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Aging and Lifespan

$720 Million Worth of Sirtuin Research

Well, I’m back from a brief vacation, and catching up with the news. It looks like the big headline is GlaxoSmithKline’s offer for Sirtris: $720 million, which is a hefty premium (84%!) to what the company was trading for previously. Reckless waste of money, or canny deal?
I lean toward the latter, but I’ve long had a place in my heart for sirtuin research and its potential. It’s still a long shot, but it’s one of the most intriguing ones in the history of medicine. Actually, from one perspective, you wonder how long a shot it is: a biochemical pathway that seems to extend healthy life in yeast, roundworms, flies, and mice would seem to have some odds of doing the same thing in man. A lot of drug programs have been started with a lot less backing them up, albeit for rather less earth-shattering indications.
Of course, Sirtris hasn’t officially been targeting life extension drugs, at least not in the near term. A number of these potential life-extending biochemical pathways are tied up with insulin signaling, which makes sirtuin-targeted drugs a natural for diabetic therapy as well. Sirtris has reported encouraging data for just that indication. If a sirtuin-based drug is going to make it to market, that’s a good bet for how it’ll do it. I note, though, that the company has also applied for orphan-drug status for resveratrol itself for a rare muscle disorder. But they don’t own that parent compound, just its use in this case – the diabetes work is being carried on with second- and third-generation analogs that address some of resveratrol’s problems. (It’s not a particularly stable compound, for one thing).
Once one of these drugs is approved, it’ll have the biggest, strangest potential for off-label use that anyone has ever seen. Oh, that’s going to be something to watch. GSK is well aware of this – I’m not saying that it’s part of their business plan, but when you see their head of drug discovery talking to Forbes and tossing the word “transformational” around, you know that they’ve thought beyond a replacement for Avandia. The Wall Street Journal headlines it like it is: “Glaxo to Buy Sirtris in Bet on Antiaging Reseach”.
That’s the truth, all right, and it’s going to be fascinating to watch things develop. As I was saying here the other day, a drug for aging is a perfect example of something the FDA has absolutely no idea of how to approach. Well, it’s not just the FDA, come to think of it: how on earth would you design a Phase II trial for life extension? How long would it take? What’s your clinical endpoint? And further on, how long will you want to monitor your Phase III patients (recall Pfizer’s recent follow-up of Exubera trial participants? How long will it take before you could be sure that some horrible bargain wasn’t struck along the way?
That’s the lurking fear behind all this research, fit to give Leon Kass the shakes. Life extension tends to give some people the same “Things Man Was Not Meant to Know” shivers as (for example) germ-line genetic manipulation. I’m tempted to cue the theramin music in the background, but I can’t really make fun of this attitude, since I understand where the uneasiness is coming from. In all these cases, we’re looking at real alterations of what we think of as human. Personally, I think there’s room for improvement in what we think of as human, but I agree that we should reach for those improvements carefully. And I can see how the very thought could strike some people as coming close to crazy.
But we’re going to find out. That’s the real import of the GSK news: the money is there to find out what’s possible in this field. I’m happy to hear it. But then, I was a bit euphoric back in 2003 when this news started breaking, and I’ve never really lost that feeling. We shall see.

21 comments on “$720 Million Worth of Sirtuin Research”

  1. sroy says:

    It is nice to see big pharma investing in something that has some real novel potential.
    The very fact that it is not another atypical antipsychotic, proton pump inhibitor, chiral form of an existing antidepresant is encouraging.
    Who knows.. it might even have a therapeutic effect on people and decrease their total mortality. Till then red wine seems to be the best option.

  2. Nick K says:

    Clinical trials to examine effects on longevity would be entertaining…most of the clinicians would be dead of old age before the end-point was reached.

  3. Rev. Howard Furst says:

    Resveratrol is a fairly decent PPAR-gamma agonist (Ulrich et al., Cancer Res. 2006 66:7348-54). The clinical doses in Sirtris’ initial diabetes study were 2.5 and 5 grams per day. It will be interesting to see if the modest effects on glucose regulation seen with high-dose resveratrol were due to SIRT1 activity (and therefore amplifiable with their more potent analogs) or if the glucose effects were due to incidental PPAR-gamma activation, in which case the results with resveratrol may not be so predictive for the follow-up analogs.

  4. RKN says:

    I actually presented a journal club discussion here at .edu on one of Sinclair’s Nature papers, dealing with the life extension effects of Resveratrol in mice. I thought the evidence was pretty good for the conclusion that Resv. extended life via a SIRT-mediated pathway; others were more skeptical.
    And you’re right — trans-resveratrol is easily converted to the inactive form (cis-), but at least one company has a manufacturing process that stabilizes it in its trans- form and sells it as a supplement. The claim has supposedly been backed up by independent labs. the supplement ain’t cheap, tho.
    I recall from the paper I presented that the number of papers in pubmed looking at Resv. suddenly skyrocketed to over 2500 around year 2000. Still, I don’t think anybody knows how or if Resv. works in humans to extend life. Evidently it can activate or up-regulate a number of tumor suppressor pathways too.

  5. Merkwurdigliebe says:

    So GSK’s plan was to lay off a large number of employees so they could have this injection of cash (because as Dilbert’s boss says “firing employees is like printing money”) to bid for Sirtris, then conduct the R&D with cheap, fresh PhDs (or cheap, overseas PhDs)? Frankly I’m impressed.

  6. floyd says:

    OK, I’m gonna have to weigh in on the other side. The sirtuin targets may be viable but these resveratrol types of molecules have been around intriguing drug hunters for years. It’s the green tea, witch doctor, Shaman pharmaceutical type compounds. They have these interesting activities that can never be optimized. Many natural products chemists (the few that are left) know them as trash and routinely remove them with polyamide columns. Others continue to pursue them. I’ve had to work on them before because my boss was intrigued. I may be wrong but my gut feeling is that Glaxo has been had

  7. anon says:

    Just a thought perhaps like in cholesterol reducing clinical trials using people with hypercholesterolemia, then for anti-aging trials they could use people with progeria (http://en.wikipedia.org/wiki/Progeria). Also, potentially a cure for a horrible disease. Just a thought

  8. Wavefunction says:

    Even though reseveratrol does show some intriguing effects, my first reaction on reading Sinclair’s review on it in Nat. Rev. Drug. Disc. was “It’s going to be hard to make this into a drug”, because it seemed to hit every damn receptor in the body. And I was reminded of curcumin which is touted as having beneficial effects against almost every disorder you can think of. Reseveratrol also seems to be like curcumin; non-selective with weak potency. Naturally these are the kinds of things you pick up as initial hits. But it could be a long way before it becomes a potent drug.

  9. MTK says:

    Anon,
    Chapeau! Good call there on progeria.

  10. TallDave says:

    How long will it take before you could be sure that some horrible bargain wasn’t struck along the way?
    Well, if Satan shows up rubbing his hands and cackling, I think you have to consider suspending the trials.

  11. anon-e-mouse says:

    “Once one of these drugs is approved, it’ll have the biggest, strangest potential for off-label use that anyone has ever seen…”
    That’s what they call a “gateway indication”

  12. burt says:

    “And I was reminded of curcumin which is touted as having beneficial effects against almost every disorder you can think of”
    Best choice = colon cancer chemoprevention, since this constituent of Turmeric is poorly absorbed. Also good for the dry cleaning business, if you are given to spilling your curry.

  13. Morten says:

    I still think we should move everybody’s mitochondrial genes into their genome. Heck, lots of protozoans have already achieved this. We’re just poorly evolved 😉
    But looking at the wikipedia entry on Sirtuins – the drugs GSK (now) is trying to develop, they work by antagonizing the antagonistic effect of nicotinamide on sirtuin, right? What other drugs work like that? I can’t think of any.

  14. Madrid says:

    I have also found resveratrol to be active in a large number of screens, but am never sure what to make of it. The fact that it seems to hit so many targets is a bit worrisome. Perhaps if you can target the Sirtuins with a non-polyphenol non-promiscuous compound, we could better understand what role the Sirtuins actual play. Go chemical biology!

  15. kinasen says:

    The other thing is that resveratrol doesn’t activate sirtuins by a direct mechanism (there is no activation in vitro with purified protein). Two biochemistry papers published a few years ago showed that the reported activation was an artifact of the fluorescence assay the authors used in the original Nature paper. Yet somehow these molecules are still described as Sirtuin activators…

  16. RKN says:

    kinasen,
    I’d be interested in reading the cites for the claim that resveratrol doesn’t activate sirtuins, particularly SIRT1. As I recall the original screen reported by Howitz et al. (2003, Nature) nicely showed that the Km for binding of a p53 peptide by SIRT1 (recombinant) was reduced 35X in the presence of resveratrol, and resveratrol also reduced by 5X the Km of SIRT1 binding its co-factor (NAD+). Both substantially increased the activity of SIRT1. It’s true that the mechanism for how resveratrol achieved this was unknown at the time of the screen, tho iirc it was postulated to be allosteric in nature.

  17. anonymous1 says:

    Then this one may be interesting:
    doi:10.1074/jbc.M501250200

  18. anonymous1 says:

    Sorry, that doi is not working.
    link:
    http://www.jbc.org/cgi/content/full/280/17/17187

  19. PorkPieHat says:

    Wasn’t the French paradox (French eat high-fat foods, yet have a low incidence of cardiovascular disease) more a function of the amount of calories they eat being low than the resveretrol in their wine? The poison is in the dose of the food, no? So maybe (with the French at least) it actually IS a low calorie diet, instead of a compound which mimics a low calorie diet, that is the key. Maybe Floyd was right about GSK being taken…remember ArQule’s lead oncology drug from a few years back was a constituent of green tea…where is it now?
    Thoughts?

  20. Stephen B says:

    Note that while the dosage of srt-501 was 2.5 and 5 grams, srt-501 is not pure resveratrol, so the actual amount of resveratrol will be closer to 700 mg and 1700 mg.

  21. That sounds so interesting Emily, I had no idea you did all those things- I imagined your holiday was all sunshine and dollar drinks on the beach.

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