Resveratrol May Be a Longevity Molecule Discovery on red wine component points to the Holy Grail of aging research By Will Block Mixing one’s wines may be a mistake, but old and new wisdom mix admirably. — Bertolt Brecht indication is sweet. For decades, enologists (wine scientists) wrote learned articles and books regarding the supposed health benefits of wine, but their words fell mostly on deaf ears. Few people ever argued against the inestimable pleasures of wine, but most doubted that there could be significant health benefits—let alone life extension—associated with such a hedonistic product. That’s hardly surprising, considering the obvious liabilities, some of them fatal, associated with its abuse. Thus wine, celebrated throughout the ages for its sensory glories, has nonetheless also been looked upon as a major health hazard. Then, however, came the “French paradox.” The now famous 60 Minutes story in 1991 opened people’s eyes to the realization that wine—red wine in particular—may account, at least in part, for the surprisingly low incidence of heart disease in the French, despite the notoriously fat-rich foods they routinely indulge in. Could their good cardiovascular health really be attributed to the fact that they also drink a lot of wine, especially red wine? (And is a wino in France called a wineau?) Although the epidemiological evidence for this conclusion was far from conclusive, Americans sat up and took notice, then jumped up and ran to the store to buy red wine. Sales quadrupled—it was the biggest boost the wine industry here has ever received. Even the enologists were stunned, and pleased by the sudden public recognition that they had been onto something all along. Physicians Now Take Red Wine Seriously Since the French paradox burst onto the scene, scientific evidence for many healthful properties of wine—drunk in moderation, meaning at most one or two glasses per day—has mounted rapidly and is now taken seriously even by physicians who once scoffed at the very idea. And now a team of research scientists from Harvard Medical School and BIOMOL Research Laboratories (a Pennsylvania company) has made a discovery that will add greatly to the reputation of red wine as a life-enhancing health food.1 (If you can’t wait to see what it is, skip to the NEWSFLASH section below; otherwise, read on for some background on the more traditional health aspects of wine.) It’s Not Just the Alcohol, but Also the Polyphenols What is it about wine that’s so good for us? Believe it or not, one factor is the alcohol, which explains why other alcoholic beverages (white wine, beer, booze, you name it) also appear to confer health benefits—again, however, only when drunk in moderation (see the sidebar “A Sober Word to the Wise”). But it’s surely not just the alcohol, because that would not explain why red wine seems to offer the greatest benefits. There must be something else. A Sober Word to the Wise If you drink in moderation—not more than one or two glasses of wine per day, or the equivalent amount of alcohol in the form of other beveragesgood for you. You’re in control, and you may be reaping the health benefits that such modest consumption can confer. If you’re drinking to excess, however, you’re certainly harming yourself in various ways, and you may reap the whirlwind down the road. Please get help and stop drinking. Where alcohol is concerned, the line between moderation and excess is subtle, and the transition from modest health benefits to major health liabilities can be precipitous. The dangers of alcohol abuse are so great that even doctors who are enthusiastic about the health benefits of moderate drinking (red wine in particular) are loath to recommend to people who are currently not drinking that they should start. We make no such recommendation either—it’s too much like playing with fire.* *In the Prometheus legend, the gods’ objection to humans’ having fire was not that they might burn themselves, but that they might become too much like the gods—who were, among other things, immortal. What we do recommend, however, is that you avail yourself of nutritional supplements that can provide—consistently, on a daily basis—some of the most important health benefits of red wine. Fortunately, these benefits derive not so much from the alcohol (you’ll notice that there are no alcoholic nutritional supplements!) as they do from certain polyphenolic compounds, notably resveratrol. Taking resveratrol in a capsule every day may not be quite as pleasurable as savoring a glass of soft, luscious Pinot Noir, but it’s a lot more reliable and a lot less expensive—and besides, if you’re an in-control wine lover, who says you can’t also have that glass of Pinot Noir? Wine is one of the most complex biological liquids known to man. It contains hundreds of identified chemical compounds of many different classes (and perhaps hundreds more that have yet to be identified), whose subtle interplay leads to the infinite variety of the wine experience. From the health perspective, a particularly important class of compounds is polyphenols, which are found at much higher levels in red wines than in white wines (they are also found in various other plant products, such as green tea, apples, berries, pomegranates, and dark chocolate).* *Polyphenols are a large class of compounds, part of an even larger class called flavonoids, which are found in many plants, notably brightly colored fruits and vegetables. Flavonoids are known for their potent antioxidant properties and a host of documented benefits against cancer, heart disease, vision disorders, allergies, viral infections, and more. Resveratrol Is the Most Beneficial Grape Polyphenol Polyphenols are found in all parts of the grapevine, but the highest concentrations are found in the grape skins. Because the skins figure prominently in the making of red wines but not of white wines, it’s the reds that provide the lion’s share of the health benefits. One grape polyphenol stands out as having the strongest health benefits of all: resveratrol (rez-VEER-a-troll), whose apparent connection with the French paradox was discovered in 1992.2 Epidemiological data support the view that moderate consumption of red wine leads to a significantly decreased risk for heart disease (including heart attack and stroke), and animal and laboratory studies suggest that resveratrol and other polyphenols found in grapes and wine are primarily responsible for this effect.3 (For more on the health benefits of resveratrol, see the sidebar “Resveratrol—To Your Health!”) Resveratrol—To Your Health! Japanese knotweed (Polygonum cuspidatum) Resveratrol is found in relative abundance not only in grapes and red wine, but also, not surprisingly, in raisins and purple grape juice. And it is found in peanuts, mulberries, eucalyptus trees, and the root of the Japanese knotweed (Polygonum cuspidatum), the source of most of the resveratrol sold in nutritional supplements. In vineyards, the leaves and grapes produce resveratrol not routinely, but in response to environmental stresses, such as dehydration, nutrient deprivation, and attack by pathogenic organisms, which the compound is there to combat. Such defensive molecules are known as phytoalexins, from the Greek words for “plant” and “protector,” but we might well consider resveratrol to be a “people-alexin” too, considering all that it does to protect our health—and even, perhaps, extend our lifespan, as discussed in the accompanying article. There is growing evidence that resveratrol has cardioprotective effects through a variety of mechanisms: it inhibits platelet aggregation, the proliferation of smooth-muscle cells, and the oxidation of LDL-cholesterol (probably through its strong antioxidant effects); it reduces the synthesis of certain lipids and eicosanoids that tend to promote atherosclerosis; and it suppresses certain cardiac arrhythmias (irregular heartbeats). Some of these effects may be due in part to resveratrol’s being a phytoestrogen, i.e., a plant compound that has biological activities similar to those of estrogens.1 Furthermore, resveratrol has demonstrated anticarcinogenic activity: it inhibits cellular events associated with the initiation, promotion, and progression of tumors through a wide range of actions that are still poorly understood. It appears to help detoxify carcinogens, to inhibit the synthesis of various cancer-related compounds, and to stimulate the genetic mechanism for the apoptosis (programmed death) of cancer cells. Much of the scientific evidence for resveratrol’s benefits is discussed in the PDR for Nutritional Supplements, which provides 35 references to the literature on the subject.2 The authors emphasize that most of the evidence is derived from animal and laboratory studies (which can sometimes be misleading), and that more and better human clinical trials are needed to confirm the results. Nonetheless, there is no doubt that resveratrol is a genuinely important molecule for good health. Gehm BD, McAndrews JM, Chien PY, Jameson JL. Resveratrol, a polyphenolic compound found in grapes and wine, is an agonist for the estrogen receptor. Proc Natl Acad Sci USA 1997 Dec;94:14138-43. Hendler SS, Rorvik D, eds. PDR for Nutritional Supplements. Medical Economics Company, Montvale, NJ, 2001, pp 397-401. NEWSFLASH: Resveratrol Extends Lifespan In light of all the above, imagine how surprised and pleased the Harvard/BIOMOL scientists were by the results of their search for a chemical compound that could help extend the lifespan of baker’s yeast (Saccharomyces cerevisiae), a simple fungal organism. After screening a great many candidate compounds, the most potent one turned out to be . . . resveratrol, a substance that, as we have seen, already has a number of major health benefits for humans to its credit.1 Preliminary results reported by the same research group indicate that resveratrol can also extend lifespan in certain species of roundworms (Caenorhabditis elegans) and fruit flies (Drosophila melanogaster). Experiments with mice are currently being planned, and after that, monkeys (the tests on monkeys will take several decades to complete). If extending the lifespan of yeast and worms and flies doesn’t sound all that exciting, consider this: the researchers also used cultured cells from a much higher organism—a human being—to test resveratrol’s ability to promote cell survival after DNA damage caused by ionizing radiation. Resveratrol did exactly that, convincingly. What is most remarkable about these results, however, is that in all four cases—fungus, worm, fly, and human cells—resveratrol apparently exerted its life-extending effect by stimulating the action of the same genes! Sirtuins—Proteins from Longevity Genes Early in the history of life on earth, a class of genes evolved whose apparent purpose was to confer a survival advantage on organisms during exceptionally stressful times, such as when food was scarce and reproduction would be imprudent because the offspring would probably starve to death. The genes accomplished their task in certain ways that gave cells additional time to repair DNA damage and avoid unnecessary death, thereby extending their life. If, as a result, the organisms did manage to survive the hard times, they could then resume normal life functions, including breeding to propagate their species. It turns out that these longevity genes, called Sir2 genes, were evolutionarily conserved, meaning that they’re now found (with some variations in form and function) in the DNA of virtually all living things—not just bacteria and fungi, but also plants and animals. And that means that, if they can extend lifespan in yeasts (and probably in roundworms and fruit flies, and perhaps in mice and monkeys), then perhaps they can do the same in humans—whole humans, not just their cultured cells. The actual mechanism of life extension occurs through a process called gene silencing, which is carried out by the proteins that the Sir2 genes code for (that’s what genes do—they provide coded information for the synthesis of specific proteins). These proteins now have a catchy name, sirtuins (sir-TWO-ins), as befits their growing celebrity status in the scientific world. Exactly how they accomplish their mission is naturally of intense scientific interest. How Much Resveratrol Does Wine Contain? The concentration of resveratrol in red wines is typically about 10 times higher than in white wines. In either case, it varies widely, depending mainly on the type and severity of microbial attack on the vines that year, but also on many factors in both the grape-growing and winemaking practices, such as pruning methods and fermentation conditions. The concentration typically ranges from zero to a few micrograms per milliliter (mcg/ml). Since a reasonably full wine glass contains about 150 ml (5 fl oz), a concentration of 1.5 mcg/ml of resveratrol (which is about average) would give 225 mcg, or 0.225 mg, per glass—far less than the multimilligram amounts of resveratrol found in nutritional supplements. Wines that tend to have the highest amounts of resveratrol come from cooler growing regions or regions that are subject to greater disease pressure, such as Burgundy (Pinot Noir is a prime example) and New York. Wines from hot, dry regions, such as California and Australia, usually have lower amounts. An environmental factor that appears to have a significant effect on resveratrol content is high altitude (such as that of Argentina’s Cafayate Valley, at 6000 feet), where solar ultraviolet radiation is intense. This stimulates the abundant synthesis of polyphenols—a bonus that, by a nice coincidence, not only enhances our health but also gives the wines greater complexity. Resveratrol Mimics the Effects of Caloric Restriction Which brings us back to resveratrol. The researchers wanted to find a compound that could stimulate sirtuins to “do their thing” even in the absence of the stress caused by food deprivation. In other words, they wanted to fool the body into thinking it was being calorically restricted, i.e., getting nutritious food, but a lot less of it than would normally be consumed. Resveratrol filled the bill better than any other compound tested: not only did it extend the yeasts’ average lifespan—by 70%!—but it significantly extended their maximum lifespan as well. Real caloric restriction—a 30% reduction in caloric intake, indefinitely—is the only mechanism known to extend the lifespan of laboratory animals, and it works in many lower organisms as well (it would probably work in humans too, but for some reason, we’ve never exactly embraced this means of living longer). In mammals, it reduces the incidence, or delays the onset, of various age-related diseases, such as diabetes, osteoporosis, and some cancers and neurodegenerative diseases. It can extend lifespan by up to 50% in some mammals, and by as much as 90% in certain fruit flies. Is Resveratrol the Holy Grail? Baker's yeast, Saccharomyces cerevisiae It may be no coincidence that resveratrol, a molecule designed by nature for the purpose of protecting grapes from microbial attacks and other environmental stresses, also extends lifespan in yeast (the same yeast, by the way, that plays such a prominent role in converting grape juice to wine) and, apparently, in roundworms and fruit flies. Perhaps it will prove to have the same effect throughout the entire animal kingdom. To find such a universal life-extending molecule that works directly on the longevity genes (or on the proteins they code for) is the Holy Grail of aging research, and it appears that this goal may now be in sight. It will take much more research to tell for sure, however, and the world will be waiting expectantly for every bit of news from the laboratories devoted to this pursuit. You can bet that Life Enhancement will stay on top of this story. Meanwhile, it couldn’t hurt to get on the resveratrol bandwagon by taking it in its most reliable form: nutritional supplements. References Howitz KT, Bitterman KJ, Cohen HY, Lamming DW, Lavu S, Wood JG, Zipkin RE, Chung P, Kisielewski A, Zhang LL, Scherer B, Sinclair DA. Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature 2003 Aug 24:5 pp (online). Siemann EH, Creasy GL. Concentration of the phytoalexin resveratrol in wine. Am J Enol Viticult 1992;43:49-52. Hendler SS, Rorvik D, eds. PDR for Nutritional Supplements. Medical Economics Company, Montvale, NJ, 2001, pp 397-401. Will Block is the publisher and editorial director of Life Enhancement magazine.