http://www.washingtonpost.com/ac2/wp-dyn/A39677-2003Aug24?language=printer
Enzymes Found to Delay Aging Process Discovery Could Lead to Drugs to Extend Life Span By Rick Weiss Washington Post Staff Writer Monday, August 25, 2003; Page A02 Scientists have found for the first time a way to rev up a potent "anti-aging" enzyme in living cells, an advance they said could speed the development of drugs to extend human life span and prevent a wide range of geriatric diseases. The novel approach has significantly increased the life spans of yeast and human cells in laboratory dishes and extended the lives of flies and worms -- organisms that, on the level of molecular biology, age much as humans do. Indeed, the researchers said, the compounds seem to have the same anti-aging effect as a drastic reduction in calories, the only strategy ever proven to extend life in mammals but one that most people find difficult to stick to. It is too soon to say whether the latest findings will ever make the leap from the lab bench to the geriatrics clinic -- though some may choose not to wait: Of all the compounds the researchers tested, the one that boosted the anti-aging enzyme the most was resveratrol, an ingredient in red wine that has been credited with that beverage's ability to lower the risk of heart disease. But the findings strengthen an increasingly popular notion among many scientists that the cellular enzymes at the core of the experiments -- called sirtuins -- are universal regulators of aging in virtually all living organisms and represent a prime target for new anti-aging drugs. "It's looking like these sirtuins serve as guardians of the cell," said Harvard Medical School researcher David Sinclair, who led the new work published in yesterday's online edition of the journal Nature. "These enzymes allow cells to survive damage and delay cell death." Now the race is on, Sinclair said, to find the most potent sirtuin stimulators -- or create synthetic ones -- and test their ability to extend the lives not only of cells, flies and worms but also of mice, monkeys and humans. Other researchers were more cautious, warning that aging is a complex and poorly understood process that is unlikely to be slowed by any single drug. As promising as the research may appear today, they said, sirtuin would not be the first fountain of youth to prove a mirage. "Let's face it, aging isn't the same in humans and yeast," said Jef Boeke, a yeast geneticist at the Johns Hopkins University School of Medicine. Besides, he said, sirtuins are potent molecules, and in cranking them up, "one would have to be very careful about potential side effects." The new study caps a three-year string of discoveries involving sirtuins (pronounced sir-TOO-ins), a class of enzymes that are found in virtually every organism, including bacteria, plants and people. As with all enzymes, their job is to promote essential biochemical reactions inside cells. At first scientists thought sirtuins spent most of their time pulling key molecules off the proteins that surround DNA -- part of the process by which cells turn their genes on and off. But recently researchers learned that sirtuins are also involved in processes with much more medical -- and commercial -- potential: They are part of a feedback system that enhances cell survival during times of stress, especially if that stress is a lack of food. For years researchers have known that life span can be extended by 50 percent or more in many kinds of creatures, including flies, worms and mice, if the animal is fed a diet that is nutritious but contains about 30 percent fewer calories than usual. Recently scientists found that the life-extending benefits of calorie restriction do not occur if the animal has been genetically altered to lack sirtuins, indicating these enzymes are crucial to this process. Now scientists are coming to understand sirtuins' role in that life-extending response. In people, they seem to halt the normal cellular cycle that ends with old cells committing suicide and instead help rejuvenate them by beefing up their DNA repair processes and stimulating production of protective antioxidants. "What we think is that if a cell is at a point of deciding whether to live or die, these sirtuins push toward the survival mode and let the cell try a little harder and longer to fix itself," said Sinclair, who has a financial stake in a new effort to develop sirtuin-related products with BIOMOL Research Laboratories of Plymouth Meeting, Pa. Leonard Guarente, a researcher at the Massachusetts Institute of Technology in Cambridge, is also enthusiastic about the compounds' potential as anti-aging aids. "We're very keen on the idea that this is it" -- that sirtuins are the central regulator of the aging process -- Guarente said. He is a founder of Elixir Pharmaceuticals of Cambridge, Mass., which, like Sinclair and BIOMOL, hopes to capitalize on chemicals that can boost sirtuin activity. The goal is to make drugs or nutritional supplements that can fool the body into thinking it's living on a radically calorie-reduced diet, in effect allowing people to eat their cake and live longer, too. The new report from Sinclair's team is the first to show that it is indeed possible to tweak the sirtuin pathway. The group screened a large number of biologically active chemicals -- simple compounds that can be made into drugs with relative ease. They found several that increase sirtuin activity at least two-fold, including resveratrol. When they added some of these compounds to yeast cells growing in culture dishes, the cells produced 70 percent more daughter cells than normal -- a common measure of yeast youthfulness. Human cells seemed to benefit, too. Those treated with sirtuin boosters enjoyed long lives in laboratory dishes even after being exposed to ionizing radiation, which damages DNA and usually shortens a cell's lifespan. And in experiments not yet completed, Sinclair said, the compounds have shown evidence of being able to extend the life spans of two full-blown organisms: the soil-dwelling nematode worm known as C. elegans and the common fruit fly. Both are popular stand-ins with scientists trying to understand human biological processes. Sinclair said his group plans to start feeding sirtuin boosters to mice in the next few months and then move up to testing in monkeys. The immediate goal in people would be to slow the progression of diseases of aging such as Alzheimer's, because a more generic slowing of the aging process could take decades to prove. But others warned against exaggerated expectations. Richard Weindruch, a gerontologist and expert in calorie restriction at the University of Wisconsin in Madison, said the work was "very interesting and deserves to be carefully explored in mammals." But he questioned the relevance of the yeast experiments -- which, strictly speaking, measured not life span but the number of times a yeast cell could divide and produce daughter cells. "Clearly, numbers of generations are related to time, but it's not the same in my mind as following a single animal over its lifetime," Weindruch said. Indeed, he noted, "What they are really looking at here is increased proliferative capacity," which he and others noted is akin to cancer. David Finkelstein, an expert in metabolic regulation at the National Institute on Aging, which funded some of Sinclair's work, said the work was "very nice science" but also warned against leaping to conclusions. "We have results in a lower organism," he said, "and at this point, there's a lot of hand waving because of how little we know." Finkelstein also advised against taking the resveratrol results too literally. "Would the National Institute on Aging recommend you drink red wine every day? The answer is 'no,' " he said. "If you were to add a glass of red wine every day without changing your caloric intake, you're going to gain weight. And we know -- we know -- that if you gain weight, that's going to be harmful while this 'benefit' is a benefit that may or may not occur." "People are always looking for a quick fix," Finkelstein said. "Tell people to eat a healthy diet." -------- http://www.lenzwine.com/faq/faq-21-resveratrol.htm "What is resveratrol, and is there any in my wine?" . The findings from medical research, on the effects of wine consumption, are by now fairly overwhelming: moderate consumption is certainly very good for you. But why? In a typical study, the relationship that may be shown between presumed cause and presumed effect should be treated cautiously unless and until a specific mechanism can be found that explains the link. . The beneficial effects of wine consumption come, in part, from the alcohol itself. Most studies of the effects of alcohol consumption upon health give similar results no matter whether the source of alcohol is wine, whiskey or weissbier. But wine, red wine in particular, has shown in some studies that it has an added effect. Searching for a mechanism that might explain such a wine-linked benefit, researchers have isolated a compound which goes by the awkward name resveratrol. . Resveratrol (sometimes called trans-resveratrol) is a phenolic compound found in grape skins. Having isolated the compound, researchers are able to study its effects directly. The current focus is on its role as an anti-oxidant (it may help protect cells against the harmful effects of naturally occurring free radicals in the body that would otherwise cause cell damage), as a phytoestrogen (it may modulate levels of estrogen, reducing the suspected effects of high estrogen in inducing cancer - - especially breast cancer in women), and as a cytotoxin (it may actively destroy cancer cells). . Wow! And we just thought wine tasted good and went well with food. . This is a very exciting research direction and it is a very active field. New findings emerge every couple of months, yet very little seems to make the pages of our newspapers, for some reason. . The role of resveratrol in the grape is also the subject of research. It is supposed that it forms part of the grape�s own defense against disease. Specifically, it is thought to be a defense against fungus infection which particularly afflicts vinifera grape varieties, the kind used to make most fine wines. It is seemingly present in both red and white grapes but the different winemaking process results in far higher concentrations in red wines than in white wines. The levels of resveratrol that you find in a wine also differ by variety, with pinot noir (which is notoriously susceptible to the botrytis fungus) often the highest. Merlot also tends to be high and cabernet (which is very thick-skinned and hardy) is much lower. . Geography matters too. Long Island wines turn out to have very high resveratrol levels, presumably reflecting the humid summer climate that puts the vines and the grapes under continuing fungus pressure. . We recently had Lenz merlot analyzed and found that it had the highest level the lab had ever tested in a merlot! Enjoy! ------- http://www.news.cornell.edu/Chronicle/98/2.5.98/resveratrol.html N.Y. red wines By Blaine P. Friedlander Jr. New York state red wines have higher levels of resveratrol -- a naturally occurring substance in grapes that has been found to reduce the chance of heart disease and cancer -- than comparable wines from other regions of the world, according to Leroy Creasy, professor of fruit and vegetable science. Creasy recently completed an analysis of more than 100 red wines from five states and foreign countries. Although resveratrol is a compound found in some other plants, grapes and grape products -- particularly wine -- are the most substantial sources. (The first study showing resveratrol's cancer preventative properties was written by Jang, M., et al., "Cancer Chemopreventive Activity of Resveratrol, A Natural Product Derived From Grapes," Science, January 1997. One of the early references of resveratrol's properties beneficial to the heart include a paper written by Evan H. Siemann and Creasy, "Concentration of the Phytoalexin Resveratrol in Wine," The American Journal of Enology and Viticulture, Vol. 43, 1992.) Creasy's study, consisting mostly of 1995 vintages, included 70 New York state red wines, 19 from California and 22 from other states or countries. New York wines had the highest resveratrol concentration compared with wines from other regions, he found. "Some of New York wines, particularly in the pinot noir category, have extraordinary levels," he said. Resveratrol concentration is measured in units called micromolar (�M), and an average red wine could have 3 to 4 �M. Wines above 5 �M of resveratrol are considered high, those above 7 are considered very high and any product above 10 is extraordinary, Creasy said. New York wines used for this study came from Long Island, the Hudson Valley, the Finger Lakes and the Lake Erie regions. The California wines came from the Central Coast, Mendocino, North Coast and Sonoma. And the other U.S. wines came from Mississippi, Oregon and the state of Washington. Countries represented include Argentina, Australia, Canada, Chile, France, Italy, Slovenia and South Africa. The average resveratrol content of all New York wines tested was 7.5 �M, compared with 5.8 �M for non-New York reds and 5 �M for California red wines. The type of wine with by far the highest resveratrol levels was pinot noir, with 11 of the 17 New York wines registering above 10 �M. For pinot noir, the average levels were 13.6 �M for New York, 11 �M for all non-New York and 10.1 �M for California. Variations were striking in the cabernet sauvignon category. New York wine had an average of 8.3 �M in this category, with all non-New York cabernet sauvignons at 3.7 �M, and California's at 1.7 �M. New York cabernet sauvignon Francs averaged 8.6 �M, but non-New York wines were not analyzed for comparison in this category. New York merlots averaged 6.5 �M compared with all non-New York merlots at 4.7 �M and California merlots at 5.3 �M. New York wines also had the highest individual levels in each of these categories, with one merlot at 10.7 �M, a cabernet sauvignon at 19.2 �M, a pinot noir at 46.1 �M, a New York cabernet Franc at 16.9 �M and a lemberger at 15.3 �M. "New York's relatively humid climate explains the higher concentrations of resveratrol in the wines," Creasy said. "Resveratrol is a natural fungicide, and the more humid the climate, the more is produced to combat mildew. During the long contact between the grape skins and the juice in producing red wines, the resveratrol is transferred into the wine." The importance of the wine-making process in enhancing the resveratrol content was dramatically illustrated by Creasy's analysis of white wines -- eight from New York and five others -- which do not involve prolonged grape skin contact in the wine-making process and have negligible amounts of resveratrol. The New York white wines averaged 0.58 �M and the others, 0.6 �M. The New York Wine and Grape Foundation, which gets matching funds from New York state, funded Creasy's study. "Every year wines are bound to have different amounts of resveratrol, and this makes it difficult for the consumer to figure out which kind of wine has more resveratrol over another," said Creasy. "So, the consumer is better off with a New York red than other reds, and the odds are better that the pinot has more resveratrol than cabernet. Consumers should buy a variety of wines, from different years and from different wineries." _______________________________________________ http://www.mccmedia.com/mailman/listinfo/brin-l
