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Resveratrol as a Cautionary Tale

For those who haven't yet got the message, the article linked here points out just how little came of resveratrol as a drug candidate and sirtuin research as a whole from the past decade. Resveratrol and the study of sirtuins were hyped up at the time, as I'm sure many of you recall, and yet nothing came of it beyond a little more knowledge of cellular metabolism. Sirtuins do not have any meaningful influence on aging from the perspective of producing therapies and neither does resveratrol. The hype resulted from a confluence of the tendency for venture investment to talk up a position (in the company Sirtris, acquired for more than $700 million in the end, money written off by the acquirer since nothing of practical use ever came from it), and the "anti-aging" marketplace finding yet another set of potions its members could market to the gullible. A lot of resveratrol was sold, and many people who really should have known better bought some.

Whenever a new drug candidate emerges with claims that it allegedly slightly slows the aging process, the first thing you should think of is resveratrol, and be wary of hype driven by the profit motive. Resveratrol was just the latest in a line of hyped products allegedly providing benefits to health in aging, and in fact doing nothing of any significance other than helping some people to find profits. Mining the natural world for compounds that can alter the operation of metabolism has shown itself incapable of reliably producing results that matter when it comes to aging: decades of work on this and nothing to show for it but the continued ability to sell useless products to people who hope for something that works.

There is only one useful road ahead here when it comes to aging and health. It is the construction of new biotechnologies that deliberately and usefully repair the cellular damage that causes aging. Don't alter metabolism, instead fix it by removing the dysfunction that causes it to run awry in a careful, targeted way. The future is clearance of damaged cells, gene therapies to repair mitochondrial DNA, manufactured enzymes that break down specific forms of persistent metabolic waste, and so on - a world away from screening random compounds from plants in the hope that they will do more good than harm.

Resveratrol is a compound that gained a lot of notoriety in the mid-2000's as sort of a multipurpose pro-health molecule. In its heyday, it spawned companies and a plethora of enthusiastic articles that recommended binging on resveratrol-containing foods as an all-purpose health enhancement. Interest has since waned on this compound, but it's worth revisiting the story to see how an exciting, trendy scientific discovery can lose steam when scientists better understand its limitations. A first hint of Resveratrol's pro-health effects came in 2003 out of the lab of David Sinclair, a young investigator at Harvard. Sinclair's lab found that resveratrol could extend lifespan in yeast. The extension was thought to be dependent on the protein Sir2, the founding member of a family of related proteins called sirtuins. The idea that small molecules could be used to extend healthspan was gaining excitement and attracting funding. A year later, Sirtris went public, eventually being bought up by pharma giant GlaxoSmithKline. The resveratrol supplement industry grew.

However, later reports led to questioning resveratrol's benefits. Work out of the lab of Linda Partridge, a well-respected Drosophila researcher, was unable to reproduce earlier findings of lifespan extension in Drosophila and produced only variable effects in C. elegans. There has also been a broader controversy over the role of resveratrol's reported target SIRT1. A major stain on the field came in 2012, when resveratrol researcher Dipak Das was fired from UConn for allegedly committing 145 instances of scientific fraud including "fabrication and falsification of data". Much of Das' work formed the basis for supposed cardioprotective benefits of resveratrol. As a result, resveratrol's efficacy for this application is now in serious doubt.

But even before the Das controversy, there were indications that people in the know had cooled on resveratrol related formulations as therapeutics, possibly due to inherent limitations with the compound. One of the co-founders of Sirtris left the company in 2011, and GlaxoSmithKline eventually shut down Sirtris and folded it into its broader business. This diminished industry interest in resveratrol may stem from two unfortunate issues: 1) research suggesting resveratrol does not act via SIRT1 makes it difficult to develop resveratrol into a drug; and 2) resveratrol is rapidly degraded by the liver after ingestion, making it naturally a poor drug. The first is an even bigger problem than it seems because FDA approval of new drugs requires knowing their mechanism of action. The second is a problem because it means it's difficult to increase the levels of resveratrol in the body by taking a pill, and medicines usually need to be administered by pill for average patients to be able to use them.

Link: http://sage.buckinstitute.org/resveratrol-placebo-or-youth-in-a-pill/

Comments

Hi Jim,

While I can't read Reason's mind, it's pretty clear he uses a variety of criteria to choose which articles to link on a given subject, and they aren't always simply the most recent progress report in some area: often links older articles are more useful because they're good intros or because they're most germane to the angle of the originating post.

SRF-funded research at Rice University has made significant progress in developing rejuvenation biotechnology against atherosclerosis, and you can see Dr. Mathieu's presentation at the Sixth SENS scientific conference for his subsequent progress in targeting intracellular aggregates as regenerative medicine for atherosclerosis.

Our 2013 Research Report covered progress on clearance of A2E as rejuvenation biotechnology against age-related macular degeneration, and again further progress in removing intracellular aggregates to prevent blindness from ARMD was presented at SENS6.

There will be updates on the developments in both of these initiatives, along with SRF-funded work on lipofuscin at Rice, in our upcoming Annual Report, to be released at Rejuvenation Biotechnology 2015 (RB2015) (I'm not sure about online vs. print rollout); we may release a more detailed report on all of this in the subsequent months.

Posted by: Michael at July 18th, 2015 1:17 PM

Gene targeted therapies have been disappointing. The broad influence of molecules such as resveratrol over the epigenome has been emphasized as its advantage since aging and disease involve networks of genes. Dipak Das' research has been duplicated and vindicated by researchers in Canada, Italy and elsewhere. Cellular repair therapies are in vogue and resveratrol slows the cell cycle thus allowing more time for DNA repair. Research involving resveratrol is still vigorous and the Sirtuin1 gene is involved in the critical gene-controlled molecular pathways (NF-kappa B, AMPK, Nrf2, FOXO1, Sirtuin3) are all influenced by resveratrol. Resveratrol still stands as the most potent Sirtuin1 and Sirtuin3 activator tested. Its dismissal by a major drug company suggests it posed too much of a commercial threat to synthetic analogs. The road to producing expensive man-made anti-aging suggests a day when only 1% of the world could afford to obtain them. Such elitist directions should be shelved. Cast resveratrol aside, there are a whole class of polyphenols ready to fill its space -- apigenin, curcumin, quercetin, others. Metformin is now being posed as the first anti-aging drug to undergo human clinical trials. Metformin's primary mode of action is via activation of cell-energy sensing AMPK. Yet resveratrol activates AMPK 50-200 times better than metformin.

Posted by: Bill Sardi at July 19th, 2015 8:54 AM

But, Mr. Sardi: on the key issue, resveratrol has now repeatedly failed to extend the lifespan of normally-aging mice or rats, at multiple doses and at several ages of initiation. The rest is details.

Also, while I don't believe that metformin will prove to be an effective intervention in aging either, your emphasis on the two agents' effects on AMPK is both mechanistic speculation rather than in vivo data, and is predicated on a still-disputed single mechanism of action for a subset of metformin's biological effects.

And Mr. Das' reports were fraudulent, irrespective of what other researchers found.

Posted by: Michael at July 19th, 2015 10:47 AM

"Gene targeted therapies have been disappointing."

The quickest of Google searches reveals credible sources stating that gene-targeted therapies are some of the better approaches to attacking cancer.

"The broad influence of molecules such as resveratrol over the epigenome has been emphasized as its advantage since aging and disease involve networks of genes."

This is a Gish gallop of totally unrelated concepts. "Aging is complicated, so this simple little molecule is just the thing to solve it!" Go away.

"Dipak Das' research has been duplicated and vindicated by researchers in Canada, Italy and elsewhere."

Which research is that, the research proven to have been fabricated and that has since been retracted?

"Cellular repair therapies are in vogue"

This means nothing.

"and resveratrol slows the cell cycle thus allowing more time for DNA repair."

Mmm-hmm, this sure sounds credible. Care to back that statement up, chief?

"Research involving resveratrol is still vigorous"

Research based on a thoroughly discredited study is still "vigorous" in serious circles? Nope.

"and the Sirtuin1 gene is involved in the critical gene-controlled molecular pathways (NF-kappa B, AMPK, Nrf2, FOXO1, Sirtuin3) are all influenced by resveratrol. Resveratrol still stands as the most potent Sirtuin1 and Sirtuin3 activator tested."

No it doesn't. Did you even read the actual study just posted?

"Its dismissal by a major drug company suggests it posed too much of a commercial threat to synthetic analogs."

Oh boy, here we go with the conspiracy crap...

"The road to producing expensive man-made anti-aging suggests a day when only 1% of the world could afford to obtain them. Such elitist directions should be shelved."

Yup, it's More of the Same, from your friends at Paranoia Industries and Complete Lack of Foresight, Incorporated! None of this has anything to do with resveratrol, because resveratrol is totally worthless, but it needs rebuttal anyway: the richest people in the world will not make functional anti-aging available solely for themselves, because as Aubrey de Grey pointed out multiple times, they can't. At least not for long. He used the term "mayhem", which refers to the fact that too many people have guns and don't have death wishes.

"Cast resveratrol aside, there are a whole class of polyphenols ready to fill its space -- apigenin, curcumin, quercetin, others."

Equally worthless. But you know that; you posted on that topic with the same kind of "It's all a pharma company lie!" BS. Only back then, you labeled yourself part of "Resveratrol Partners LLC"- because Dipak Das hadn't yet been so thoroughly exposed as a fraud to the public.

"Metformin is now being posed as the first anti-aging drug to undergo human clinical trials. Metformin's primary mode of action is via activation of cell-energy sensing AMPK. Yet resveratrol activates AMPK 50-200 times better than metformin."

That last statement is probably false, but the real big lie in this whole thing is "anti-aging". This stuff is not anti-aging, as it does not solve any of the human degeneration that makes up aging. Supplements, metformin, resveratrol- none of it could even theoretically increase lifespans by more than a small amount in the general human population (metformin is, first and foremost, a diabetes drug), because there's no mechanism for that. Even if you had a perfect method of influencing all of the sirtuins and AMPK, combined, it still wouldn't be actual anti-aging because the cells are still breaking and not being cleared out and replaced, just possibly a little bit more slowly. You can screw with a car's fuel balance all you like; the car's still going to slowly break down.

In other words, even if resveratrol worked- which it obviously doesn't- it still wouldn't work.

For some snake oil peddler like you to come in and spout bullcrap about a completely discredited researcher's "work" right after Michael just got done telling us how SENS plans to actually start taking bites out of this elephant is disgusting. Now I know why Reason had pre-moderated comments in here for a while. Cripes.

Posted by: Slicer at July 19th, 2015 11:29 AM

Resveratrol didn't work in mega-doses (human equivalent 1565 mg) to prolong life in animal experiments. Resveratrol works via hormesis, a low-dose biological stressor activates the body's defenses via Nrf2 mechanism which is negated by high doses.
And do you know Dipak Das committed scientific fraud or have you just heard that? Why did Univ. Connecticut take down the website that reportedly showed all of his doctored science? UCONN made comments about Das locking the door to his office; I visited there and his office door was wide open for students to come in an plug in data to his computer. UCONN said Das fired a student who learned of his fraud but that student was just transferred to another researcher who needed assistance. UCONN seized Das' computer and failed to present the evidence disc at a hearing over the matter. Did UCONN tamper with the evidence? My company received threatening unsigned letters (twice) on UCONN letterhead that if we didn't cease conducting research our company would be put out of business. Why?

Posted by: Bill Sardi at July 20th, 2015 4:40 AM

You can't actually reply to facts, can you? You've just got a stored bank of replies, most of them involving total bullcrap, and today you figured that lying about the University of Connecticut might work.

Again, just peddle this crap somewhere else. You've already been blown out and exposed as an obvious, laughable fraud (not just Das, you, personally) on comment sites, forums, and pretty much everywhere else around the Internet; you're among people who actually know how to use Google.

It doesn't matter what you reply with; it's not going to get a single resveratrol pill sold.

Posted by: Slicer at July 20th, 2015 8:56 AM

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