If you haven't seen it, the Sinclair group and numerous co-workers at the NIH and elsewhere now report that the SIRT1 activator SRT1720 extends the lifespan of mice on a diet of normal chow, and they see a number of good metabolic indicators - increase fat oxidation, decrease fat mass, increased insulin sensitivity, and so on.
There are several things to note about this effect, though. The mice were started on the compound at six months of age, and the compound was supplemented in chow to a dose of 100 mpk, which was maintained from there on out. (I don't have any allometric tables to hand,
but it's safe to say that this would translate to a daily multigram dose in humans Absolutely wrong: it's about 8.8 mpk, a 600mg dose or so. Good thing I'm not a clinician). The lifespan extension was mean lifespan (up 8.8%) - they saw a trend towards extended median lifespan, but it didn't reach significance. (That sounds, at first, like there were some long-lived responders in the treatment group). There was no difference in 90th-percentile survival, which as the authors note, is consistent with the idea of the compound delaying age-related illness. There was also a high-fat-fed group of mice, supplemented in the same fashion, and consistent with earlier reports, these had their mean lifespan extended over 20%.
Blood markers of liver and kidney function seemed to hold up fine. Other than less steatitis (fatty tissue inflammation) in the liver, histology didn't appear to show any major changes (good or bad) in the treated mice compared to controls, especially considering that the treated mice were older when assayed. Gross pathology was also the same, which is worth noting because SIRT1 pathways have been implicated in slowing down some cancer phenotypes but speeding up others. Getting down to DNA microarrays, the most altered genes were found in liver and muscle tissue, and were associated with lower levels of inflammation.
This paper is not going to clear up the sirtuin controversies, but it is interesting and worthwhile. 100mpk, q.d. for life, is a hard and heavy dose, though, and if SRT1720 really is an efficacious sirtuin activator (a point subject to plenty of disagreement in the literature), then it's worth wondering if the pathway is really within range of therapeutic effects in humans. Resveratrol has been studied in a human trial, but resveratrol is polypharmacologic, to the point that in vivo data with it are probably only capable of telling us about the effects of resveratrol itself.
A couple of the authors on this new paper have their affiliations listed as "Sirtris, a GSK company", but there's no such thing any more. When last heard from, GSK was continuing sirtuin work on its own, but if there have been any notable announcements from them, I've missed them. What a selective SIRT1 activator does, long-term in normal humans, no one yet knows. Will anyone, ever?