Dov Michaeli MD, PhD, explores myths in medicine, starting with the myth that resveratrol mediates health benefits of red wine
This is Part 1 of RIP: The Death of Two Myths. You can find Part 2 here.
“To your health”! “Santé”! “Zaz darovje”! “Zu Gesunt”! “Lehaim”!
So goes the cheer in dozens of cultures and languages when we raise a glass of red wine, the color of ruddy good health. For ages (over 10,000 years, to be more precise) we took it on faith that drinking red wine will make you healthy, and a lot happier. Then came the scientific foundation: Resveratrol, the antioxidant polyphenol found in the skin of red grapes, interacts with a family of transcription proteins called sirtuins that modulate the expression of genes that regulate cell metabolism.
A bit of resveratrol history
Resveratrol was discovered when the theory that antioxidants inhibit the damage wrought by oxygen free radicals enjoyed enthusiastic acceptance. Their benefits were extended to cardiovascular health and to longevity in general. The initial evidence was based on in vitro studies, followed by in vivo studies on fruit flies and roundworms. The in vitro studies suffered from many deficiencies. To name a couple, the concentrations used in these studies varied widely, and in many of them were of industrial strength. Also, polyphenols are pleiotropic, meaning that they affect many biological pathways, some that have nothing to do with free radicals. This of course makes it difficult, if not impossible, to ascribe any effect to a particular mechanism.
Yet, polyphenols were the rage, red wine and chocolate are a pleasure to take, and voilà, we could eat and drink and live forever like the gods on Mt. Olympus. I have admit it. I loved the concept. I didn’t let the murkiness of the polyphenol evidence keep me awake at night. With such pleasurable rewards, why bother with trivial misgivings? I forgot a basic maxim that had kept me out of trouble in science: if it sounds too good to be true, it probably is.
After the intoxicating glow of the first love affair, the cold light of the morning after invariably follows. The in vitro studies came under critical scrutiny. The animal studies showed a disturbing trend: In insects, the longevity effects of Resveratrol were spectacular; on roundworms less so, but still impressive. But climbing up the phylogenetic ladder to mice yielded downright contradictory result.
To make matters worse, a prominent researcher in the field, Dipak Das, Ph.D, director of the University of Connecticut Cardiovascular Research Center, fabricated and falsified data in 23 papers published from 2005 to 2009. How did he get away with it for so long? By publishing in such obscure journals as Agriculture and Food Chemistry and Free Radial Biology. The impact his papers had on scientific thinking in the fields of cardiovascular health and longevity is still undergoing damage assessment.
What about resveratrol in humans?
Regardless of all the sturm and drang of scientific controversies, sometimes the biological benefit is there for all to see. Take aspirin, for instance. It has been in clinical use for over a century. Mechanisms galore were proposed, dismissed, demonstrated only to be debunked, and finally incontrovertibly established as a prostaglandin inhibitor. So now we know everything there is to know about aspirin? Not by a long shot. Many clinical effects cannot be accounted for by pure inhibition of cyclooxygenase 1 and 2, the target enzymes of aspirin. As they say, more research is needed.
Likewise, the fact that resveratrol is engulfed in so much scientific controversy does not, per se, mean that it does not have beneficial effects in metabolism in general and longevity in particular. I, for one, clung to this belief, until a recent paper in JAMA Internal Medicine dashed my hopes. Richard Semba and his colleagues of Johns Hopkins University followed 783 older men and women in Tuscany (the Chianti region) for 9 years, measuring their wine intake by urine metabolites. They divided the population into quartiles, depending on the baseline level of 24-hour urinary resveratrol metabolites (the lowest level defined as less than 1,554nmol/g creatinine and the highest quartile as 15,010/g creatinine).
Here are the results for mortality (percent of people in each group who died) in the different quartiles, in ascending order:
- Lowest quartile (lowest wine consumption, meaning lowest Resveratrol intake): 34%
- Next quartile up: 32%
- Next up: 34%
- Highest quartile (highest wine/resveratrol intake): 37%
It is obvious that there was no dose-response relationship across all the categories. In fact, there was no effect at all. The highest category actually had a higher mortality rate, but this is good only for a rueful chuckle—it was not a statistically significant difference. The authors were also careful to exclude all candidates who consumed more than 4 glasses a day, so we couldn’t ascribe the higher mortality to the presence of winos in the group.
What about cardiovascular health and cancer? Sad to say, no effect!
What’s the bottom line for resveratrol?
There are many lessons here, but I think the most important one is that our stubborn search for a silver bullet is doomed to failure. Nature simply doesn’t work this way. Bio-organic molecules are designed for their protection from climatic stress and predation, not to increase our longevity. Because these substances are the product of eons of natural selection, they are pleiotropc. That is to say their effect is on multiple pathways, more bang for the buck, to use a more scientific terminology. Vitamins work in cases of extreme deficiencies, and so do other supplements. But in a normal diet, these supplements are totally superfluous. At best, they are flushed out harmlessly in the urine; at worst, some of them are toxic.
The last redoubt of supplement advocates is the argument that our diet is deficient. But what we call a “normal diet” has tremendous range. Just consider the Inuit (Eskimo) diet, the Scandinavian diet, the Mediterranean diet, the Chinese diet, the sub-Saharan diet, even the San diet of the forbidding Kalahari desert—they vary greatly, but all are what we consider “normal”. The way food works is through the combination and interactions of millions of dietary substances. There is no computer in the world powerful enough to decipher even a small fraction of them. So why even try? The easy way (yes, there is one) is simply eat a well balanced diet and enjoy every bite of it.
And yes, I include in this also red wine. Forget resveratrol; Just sit back and enjoy a robust cabernet or an elegant Pinot Noir. It will make your life a lot more pleasurable, if not longer.
Featured photo credit: Photl.com