Resveratrol and the Big Red Lever, Revisited

Back in 2006 I had this to say on the topic of what was then the first flush of popular interest in resveratrol, back when far less was known about it:

Our metabolic biochemistry looks like a big wall full of levers. Some of them are painted red, and we think we understand what the instructions beneath these red levers say. Maybe. How much information do you feel you would like before you pull the big red levers in your own personal metabolism? What level of risk due to disease would you presently need to be suffering in order to take the risk represented by a new compound? How do you evaluate these levels of risk?

Resveratrol has turned out, almost predictably, to be another heaped mound of hype that buries a modest kernel of interesting-but-not-terribly-applicable metabolic research. At this stage it seems fairly certain that resveratrol does not extend life in mammals to any great degree - when you find compounds that can do that, there is little uncertainty once the life span studies are in and replicated. See the past couple of years of work on rapamycin in mice as a contrasting example to the uncertainty and lack of verifiable effects for resveratrol and its derived compounds.

In any case, I was reminded of the topic by a recent post at In the Pipeline that echoes many of the same sentiments in my 2006 post:

I've written many times here about sirtuins, and their most famous associated small molecule, resveratrol. And I've been asked more than once by people outside the med-chem field if I take (or would take) resveratrol, given the available evidence. My reply has been the same for several years: no, not yet. Why so cautious, for a compound that's found in red grapes and other foods, and to which I've presumably been exposed many times? Several reasons - I'll lay them out and let readers decide how valid they are and how they'd weight these factors themselves.


So what do we know about what resveratrol does? A lot, and not nearly enough. Its pharmacology is very complex indeed, and the one thing that you can clearly draw from the (large) scientific literature is that its (a) a very biochemically active compound and (b) we haven't figured out many of those actions yet. Not even close. Even if all it did was act as on one or more sirtuins, that would be enough to tell us that we didn't understand it.


There's room to wonder about the mechanisms of a number of drugs. Indeed, there have been many that have made it to market (and stayed there for many years) without anyone knowing their mechanisms at all. We're still finding things out about aspirin; how much can one expect? Well, one response to that is that aspirin has been used widely in the human population for quite a long time now, and resveratrol hasn't. So the question is, what do we know about what resveratrol actually does in living creatures? If it has beneficial effects, why not go ahead and take advantage of them?

Unfortunately, the situation is wildly confusing (for an overview, see here). The first thing that brought resveratrol into the spotlight was life extension in animal models, so you'd think that that would be well worked out by now, but boy, would you be wrong. The confusion extends up to mouse models, where some of the conclusions - all from respectable groups in respectable publications - seem to flatly contradict each other. No, the animal-model work on resveratrol is such a bubbling swamp that I don't see how anyone can safely draw conclusions from it.

We can conclude that it doesn't straightforwardly extend life at this point. So you have on the one hand a distinct lack of knowledge as to long term effects and on the other hand it clearly isn't doing anything spectacular in laboratory animals. That looks like the worst of both worlds from where I stand.

The sensible thing to do whenever another of these oral-fixation ingested substance hype machines emerges from the juncture of the scientific and business worlds is to balance the purported results against the clear, proven, and solid benefits of exercise and calorie restriction. The risks in moderate exercise and calorie restriction are minimal, while the evidence for great benefit to long-term health is gold-plated and voluminous. When someone is trying to convince you to spend money on something that seems unlikely to produce even a pale shadow of the health benefits of either exercise or calorie restriction, and has largely unknown long term risks - then why even try? It just doesn't make sense.

The research community, and just as importantly the public at large, needs to move beyond their enthusiasm for metabolic manipulation through ingested substances as a path to extending healthy life. It's a grand example of looking for the lost keys under the lamp post - doing something just because it's easier and the path of least resistance, regardless of the likelihood of significant results at the end of the day. Real progress towards longer lives is only going to come through building medical technology capable of repair and rejuvenation at the level cells, organs, and systems within the body: very specific biotechnologies engineered to perform very specific jobs within and around cell structures, and aim to exactly reverse aging by doing so. That couldn't possibly be further removed from the present dominant strategy of mining the natural world for compounds that might or might not cause more minor benefits than minor disadvantages.

It's a common refrain here, but no less true for it: work on rejuvenation biotechnology must displace the present longevity science mainstream if we want to see significant progress towards radical life extension occur before we run out of time, aged to death on the very verge of success.


This we know -- mega-dose resveratrol doesn't extend life in laboratory animals. But modest doses, particularly when combined with other small molecules, may more clearly mimic the longevity effects of a calorie restricted diet. It is said that the effect of resveratrol and polyphenols in general is to produce a hormetic effect -- that is, a low-dose biological stressor that activates endogenous antioxidants (glutathione, SOD, catalase, adenosine, heme oxygenase and nitric oxide) which exert a far greater effect than any medicine yet invented. The fact a recent human study shows a modest dose of resveratrol produces a far higher blood concentration than produced in rodents suggests humans are being overdosed. The experiments using resveratrol in laboratory mice did not employ modest doses but actually utilized mega-doses known to exert toxicity. Resveratrol is an antioxidant that binds copper at low doses and is pro-oxidant at high doses and releases copper. It is as if the researchers have intentionally taken resveratrol and attempted to smudge its promise. There is a way to make a resveratrol pill that exhibits no toxicity at high dose and this was demonstrated by researchers in Europe, but ignored by the research community. Humanity may never conclusively know whether resveratrol extends life in humans because a 80-100 year study would have to commence which is obviously impractical. We do know that mortality risk from coronary artery disease is dramatically reduced (90 per 100,000 in French wine drinkers vs 200 per 100,000 in North America). The idea of taking the red wine solids and putting them into a pill and removing the alcohol has still not been fully put to the test. It has been repeatedly shown that low doses of polyphenolic molecules in red wine have a greater genomic and biological effect that resveratrol alone. That the primary gene targets are still being worked out is still a puzzlement. Sirtuin-1 is involved, but not directly and not initially. NIH researchers now say inhibition of phosphodiesterase-4 (PDE4) is the initial gene/transcription factor target. However, we cannot find any data indicating PDE4 is inhibited in calorie restriction as yet. This would be important to know. Furthermore, PDE-4 may or may not be the key activating gene target, possibly Sirtuin-3 is the target. What we also know is that aging and disease involves many genes and to design nutriceuticals that target single genes is the same misdirection that modern medicine made with largely ineffective gene-targeted drugs (Herceptin, Erbitux, etc). What can be said is, 8 years since resveratrol pills became widely available, not a single human trial using resveratrol has been launched in cardiology or oncology. Modern medicine appears to be fearful to put resveratrol to the test. Most of the resveratrol pills on the market are produced by companies that have little or no scientific understanding. Few if any of these pills have undergone animal or human testing. One human study does show that a brand of resveratrol abolishes the first sign of blood vessel disease (loss of flow mediated dilatation) and an upcoming human study will show that same resveratrol pill dramatically restores vision to patients with wet macular degeneration. So writing off resveratrol is premature.

Posted by: Bill Sardi at April 11th, 2012 3:40 AM

"The risks in moderate exercise and calorie restriction
are minimal, while the evidence for great benefit to long-term health
is gold-plated and voluminous."

While the evidence for benefit of calorie restriction may be gold-plated for lower organisms, I don't believe there is yet such evidence for primates and humans. Perhaps I have missed something?


Posted by: J at April 15th, 2012 4:46 PM

I guess I do not understand your objection to resveratrol as compared to aspirin. We have been eating grapes and berries for millions of years, probably long before we found that chewing willow bark made our pains go away. Why should we abjure resveratrol? It worked for some fat mice. Being on the chubby side, I hope I can make it work for me. Calorie Restriction doesn't work form me. It just sets up a cycle of low eating to binge eating.

Posted by: Llewellyn Drake at April 16th, 2012 7:38 PM
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