Source: New York Times
Date: 24 August 2003

Life-Extending Chemical Is Found in Certain Red Wines

reservatrol figure

By NICHOLAS WADE

Biologists have found a class of chemicals that they hope will make people live longer by activating an ancient survival reflex. One of the chemicals, a natural substance known as resveratrol, is found in red wines, particularly those made in cooler climates like that of New York.

The finding could help explain the so-called French paradox, the fact that the French live as long as anyone else despite consuming fatty foods deemed threatening to the heart.

Besides the wine connection, the finding has the attraction of stemming from fundamental research in the biology of aging. However, the new chemicals have not yet been tested even in mice, let alone people, and even if they worked in humans, it would be many years before any drug based on the new findings became available.

The possible benefits could be significant. The chemicals are designed to mimic the effect of a very low-calorie diet, which is known to lengthen the life span of rodents. Scientists involved in the research say that human life spans could be extended by 30 percent if humans respond to the chemicals in the same way as rats and mice do to low calories. Even someone who started at age 50 to take one of the new chemicals could expect to gain an extra 10 years of life, said Dr. Leonard Guarente of the Massachusetts Institute of Technology, one of the pioneers of the new research.

The new result was announced last week at a scientific conference in Arolla, a small village in the Swiss alps, by Dr. David A. Sinclair of the Harvard Medical School.

The new development has roused the enthusiasm of many biologists who study aging, because caloric restriction, the process supposedly mimicked by the chemicals, is the one intervention known for sure to increase longevity in laboratory animals.

A calorically restricted diet includes all necessary nutrients but has some 30 percent fewer calories than usual. The diet extends the life span of rodents by 30 to 50 percent, and even if it is started later has a benefit proportionate to the remaining life span. Scientists hope, but do not yet know, that the same will be true in people.

A similar mechanism exists in simpler forms of life, making biologists believe that they are looking at an ancient strategy, formed early in evolution and built into all animals. The strategy allows an organism, when food is scarce, to live longer, postpone reproduction and start breeding when conditions improve.

Two experiments to see if caloric restriction extends life span in monkeys are about at their halfway point rhesus monkeys live some 25 years in captivity and the signs so far are promising, though not yet statistically significant. But even if caloric restriction did extend people's life spans, the current epidemic of obesity suggests how hard it would be for most people to stick with a diet containing 30 percent fewer calories than generally recommended.

Biologists have therefore been hoping to find some chemical or drug that would mimic caloric restriction in people by tripping the same genetic circuitry as a reduced-calorie diet does and give the gain without the pain.

Dr. Sinclair and his chief co-author, Dr. Konrad T. Howitz, of Biomol Research Laboratories in Plymouth Meeting, Pa., say they have succeeded in finding a class of drugs that mimic caloric restriction in two standard laboratory organisms yeast and fruit flies. Both mice and humans have counterpart genes that are assumed to work in a similar way, though that remains to be proved.

Independently, Elixir Pharmaceuticals, a company in Cambridge, Mass., found a different set of chemicals that mimic caloric restriction, Ed Cannon, the chief executive, said. "We can do the same things he can do," Dr. Cannon said of Dr. Sinclair's findings. Because of testing and regulatory requirements, "we are 8 to 10 years away from having an approved drug," Dr. Cannon added.

In an interview from Arolla, Switzerland, where he presented his findings, Dr. Sinclair said, "I've been waiting for this all my life," adding, "I like to be cautious, but even as a scientist, it is looking extremely promising."

So far, Dr. Sinclair and his colleagues have shown that resveratrol prolongs life span only in yeast, a fungus, by 70 percent. But a colleague, Dr. Mark Tatar of Brown University, has shown in a report yet to be published that the compound has similar effects in fruit flies. The National Institute of Aging, which sponsored Dr. Sinclair's research, plans to start a mouse study later in the year.

Despite the years of testing ahead to prove that resveratrol has any effect in people, many of the scientists involved in the research have already started drinking red wine.

"One glass of red wine a day is a good recommendation. That's what I do now," Dr. Sinclair said, adding he hoped the finding would not lead people to drink in excess. "One glass of wine is enough," he said. However, resveratrol is unstable on exposure to the air and "goes off within a day of popping the cork," he said.

Dr. Tatar, asked if he had changed his drinking habits, said, "No, I have always preferred red wine to white."

The new finding is so novel that health authorities have not yet had time to make a detailed evaluation of the research. Dr. David Finkelstein, the project officer at the National Institute of Aging, which financed the study, said that he would not advise anyone to start drinking red wine. "At this point, we have no indication that there will be a benefit in people," he said, adding that the calories in a glass of wine would lead to weight gain.

Dr. Toren Finkel, the head of cardiovascular research at the National Heart, Lung and Blood Institute, said that "I would be cautious in sending out the message that one glass of wine a day will make you live 10 years longer." "The concentration of resveratrol in different wine differs," he said. "As a drug, it is not ready for prime time." But he acknowledged that the concept of a drug that mimicked caloric restriction "is a great idea.".

Dr. Sinclair said that he and Dr. Howitz were working on chemical modifications of resveratrol that would be more stable. Ownership of the patent will be split 50:50 between their parent institutions, the Harvard Medical School and Biomol.

Resveratrol is synthesized by plants in response to stress, like a lack of nutrients or contracting a fungal infection. It exists in the skin of both red and white grapes but is found in amounts 10 times higher in red wine because of differences in the manufacturing processes.

According to the Oxford Companion to Wine, Pinot Noir tends to have high levels of the chemical, while Cabernet Sauvignon has lower levels. "Wines produced in cooler regions or areas with greater disease pressure, such as Burgundy and New York, often have more resveratrol," the book says, whereas wines from drier climates like California or Australia have less.

Besides resveratrol, another class of chemical found to mimic caloric restriction is that of the flavones, found abundantly in olive oil, Dr. Howitz said.

The enthusiasm scientists are showing for the new discovery, despite its preliminary nature, stems in part from a train of fundamental discoveries stretching back a decade. In 1991, Dr. Guarente decided to study the basis of aging, then considered an unpromising field of research. He spent four years searching for strains of yeast, a common laboratory organism, that lived longer than others. By 1997, he and Dr. Sinclair, who worked in his laboratory at the time, had discovered the reason for the new strains' longevity. It centered on a gene called sir2, for silent information regulator.

Dr. Guarente next found that when yeast live longer because of starvation, sir2 is the gene that mediates the response. His research then started to fuse with longstanding work on caloric restriction as he and others showed that starvation is sensed by sir2, which triggers the cellular changes that lead to increased life span.

What Dr. Sinclair and Dr. Howitz did was to take the human version of sirtuin, the enzyme produced by the sir2 gene, and devise a test to tell when the enzyme was activated. They then screened a large batch of likely chemicals to see if any made the enzyme more active. Their screen produced two active chemicals, both of a similar chemical structure and known as polyphenols. That led them to expand the search to more polyphenols. The most active compound in the second screen was resveratrol. Dr. Sinclair said he was amazed "that in an unbiased screen we pulled out something already associated with health benefits."

Much attention has been paid to resveratrol in the last few years because it is a candidate for explaining the apparent innocuousness of the French diet despite its artery-weakening ingredients. Epidemiological studies point to red wine as containing some beneficial antidote, but it is not yet certain whether alcohol, or resveratrol, or both, are the active ingredients.

Why should chemicals like resveratrol play a role both in the French paradox and in caloric restriction? Dr. Sinclair believes the chemicals are produced by plants in response to stresses like starvation and that browsing animals may have evolved to make use of the chemicals as a signal of hard times ahead. Other scientists said this idea was possible but not particularly plausible.

Dr. Guarente, his former mentor, founded Elixir Pharmaceuticals to pursue the same goal of developing drugs that mimic caloric restriction. Dr. Guarente said Dr. Sinclair's results were plausible and exciting. He said diet-mimicking drugs might add a decade of life to someone starting them at age 50, based on the calculation that the 30 or so years of life expected at that age could be increased by one third, and assuming that humans would benefit from caloric restrictions to the same degree as mice.

Dr. Cynthia Kenyon, of the University of California, San Francisco, an expert on aging in roundworms and a cofounder of Elixir, said from Arolla that Dr. Sinclair's work was "really remarkable."

Elixir uses the same screen for sirtuin activity as Dr. Sinclair did, one provided by Biomol. It is not yet clear if the efforts by Dr. Sinclair and Elixir will be competitive or collaborative, Dr. Howitz said.

In either case, considerable testing lies ahead to see if the promise of the new research can be fulfilled.




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