Big Pharma Attempts to Extend Own Lifespan by Activating Sirtuins
Can drugs that supposedly “activate” a controversial target—sirtuin proteins—stop or even reverse the aging process? A new report this week said “No.” According to this report, published Wednesday night in Nature, sirtuin activators do not extend lifespan in roundworms and flies and earlier studies that said they did were flawed. Nonetheless, GlaxoSmithKline (GSK) continues to invest hundreds of millions of dollars into developing drugs to hit these targets—more about their findings below—and if the drugs work, for whatever reason, the scientific squabbles will not matter.
I recently had the chance to hear Harvard professor David Sinclair talk publicly about his and GSK’s research into sirtuin activators. Sinclair was the scientific founder of Sirtris and he reported at a forum on longevity in Cambridge, MA, that GSK has high hopes of near-term confirmation in mice that some sirtuin activators do extend lifespan. Based on its continued investment, GSK still believes that the $720 million acquisition of Sirtris in 2008 was a smart one.
The Nature report, just the latest in a series of publications that question the sirtuin-longevity link, will be even tougher for Sinclair and other sirtuin researchers to overcome. The new research reported that sirtuin proteins, when overexpressed in nematode worms and fruit flies, do not actually have an effect on longevity. This directly contradicts the original publications linking Sir2 and other sirtuins with increased lifespan. The new report further goes on to contradict the landmark 2006 paper, also published in Nature, in which Harvard researchers led by Sinclair reported that mice fed resveratrol which, they demonstrated using expression analysis, activated sirtuins, live on average 20 percent longer and in some cases much longer than that.
The same researchers, both at University College London, went on the record as sirtuin skeptics in 2007. David Gems and Linda Partridge then set out to prove their claim that the original sirtuin and resveratrol findings, which led to the founding and eventual acquisition of Sirtris, were irreparably flawed. Building on earlier reports that the round worms used in the original studies carried a gene that control organisms did not carry, and that it was this gene that predisposed the worms to live longer, Gems and Partridge showed in this paper that organisms identical to one another except for the expression level of sirtuins could not be made to live longer.
Sirtuin research is nothing if not contentious. Apparently eager to fan the flames, Nature in the same issue this week published a rebuttal from Leonard Guarente, the author of the original 2001 paper on worm life extension and founder of a rival sirtuin biology company Elixir.* Guarente told the New York Times that he did not realize at the time that the experimental, but not the control, worms in his 2001 study carried the mutation. When he learned of this fact, he repeated the experiments and reported in this week’s brief communication that, without the mutation, the worms lived ten to fourteen percent longer, not fifteen to fifty percent as originally reported.
But the apparent un-validation of sirtuins as an anti-aging target will certainly not deter GSK, which Sinclair said is spending a hundred million dollars a year on sirtuin research. Unlike in the early days of sirtuin research, GSK has tightly focused on specific indications such as inflammation and metabolic disease and is apparently starting to see biochemical results, although the clinical outcomes have yet to be reported.
In his Cambridge talk, Sinclair reported that three resveratrol-like compounds are in clinical Phase 2. So far, he said, all are safe and well-tolerated. One compound, SRT2104 showed an anti-inflammatory signal in human endotoxemia, which is a harmless model of inflammation. Another one, SRT2379 showed strong TNF-alpha suppression, he said, which is “just what you want to see.” The drugs might be used as oral replacements for corticosteroids, Sinclair said. “The clinical data is generally consistent with comparable pre-clinical data in mice.”
Just as important for the future of sirtuin activators-as-drugs, Sinclair reported that longevity studies are ongoing with the second-generation compounds. “Lean mice lived 14 percent longer on first-generation resveratrol,” Sinclair said. “Obese mice lived 44 percent longer on second-generation resveratrol. So everyone wants to know: what happens when second-generation resveratrol is given to lean mice? We are waiting for those results.” In the meantime, publications are in preparation, Sinclair said, describing exactly how resveratrol analogs hit sirtuins and alter their activity.
None of this back-and-forth is new. Drug development often follows a circuitous path, from an exciting target in animals to more complex biology in humans and back into animal research. Both the animal and the human studies shed light on the direction that the development process has to go.
The future of sirtuins and resveratrol derivatives will remain in doubt for at least a year or two, perhaps much longer. But GSK’s motivation for pushing so many resources into a controversial field is clear. The pharma industry stands under a well-known existential threat: the demise of blockbusters. Pharma’s initial attraction to Sirtris reflects a recognition on the part of pharma that an “anti-aging” drug could let them keep selling a drug to everyone, instead of to a narrow patient population. Such a drug could extend the lifespan not only of some of those individuals but also that of the company—and indeed, indirectly, that of the entire pharmaceutical industry.
An anti-inflammatory to be prescribed in lieu of steroids, while it would be a big seller, is both more mundane and lower risk. The patients would not include healthy people, for example, with the concomitant extremely high bar for safety. In that sense, the acquisition of Sirtris, even if it was only ten per cent likely to result in a new blockbuster, was a reasonable bet for GSK to make. The continuing work on the inflammation and diabetes products represents downside protection. Any one of these could easily pay back the initial investment as well as the accrued research and trial costs. If more than one of them makes it to market, the investment becomes a net positive. Sirtuins and their activators may not turn out to be an elixir for pharma, giving them eternal life. But for some executives and companies like GSK, even a ten per cent lifespan extension would make it plenty worthwhile.
*An aside: Guarente, a professor at the Massachusetts Institute of Technology (MIT), was the founder of a rival company to Sirtris called Elixir (no web site found), which most recently was reported in 2010 to be testing a sirtuin inhibitor (not activator) in Huntington’s disease. I looked at Elixir as a potential venture investment back in 2000 but decided not to recommend that my fund invest. Guarente and his work were very impressive and I would have loved to do a deal based on MIT science. However, I could not get comfortable with the uncertainty surrounding indication areas for sirtuins. Guarente himself apparently became uncomfortable too and left Elixir’s scientific advisory board (SAB) to become co-chair of Sirtris’ SAB in 2007.