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.

First off, we can dispose of the “it’s in food already, and it’s natural, so why worry?” line of thinking. Strychnine is all-natural too, as are any number of other hideous molecules that are capable of terrible effects, so that’s no defense at all – it never is. And as for being exposed to it already, that’s true – but the dose makes the poison, and the dose makes the drug. I’ve no idea how much resveratrol I’ve ingested over the years, but it’s safe to say that it’s been in small amounts and at irregular intervals. Going from that to regular higher dosages is worth some forethought.

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.

That’s because the sirtuins, along with many other enzymes, are involved in epigenetic signaling, a catch-all term for everything in the DNA-to-RNA-to-protein sequence that doesn’t depend on just the DNA sequence itself. (And as everyone discovered when the number of human genes came in on the low end of the low estimates, these processes are very important indeed). There are a lot of mechanisms, and it’s safe to say that we haven’t found them all, either, but the sirtuins modify histones, the proteins that DNA is wrapped around, and thus affect how genes are transcribed. All these transcriptional processes are wildly complex, with hundreds and thousands of genes being up- (and down-) regulated in different tissues, at different times, under different conditions. Anyone that tells you that we’re close to unraveling those balls of yarn is not keeping up with the literature, or not understanding what they read.

Of course, one of the controversies about resveratrol (and some of the other sirtuin modulators) is whether they act directly on these enzymes or not. Opinion is very much divided on that, but resveratrol seems to have a number of other effects, mediated through processes that (again!) are best described as “unclear”. For example, its metabolic effects seem to be at least partially driven by its actions on an enzyme called AMPK, a key enzyme in a number (brace yourself) of important cellular processes. It might well be that AMPK (activated by resveratrol) is what’s having an effect on the sirtuins. A very recent paper implicates another step in the process: resveratrol may well be acting on a set of phosphodiesterase (PDE) enzymes, which affect AMPK, which affect sirtuins. But then again, there’s another paper from earlier this year that suggests that resveratrol’s activity against sphingosine kinase might be the key. So your guess is as good as mine.

One objection to all this is that 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.

How about people, then? There have been some clinical trials reported, with this one the most recent, and these are summed up in this open-access paper. The longest reported trials are on the order of weeks, which is useful, but not necessarily indicative of what might happen out in the real world. But there have been some beneficial metabolic effects seen (although not in all trials), and these constitute some of the biggest arguments for taking resveratrol at all.

One of the things that seems to be possible, from both the animal and human studies, is that the compound might exert these beneficial effects mostly in systems that are already under metabolic stress. Does this translate to people as well? If you’re healthy already, which does resveratrol do for (or to) you? No one knows yet, and no one knows how much resveratrol you’d have to take to see things happen. Here’s another article (PDF) summarizing the known effects, and here’s the way the authors sum up:

“It is no exaggeration to say that the literature on resveratrol is contradictory and confusing. The wide range of concentrations and doses used to achieve the various effects reported for resveratrol in both in vitro cell culture and animal studies raises many questions about the concentrations achievable in vivo. . .

The bottom line? Resveratrol is a very interesting compound, and potentially useful. But the details of its actions aren’t clear, and neither, honestly, are the actions themselves. Given the importance of the processes we’re talking about – cellular metabolism, which is intimately involved with aging and lifespan, which is intimately involved with defenses against cancer – I don’t feel that the situation is clear enough yet to make an intelligent decision. So no, I don’t take resveratrol. But I’d be willing to if the fog ever clears.

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