and, at least in small-scale trials, has reduced the patients’ glucose levels.

The other drug is a small synthetic chemical that is a thousand times as potent as resveratrol in activating sirtuin and can be given at a much smaller dose. Safety tests in people have just started, with no adverse effects so far.

The hope is that activating sirtuins in people would, like a calorically restricted diet in mice, avert degenerative diseases of aging like diabetes, heart disease, cancer and Alzheimer’s. There is no Food and Drug Administration category for longevity drugs, so if the company is to submit a drug for approval, it needs to be for a specific disease.

Nonetheless, longevity is what has motivated the researchers and what makes the drugs potentially so appealing.

Dr. Christoph Westphal, the chief executive of Sirtris, said of the potential of the drugs, “I think that if we are right, this could extend life span by 5 or 10 percent.” He added that his goal was to develop drugs against specific diseases, with the extension of life being “almost a side effect of our medicine.”

Sirtris was founded in 2004 after Dr. Westphal, then working at a Boston venture capital firm, approached Dr. Sinclair. Because of widespread interest in the sirtuin activation idea, Dr. Westphal had little difficulty raising money and recruiting distinguished scientists to Sirtris’s advisory board.

He later decided to sell the company to GlaxoSmithKline, he said, because it was getting harder to raise money and clinical trials could proceed faster with the larger company’s resources. Sirtris was acquired at an 84 percent premium, better than the 50 percent at which most companies are bought, Dr. Westphal said.

The impact of Sirtris’s drugs, if successful, could extend beyond the drug industry. Dr. Guarente believes that many people might start taking them in middle age, though after having started a family because they may suppress fertility.

Mice on the drugs generally remain healthy right until the end of their lives and then just drop dead.“If they work in people that way, one would look to an extension of health span, with an extension of life as a possible side effect,” Dr. Guarente said. “It would necessitate changing ideas about when people retire and when they stop paying into the system.”

GlaxoSmithKline could put SRT501, its resveratrol formulation, on the market right away, selling it as a natural compound and nutritional pharmaceutical that does not require approval by the F.D.A. “We haven’t made any decisions, but that clearly is an option,” Dr. Vallance said.

If GlaxoSmithKline decides instead to seek F.D.A. approval, it will need to prove that resveratrol is safe in the large doses required for efficacy. Resveratrol seems to exert many influences on the body, some of which are not exerted through sirtuin. “None of us should be naïve enough to think resveratrol won’t have multiple effects, including some you don’t want,” Dr. Vallance said.

GlaxoSmithKline’s purchase of Sirtris has pushed the optimism of sirtuin researchers and others to new heights. “We are all holding our breath,” said Dr. Huber Warner, editor of the Journals of Gerontology. But the success of the drugs is far from assured.

Most potential drugs fail to make it past clinical trials, and the same may prove true for Sirtris’s candidates. The sirtuin-activating chemicals the company has designed could turn out to be toxic. Another uncertainty is that the underlying science is still in flux and debate rages among academic researchers over many details of how caloric restriction works.

Some biologists think that sirtuin is not the only mediator of the famine reflex, and that resveratrol may not work through sirtuin at all in exerting its beneficial effects on mice. “There are data both for and against that hypothesis, though that doesn’t dissuade one from pursuing it as a potential benefit,” said Dr. Thomas Rando, who studies aging in stem cells at Stanford University.

In initial tests in mice, resveratrol has doubled muscular endurance, lowered the bad form of cholesterol, protected against various bad effects of a high-fat diet and suppressed colon cancer. New reports are confirming some of these benefits, but others are ambiguous or puzzling.

According to a study published on July 3 in the journal Cell Metabolism by Dr. Sinclair and Dr. Rafael de Cabo of the National Institute on Aging, resveratrol given to aging mice reduced their cataracts, strengthened their bones, improved coordination and enhanced their health in several other ways. Yet despite their better health, the mice lived no longer than usual.

“Minimally this calls into question one pillar of the GSK investment,” said Dr. Ronald Evans, a leading expert on hormonal responses at the Salk Institute. Dr. Evans said that sirtuin research was promising but unproved, and that he did not agree that sirtuin was the probable mediator of the famine reflex, a concern that “calls into question the second pillar of the GSK investment.”

The frontiers of science are often turbulent, and it can take years for clarity to emerge from confusion. Dr. Westphal said the decision to ignore the academic debate about exactly how resveratrol may work was one of two principal reasons for Sirtris’s quick success. The other was to focus the company’s limited resources on developing just two drugs.

The researchers at Sirtris are no strangers to skepticism. Dr. Guarente and Dr. Sinclair were ridiculed when they first started looking for longevity genes more than 15 years ago, because aging was then considered to be an intractable problem. His colleagues, Dr. Guarente said, “thought I was nuts.”

Dr. Sinclair, when he first arrived as a young postdoctoral student in Dr. Guarente’s lab to work on longevity, was downcast to learn of the other students’ severe doubts. “The view even in Lenny’s lab was that this problem was going nowhere, it was a house of cards that would fall down any month now.” He called his parents in Australia to tell them he may have made a big mistake. But the research led eventually to the discovery of the sirtuinlike proteins and their role in extending the life span of yeast, worms and flies.

He and Dr. Guarente developed the sirtuin field with the hope of increasing longevity. But because of Sirtris’s focus on developing drugs that have the F.D.A.’s approval for specific diseases, both are being less explicit about their hopes of reversing aging. “There’s a much greater chance of a drug that can treat disease than of extending life span,” Dr. Sinclair said.

“I’m becoming more boring in my old age,” he added apologetically.

GlaxoSmithKline’s press releases refer to the sirtuins as “enzymes that the company believes control the aging process.” But Dr. Vallance is more guarded, saying aging is too hard to measure. The goal is not the extension of human life span; rather, “The prolongation of health is the aim,” Dr. Vallance said.

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