You'll recall that we recently had the flap over two GSK/Sirtris executives running their own sideline business selling resveratrol as a dietary supplement. There's a lot of it out there, understandably, since the publicity around the compound has been intense for several years now. But even if it works, how likely is it that a person could take enough of it to show an effect?
A new paper goes back to the C. elegans nematode model to try to answer that question. The original life-extending results in this organism were done at 100 micromolar concentration, which is way more than any human being is going to be exposed to. Unless you're showering in the stuff, I suppose. The current study dials that back to levels that could be reached in human dosing.
What they saw was no effect on lifespan at 0.5 micromolar, which would be a realistic blood level for humans. When they turned up the concentration to 5 micromolar, there was a slight but apparently real effect of just under 4%. Now, 5 micromolar is a pretty heroic level of resveratrol - I think you could hit that as a peak concentration, but surely not hold it. The medicinal chemists in the audience will appreciate that some drug effects are driven by their Cmax, and others by their AUC, but this still seems to be a likely shortfall.
Oh, and there's another interesting part to this paper. The authors also looked at SRT1720, the resveratrol follow-up from Sirtris that has been the subject of all kinds of arguing in the recent literature. This compound is supposed to be several hundred times more potent than resveratrol itself at SIRT1, although if you've been following the story, you'll know that those numbers are widely believed to be artifacts of the assay conditions. And sure enough, the authors saw no effect on C. elegans lifespan when dosing with physiological concentrations of SRT1720. The authors finish, dryly, with:
Given the above-mentioned and conflicting findings for the efficiency of SRT1720 and the metabolic state in rodents, it is interesting to note that, as shown here, SRT1720 exerts no detectable effects on lifespan of an established model for the analysis of longevity. . .
Indeed it is. Given the recent follow-up work in this area, I can't say I'm surprised, but I am disappointed. And yes, in case anyone's wondering, I do actually hope that the Sirtris work (and other research on sirtuin compounds) leads to something good. It's just that the story is a lot messier than anyone would have liked, so far. All I have to do is look back on what I wrote just four years ago, and wonder if it really had to be this way. Did it?