Revisiting Resveratrol

Julian Whitaker, MD

When resveratrol burst onto the scene a few years ago, it was the toast of the town. The “red wine pill” was heralded as a potential cure for everything from heart disease to cancer and the answer to aging. Has it lived up to its hype? Let’s take a look.

Turns on Survival Genes

Resveratrol is a naturally occurring compound that is concentrated in the skins of red grapes and thus in red wine. It is also found in smaller amounts of peanuts, cranberries, blueberries, and dark chocolate and is particularly abundant in the roots of a plant called Japanese knotwood (Polygonum cuspidatum), which is a primary source of resveratrol in nutritional supplements.

Most of the buzz surrounding this phytonutrient focuses on its effects on the sirtuin family of enzymes. Enzymes are proteins that catalyze (initiate and speed up) chemical reactions, and sirtuin enzymes play multiple roles in health and longevity. They facilitate DNA repair and maintain genome stability, protect against oxidative stress, and reduce inflammation. Bottom line, these enzymes increase cell survival. In lower organisms such as yeast, flies, and worms, a sirtuin called SIR2 is a key mediator of lifespan, and its counterpart in mammals, SIRT1, has similar though more complex functions.

We’ve known since the 1930s that calorie restriction reduces age-related disease and increases lifespan—this has been demonstrated in every species from fruit flies and nematodes to mice and monkeys. We now know that this is due in large part to sirtuins. Calorie restriction switches on the genes that kick these protective enzymes into high gear. It’s an elementary, evolutionary mechanism that ensures survival during times of famine and food deprivation.

Well, resveratrol does the same thing. It, too, turns on sirtuin genes—even when you’re eating a normal or high-calorie diet.

Astonishing Animal Studies

In a landmark study published in 2006, David Sinclair, PhD, and colleagues at Harvard University showed that when mice ate a high-fat, high-calorie diet plusresveratrol beginning at 12 months of age (equivalent to age 40 in humans), they not only lived about 30 percent longer than a control group, but they also had significantly fewer age-associated health problems. All of the mice on this rich diet got fat. However, the supplemented animals had enhanced insulin sensitivity, fewer fatty deposits in the arteries and liver, lower levels of inflammation, and better balance and motor skills. Resveratrol in essence negated the damaging effects of a poor diet, obesity, and aging.

These remarkable results ignited interest in the scientific community, and to date, more than 3,400 peer-reviewed journal articles have been published on this compound. Although most of the studies have involved rodent models of human disease, they leave no doubts about resveratrol’s therapeutic potential. This phytonutrient has been shown to reduce risk of cataracts, kidney dysfunction, and inflammatory bowel disease. It staves off strokes and heart attacks, strengthens bones, and improves lung function. And it protects against neurodegenerative disorders such as Alzheimer’s and improves memory, learning, and brain plasticity.

Resveratrol also positively influences multiple aspects of metabolic syndrome. In addition to increasing insulin sensitivity, it enhances endothelial function and reduces arterial stiffness. Coupled with its ability to increase exercise endurance, stimulate fat burning, and hinder fat storage, resveratrol just may be able to help stem the tide of three of our most widespread problems: obesity, type 2 diabetes, and heart disease.

Last but not least, resveratrol protects against several types of cancer, including  colon, stomach, esophagus, liver, lung, pancreas, breast, ovary, cervix, prostate, prostate, skin, thyroid, melanoma, leukemia, and lymphoma.

Beyond Sirtuins

In addition to its effects on sirtuin enzymes, resveratrol works its magic in other ways, and one is inhibition of angiogenesis. Under some circumstances, angiogenesis is a good thing—it’s necessary, for example, for wound healing and tissue repair. But it also has a destructive side. In many types of cancer, angiogenesis creates networks of blood vessels that feed tumors. And in degenerative eye disorders such as age-related macular degeneration and diabetic retinopathy, overgrowth of blood vessels causes leakage and scarring that lead to vision loss.

Researcher from Washington University in St. Louis recently discovered that oral resveratrol put the brakes on angiogenesis in the retina. Abnormal blood vessels simply disappeared! This is promising for the treatment of not only macular degeneration and retinopathy but also cancer—and may partially explain resveratrol’s proven anti-cancer effects. It also suggests that resveratrol has multiple mechanisms for enhancing health, and findings to date may only be the tip of the iceberg.

Effective and Safe

To return to the original question, whether or not resveratrol has lived up to its hype, the answer is a resounding yes.

Some say it’s best to wait for the results of human studies, but that could be years. Clinical trials are just getting underway examining resveratrol’s effects on patients with type 2 diabetes, metabolic syndrome, Alzheimer’s disease, lymphoma, metastatic colorectal cancer, and multiple myeloma. Sure, animal data isn’t 100 percent applicable to people, but solid epidemiological evidence—much of it on the health effects of red wine—and clinical experience of thousands of patients underscore resveratrol’s effectiveness in humans.

Others point to lack of proof of safety. I disagree. First, this natural, nontoxic, compound has been part of the human diet for millennia; and in concentrated form as a traditional Chinese medicine remedy, hu zhang, it has long been used to treat a variety of ailments. Second, although I don’t recommend doses this high, study volunteers have taken up to 5,000 mg per day for prolonged periods with no adverse effects. And third, untold numbers of people have been taking resveratrol for years on end. Thanks to intense media exposure—including coverage on Oprah, 60 Minutes, and Good Morning America—supplement sales have exploded. If it were causing problems, believe me, we’d hear about them. But, according to the National Institutes of Health, no serious adverse side effects have been reported. What we hear instead is how resveratrol improves endurance, energy, concentration, and other parameters of well-being.

High doses of most anything may cause gastrointestinal upset in sensitive individuals. However, the only potential safety issue I’m aware of—and it is far from definitive—involves not natural resveratrol but a patented, far more potent resveratrol-based experimental drug called SRT501. SRT501 was formulated by Sirtris Pharmaceuticals, a biotech company cofounded by David Sinclair, the Harvard researcher who conducted the groundbreaking 2006 study, and sold to GlaxoSmithKline in 2008 for a cool $720 million! Their multiple myeloma phase 2 clinical trial was recently temporarily suspended due to safety concerns. However, it is not unusual for Big Pharma to change the chemistry of a safe, natural substance in order to patent it and turn it into a blockbuster drug that is almost always far more toxic than the original compound.

Should You Take Resveratrol?

I believe that resveratrol is a good addition to a daily supplement regimen for anyone who is concerned about the degenerative diseases of aging—and who over a certain age isn’t? In some of the studies I mentioned earlier, the best results were observed in mice who started taking resveratrol at 12 months of age (about 40 human years), but positive effects have also been noted when it was begun at 19 months (corresponding to 60-year-old people).

Of course, you’ll get some resveratrol if you drink red wine, 1-2 mg per glass, but you’d have to drink dozens of bottles a day to get therapeutic levels of 100-250 mg. You could also get similar sirtuin enzyme-related benefits by cutting your daily caloric intake by about one-third. But the easiest, most prudent way to boost your anti-aging defenses is to take resveratrol supplements—and the sooner you start the better.

Recommendation

• The recommended dose of resveratrol is 100-250 mg per day. Be aware that the market is saturated with resveratrol supplements, so read labels carefully and buy from a reputable manufacturer. I suggest looking for a standardized extract of trans-resveratrol such as ResVinol-25, which contains trans-resveratrol from both Japanese knotweed root and red grapes. Look for it in stores and online or call (800) 810-6655 to order.

References

• Baur JA et al. Resveratrol improves health and survival of mice on a high-calorie diet. Nature. 2006 Nov 16;444(7117):337-42.
• Fischer-Posovszky P, et al. Resveratrol regulates human adipocyte number and function in a Sirt1-dependent manner. Am J Clin Nutrition. 2010; 92:5-15.
• Khan AA, et al. Resveratrol regulates pathologic angiogenesis by a eukaryotic elongation factor-2 kinase-regulated pathway. Am J Pathol. 2010 Jul;177(1):481-492.
• Sinclair DA et al. The Resveratrol Fact Book. Resforum.org. 2009.http://www.resforum.org/index.php/e-book/resveratrol_fact_book

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