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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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« Europe Wants Some of That Molecular Library Action | Main | Biomarker Caution »

April 9, 2012

Would I Take Resveratrol? Would You?

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Posted by Derek

I've written many times here about sirtuins, and their most famous associated small molecule, resveratrol. And I've been asked more than once by people outside the med-chem field if I take (or would take) resveratrol, given the available evidence. My reply has been the same for several years: no, not yet.

Why so cautious, for a compound that's found in red grapes and other foods, and to which I've presumably been exposed many times? Several reasons - I'll lay them out and let readers decide how valid they are and how they'd weight these factors themselves.

First off, we can dispose of the "it's in food already, and it's natural, so why worry?" line of thinking. Strychnine is all-natural too, as are any number of other hideous molecules that are capable of terrible effects, so that's no defense at all - it never is. And as for being exposed to it already, that's true - but the dose makes the poison, and the dose makes the drug. I've no idea how much resveratrol I've ingested over the years, but it's safe to say that it's been in small amounts and at irregular intervals. Going from that to regular higher dosages is worth some forethought.

So what do we know about what resveratrol does? A lot, and not nearly enough. Its pharmacology is very complex indeed, and the one thing that you can clearly draw from the (large) scientific literature is that its (a) a very biochemically active compound and (b) we haven't figured out many of those actions yet. Not even close. Even if all it did was act as on one or more sirtuins, that would be enough to tell us that we didn't understand it.

That's because the sirtuins, along with many other enzymes, are involved in epigenetic signaling, a catch-all term for everything in the DNA-to-RNA-to-protein sequence that doesn't depend on just the DNA sequence itself. (And as everyone discovered when the number of human genes came in on the low end of the low estimates, these processes are very important indeed). There are a lot of mechanisms, and it's safe to say that we haven't found them all, either, but the sirtuins modify histones, the proteins that DNA is wrapped around, and thus affect how genes are transcribed. All these transcriptional processes are wildly complex, with hundreds and thousands of genes being up- (and down-) regulated in different tissues, at different times, under different conditions. Anyone that tells you that we're close to unraveling those balls of yarn is not keeping up with the literature, or not understanding what they read.

Of course, one of the controversies about resveratrol (and some of the other sirtuin modulators) is whether they act directly on these enzymes or not. Opinion is very much divided on that, but resveratrol seems to have a number of other effects, mediated through processes that (again!) are best described as "unclear". For example, its metabolic effects seem to be at least partially driven by its actions on an enzyme called AMPK, a key enzyme in a number (brace yourself) of important cellular processes. It might well be that AMPK (activated by resveratrol) is what's having an effect on the sirtuins. A very recent paper implicates another step in the process: resveratrol may well be acting on a set of phosphodiesterase (PDE) enzymes, which affect AMPK, which affect sirtuins. But then again, there's another paper from earlier this year that suggests that resveratrol's activity against sphingosine kinase might be the key. So your guess is as good as mine.

One objection to all this is that there's room to wonder about the mechanisms of a number of drugs. Indeed, there have been many that have made it to market (and stayed there for many years) without anyone knowing their mechanisms at all. We're still finding things out about aspirin; how much can one expect? Well, one response to that is that aspirin has been used widely in the human population for quite a long time now, and resveratrol hasn't. So the question is, what do we know about what resveratrol actually does in living creatures? If it has beneficial effects, why not go ahead and take advantage of them?

Unfortunately, the situation is wildly confusing (for an overview, see here). The first thing that brought resveratrol into the spotlight was life extension in animal models, so you'd think that that would be well worked out by now, but boy, would you be wrong. The confusion extends up to mouse models, where some of the conclusions - all from respectable groups in respectable publications - seem to flatly contradict each other. No, the animal-model work on resveratrol is such a bubbling swamp that I don't see how anyone can safely draw conclusions from it.

How about people, then? There have been some clinical trials reported, with this one the most recent, and these are summed up in this open-access paper. The longest reported trials are on the order of weeks, which is useful, but not necessarily indicative of what might happen out in the real world. But there have been some beneficial metabolic effects seen (although not in all trials), and these constitute some of the biggest arguments for taking resveratrol at all.

One of the things that seems to be possible, from both the animal and human studies, is that the compound might exert these beneficial effects mostly in systems that are already under metabolic stress. Does this translate to people as well? If you're healthy already, which does resveratrol do for (or to) you? No one knows yet, and no one knows how much resveratrol you'd have to take to see things happen. Here's another article (PDF) summarizing the known effects, and here's the way the authors sum up:

"It is no exaggeration to say that the literature on resveratrol is contradictory and confusing. The wide range of concentrations and doses used to achieve the various effects reported for resveratrol in both in vitro cell culture and animal studies raises many questions about the concentrations achievable in vivo. . .

The bottom line? Resveratrol is a very interesting compound, and potentially useful. But the details of its actions aren't clear, and neither, honestly, are the actions themselves. Given the importance of the processes we're talking about - cellular metabolism, which is intimately involved with aging and lifespan, which is intimately involved with defenses against cancer - I don't feel that the situation is clear enough yet to make an intelligent decision. So no, I don't take resveratrol. But I'd be willing to if the fog ever clears.

Comments (73) + TrackBacks (0) | Category: Aging and Lifespan


COMMENTS

1. Anonymous on April 9, 2012 7:49 AM writes...

The Atkins Diet is also a wonderful panacea short term. The fog has to more than clear on sirtuins. There has to be unequivocal evidence of long term efficacy.

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2. Virgil on April 9, 2012 8:35 AM writes...

I think you could reasonably take the word resveratrol in the above article, and replace it with "polyphenolic compound found in plants", and it would read the same. The entire field of "nutriceuticals" is like this. Billions of dollars have been spent on investigating flavonoids, triterpenoids, polyphenols, curcuminoids, phytoestrogens etc. The source is invariably some plant used in Eastern medicine for centuries. The effects are almost always attributed to it being an antioxidant. All of these things hit multiple pathways, usually including estrogen receptors, a swath of tyrosine kinases, or some effect on apoptosis. The "science" is almost always published in low-impact specialist journals. There's usually a company shilling the encapsulated form of said biological, with the lead author of the paper somehow embroiled financially. These are just some of the reasons why people refer to this type of science as "jungle juice".

Seriously though, the pleiotropic effects of any biologically available molecule should not be surprising... it behooves organisms to exploit the molecules they evolved in the company of, for multiple end-points. Why, having evolved in an environment containing sulforaphane (the thing in brocolli) would mammals choose only to let that compound activate a single pathway such as Keap/Nrf? I doesn't make sense from an evolutionary perspective. Clearly, having found that this stuff can activate one pathway for beneficial effect, the evolution of other pathways to exploit the same molecule was favored. Ergo, the only molecules which are going to hit single pathways are those which evolution has not yet encountered, i.e. man-made compounds. Anything biologically derived will hit multiple targets for the simple reason that billions of years of evolution has made it precisely that way. I thought this was pharmacology 101 for everyone in the drug industry?

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3. Bill Sardi on April 9, 2012 8:36 AM writes...

Most Americans have not bought into the idea of taking resveratrol pills, to their own demise. Maybe 100,000 Americans take resveratrol pills. The science is confusing because mega-doses are often used by laboratory scientists which are counter-productive. Resveratrol is antioxidant at low dose (copper chelator) and pro-oxidant at high dose (releases copper). The idea behind resveratrol pills and other similar small molecules from nature is that they exert a small amount of biological stress that then activates the body's defenses via a gene/transcription factor called NRF2 (activates enzymatic anti-oxidants glutathione, SOD, catalase as well as adenosine, heme oxygenase and nitric oxide). This low-dose biological stress concept is called hormesis. Hormesis is observed in wine which provides greater than dietary levels of resveratrol and other molecules but not mega-doses. Begging for more studies will result in a long wait. There is not a single human study of resveratrol for heart disease since resveratrol pills became prevalent 8 years ago. Human cancer trials are also nearly non-existent. Modern medicine doesn't want to put resveratrol to the test. Begging for long-term studies means one would have a long wait. The idea behind resveratrol pills is that they would mimic a calorie-restricted diet and double human lifespan/healthspan as is seen in food restricted animals. However, it would take 8-10 decades to conclusively prove this in humans, which is impractical. What we do know is that short-term (6 months) use of a modest dose of resveratrol among patients with metabolic disease abolished the first sign of arterial disease (decline in flow mediated dilatation). What we do know is that resveratrol works better than any chemotherapy drug in the laboratory (blocks all three stages of cancer -- initiation, growth, spread) which no anti-cancer drug can claim. There are ways to make mega-dose resveratrol completely non-toxic and this was demonstrated in a lab in Europe and ignored by the scientific community. The rationale to wait till science understands all the genetic mechanisms means all current drugs should be abandoned till that is known in this era of a mapped genome and epigenetics. Actually, an available resveratrol pill switched 677 of 831 longevity gene in lab mice in the same direction as calorie restriction, which also was ignored by mainstream science. It's obvious modern medicine doesn't want anything to do with resveratrol.

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4. Chemjobber on April 9, 2012 8:49 AM writes...

I think it's important to note that Bill Sardi is worth a Google search for his writings.

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5. PPedroso on April 9, 2012 9:01 AM writes...

@2. Virgil,

Although I agree with most of your comment I think man-made compounds are not the only ones which evolution has not yet encountered. We have marine products that are still a big reservoir for potential interesting molecules.

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6. Chemjobber on April 9, 2012 9:02 AM writes...

...in that he's quite the supplement booster.

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7. HelicalZz on April 9, 2012 9:06 AM writes...

As part of a regular glass of wine, sure. Other than that, there is the question of dose and frequency etc. etc., not to mention 'quality' of product.

Zz

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8. PPedroso on April 9, 2012 9:06 AM writes...

@3 Bill Sardi,

you talk about modern medicine as if it is an unknown abstract entity. We are modern medicine and if someone thinks that way about a compound, that someone should create a start-up, get some funding and take it all the way to FDA for approval. If it is indeed a good molecule it will pass with flying colours.

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9. John on April 9, 2012 9:08 AM writes...

@3:

Bill, it's refreshing to see someone trolling under his own name, but the audience of this site will not generally be receptive to your theories of a vast pro-illness FDA conspiracy.[1]

As for resveratrol, it has a scent of the magic rock that keeps tigers away. Maybe the rock does have special powers, but the data so far has been unimpressive.

[1] http://knowledgeofhealth.com/news-media-cherry-picks-negative-multivitamin-study-over-major-story-that-sufficient-amounts-of-vitamin-d-would-lower-world-mortality-rates/

Permalink to Comment

10. intrigued on April 9, 2012 9:10 AM writes...

@3 Mr Sardi-

I am intrigued by your description of the benefits of resveratrol. Could you recommend a website that contains more of this type of information and supplies of resveratrol pills?

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11. milo on April 9, 2012 9:11 AM writes...

@chemjobber,
Comment on what he said, not on who said it.

The GOP, "climate change does not exist because Al Gore says it does exist"

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12. luysii on April 9, 2012 9:25 AM writes...

Things are not always simple when risk reduction is involved. For a few examples where well intended attempts went horribly wrong (the HERS study, antioxidants to prevent cancer, even taking vitamin supplements) see

http://luysii.wordpress.com/2011/10/13/the-risks-of-risk-reduction/

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13. Anomymous II on April 9, 2012 10:00 AM writes...

As Virgil points out in his comment, a large number of “nutriceuticals” seem to exert similar biological effects, e.g. life extension in worms, efficacy in the treatment of neurodegenerative diseases or type 2 diabetes, and at higher doses induction of apoptosis and selective killing of cancer cells. Further, Virgil points out correctly that “the effects are almost always attributed to it being an antioxidant” in other words many of these “nutriceuticals” are chemically reactive molecules and contain an a,b-unsaturated ketone moiety. So to me it is not too surprising that in vitro, high doses of these “nutriceuticals” covalently modify various signaling molecules, which many authors have use as an explanation for the various observed biological activities. However, in vivo one of the most plausible scenarios is that these “nutriceuticals” or a metabolite react with the endogenous antioxidant glutathione followed by a mild and short duration increase in the cellular levels of reactive oxidant species (ROS). This increase in ROS will then trigger various adaptive/repair gene programs including the nrf2/antioxidant response, heat shock response, unfolded protein response. In other words, a low dose of stressor or damaging agents (above mentioned “nutriceuticals”) will trigger various repair mechanism, an approach that has been named hormesis. Therefore, by and large the therapeutic effect of the discussed class of “nutriceuticals” may not come from working on a specific molecular target or targets, but through mild depletion of endogenous antioxidants such as glutathione and the initiation of adaptive stress responses. While a small amount of stress once in a while may turn out to be good for your health, I would certainly see a problem with causing long-term or very high levels of stress. So Derek taking a small dose of resveratrol (glass of red wine) once in a while may do you some good, but I would have reservations taking it every day for a long time. By the way physical exercise triggers many of the same adaptive responses.

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14. Curious Wavefunction on April 9, 2012 10:25 AM writes...

I think Bill Sardi raises an important question even if I may not agree with his specific points about resveratrol. What do you do when comprehensive clinical trials of a medicinal substance are impractical because of length of time or expense? Do you withhold judgement until enough time has passed for the results to look conclusive, or do you rely on anecdotal evidence and small-scale studies to draw your own conclusions? The scientifically valid thing to do would be to withhold judgement (and that's what I would do in this case), but I can't entirely blame people for starting a regimen based on anecdotal evidence, as long as they are willing to shoulder the risks and to not draw unreasonable conclusions based on personal experience.

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15. PPedroso on April 9, 2012 10:31 AM writes...

@13

First of all I would like to see a complete PK and Tox GLP Package demonstrating that the molecule (either resveratrol or other) are ok to dose in humans.

Then at least a long term study in humans with safety endpoints. I mean if the metabolic syndrome molecules have to go through it why does this kind of molecules shouldn't?

ps- I am sorry if some of this is already available but I am in Europe and these natural stuff does not have much impact here.

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16. Morten G on April 9, 2012 10:35 AM writes...

No, I wouldn't.
There's no such thing as a free lunch. Somebody always picks up the tab and I don't want it to be me. And if resveratol made us superhuman evolution would have slowly lumbered us that way - even in humans where selection is very weak.

Resveratol got picked out because it turned out that a very moderate wine consumption (1 unit of alcohol per day) was actually health promoting. This was back when antioxidants were big - before people realised that exogenous antioxidants are a drop in the ocean compared to endogenously produced antioxidants and in addiction actually didn't reduce ROS.
(Now we have supplement idiots saying that antioxidants work because they increase ROS production but since antioxidants were not actually ever shown to make people healthier - only that veggies etc. that contained the antioxidants were shown to promote health - this is absolute horse shit)
Later it turned out that very moderate alcohol consumption in general reduced cardiovascular health. Alcohol is a vasodilator so that makes good sense. Reducing blood pressure is a widely recognized way of reducing CVD risk.

I should be a consultant for GSK. They don't get upset if you point out that their ideas are fucking moronic, do they?

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17. HelicalZz on April 9, 2012 10:37 AM writes...

#3 - Bill Sardi

It's obvious modern medicine doesn't want anything to do with resveratrol.

Is that right? Funny, NCI, Universtity of Washington, University of Florida, and a slew of others beg to differ. Quite a lot of clinical research going on here.

http://clinicaltrials.gov/ct2/results?term=resveratrol

While it is true that GSK halted a trial and that commercial pharmaceutical appeal may be limited due to IP restrictions (or lack thereof), that sure doesn't mean research won't be / isn't being conducted.

Zz

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18. partial agonist on April 9, 2012 10:37 AM writes...

Mr. Sardi,

You made some pretty strong claims in your post, so as a scientist I would sure like to see links to the evidence.

Let's start with this claim:

"resveratrol works better than any chemotherapy drug in the laboratory (blocks all three stages of cancer -- initiation, growth, spread) which no anti-cancer drug can claim"

I would like to read such a report, with effective doses, cell types studied, etc. As a member of the scientific community, I promise not to ignore it.

Thanks in advance!

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19. HelicalZz on April 9, 2012 10:44 AM writes...

And by the way, the antioxidant responses via NRF2 are hardly exclusive to resveratrol. Neutracuetical lipoic acid has shown these effects too. So has ischemic preconditioning, a mechanical restriction of blood flow / oxygenation.

So, if you are 'holding your breath' waiting for more resveratrol research -- perhaps you are deriving a similar benefit?

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3166574/

Zz

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20. Morten G on April 9, 2012 10:44 AM writes...

Just to point out that I'm not some kind of nazi: When I say that selection is weak in humans I mean it is weak compared to viruses, bacteria, and archea. This is because of effective population sizes and even if we left "the weak" to die in the streets it wouldn't change that metazoans have weak selection. Read Eugene Koonin's 'The Logic of Chance: The Nature and Origin of Biological Evolution' for an update on where the science of evolution stands today.

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21. partial agonist on April 9, 2012 11:02 AM writes...

I assume the cancer efficacy claims go to the 1997 Pezzuto science paper,

w w w dot
sciencemag.org/content/275/5297/218.abstract

interesting glimmers of antitumor activity, but hardly earth-shaking and not indicating anything about mechanism or about the various stages of tumor growth

More troubling to me is the result of the google search I did, as Chemjobber suggested, with the result being links to anti-vaccine gibberish and "Buy all of my books to tell you how scientists in industry are evil" opportunities

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22. JAB on April 9, 2012 11:19 AM writes...

@2: There exist a continuum of substances in organisms which can affect other organisms, usually in a defensive mode. Some of these are extremely non-specific, such as polyphenolics (tannins), and some of them are exquisitely specific (e.g., strychnine certainly is specific for glycinergic CNS receptors, and I could go on for pages with other examples). I agree that much of antioxidant work is meaningless. I disagree that synthetic compounds are the only place to find new drugs.

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23. milo on April 9, 2012 11:32 AM writes...

@ partial agonist,
I guess you missed the recent aspirin study results out of the UK? Huge.

Aspirin is a natural substance, with many targets, just like resveratrol.

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24. rodentrancher on April 9, 2012 12:03 PM writes...

@23 milo

Aspirin is synthesized from a phytochemical, salicylic acid. Aspirin itself is not a naturally occurring compound.

It's interesting to note that the motivation for producing aspirin is that it is less toxic and irritating than the naturally occurring salicylates.

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25. partial agonist on April 9, 2012 12:24 PM writes...

#23 (milo)

I asked about resveratrol, and evidence to back up extraordinary claims about anti-cancer efficacy "beyond what any other drug can claim"

Resveratrol is not the same as aspirin.

As a late 40ish male, I take aspirin every day.

I don't take resveratrol, and I am not likely to do so unless there is scientific evidence to take that action. The fact that such evidence exists for aspirin debunks the whole argument that crooked scientists don't ever want to look for new uses of old substances, presumably for some nefarious reason.

I want data, not empty claims and 3rd person anecdotes

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26. anon the II on April 9, 2012 12:25 PM writes...

I agree with the first part of what #2 Virgil had to say but he had to keep talking. I'd say #22 JAB pretty much straightened it out. I remember back in the late 80's and early 90's when ellagic acid had many of the magical powers currently attributed to resveratrol. It showed up as a hot hit in some of the NIH's Molecular Libraries Initiative early screens. I believe most of the science (?) around these compounds is meaningless and a pretty good waste of resources. But to answer the original question, I am willing to ingest resveratrol as long as it comes in a good cabernet.

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27. Hanibal Lechter on April 9, 2012 12:31 PM writes...

@anon the II: I prefer mine with fava beans.

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28. milo on April 9, 2012 12:51 PM writes...

@ partial agonist.

The fact is, the money lies w big pharma and governments.
Big pharma is not going to undercut its business by promoting non patentable substances. As such, it takes a Long time for Truth to emerge....ie studies to be conducted AND published. Enter aspirin as a cancer preventer and fighter...a Century later.

I think ill go pop a celebrex.

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29. dichotomous on April 9, 2012 1:02 PM writes...

@milo #28 - if, as you claim, money lies with governments, ashouldn't they be aggressively funding research into non-patentable substances? Governments are the largest purchasers of pharmaceuticals in Europe and the US, so they would have every motivation to undercut the pharmaceutical industry with non-patentable medicines if they worked.

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30. milo on April 9, 2012 1:21 PM writes...

You are correct, but governments are slow. Also, lobbying and employment and stock price concerns are also a factors.

My advice. Take high dose of omega 3 and low dose resveratrol (250 mg/day) and one baby aspirin/day.

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31. anonie on April 9, 2012 1:30 PM writes...

Why does it take so many words for you to say that snake-oil is still snake-oil, no mater who sells, packages, or advertises it?

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32. Haiku on April 9, 2012 1:32 PM writes...

Resveratrol likely has more benefits as an anti-cancer agent than anti-aging.


Still you guys are missing the big headlines!Foreign spies everywhere!!

http://www.bloomberg.com/news/2012-04-08/american-universities-infected-by-foreign-spies-detected-by-fbi.html

But I guess if your business model is getting Chinese to come to your University at full tuition that's likely to happen.

//online.wsj.com/article/SB10001424052702304750404577319922446665462.html

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33. milo on April 9, 2012 1:36 PM writes...

@anonie,
Being a simpleton might make your life easier, but it does not mean you are correct.

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34. dichotomous on April 9, 2012 1:39 PM writes...

@#28/30: I think the US Healthcare Reform Act (PPACA), which will transfer ~$100B from pharmacos to the US government in various forms, shows the government cares more about saving money on healthcare than pharma industry employment and stock prices.

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35. anonie on April 9, 2012 1:41 PM writes...

#32:

Maybe, lashing out by calling people unfavorable names makes you feel good, but it's not helpful, useful, necessary, or even true. The compound will never be an approved drug by FDA.

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36. milo on April 9, 2012 1:49 PM writes...

Anonie,
Maybe in your world that is the holy grail...but not in mine. I know too many people who are not being helped by FDA approved medications...not to say that many are not wonderful, because they are.

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37. Vader on April 9, 2012 1:52 PM writes...

Derek,

I share all your concerns except the upregulation of AMPk. As I understand it, this is basically the mechanism of action of metformin, which is the closest thing there is to a wonder drug in the diabetes world.

Of course, that raises a new objection: Is resveratrol going to do anything metformin doesn't? If so, are those things actually beneficial?

And I note that you can Google up accounts of folks taking metformin off-label as a "life prolongation drug." I should buy stock in tinfoil.

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38. plm on April 9, 2012 1:55 PM writes...

Thanks for the very interesting post -and the whole blog.

If not resveratrol, what (broadly targeted) life-improving drug would or do you take regularly? Do you take vitamin or mineral supplements? Any other comments, thoughts on those matters? I am greatly interested in your opinion as a sage of the pharmaceutical industry.

The remarks of Morten G are also very interesting. What could make a natural compound significantly life-enhancing for humans, in unnatural doses? Should we expect such compounds to work specifically on humans, mammalians, or all animals? What concepts from standard evolutionary theories could give clues to answer these questions?

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39. Crashpanic on April 9, 2012 1:56 PM writes...

One word: pterostilbene.
http://www.ncbi.nlm.nih.gov/pubmed/21982274

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40. r.pal on April 9, 2012 2:05 PM writes...

As Hippocrates put it " Food is they medicine and medicine is they food . If a physician does not understand food how can he heal the diseases of men.:

The clue to disease will be more enhanced if we design i gradients with a human evolutionary approach

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41. RKN on April 9, 2012 2:08 PM writes...

It's worth noting that Resveratrol exits in two isomeric forms: trans- and cis-. Supposedly, only the trans- form has activity, which quickly changes to the cis- form under exposure to ultraviolet radiation.

Yet I wonder if all the research done with Resveratrol takes care to prevent isomerization during the experiment. If not, might it be that the cis- form really is active in some animal models under specific conditions where the trans- form is not?

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