Readers of this blog will be fairly familiar with the long, interesting story of sirtuin activators. Today we will speak of SRT1720, of which we have spoken before. This molecule was described in 2007 as an activator of Sirt1 with beneficial effects in rodent models of diabetes. But both of those statements were called into question by a series of papers which found difficulties with both the in vitro and the in vivo results (summarized here). The GSK/Sirtris team fired back, but that paper also served as a white flag on the in vitro assay questions: there were indeed artifacts due to the fluorescent peptides used. (Another paper has since confirmed these problems and proposed an off-target mechanism).
But that GSK response didn’t address the in vivo assay questions at all – we still had a situation where one group said that these compounds (SRT1720 in particular) were beneficial, and another said that it showed no benefit and was toxic at higher doses. Adding to the controversy, another paper appeared late last year that went back to nematodes, and found the SRT1720 did not extend their lives, either. The state of this field can be fairly described, then, as “extremely confused”.
Now we have a new paper whose title gets right down to it: “SRT1720 improves survival and healthspan of obese mice”. First time I’ve seen “healthspan” as a word, I might add, and another interesting sidelight is that this appears in Nature Scientific Reports, the publishing group’s open-access experiment. But now to the data:
What this (large) team did was place one-year-old male mice on a high-fat diet in the presence of two different doses of SRT1720 in the chow, corresponding to 30 mg/kilo and 100mg/kilo. The effects on lifespan were notable: standard-diet animals had a median lifespan of 125 weeks, and that was shortened to 94 weeks on the high fat diet. But on that diet plus the lower dose of SRT1720, the median lifespan was 103 weeks, and on the higher dose it was 115 weeks. It’s interesting, though, that this took place while the animals ate the same number of calories and gained the same amount of (extra) weight as the control group.
Blood work and histopathology revealed many more differences. The high-fat animals (with no SRT1720) showed the expected problems that you see in such studies – fat accumulation in the liver, increased numbers of beta-cells in the pancreas, higher insulin levels, and so on. But the SRT1720-dosed animals showed a good deal of reversal of all these effects. DIgging down to the molecular level, inflammatory markers, indicators of apoptosis and DNA fragmentation were increased in the high-fat animals, and these were also mitigated by SRT1720.
There are many other effects mentioned in the paper, but I’m not going to go into all the details – hey, it’s open-access, so if you’re really into this stuff you can find it all. Suffice it to say that a long list of deleterious effects of a high-fat diet on rodents seem to be partially to fully reversed on treatment with SRT1720, particularly at the higher dose, without significant evidence of toxicity. But how do we reconcile that with the report that the compound showed no benefit, and toxic effects to boot? I’ll let the authors tackle that one:
Our results continue to support the beneficial pharmacological effect of SRT1720 in models of metabolic disease despite a recent report by Pacholec and colleagues to the contrary14 where the authors report 100 mg/kg SRT1720 is not tolerable and increases mortality in mice and that the compound does not elicit beneficial effects in the Lep ob/ob mouse model of diabetes. This conclusion is inconsistent with not only our findings but also several additional studies where SRT1720 has been reported to exert positive effects in multiple models of metabolic disease including Lep ob/ob mice, diet-induced obese mice, MSG-induced hypothalamic obese mice15 and Zucker fa/fa rats. Pacholec and colleagues did report that fasting insulin levels are reduced by SRT1720 administration, which is in agreement with our findings (Fig. 2) and with data reported previously in diet-induced obese mice. The putative toxicity of SRT1720 administered at a 100 mg/kg oral dose to 8 mice over 18 days is inconsistent with a study where the compound exhibited no toxicity at a 5-fold higher dose for 15 weeks12 nor is it consistent with our long-term feeding study involving over 100 mice consuming an equivalent daily dose. In fact, our mice showed increased survival and improvement in multiple physiological parameters in response to SRT1720 treatment and did not display overt signs of toxicity even after more than 80 weeks of treatment.
So yes, there’s pretty much a flat contradiction here, and I have no idea of how to resolve it. This paper doesn’t reference the failure of SRT1720 to show effects in nematodes, but that’s another piece of the puzzle that can’t be ignored, either. One possibility is that the doses of the compound need to be rather heroic. Believe me, by the usual pharmacological standards, extended dosing at 100 mpk is pretty heavy-duty (and, I might add, basically unattainable in humans under normal conditions, especially humans on a high-fat diet).
So for now, I have to throw up my hands. This latest paper seems very thorough, and represents a really significant effort on the part of a long list of highly competent people. But there can be no doubt that the SRT1720 story (and the story of sirtuin activators in general) is still very complex and hard to evaluate, because the various problems and complications that have been found can’t be dismissed, either. There’s something here, all right, and it could well be very important. But what are we looking at?
Side note: this work was the subject of a writeup by Nicholas Wade in the New York Times the other day. It reveals that there’s another arm of this study – normal mice, on normal chow, also treated with SRT1720. Those results, out next year, will be very interesting indeed, although I can only think that they’re just going to keep the fires burning. I’d also like to note (as one comment on this blog did) the tone of most of the online comments on the Times story. They can, I think, be summed up as “Great, the big evil drug companies have found something so people can just stay big and fat and not die early, and they’re going to sell it to us for a zillion dollars while their corporate masters stay thin and healthy and laugh at us all”. Read through a few of them and see if I haven’t captured their general spirit – and think for a bit about what that tells us, both about the public perception of drug research and (perhaps) about the sort of people who leave comments over at the Times.