The legend of Resveratrol

In August 2003, when scientists revealed the life-extending powers of trans-3,4,’5-trihydroxystilbene – also known as resveratrol – its earthly form had all the allure of an apple in the garden of Eden. Ruby red, delicately fragrant, shapely in a rounded nest of glass, red wine can deliver as much as 1.5 milligrams of the plant compound resveratrol per four-ounce serving.

At concentrations present in a person’s blood after two glasses of red wine, resveratrol has been found to suppress the formation of blood clots and boost the efficiency of immune system cells.

Much larger doses increase the life span of yeast, flies, fish and roundworms, studies have shown. A feeding regimen that includes resveratrol makes obese mice just as healthy, spry and long-lived as those who have been raised on near-starvation diets.

So leave it to American entrepreneurs to gin up a thriving market for a resveratrol supplement rather than urge consumers to enjoy the food – or in this case, savor the drink – linked to better health and longer life.

Remarkable claims for resveratrol supplements abound: They will forestall or prevent such age-related scourges as cancer, diabetes, arthritis and Alzheimer’s disease; they will restore vitality, endurance and strength to the middle aged and older; they will make aging brains sharper and more agile.

But the business of selling the supplement touted as an “anti-aging miracle” rests on a foundation of science that is as unstable and incomplete as it is promising.

“I am surprised at the interest, if you consider that the long-term effects in humans are not known,” says David Sinclair, the Harvard Medical School pathology professor who has pioneered research on resveratrol and the family of genetic pathways on which the plant compound acts.

“The short-term effects are fine,” Sinclar says. “But we don’t know what happens if you take this for two decades. There are thousands of people performing a massive experiment.”

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The research on resveratrol is in its infancy.

To date, its most exciting possibilities have been demonstrated only in experiments conducted in petri dishes, on organisms such as yeast and roundworms, and in mice. A single study on rhesus monkeys is almost a year from completion.

A dozen human trials on resveratrol (or on drugs derived from it) are under way or have recently been completed. But only two are in the third and final phase of testing.

Two small studies – neither of which has been published in a scientific journal – have pointed to the possibility that resveratrol might improve exercise endurance and regulate blood sugar in diabetics. But scientists are likely years away from establishing the safety of using large quantities of resveratrol for long periods of time.

The drug giant GlaxoSmithKline, having paid $720 million last year for the commercial rights to some of the earliest research on resveratrol, is seeking ways to mimic its broad spectrum of effects in a compound created in the lab rather than grown on a vine.

Sinclair, who heads the company’s efforts, says his research focuses on some 4,000 synthetic versions of resveratrol that may more powerfully blunt inflammation, block tumor growth and boost the removal of toxins and cellular debris.

“The drugs in trials now will hopefully make resveratrol look like ancient history,” he says.

But science is slow. Sinclair said in an interview that it could be five to seven years before a drug based on resveratrol could get a nod from the Food and Drug Administration.

For the purveyors of vitamins, minerals and herbal remedies, that is a five- to seven-year opportunity not to be missed.

While they wait for science to flesh out resveratrol’s promise, consumers’ demands for the stuff can be encouraged and satisfied with products that offer plenty of promise but tread lightly around the preliminary state of the scientific evidence.

“There’s a watershed time for a good nutraceutical,” says Dr. Joseph Maroon, a University of Pittsburgh neurosurgeon, author of a book titled “The Longevity Factor” and co-founder of a company, Xenomis, which rolled out a line of resveratrol-based supplements last May.

Compared with the markets for many other dietary supplements – Omega-3, CoQ10, Vitamin D and calcium – the market for resveratrol supplements is tiny.

James Betz, managing director and founder of Biotivia, one of the leading suppliers of resveratrol products, estimates that the worldwide market for resveratrol supplements may stand at just $20 million per year – making it a modest newcomer on the dietary supplements block.

“But our sales are ticking up rather dramatically now,” Betz says. “I think it could become as popular as, let’s say, multivitamins.”

The supplements sell on the Internet and in stores for prices that range from about $15 to close to $150 per bottle (typically a one- or two-month supply, since dosage recommendations vary widely).

To bring resveratrol to a growing market inexpensively, supplement makers have taken to extracting the plant compound not from grapes or wine but from an exotic weed: Polygonum cuspidatum, or Japanese knotweed.

They are mixing it with a wide variety of other dietary supplements (including the antioxidant acai, which also has taken the supplements world by storm), capturing it in a pill, capsule, powder and even a topical cream.

Among its many commercial manifestations, resveratrol is sold as Trans-Max, Nitro-250, Vindure, Sustain-Alpha, Resveratrol-Forte and Resveratin. Supplements may contain as little as 25 milligrams and as much as 1 gram of resveratrol per dose.

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The flurry of commercial activity has taken off despite the fact that researchers don’t know exactly what resveratrol does.

Betz and others vying for a share of the market say there is no need to wait until a welter of slow-moving clinical trials has established resveratrol’s life-extending powers in humans, not to mention its safety, to encourage the use of large doses.

“I feel there is virtually no evidence so far – and resveratrol has been around for quite a while – of harm,” he says.

“And I feel given the data we have now, which concludes it has benefits in terms of so many diseases … that it will do more harm than good not making it available.”

But until clinical trials provide the answers to questions on, among other things, the proper dose, Rafael de Cabo, a National Institute on Aging investigator who has co-written most of the pioneering studies on resveratrol, says he wouldn’t consider taking a resveratrol supplement. And he certainly would not recommend them.

At the same time, DeCabo acknowledges that many scientists and physicians, impressed by research suggesting resveratrol’s potential to forestall diseases of aging, have set aside such scientific discretion and publicly acknowledged they take resveratrol supplements.

“I know many intelligent people who are taking it,” DeCabo says. “They are taking their health in their own hands.”

Web sites selling resveratrol supplements routinely feature videos and links to talk show host Oprah Winfrey and her medical adviser, Dr. Mehmet Oz. Harvard Medical School is quoted, movie-blurb-style, as calling resveratrol “the biggest medical discovery since antibiotics!”

Although Oz did appear on Winfrey’s show with concentrated resveratrol capsules in his hand and tell viewers they “might want to try it out,” both of them have insisted they endorse no products, and Harvard Medical School has issued no such assessment.

While resveratrol has appeared generally free of side effects in animals, DeCabo warns that “everything has a toxicity” and that the limits of safety are far from clear.

He and his colleagues have found that at very high doses – far higher than any supplements currently on the market – resveratrol was toxic to mice after six months.

“We need to understand exactly how these molecules work, at what doses and for what disease,” DeCabo says. “Unless you have scientific evidence, you’re a snake oil seller.”