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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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May 2, 2012

Resveratrol Explained. A Little Bit.

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Posted by Derek

There's a new paper out in Cell Metabolism on resveratrol and SIRT1, and the press release from Elsevier (Cell Press) is just a tiny bit optimistic. "Study resolves controversy on life-extending red wine ingredient, restores hope for anti-aging pill", says the headline, but believe me, no one paper is going to do that. (This entry has links back to some of the history of the compound and the target, as covered here, but it's a convoluted story indeed). The EmbargoWatch web site calls it a "truly appalling" press release, and while I can't disagree with that, I don't think it particularly stands out: a lot of press releases are appalling.

And I disagree with them when they say that studies like this "probably don't deserve any coverage at all". It's actually a very interesting paper, even if it's not going to resolve any major controversies all by itself. It's from David Sinclair and co-workers (a large international team), and it presents the results of a long-running effort to see if what resveratrol does in animals that don't have the SIRT1 protein at all. That's a good experiment, which cuts right to the question of whether resveratrol's effects are SIRT1-driven or not. Problem is, the traditional knockout mouse model is almost always embryonic lethal in that case, so it's not so simple that generate such animals. The team was able to develop inducible whole-body conditional knockout adult mice, though, and set about dosing them with resveratrol to see what happened then.

Well, quite a few things did. From what I can see, the marquee items are these: normal mice fed a high-fat regimen showed beneficial effects on their mitochondria when given resveratrol, but the knockouts didn't, so that might be a clear connection to SIRT1. Resveratrol's effects on AMPK appear to be SIRT1-dependent (there are several links in this post about that connection, some of which led to papers that hypothesized a SIRT1-independent effect). But resveratrol treatment had good effects on glucose levels in mice, whether or not they had SIRT1 present, so that part seems to be going through some other pathway.

Sinclair's quoted in this Nature News piece as saying that this reflects the nature of resveratrol as a compound. “Resveratrol is a dirty, dirty molecule, very non-specific", he says. I think that's a very fair characterization, which is one of the reasons why I wouldn't take it myself. (That does shed an interesting light on the 2010 controversy when two former Sirtris executives set up their own reveratrol distribution effort, though, doesn't it?)

It would be quite interesting, for the sheer science of it, to take one of the later (apparently cleaner and more targeted) SIRT1 activating compounds that have come out of the GSK/Sirtris work and run it through the same animal model. You might expect the same sorts of SIRT1-driven effects, and perhaps much less of an effect on blood glucose, if that's really some off-target resveratrol thing. But since we're talking about epigenetic enzymes here, prediction is a chancy business. I wonder if this experiment is being done somewhere?

Comments (19) + TrackBacks (0) | Category: Aging and Lifespan


COMMENTS

1. milo on May 2, 2012 8:18 AM writes...

In fact, resveratrol seems to be superior to targeted Sirt1 activators as it improves blood sugar levels and liver health.
Leave it to 'modern science' to attempt to disparage a wonderful, multifaceted, Natural molecule. Follow the money - its not that complicated.

Dr. Sinclair is Jeckl and Hyde. Look at his contradictory statements over the years. Follow the money.

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2. Ewen Callaway on May 2, 2012 8:49 AM writes...

Derek,

Nice post.

They have published at least one experiment testing other suspected Sirt1 activators in these mice (http://www.nature.com/srep/2011/110818/srep00070/full/srep00070.html).

SRT1720 improved some measures of mitochondrial respiratory capacity in wild type mice on a high fat diet, but not in the knockouts.

Ewen

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3. lynn on May 2, 2012 10:12 AM writes...

And have they tested all kinds of compounds that are NOT supposed to have Sirt1 activity in that mouse model? I.e. negative controls.

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4. cancer_man on May 2, 2012 12:10 PM writes...

I can't believe how many here have written off resveratrol and/or the GSK pills. Resveratrol looks promising based not only on animal studies but now at least 7 very small human studies.

I used to be more optimistic but since 2012 just agnostic.

Sinclair took Longevinex at 300-400mg a day from 2003 to sometime in 2007 before switching to SRT501. Westphal also said he was taking SRT501 in 2010. I didn't understand what Derek meant by that shedding light on the 2010 controversy.
This was a *really* odd story that no one has explained. No one knows if Westphal sold any SRT501 except maybe to friends who he might have told in advance.

By the way, the SRT2104 GSK pill phase II trials have recently ended. Can someone explain to me how this works? Should we expect a paper or announcement this year? GSK announced early findings in Paris last year , but I do not know what they were. Does anyone here know? Thanks in advance.

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5. idiotraptor on May 2, 2012 12:28 PM writes...

Milo #1

Commentaries such as you offer are tedious and tiresome.

Agreed, there have been abundant negative and dismissive reactions by many scientists to the alleged health benefits of resveratrol.

Simply stated, data demonstrating the compelling therapeutic benefits of the compound are lacking or ambiguous at best. "Follow the money" can be aptly applied to those who shill resveratrol and related compounds as somehow beneficial because they are "natural"

To paraphrase and extend a comment by Derek in one of his early posts this year, benzene, aflotoxin, ricin, and tetrodotoxin all are "natural" products. The fact they are "natural" doesn't prompt my enthusiasm to ingest them.

It's emblematic of "New Age" thinking i.e. substitution/confusion of emotion for rational thinking.

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6. Jim Franklin on May 2, 2012 1:03 PM writes...

This study is not surprising as there have been hundreds of studies on the benefits of polyphenols like resveratrol and many on pterostilbene which may be even more powerful than resveratrol and comes from blueberries. Cutting edge supplements now exist which contain both pterostilbene and resveratrol in optinal quantities such as biotivia pteromax. The combination of these two molecules is complementary and synergistic without any side effects. The benefits are higher energy, better sleep , increased endurance and natural weight loss.

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7. Frank Jimlin on May 2, 2012 1:17 PM writes...

Don't listen to Jim. Supplements that are even more cutting edge such as NatureTivia's StilbeMAX have a better balance of resveratrol and pterostilbene. This greater synergy provides even higher energy, even better sleep, even more endurance (wink, wink), and even more natural weight loss. And of course, because it is all natural there cannot be any side effects.

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8. James on May 2, 2012 2:10 PM writes...

Good God - do the trolls and have a Google alert set for "resveratrol"? I love this site for the insight on the industry, but every time one of these topics comes up, it starts to look like the Huffington Post around here...

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9. processchemist on May 3, 2012 5:30 AM writes...

@cancer_man

Resveratrol disappeared in the last GSK pipeline both from oncology and metabolic areas. There's a last standing SIRT1 activator in Phase II for psoriasis. As Sir Witty said, a storm in a cup of tea...

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10. Bill Sardi on May 3, 2012 6:08 AM writes...

First, the very advantage of small molecules like resveratrol is that they differentiate so many genes. The term "dirty" or "promiscuous" has a negative tone, but aging involves many genes, not one. Single-gene targeted drugs (ie. Erbitux, Herceptin) have only been marginally successful.

In mice, if you calorie restrict (CR) them over a lifetime there are 831 genes that are differentiated (work of Weindruch, Prolla). Over a short term resveratrol differentiates 198 of these 831 genes. If resveratrol is combined with other small molecules, it has been show that 1711 genes can be activated over a short term and 677 of the 831 genes can be switched in the same direction as CR. (Exp Gerontology 2008) This suggests it would take a lifetime of taking resveratrol to achieve the broad epigenetic effect that a combination of small molecules can achieve in a short time.

Second, pterostilbene's proposed advantage is better bioavailability. But this is mistaken science. Virtually all resveratrol is conjugated with detoxification molecules in the liver, being perceived as a "biological threat." This is how resveratrol works -- by activating the body's defenses via the NRF2 transcription factor, particularly enzymatic antioxidants glutathione, catalase and SOD along with adenosine, heme oxygenase and nitric oxide. The dose must be low to do this (hormesis effect). The detoxification process in the liver binds resveratrol to carrier molecule sulfate and glucuronate, which makes resveratrol temporarily non-bioavailable (too big to pass through cell walls and enter genetic machinery). But glucuronidation and sulfation extends the half life of this molecule from minutes to hours. It is unzipped from glucuronate by an enzyme (glucuronidase) that is abundant at sites of infection, inflammation, malignancy. This is called nature's drug delivery system. Systemic effects are observed when resveratrol is given to lab animals and humans -- it is bioavailable.

Third, the statement in one of the postings that something that is all natural is safer is mistaken. Resveratrol is a very toxic (pro-oxidant molecule) at high dose (releases copper) and an antioxidant at low dose (binds to copper). This is why the 5000 mg resveratrol dose induced kidney failure among multiple myeloma patients (study was halted, never published). The potentially toxic properties of resveratrol can be completely negated when delivered in a complex of other molecules (Exp Clin Cardiology 15(4) e134, 2010) Given the current science, it is irresponsible to give humans mega-doses of resveratrol. Sinclair has misled many with his personal overdosing of resveratrol (he suffered with side effects from it -- flu-like symptoms) and unfounded claim that it takes 1000 bottles of wine to re-produce the same effect seen in the animal lab.

Sinclair himself wrote a paper about xenohormesis, how plants up regulate defenses when exposed to biological stress and then pass along defensive molecules like resveratrol to humans when they consume grapes, etc. The hormesis effect is only achieved at low dose.

Let it be said that resveratrol has been shown in the animal lab to (a) protect the heart from damage by a heart attack before the event, something no other drug has been demonstrated to do; (b) block cancer at all three stages (initiation, growth, metastasis), again something anti-cancer drug can do; (3) restore vision via anti-angiogenic properties to humans (paper in press). Imagine, a molecule that conquers mortal heart attacks (something aspirin and statin drugs do not do), blocks cancer and restores vision, the three most feared health problems.

Yet, as Dr. Frank Sellke at Brown University laments, in the past 8 years since Sinclair and Guarente uncorked this molecule, resveratrol has not entered into a single human clinical study for heart disease. Modern medicine is dragging its feet here. Understand, you can't ethically conduct a placebo controlled study using resveratrol in at-risk humans to prevent mortal heart attacks. It has to come into common use like aspirin did and then studied retrospectively.

While Sirtuin1 is involved in a longevity effect cannot be argued now, but the question remains whether this is an indirect effect via some other upstream gene. The NIH study said phosphodiesterase-3 was inhibited first which then downstream affects AMPK, FOXO and SIRTUIN family genes. There is growing evidence pointing to Sirtuin3 as a more important player. Just remember, while scientists are sorting out all the mechanisms, you are getting older.

Permalink to Comment

11. processchemist on May 3, 2012 6:27 AM writes...

"While Sirtuin1 is involved in a longevity effect cannot be argued now"

Maybe the correct sentence is "While Sirtuin1 is involved in a longevity effect IN SOME ANIMAL MODELS cannot be argued now". Anyway I see that the whole matter CAN be argued, because of the many failures in obtaining the same result from groups not involved in selling/promoting resveratrol and SIRT1 activators.
There's something that sounds strange to me in the metabolic pathway of resveratrol as depicted by Mr Sardi, and maybe some with a deeper knowledge of ADMET can be of help about it....

"Just remember, while scientists are sorting out all the mechanisms, you are getting older. "

Sure, and guess what, we all are going to die too: so I suggest a combination of resveratrol and Lourdes water to promote healty aging and safe trip to Heaven after the eventual death.

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12. wanttobuysomelandintheeverglades on May 3, 2012 8:08 AM writes...

Everyone knows what was going on in that company and what GSK was trying to do, as embarrassing as it turned out to be, when they bought them.

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13. anonymous on May 3, 2012 9:31 AM writes...

With all the excess verbage on resveratrol, independent of it's proven multiple targets (eg published as an inhibitor of PDE IV), there remains a simple basic in practicality. It will very unlikely ever be an FDA approved ethical chemical entity. Why? It is in the "public domain" with very little opportunity for new proporietary IP, so there very small incenitive for anyone to burn resources on proper preclinical tox, and hence clinical, studies.

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14. anon2 on May 3, 2012 9:48 AM writes...

12. wanttobuysomelandintheeverglades: So, what is it that everyone knows?

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15. Virgil on May 3, 2012 9:52 AM writes...

@Jim Franklin, a quick Google brings up numerous examples of you talking up Biotivia's Transmax resveratrol all over the web. Care to declare what your link to them is?

@Bill Sardi, you are well known as a vocal defender of the fraudster Dipak Das, as well as having a significant conflict of interest due to your company longevinex which sells resveratrol Regarding your claim that RV prevents heart attack which no other drug can do - about 8000 articles on PubMed demonstrating cardioprotection by drugs would suggest otherwise.

Here's a suggestion... apparently Biotivia has "sold over 254,000 bottles" of resveratrol. At $40 a pop, maybe between the two of you, you can put that $10m toward a new computer to access PubMed?

In the mean-time, with the politest possible sentiment intended, please go back to your caves and let the real scientists have an adult conversation.

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16. alig on May 3, 2012 1:32 PM writes...

@ #13, Sirtris then GSK had resveratrol in clinical studies until a year ago. So obviously there was enough incentive to put into the clinic (about 720 million in incentives). GSK also bought prescription strength fish oil, but I think they feel better about that purchase.

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17. milo on May 3, 2012 3:57 PM writes...

@ alig,
Resveratrol was part of the sirtris program when wesphal and Sinclair were in charge...soon after they left, it was abandoned...my two cents is listen to what Dr. Sinclair says with caution....he is paid by Sirtris still....he has a financial interest - as well as all pharma cos. - to 'downplay' the potential of this "dirty, dirty" molecule...

Permalink to Comment

18. dichotomous on May 4, 2012 1:20 PM writes...

milo, it's fair to note that Sinclair may have a financial interest, but only if you note that many posters (such as Sardi above) have similar if not greater financial interest to 'play up' the potential of the molecule. So the debate needs to be on the science, not ad hominem attacks, and not the same few people saying the same few things more loudly in hopes that more people will listen to them.

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19. Ben on May 10, 2012 1:37 AM writes...

Bill Sardi,

What's the known optimal dose of resveratrol for humans? Per kg in body weight?

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