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The Latest Sirtuin Controversy

As promised, today we have a look at a possible bombshell in longevity research and sirtuins. Again. This field is going to make a pretty interesting book at some point, but it’s one that I’d wait a while to start writing, because the dust is hanging around pretty thickly.
Some background: in 1999, Sir2 the Guarente lab at MIT reported that Sir2 was a longevity gene in yeast. In 2001, theyextended Sir2 these results to C. elegans nematodes, lengthening their lifespan between 15 and 50% by overexpressing the gene. And in 2004, Stephen Helfand’s lab at Brown reported similar results in Drosophila fruit flies. Since then, the sirtuin field has been the subject of more publications than anyone would care to count. The sirtuins are involved, it turns out, in regulating histone acetylation, which regulates gene expression, so there aren’t many possible effects they might have that you can rule out. Like many longevity-associated pathways, they seem to be tied up somehow with energy homeostasis and response to nutrients, and one of the main hypotheses has been that they’re somehow involved in the (by now irrefutable) life-extending effects of caloric restriction.
As an aside, you may have noticed that almost every news about something that extends life gets tied to caloric restriction somehow. There are two good reasons for that – one is, as stated, that a lot of longevity seems – reasonably enough – to be linked to metabolism, and the other one is that caloric restriction is by far the most solid of all the longevity effects that can be shown in animal models.
I’d say that the whole sirtuin story has split into two huge arguments: (1) arguments about the sirtuin genes and enzymes themselves, and (2) arguments about the compounds used to investigate them, starting with resveratrol and going through the various sirtuin activators reported by Sirtris, both before and after their (costly) acquisition by GlaxoSmithKline. That division gets a bit blurry, since it’s often those compounds that have been used to try to unravel the roles of the sirtuin enzymes, but there are ways to separate the controversies.
I’ve followed the twists and turns of argument #2, and it has had plenty of those. It’s not safe to summarize, but if I had to, I’d say that the closest thing to a current consensus is that (1) resveratrol is a completely unsuitable molecule as an example of a clean sirtuin activator, (2) the earlier literature on sirtuin activation assays is now superseded, because of some fundamental problems with the assay techniques, and (3) agreement has not been reached on what compounds are suitable sirtuin activators, and what their effects are in vivo. It’s a mess, in other words.
But what about argument #1, the more fundamental one about what sirtuins are in the first place? That’s what these latest results address, and boy, do they ever not clear things up. There has been persistent talk in the field that the original model-organism life extension effects were difficult to reproduce, and now two groups (those of David Gems and Linda Partridge) at University College, London (whose labs I most likely walked past last week) have re-examined these. They find, on close inspection, that they cannot reproduce them. The effects in the LG100 strain of C. elegans appear to be due to another background mutation in the dyf family, which is also known to have effects on lifespan. Another mutant strain, NL3909, shows a similar problem: its lifespan decreases on outcrossing, although the Sir2 levels remain high. A third long-lived strain, DR1786, has a duplicated section of its genome that includes Sir2, but knocking that down with RNA interference has no effect on its lifespan. Taken together, the authors say, the correlation of Sir2 with lifespan in nematodes appears to be an artifact.
How about the fruit flies? This latest paper reproduces the lifespan effects, but finds that they seem to be due to the expression system that was used to increase dSir2 levels. When the same system is used to overexpress other genes, lifespan is also increased. They then used another expression vector to crank up the fly Sir2 by over 300%, but those flies did not show an extension in lifespan, even under a range of different feeding conditions. They also went the other way, examining mutants with their sirtuin expression knocked down by a deletion in the gene. Those flies show no different response to caloric restriction, indicating that Sir2 isn’t part of that effect, either – in direct contrast to the effects reported in 2004 by Helfand.
It’s important to keep in mind that these aren’t the first results of this kind. Others had reported problems with sirtuin effects on lifespan (or sirtuin ties to caloric restriction effects) in yeast, and as mentioned, this had been the stuff of talk in the field for some time. But now it’s all out on the table, a direct challenge.
So how are the original authors taking it? Guarente, who to his credit has been right out in the spotlight throughout the whole story, has a new paper of his own, published alongside the UCL results. They partially agree, saying that there does indeed appear to be an unlinked mutation in the LG100 strain that’s affecting lifespan. But they disagree that sirtuin overexpression has no effect. Instead of their earlier figure of 15 to 50%, they’re claiming a 10 to 14% – not as dramatic, for sure, but the key part for the argument is that it’s not zero.
And as for the fruit flies, Hefland at Brown is pointing out that in 2009, his group reported a totally different expression system to increase dSir2, which also showed longevity effects (see their Figure 2 in that link). This work, he’s noting, is not cited in the new UCL paper, and from his tone in interviews, he’s not too happy about that. That’s leading to coverage from the “scientific feud!” angle – and it’s not that I think that’s inaccurate, but it’s not the most important part of the story. (Another story with follow-up quotes is here).
So what are the most important parts? I’d nominate these:
1. Are sirtuins involved in lifespan extension, or not? And by that, I mean not only in model organisms, but are they subject to pharmacological intervention in the field of human aging?
2. What are the other effects of sirtuins, outside of aging? Diabetes, cancer, several other important areas touch on this whole metabolic regulation question: what are the effects of sirtuins in these?
3. What is the state of our suite of tools to answer these questions? Resveratrol may or may not do interesting things in humans or other organisms, but it’s not a suitable tool compound to unravel the basic mechanisms. Do we have such compounds, from the reported Sirtris chemical matter or from other sources? And on the biology side, how useful are the reported overexpression and deletion strains of the various model organisms, and how confident are we about drawing conclusions from their behavior?
4. Getting more specific to drug discovery, are sirtuin regulator compounds drug candidates or not? Given the disarray in the basic biology, they’re at the very least quite speculative. GlaxoSmithKline is the company most immediately concerned with this question, since they spent over $700 million to buy Sirtris, and have been spending money in the clinic ever since evaluating their more advanced chemical matter. And that brings up the last question. . .
5. What does GSK think of that deal now? Did they jump into an area of speculative biology too quickly? Or did they make a bold deal that put them out ahead in an important field?
I do not, of course, have answers to any of these. But the fact that we’re still asking these questions ten years after the sirtuin story started tells you that this is both an important and interesting area, and a tricky one to understand.

32 comments on “The Latest Sirtuin Controversy”

  1. anchor says:

    DereK; ” What does GSK think of that deal now? Did they jump into an area of speculative biology too quickly? Or did they make a bold deal that put them out ahead in an important field.”- I ask, when was the last time the management at GSK (or for that matter other pharma companies as well) admitted their mistakes or oversights? Shenanigans, eliminated many jobs to recoup their loses!

  2. 3TC says:

    My guess is they (GSK) will react along these lines:
    Firstly say nothing about it and hope it all blows over
    Secondly, if some staff member is brave enoug, or perhaps foolish enough, to ask awkward questions, they’ll try to say the “jury is out” or else spout some platitudes about a “risk-taking”.
    One thing they definitely will not do is admit that they’ve paid a load of money for a crock of crap.
    As for accountability and holding people to account, don’t fool yourselves!

  3. imatter says:

    It seems like the literature is handling itself the way it should be. Too bad a pharma had to make a bet that didn’t really pan out.
    Was the assay purely phenotypic (longevity) or was there a classic pure enzyme assay?

  4. pete says:

    Thanks for a useful overview, Derek.
    So what it will take (in the way of research results) to finally settle this controversy to everyone’s satisfaction ? 64 bucks to whoever can answer that question.
    Or maybe it’ll come to pass that Sirtuins retain a mystical, vitalist quality, never fully penetrable by reductionist methods.

  5. anon the II says:

    I know the answers to the last two questions of #5.
    Yes and No.

  6. Paul Brookes says:

    Outside ofthe aging red-herring, one thing we do know about sirtuins is they play a pretty important role in endogenous signaling pathways that protect against oxidative stress. So, while their role in aging mght now be less important, last time I looked oxidative stress in disease pathgenesis was still a pretty big deal. If sirtuin tareted drugs (if such things really exist) show promise in these diseases, then GSK/Sirtris cold still be looking at some decent returns. One example… we just published that SIRT1 is required for acute cardiac ischemic preconditioning, on a time scale of 20 minutes (PMID: 21856913). Thus, messing with SIRT1 activity could lead to some interesting drugs to treat heart attack. And yes, we did control for background strain – everything was compared to WT littermate control mice.
    Of course, GSK will market this latest debacle as “combatting aging was never the intenton, we just used it to get a handle on a novel series of targets which are important in a broad range of diseases”.
    FWIW, small mistake in your commentary above, in referring to sirtuins as “histone deacetylases”. They are lysine deacetylases, and some of them work on histones, but they also work on a lot of other proteins. Most of the field on SIRT1 focuses on its role in the nucleus, but it is also in the cytosol and has a lot of targets there. These effects can happen on an acute time scale that has nothing at all to do with gene regulation.
    Looking beyond sirtuins, one might consider them as “first in class” deacetylases, for which the corresponding acetylases are not well understood. The entire field of proein acetylation is about where the protein kinase field was 25 years ago – there were a handful of kinases and everybody thought that was it. Now that the genome project tells us there are >700 Tyr kinases alone, the field is a lot bigger than anyone anticipated. Right now we have 7 sirtuins, a few class I/II HDACs, and half a dozen acetyltransfrases. In the coming years, I fully anticipate new Ac-ases and deAc-ases being reported every month. Some of them will no doubt be more important than SIRTs, but credit should be given to the SIRT field for kicking off a renewed interest in protein acetylation as a regulatory mechanism in cells.

  7. gippgig says:

    Then there’s the question of whether activating AMPK extends lifespan. I think that’s still confused too…

  8. sgcox says:

    #6 Paul: “>700 Tyr kinases alone”
    I make a very deep pause and say “Are you sure ???”

  9. Chrispy says:

    Wow, between the Sirtris purchase, the open office absurdity, and the Formula 1 partnership, GSK is looking pretty ridiculous right now. Anyone who works there care to comment?

  10. biotechbaumer says:

    I would imagine that when GSK bought out Sirtris, they weren’t just thinking of using Sirtuin activators for extending lifespan—practically speaking, how in the world would you ever design a clinical trial to test this???! Like #6 said, these proteins have pleiotropic roles and are implicated in a variety of disease states, so GSK is playing the field in terms of which indications Sirtuin activator/inhibitors might be used for. Of course, we should acknowledge that they likely would have never got into the field so soon, and/or overpaid for Sirtris, had it not been for this apparently erroneous data. Nonetheless, I think the jury is still out on whether these will be valid drug targets for some disease…

  11. KW's hairdresser says:

    I will toss in the added absurdity of importing non-English speaking chemists at the expense of trained, experienced medicinal chemists with the laziness and arrogance of the C-Band class (where everyone thinks he is entitled to sit in his office all day long) and it is not hard to see why morale is so bad at GSK. Do not forget that many outstanding chemists lost their jobs (at UM) when Moncef and Patrick embarked on the Sirtris charade.

  12. Anonymous says:

    @10 “practically speaking, how in the world would you ever design a clinical trial to test this???!”
    Yeah, well that’s always been a puzzler in evaluating the “anti-aging” Biotechs that have appeared and disappeared from the scene.
    Trial design: Let’s start with a large N and a decade…

  13. UnSirtain says:

    Thank you for your posts on this topic, I have been following them for the last few years. I know the sirtuin science very well and have been frustrated time and time again in the lab over the last 5 years being completely unable to replicate published sirt1 ko or resveratrol data in mice.
    Every time some lab that has expertise in a certain field tries to replicate sirtuin data published by Gurarente, Sinclair and others they find some serious methodological flaw that explains the spurious sir2 result. This goes for yeast, flies, worms, sirtuin activators and my prediction is mice data will be next. Two of Guarente’s former post-docs already get opposing results for the role of sirt1 in mouse liver. And there is internal disagreement between the effect of Sirt1 on GH and IGF-1 in at least 2 of Guarente’s papers (early science paper Chen et al. and later paper with sirt1 ko in brain). To me this reeks of sloppy or fraudulent science.
    Yet there are still sirtuin apologists. “Well longevity isn’t the only thing sir2 does…”, “It’s not Sirt1, it’s all about Sirt3…”. When will this madness stop?
    So it is clear that GSK got taken on this deal, but they should have known what they were getting into. My question is what about the millions of dollars of tax payer money that has gone into NIH funding of this sloppy science. What about the post-docs and graduate students who were first authors on the sensational sir2 papers that were severely methodologically flawed? They took jobs from good scientists who refuse to claim that their molecule of interest was some fountain of youth.
    Everyone, please jump off the sir2 bandwagon now, or you might find yourself the last sane person on it.

  14. Paul Brookes says:

    Re: #13 UnSirtain
    We like you have also been stung trying to replicate sirt data, in particular the effect of SRT1720, which appears only to work in animals with long term dosing (days/weeks). How you explain that if it’s working as an allosteric activator of the enzyme as is being claimed, is beyond me. Either it is activating indirectly via an upstream pathway (pick a receptor), or it gets metabolized in the gut to the active component, but there’s just no way SRT1720 is directly acting on the enzyme. Same probably goes for resveratrol.
    Regarding SIRT assays, it is a mess… The flour-de-lys is a joke. p53 k379 acetylation is not bad, but the antibodies are not great. Whoever comes up with a specific enzymatic activity assay, will make a lot of money and make a lot of researchers very happy.
    Regarding SIRT inhibitors, splitomicin is OK but needs reasonably hi concentration (10uM). Nicotinamide is a joke… How can you take anything seriously if you need 20mM to see an effect? Carbazide (Calbiochem calls it SIRT1 inhibitor3 and others sell it as EX#something) is no good in our hands. Sirtinol is toxic as shit to the heart (our organ of interest) and there are hidden data in papers showing neurons don’t like it either. There are really no high potency SIRT inhibitors, and for absolute sure you can bet they’re all hitting other SIRT members (3 in particular) and are not specific for SIRT1.
    Regarding the knockouts, there’s some debate as to the lethality of the SIRT1 ko. Some claim the homozygote is embryonic lethal (it is for us), while others claim it lives but has “issues”. We see cardiac effects with the het’ mice, so it’s not necessary to go to the full ko. Background is also important… we crossed it a few more generations onto C57 before trying any experiments. The same goes for the SIRT1 overexpressors… back crossing to C57 and using LITTERMATES for controls, is absolutely essential.
    So yes, the SIRT1 field, for want of a better term, is a complete dog’s breakfast right now. However, if you put in the effort and do the right controls, there are some definite and interesting effects of these molecules, which are relevant to human disease. Call me a SIRT apologist if it makes you feel better. I’m happy with the data we have generated and published (none of it at all related to aging) and I don’t see that a few problems in the SIRT/aging field impacts the rest of the SIRT story.

  15. Jose says:

    A serious meta-question: how many biotech “breakthroughs” have ever panned out?

  16. Nictorius says:

    Re: #14 Paul Brookes
    Nicotinamide is very well established as a sirtuin inhibitor, see ie from the Denu lab, with inhibitory concentrations in vitro in the low uMs. One can theorize a lot of explanations as to why higher concentrations are required in vivo – but by way of comparison, both caffeine and aspirin require mM concentrations against various targets too.

  17. pete says:

    @15 Jose
    As a biotechie I’d have to say, there are some:
    – Immunex’s Enbrel (TNFR-Fc fusion) took RA therapy to a new place.
    – Then there’s all the recombinant proteins from the olden days: EPO, insulin, HGH, GM-CSF, etc., each a big deal if you needed them.
    – Then there’s antibodies of various flavors +/- conjugates, that have achieved success in a number of indications.

  18. Anonymous says:

    @ #9 & 11
    You guys are right!
    GSK is a master of disguise and non-sense! Why didn’t they listen to their scientists who were against the Sirtris science? Why are there only two managers left at Sirtris (ie: top brass)?? Looks like a mess but unfortunately will probably be forceably pushed under the rug so that all is forgotten…business as usual. Unfortunately, a lot of GSK scientists suffered from the outcome of the GSK purchase of Sirtris for ca. $750 million. Heads should roll…
    Bottom line: justice always prevails in the end. Let’s wait and see!

  19. Vince says:

    Paul Brooks,
    I enjoyed your last comment very much as it resonates.
    While I’m annoyed at the difficulty the sirtuins are presenting, every time I see someone inject ‘GSK and the $700 million deal’ into a conversation on the science, my eyes roll and my brain filters them out. Was it the most optimal deal, likely not. Was the science as firm as we all hoped, likely not. But, that’s life: shut up and push on with what you have. Derek’s decoupling of these different aspects was spot-on.
    On the related topic of if sirtuin-targeted drugs (STACs) exist, they do as evident in stein’s paper in J Bio Chem (PMID:20702418); they are just not what we’ve been running our tests with. Hell, I’m quite sure we still don’t know the structure of the three NCEs in trials (SRT2104, SRT2379 and SRT3025). 2104 has completed it’s first phase 2.
    GSK has moved on from SRT1720, hopefully soon to can we.

  20. Gambler says:

    All fine, but the issue many of us have is the excessive hype and lust for media attention that appears to have driven at least 2 of the principals in the field. And the GSK deal is relevant both because of the opportunity cost, and the fact that the size of the deal itself drove more hype and made it even more difficult for the scientists involved to acknowledge the uncertainties.
    I know this type of behavior is all too common, but I’m with Jonathan Auwerx and other commentors above – let’s focus on the science and see whether these are useful targets or not. All the hyperventilating about sirtuins as ‘master regulators’ of anything is counterproductive.

  21. Anonymous says:

    No mention of Sirtris but a few interesting points nevertheless for CEO Witty:

  22. Anonymous says:

    Vince (#19) wrote “While I’m annoyed at the difficulty the sirtuins are presenting, every time I see someone inject ‘GSK and the $700 million deal’ into a conversation on the science, my eyes roll and my brain filters them out.”
    Maybe you were speaking to one of the 50% of the metabolic scientists at RTP or 66% of the cardiovascular scientists at UM that were thrown out in the street to finance that acquisition after the management had been told emphatically not to buy the company. Show some respect, asswipe. Most of us have never recovered professionally or financially from that “deal”.

  23. NH_chem says:

    The next victim of over-hyped science and millions spent on alliances and deals?
    I nominate RNAi therapeutics

  24. exGSKoid says:

    As a previous GSK Scientist, I can verify that a number of GSK scientists did in fact investigate the data from Sirtris, and found a number of troubling issues, several years before the purchase, which were not published. If management had seriously looked at ANY of this data, they should have have serious questions to the quality of all of Sirtris’ science.
    The same can be said for a number of previous deals made by GSK in the past few years, as well as some internal pet projects which were funded well past their usefulness. Had GSK spent their money on simple basic research and not laid off their best scientists over the past few years, I have no doubt that they would be in far better shape now.
    BTW, I don’t claim to be among one of the best scientists. But, some of the laid off scietists were considered top in their field and had one or more drugs on the market. What idiot would get rid of the few people able to get a drug to market?
    #22, I second your RNAi, based on Merck’s even bigger payment for their magic beans…

  25. Don't blame sirtuins says:

    The issue is not that the biology changed, or that something didn’t pan out. That is science and in our business that risk is necessary.
    The issue is not even the hype, or that funding the risk required large cuts.
    The only issue that matters is how was it vetted, and was it vetted in a manner consistent with the scale of the claims? You know, extraordinary claims, extraordinary justification.
    All the *visible* input suggests that this was not done. In addition, GSK had a wealth of people to assess the claims. If that evaluation was mishandled, especially given the scale of the impact, then I would hope those who ran that are taken out of decision making, for the good of GSK.
    If, on the other hand, the assessment was the best that could be done in such a confidential and behind the scenes activity, then I don’t fault the assessors.
    At that point it comes down to the board adopting a high risk acceptance and being willing to trade many experienced people that will have been perceived as not producing drugs, for the possibility of transformative biology and a new direction.
    A big gamble indeed and much easier to call in hindsight.
    But, the final question we don’t have the answer to is: does the board and senior management have a risk assessment and tolerance that is in line with the realities of the science or of Hollywood?

  26. Bob says:

    Funny nobody mentions Dr. Westphal, who successfully sold this whole mess to GSK and became fabulously rich doing so, and, what actually is truly troubling, is by many considered a rock star of biotech world now, a model of a successful biotech CEO and entrepreneur….

  27. KW's hairdresser says:

    Spot on! One of the causalties of the bloodbath in CVU was the creator of darapalib a potential cardiovascular blockbuster! Perhaps Vince, he should just move on huh! Got to make room for “real” innovators like Westphal huh Vince!
    Tragically, there was over 50% cuts in infectious diseases this year at GSK. Deep cuts in oncology are rumored. Gotta get over it I suppose, eh Vince.
    The problem with big Pharma, GSK in particular, is that they are so enamored with fad science and gimmicks (see “open office concept and “transparency”)and are more concerned with lining upper management’s pockets, outsourcing to CROs, and patting each other on the back than they are with real science. GSK has become nothing more than a bizarre cult of Moncef. At least he is having fun!!

  28. AC says:

    As an undergraduate in one of Steve Helfand’s courses, I can verify that “not too happy” is a dramatic understatement. It does seem unusual that the 2009 work wasn’t cited, and I’m eager to see what comes of this sirtuin controversy.

  29. Anonymous says:

    Heart-warming stuff, Spiny Norman, a great antidote to the depressing tales of greed, egos and wilful delusion that drove the whole GSK-Sirtis fiasco.

  30. anonymous says:

    @27. KW’s hairdresser
    You Sir (or Madam) are spot on regarding Large Pharma and fads. I had the dubious pleasure of performing an in depth due diligence on Sirtris for a major GSK competitor. I was, in a nutshell, appalled by the sloppiness of the science I reviewed (drawing conclusions from cellular assays using cytotoxic compounds) and wrote a scathing DD report, which was promptly returned to me as “too biased / too harsh”. Needless to say, these criticism’s were removed from the final version sent to our Senior Mgmt and the Company did indeed make a very substantial offer which (happily for me) was rejected by Sirtris as being too low (thanks GSK). At the time, it seemed as if virtually every Large Pharma organization was courting Sirtris, and for what? In retrospect, the “selling of Sirtris” is more reminiscent of a that of a carnival barker / snake oil salesman than that of a “value added” biotech product.

  31. Anon again says:

    There are so many levels of detail, complexity, conflict, ego, desperation, in this story that it is unlikely to ever be completely explored and documented in one place. #31’s experience is not unlike the evaluation that went on within GSK, where internal DD and knowledgable scientists were not in favor of the deal—-particularly at the size that was ultimately consumated. #25 is right in implying that judgement within GSK management (some, directly from academia) was poor…it involved relatively new people to their jobs who clearly felt they were more capable (smarter, more clever) in judging the “value potential” than those who were involved directly in the DD and internal scientist. That is they did not respect the scientists within GSK that they had inherited, preferring to believe the carelessly generated data and over hype from Sirtris, via Westphall (and Dipp). Clearly, an amount of elitism in play by these people. On this, 25 is wrong in suggesting that data quality is not important….it is one of the most critical elements in companies and people being credible.
    Yes, Westphall et al played their game…trading one offer off against another, building up hype around the new drug opportunities to where several potential big investors (eg big Pharma) felt they had to “be in the game” or miss the opportunity forever. Management (many involved within GSK never having actually been involved in any step of discovering, devloping, or making a drug) had clouded vision of real risk / reward / cost, and what their own internal data was indicating. A milestone based deal in the order of a few hundred million dollars…ok, maybe worth the risk….but the actual cost to GSK in the purchase of the company (while leaving them as “independent, largely to this day) was, and has been more negative than the same and current GSK management can appreciate. At least, Westphall (and Dipp) are finally out of GSK R&D managment roles, even though Westphall still has a hand in Sirtris oversight. Talk about the fox in the hen-house…
    And what of Westphall, Dipp et al? Would / should anyone “trust” one of their schemes again. Well, guess it always depends on the “end game” or “exit strategy” as some already have jumped onto more of their involved schemes….as long as there is a buyer and it’s not illegal.

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