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Study Spurs Hope of Finding Way to Increase Human
Life
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 chemical, a natural substance known as resveratrol, is found in red wines, particularly those made in cooler climates like that of New York State. The finding could help explain the so-called French paradox — the fact that the French consume fatty foods considered threatening to the heart but live as long as anyone else. 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 work in humans it will be many years before any drug based on the new findings becomes 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 human life span could be extended by 30 percent if people respond to the chemicals the way 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 result was announced last week at a scientific conference in Arolla, a small village in the Swiss Alps, by Dr. David A. Sinclair of Harvard Medical School. It was published electronically yesterday in the journal Nature. 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 to increase longevity in laboratory animals. A calorically restricted diet — including all necessary nutrients but 30 percent fewer calories than usual — has been found to extend the life span of rodents by 30 to 50 percent. Scientists hope, but do not yet know, that the same will be true in people. A similar mechanism exists in simpler forms of life, which has led biologists to believe that they are looking at an ancient strategy, formed early in evolution and built into all animals. The strategy allows an organism to live longer and postpone reproduction when food is scarce, and to start breeding when conditions improve. Two experiments to see if caloric restriction extends life span in monkeys are at about 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 should extend people's life span, 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 that a reduced-calorie diet does and provide 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. Mice and humans have counterpart genes that are assumed to work in a similar way, though this remains to be proved. Independently, Elixir Pharmaceuticals of Cambridge, Mass., had found a different set of chemicals that mimic caloric restriction, said Ed Cannon, Elixir's chief executive. Because of testing and regulatory requirements, he added, his company is "8 to 10 years away from having an approved drug." After presenting his results for the first time, Dr. Sinclair said in an interview from Arolla, "I've been waiting for this all my life." "I like to be cautious," he added, "but even as a scientist it is looking extremely promising." So far Dr. Sinclair and his colleagues have shown only that resveratrol, the chemical found in red wine, prolongs life span 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 that will be needed 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. Resveratrol, he said, is unstable on exposure to the air and "goes off within a day of popping the cork." Dr. Tatar, asked if he had changed his drinking habits, said, "No, I have always preferred red wine to white." Health authorities have not had time to make a detailed evaluation of the research. Dr. David Finkelstein, the project officer at the National Institute of Aging, said 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," Dr. Finkelstein said, adding that the calories in a glass of wine could lead to weight gain. Dr. Toren Finkel, who is in charge of cardiovascular research at the National Heart, Lung and Blood Institute, said: "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. As a drug, it is not ready for prime time." But the concept of a drug that mimics caloric restriction "is a great idea," he said. 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 evenly between their parent institutions, Harvard Medical School and Biomol. Resveratrol is synthesized by plants in response to stress like lack of nutrients and fungal infection. It exists in the skin of both red and white grapes but is found in amounts 10 times as high in red wine as in white because of the different manufacturing process. According to "The Oxford Companion to Wine," pinot noir tends to have high levels of the chemical, cabernet sauvignon 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 discovery, despite its preliminary nature, stems in part from a train of discoveries stretching back a decade. In 1991 Dr. Guarente decided to study the basis of aging, then considered an intractable and 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 No. 2. Dr. Guarente next found that when yeast cells 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 sets off the cellular changes that lead to increased life span. Dr. Sinclair and Dr. Howitz took the human version of sirtuin, the enzyme produced by the sir2 gene, and devised 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 screening produced two active chemicals, both belonging to the family 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, resveratrol or a combination of the two is the active ingredient. Dr. Guarente, Dr. Sinclair's former mentor, founded Elixir Pharmaceuticals to pursue the same goal of developing drugs that mimic caloric restriction. 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 additional 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. Elixir uses the same screen for sirtuin activity as Dr. Sinclair did, one provided by Biomol. It is not yet clear if the efforts of 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.
Copyright
© 2002 Global Action on Aging
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