Does Resveratrol Help You Live Longer? (Part 1)

There are all kinds of claims about the red wine compound resveratrol. One is that it helps you live longer, and it benefits your metabolic health.  So, what do the facts say? In our first story – we ask, “Is the red wine molecule responsible for the French Paradox”?

Resveratrol became a household word in 1991, when a scientist from Bordeaux University appeared on the popular TV show “60 Minutes” and attributed the so-called French Paradox to the French habit of drinking red wine. The term “French Paradox” itself was coined in the newsletter of the International Organization of Vine and Wine to explain a curious finding.

If you chart death from heart attack versus the amount of saturated fat and cholesterol consumed in different countries, there appears to be a straight line. The more animal-based foods populations eat, the higher their death rates appear to be. However, two countries didn’t fall in line with that straight line. Finland seemed to be doing worse than expected, and France appeared to be doing better than expected. Hence, the paradox. How could France have saturated fat and cholesterol intake similar to Finland, but five times fewer fatal heart attacks?

Everyone had their pet theories to explain the paradox. Was it the wining? Was it the dining? Yes, animal foods are associated with coronary heart disease mortality, but plant foods appear to be protective. So, might the fact that the French were eating four times as many vegetables help account for their lower death rates? It turns out, however, that there may be no paradox at all.

According to an investigation by the World Health Organization, French physicians were just under-reporting heart disease deaths on the death. So, if you correct for that, France basically comes right back in line with the death versus animal fat and death versus cholesterol lines, with about four times the fatal heart attack rates as Japan, and about four times the animal fat consumption. By the time of the correction, however, resveratrol research had already taken root, culminating in more than 17,000 scientific publications to date.

But only about 1 to 2 percent of the published reports were human clinical trials, and after many millions of dollars spent and many years of disappointing results, the scientific tide started to turn. Reviews began to ask whether resveratrol was a molecule whose time had come and gone: “Should we now consign resveratrol to our intellectual garbage cans and move on to better things?” Of course, it didn’t help matters when a leading resveratrol researcher was found guilty of 145 counts of fabrication and falsification of data, throwing the whole field into turmoil.

But in 2013, resveratrol was primed to make a comeback with the apparent confirmation that it was a STAC, a sirtuin-activating compound––that is, a compound that purportedly activates a longevity enzyme. This has been called into question, though. Commentaries with titles like “Is resveratrol an imposter?”, “Promising therapeutic, or hopeless illusion?”, and “The resveratrol fiasco” were published, suggesting that the seeming sirtuin activity was probably the result of experimental artifacts. “In summary,” a recent review concluded, “the jury is out.” The proof is in the pudding, though. Does resveratrol enhance longevity or not?

Yeast is the big success story, with resveratrol extending the lifespan of brewer’s yeast by up to 70 percent. Resveratrol also helped microscopic roundworms live longer, but it failed fruit flies, mosquitoes, and water fleas. Anything bigger than a unicellular fungus or a microscopic worm? Yes, resveratrol can extend the lives of honeybees, and, most excitingly, two vertebrates, short-lived fishes: Gunther’s and turquoise killifish. Unfortunately, most studies on mammals (mostly mice) failed to show a lifespan benefit.

Resveratrol is said to extend the lives of so-called model organisms by mimicking caloric restriction. But flies and mice show robust life-extension responses to dietary restriction, yet don’t seem responsive to resveratrol. That may just be true of healthy animals, though. Give resveratrol to mice in extremis, whether bombarded by radiation, poisoned with endotoxins, or having their intestines punctured to cause sepsis-induced kidney failure, and they do survive longer with resveratrol than they otherwise would under those conditions. Resveratrol can also help mediate the life-shortening effects of high-fat diets in mice.

The lifespans of healthy mice and rats fed normal diets are not affected by resveratrol, but the compound partially prevented the premature deaths of mice fed high-fat diets.

The authors of a meta-analysis of the effect of resveratrol on longevity across species concluded that, based on the fact that most mouse studies failed to show a benefit, it’s “inappropriate for resveratrol to be marketed as a life-extending health supplement.” True, no study has demonstrated resveratrol lifespan extension in healthy rodents, only in “metabolically-compromised mammals.” But isn’t that a pretty accurate description of most of the U.S. population these days?

Studies on monkeys fed diets high in butterfat and sugar found that resveratrol decreased artery and abdominal fat inflammation. Combined with the shift towards normalizing the lifespans of mice on high-fat diets, pharmacology journal commentaries were published with titles like “Resveratrol—Pills to replace a healthy diet?”, speculating whether “resveratrol is the compound that will allow us to be more and more inactive while eating too much in general and too much fat and sugar in particular.”

Yes, a nutrition journal editorial entitled “Dodging physical activity and a healthy diet” conceded, exercise and dietary modification are the “most potent, cheapest, and easiest ways to prevent lifestyle-related chronic diseases,” but might resveratrol on its own “take the edge off the consequences of your lifestyle?” No wonder annual sales of resveratrol supplements reached $30 million in the U.S. alone. Approaching the peak in interest around the time Oprah Winfrey mentioned it in 2009, it was estimated that two-thirds of people in the United States taking multiple daily dietary supplement regimens included resveratrol. But what do the human data show? I’ll cover that next.

To see if the amount of resveratrol you get from drinking red wine might be beneficial, researchers looked to the Chianti region of Tuscany to determine whether the levels achieved through diet help protect against long-term frailty, inflammation, cardiovascular disease, cancer, or death. And the answer? None of the above. The amount of resveratrol flowing through their systems didn’t correlate with any of the health outcomes studied over nine years of follow-up. This is surprising, even if only because of the confounding factors associated with wine consumption.

Wine drinkers may be less likely to smoke, and tend to have higher IQ, higher parental education levels, and higher socioeconomic status––which would be expected to correlate with better health outcomes. (In contrast, beer drinkers suffer the opposite—lower IQ, parental education, and social class. The average IQ of wine-drinking men is 113, compared to 95 among beer-drinking men). Yet still, there appeared to be no correlation between resveratrol exposure and wellbeing. This may be because wine-drinking populations may only be averaging less than a milligram of resveratrol a day.

Some “experts” recommend a daily dose of 1 gram of resveratrol, based on the dosing used in laboratory animal studies. How much red wine would you have to drink to get that much? Eight thousand glasses a day. Not a fan of red wine? A couple thousand gallons of white wine a day would do it, or 5,000 pounds of apples or grapes, 50,000 pounds of peanuts, a couple thousand pounds of chocolate, or nearly a million bottles of beer, on the wall.

The natural levels of resveratrol found in foods and beverages is not considered to be sufficient to elicit health effects, but that doesn’t necessarily mean supplements wouldn’t work. However, the bioavailability of even high-dose resveratrol has been called into question. Maximum blood levels after resveratrol supplementation can be as low as 40 nanomolar, which is more than a hundred times lower than the 5,000 to 250,000 nanomoles used in vitro to demonstrate resveratrol effects. Even a five-gram dose of resveratrol may fall short of the required level. This is in contrast to rodents, in which blood levels of 32,000 have been reported.

Resveratrol is rapidly absorbed in humans, but is rapidly metabolized in our intestine and liver. So, very little free resveratrol remains. But, there are about 20 resveratrol-derived metabolites that can end up in circulation at much higher levels, like 20,000 nanomolar, that might have biological activity of their own.

What about using the turmeric trick of adding black pepper to suppress our body’s natural detoxification mechanisms? It works in mice. The black pepper compound piperine increases maximum blood concentrations of resveratrol more than 1,000 percent. But, unfortunately, it failed to significantly alter blood levels in people.

In a 2014 medical journal editorial entitled “The resveratrol fiasco,” the editor-in-chief summarized the state of the science: “The conclusions are quite clear-cut: after more than 20 years of well-funded research, resveratrol has no proven human activity.” However, since that publication, more than 150 human clinical trials have been published. What’s the update?

Resveratrol was initially envisaged as an antioxidant, but meta-analyses of randomized controlled trials of resveratrol supplements failed to find clinically or even statistically significant effects on systemic markers of oxidative stress, helping to explain the lack of apparent DNA protection.

Maybe it only helps with the metabolically compromised? As one resveratrol review asked, “What conclusions would we draw about the efficacy of penicillin if it had been tested only among persons in the pink of condition?” Resveratrol does not appear to improve the metabolic function of nonobese, nondiabetic individuals, or even benefit overweight nondiabetics. Nor does it help people lose weight. But resveratrol may help with blood sugar control in diabetics. For almost all outcomes measured in randomized controlled trials of type 2 diabetes, metabolic syndrome, or nonalcoholic fatty liver disease, the effects of resveratrol were trivial, but a meta-analysis did find that doses ranging from 5 to 500 mg twice a day resulted in an average 20-point drop in fasting blood sugars.

There was also a significant benefit for longer-term blood sugar control, though this only appeared to be the case in shorter-term studies. What is the point of better longer-term control, if it only works in studies lasting less than three months?

Diabetic foot ulcers are the leading cause of lower-limb amputations in diabetics. A randomized, double-blind, placebo-controlled trial of 50 mg of resveratrol twice a day showed accelerated healing of diabetic foot ulcers by about 1 cm over placebo within 60 days. So, at least there’s one condition it may help.