If you’ve tuned into the resveratrol story over the past five years, you’ve probably heard that you’d need to take giant doses of the red-wine ingredient to do any good. That idea was based on mouse studies in 2006 that showed massive doses of the compound blocked bad effects of eating too much fat. A front-page New York Times story on the studies, memorably headlined “Yes, Red Wine Holds Answer. Check Dosage,” conveyed the conventional wisdom at the time that “a 150-lb person would need to drink 750 to 1,500 bottles of red wine a day to get such a dose.”
Recent placebo-controlled clinical trials with resveratrol, however, suggest that much smaller doses—maybe a tenth as much as suggested by the Times‘ story—can have significant cardiac benefits. These smaller doses are still too large to get from drinking wine—you’d need to take resveratrol pills to equal them. But evidence is plainly growing that a rethink is in order.
Before we get into rethinking, you should note that a recently published “Systematic Review and Recommendations on the Use of Resveratrol” by 21 scientists concluded that while the animal data on the compound are “promising,” it’s too early to recommend that people take resveratrol supplements. Despite the fact that there are now well over 4,000 published research papers concerning resveratrol, that’s not surprising. Until large, rigorous clinical trials with it are conducted, little can be said with confidence about its effects in people. Unfortunately, it’s likely that we’ll all be long-goners before such trials are conducted. The reason: Resveratrol supplements are low-margin products that don’t generate enough profits for their makers to support funding of large clinical trials, which could easily cost hundreds of millions of dollars. Not surprisingly, the recent trials were small and brief.
Still, the picture has become a little clearer since the 21 scientists duly weighed in as agnostics on resveratrol. As I mentioned in my recent blog on sirtuin news for mammals, the latest resveratrol studies have indicated that chronic daily doses on the order of 100 to 200 milligrams induce metabolic changes that presumably can improve cardiovascular health, including lowered systolic blood pressure. By comparison, the human-equivalent dose mentioned in the 2006 New York Times story on the tubby mice was 1,344 milligrams—about ten times as much. Some resveratrol makers encourage people to pop such megadoses by hawking pills containing 1,000 or more milligrams. That’s a lot: While resveratrol has been deemed safe at daily doses up to 5,000 milligrams in trials with healthy volunteers, transient diarrhea and nausea have reportedly occurred in some people at doses over 1,000 milligrams a day—see here for more on this.
But why would the surprisingly small doses produce readily measured benefits in people? After all, various studies have found that resveratrol is very quickly metabolized away—peak blood levels occur only about 30 minutes after doses are ingested, followed by rapid disappearance of the compound from the bloodstream.
One possibility is that resveratrol’s “metabolites”—relatively long-lasting compounds produced as the body breaks down and eliminates resveratrol—have resveratrol-like effects. A few studies (here’s a recent one) have suggested that these metabolites do have such effects on various enzymes. In addition, some of the metabolites may be slowly turned back into resveratrol in the liver. But it’s still not clear whether the metabolites have significant effects.
Another take on the dosage issue was offered in 2007 by Wisconsin researchers who spotted a glaring mistake in media reports on the topic. As they observed, medical writers (including me, by the way) naively assumed that it made sense to calculate a human-equivalent dose (HED) from the mouse data by assuming that people are, metabolically speaking, the same as heavy mice. In one of the 2006 studies, mice were given 22.4 milligrams of resveratrol per kilogram of body weight; thus we reporters presumed that the HED for a 60-kilogram person (that’s about 132 pounds ) would be 60 times 22.4 milligrams, or 1,344 milligrams—the dose specified in the New York Times piece. But that’s not how the pros do it, the Wisconsin researchers pointed out. Drug developers calculate HEDs based on body surface area, not weight. This method, officially endorsed by the FDA, goes back to the late 1800s, when it was discovered that mammals’ oxygen utilization, calorie expenditure and blood volume are much more closely correlated with body surface area than with weight. Based on the surface-area method, the human equivalent of the resveratrol dose given to the fat mice is a mere 109 milligrams for a 60-kilogram person, not 1,344. Whoops.
As it happens, some of the most interesting cardiovascular-related animal studies on resveratrol have been conducted not in mice, but in special strains of rats prone to high blood pressure. In 9 of 11 such studies, resveratrol doses were found to reduce the rodents’ elevated blood pressure, according to the systematic review cited earlier. In these studies, rats got daily doses of 10 milligrams per kilogram of body weight or higher. Based on the surface-area method, the human equivalent of a 10-milligram rat dose per kilogram of body weight would be 97 milligrams for a 60-kilogram person.
Importantly, these remarkably consistent rat studies fit nicely with the recent human clinical data on resveratrol, as well as with a well-established mechanism that may partly explain the compound’s cardiovascular benefits: Since the early 2000s researchers have known that resveratrol stimulates release of a compound called nitric oxide, or NO, from “endothelial” cells that line the inside walls of arteries. Since NO causes arteries to dilate, this probably enables resveratrol to lower blood pressure. In 2007, University of Pittsburgh researchers discovered that resveratrol likely boosts NO, at least in part, by revving up a sirtuin enzyme called SIRT1. Earlier this year, a team at the University of Colorado shed further light on the topic by showing that production of SIRT1 by endothelial cells falls dramatically with age in both mice and humans, and that aging arteries get stiffer and less elastic in tandem with this change, impairing their ability to readily dilate. (Reduced artery elasticity is closely correlated with heightened risk of atherosclerosis and heart disease.) All these parallel findings suggest that resveratrol may retard key aspects of artery aging by stimulating SIRT1.
In sum, a heartening number of mostly consistent studies in cell culture, rodents and humans indicate that resveratrol helps promote cardiovascular health, at least in part by stimulating SIRT1. The studies still fall short of what it would take to convince medical authorities to recommend that people at elevated risk of heart disease try resveratrol. But I wonder how many of those experts are now quietly taking the stuff themselves—at modest doses, of course.