Substance in Red Wine Appears To Let Mice Live Longer

Substance in Red Wine Appears To Let Mice Live Longer
By DAVID STIPP
Wall Street Jornal
November 2, 2006; Page B1

One day last summer, a researcher at a Baltimore lab gently lowered two mice onto a device resembling a spinning rolling pin. Though the rodents were old and fat, they gamely began walking in place like log-rolling lumberjacks.

Then the device sped up and forced them to run hard until they maxed out and harmlessly dropped off. Trembling like a winded octogenarian, one fell after 81 seconds. The other lasted 144 seconds -- almost twice as long.


Three 15-month-old mice from the study were fed, from left to right, a standard diet, a high-calorie diet and a high-calorie diet plus resveratrol. Although it still got fat, the mouse on the right had a 31% lower chance of dying as it aged than the control mouse next to it.


The animals were essentially twins that had lived under identical laboratory conditions. But the more vibrant mouse had been given daily doses of resveratrol, a substance in red wine that some researchers think may slow the aging process.

The mice were part of a new study showing that resveratrol at high doses can block many of the deleterious effects of high-calorie diets in mice, enabling them to survive significantly longer than they normally would on fattening fare. Results showing how much longer mice taking resveratrol may live aren't yet complete because some of them are still alive. But preliminary findings indicate they may have a lifespan extension of 20%.

The study follows several earlier ones showing that resveratrol can boost lifespan in creatures like fruit flies. It represents the first time a substance shown to slow aging in multiple species of lower animals was tested for similar effects in mammals. The results boost hopes that resveratrol, or drugs like it, may eventually be able to ameliorate many diseases of aging, and possibly to extend human life, but that would be many years and many studies away.

The resveratrol study was conducted by researchers at Harvard Medical School and the National Institute on Aging, one of the National Institutes of Health. "The significance of the study on a scale of 10 is 11 in the aging and longevity field," said Nir Barzilai, director of the Institute for Aging Research at Albert Einstein College of Medicine in the Bronx, N.Y., who didn't take part in it.

But he cautioned that the study didn't prove that resveratrol slows aging. That's because blocking the diseases associated with rich diets isn't the same as retarding general aging, which isn't considered a disease. In the study, the mice lived longer, but it isn't certain whether that's because resveratrol slowed aging or only blocked diseases associated with rich diets.

LONGEVITY RESEARCH



Antiaging Researchers Study Calorie Cutback1
10/30/06The study's authors are now examining whether resveratrol makes normally fed mice live longer. The data on that should be out next year.

The mice in the Nature study were given much higher doses of resveratrol than anyone could get by drinking red wine, which contains only minuscule amounts of the substance. A person would need to drink more than 300 glasses of wine a day to get the amount of resveratrol the mice got, according to a commentary accompanying the study, which was reported online yesterday by the journal Nature.

Dietary supplements containing concentrated resveratrol extracts, mostly obtained from a plant grown in China known as giant knotweed, let people ingest higher doses than they can get from wine. Various companies, such as Longevinex, based in San Dimas, Calif., sell the supplements over the Internet. But it isn't known what number of such pills might induce health-promoting effects in humans like those observed in mice, because resveratrol hasn't been tested in large, rigorous clinical trials.

Sirtris Pharmaceuticals Inc., a biotech start-up in Cambridge, Mass., co-founded by one of the new study's main authors, recently began testing a resveratrol-based drug in patients with adult-onset diabetes, which is closely linked with fattening diets. Within about a year, the early-stage trial may give a preliminary indication of resveratrol's potential for averting obesity-linked disease in humans. Sirtris says its novel prescription drugs are far more potent than dietary supplements containing resveratrol. Definitive clinical-trial data on the drugs' efficacy probably won't be available for at least several years.

Scientists familiar with the new mouse study generally said that not enough is known about resveratrol to warrant taking the dietary supplements right away. For now, wrote the authors of the Nature commentary, University of Washington biologists Matt Kaeberlein and Peter S. Rabinovitch, "we counsel patience. Just sit back and relax with a glass of red wine."

What has sparked controversy but most interests researchers like Dr. Barzilai about the study are signs that the compound engages the same antiaging mechanisms that calorie restriction does.

Calorie restriction, or CR, entails cutting normal calorie intake by a third or so to slow aging. Discovered in the 1930s, it has been shown to extend longevity by 30% to 40% in animals. Monkey and human studies suggest it can probably also extend human longevity. But its hunger-inducing regimen is too demanding for most people. (Thus, the standard joke about it: Even if it doesn't extend your life, it will make it seem longer.)

Several other substances have shown hints of mimicking CR. A widely used diabetes drug called metformin, for example, activates many of the same genes that CR does. But resveratrol stands out for two reasons: It is the first compound shown to boost lifespan in widely diverse species -- there are four so far -- and it is a naturally occurring molecule that people have long ingested, suggesting that it is safer to take than other potential CR-imitating compounds.


An aged mouse in Dr. Sinclair's Harvard lab like those in the study.


Hopes that resveratrol might yield CR's gain without pain were first raised in 2003 by Harvard Medical School biologist David Sinclair, who led a study showing that the compound boosted yeast cells' lifespan by 70%, apparently by mimicking CR. The finding led to speculation that resveratrol's CR-like effects might already be evident in people in the form of the "French paradox," under which France's famously bibulous citizens have anomalously low rates of cardiovascular disease despite their fatty, high-calorie diets.

Dr. Sinclair has become the leading proponent of the idea that resveratrol mimics the effects of CR. His theory is controversial, and some researchers assert that his interpretation of existing data on the issue is wrong and that resveratrol's mode of action hasn't been pinned down.

Studies that followed those on yeast cells have shown that resveratrol has antiaging effects in roundworms, fruit flies and a species of short-lived fish. They set the stage for the new mouse study, spearheaded by Dr. Sinclair.

The researchers put the mice on high-calorie diets designed to mimic the kind of fattening food many Americans eat. The study demonstrated that while the mice gained weight on their rich diets, resveratrol largely protected them from adult-onset diabetes, the buildup of harmful fatty deposits in the liver, heart-muscle degeneration and other fallout from the rich diets. The report "suggests that guilt-free gluttony might not be a fantasy," wrote the authors of Nature's commentary.

Still, the study's findings are "very important" because they suggest that resveratrol and similarly acting drugs may offer "considerable benefits" for people with obesity-linked diseases, said Massachusetts Institute of Technology biologist Leonard Guarente. Dr. Guarente co-founded Elixir Pharmaceuticals Inc., a Cambridge, Mass., biotech company that competes with Sirtris, which Dr. Sinclair co-founded to capitalize on his research.

The study's findings paralleled those obtained in another investigation of resveratrol's effects in mice on fattening diets that Sirtris reported at a recent scientific meeting.

Besides lowering the risk of diabetes, according to Sirtris's rodent data, resveratrol and like-acting drugs may limit weight gains from rich diets. (Sirtris's chief executive, Christoph Westphal, is married to a reporter for this newspaper.)

Resveratrol pills for people haven't been tested in large clinical trials, so their efficacy isn't proven, nor is it clear what dose would yield desired effects. Still, Dr. Sinclair believes that long-term ingestion of relatively small doses of resveratrol via dietary supplements may help lower the risk of various diseases.

Resveratrol is considered safe at the modest doses available in the dietary supplements. But massive doses given to rats induced signs of kidney damage, anemia, diarrhea and other side effects, according to a 2002 toxicity report on resveratrol by the National Institute of Environmental Health Sciences.

The toxic doses were roughly equivalent to a person taking many thousands of resveratrol pills a day. The study noted that there were no observable adverse effects in rats at doses comparable to a human taking hundreds of the pills daily, a dose far higher than that used in the study described in Nature.

Resveratrol can inhibit formation of new blood vessels in mice with skin wounds, according to the federal institute's safety study. That could potentially retard wound healing. But it may also have benefits by blocking tumor growth. Resveratrol may also inhibit blood-clotting, according to some studies, potentially risky for people undergoing surgery.

Several of the new study's findings support Dr. Sinclair's view that resveratrol mimics the effects of CR. One of the most striking results was the dramatic edge in running endurance among mice on resveratrol compared with their undosed peers. The longer mice were on resveratrol, the perkier they got. After taking it for a year beginning in middle age (the rodents generally live two to three years), elderly mice had about twice the running endurance of undosed peers. Such late-life sprightliness is also observed in old mice long subjected to CR.

Last spring, Italian scientists reported similar vigor in aged fish treated with resveratrol. The substance also boosted the animals' life span by more than 50%. Another research group, whose data aren't yet published, has reportedly seen the same effect in mice on high doses of resveratrol.

Recent studies by Dr. Sinclair's group and others suggest one reason why this energizing occurs: Resveratrol and other compounds that stimulate an enzyme called SIRT1 engender new mitochondria, tiny dynamos within cells that churn out energy for everything from moving muscles to sending signals between neurons. CR is thought to do the same thing, says Eric Ravussin, an authority on CR at the Pennington Biomedical Research Center, an obesity research center affiliated with Louisiana State University, and an adviser to Sirtris.

Dr. Ravussin adds that the fresh mitochondria appear to spew fewer damaging "free radicals," molecules whose DNA-fraying action has been linked to aging, than do the older mitochondria they replace. "It's like replacing the engine of a polluting gas guzzler with an efficient, cleaner-burning new one," he says.

URL for this article:
http://online.wsj.com/article/SB116239800769710272.html


Hyperlinks in this Article:
(1) http://online.wsj.com/article/SB116217874933807498.html