What does resveratrol do?

Up until a couple of months ago, the answer seemed very clear to me.  Resveratrol offers a number of powerful health-promoting effects.  Also, it turns on the SIRT1 gene activating the same evolutionary-conserved pathway that is known to confer longevity in case of calorie restriction.  But a pair of recent publications cast doubt on this picture.  This blog entry reviews research on the beneficial health effects of resveratrol and whether or not it indeed activates the SIRT1 gene.  I also touch on other substances being developed to turn on the SIRT1 gene and how certain big pharma and biotechcompanies appear to be lining up taking conflicting viewpoints.  Large stakes are involved.   

Resveratrol  (trans-resveratrol, 3,4′,5-trihydroxystilbene) is a substance occurring naturally in several plants in response to stress, attack by pathogens such as bacteria or fungi, or ultraviolet  radiation.  Discovered to be in red wine in 1992, the substance has been extensively studied for its medicinal and possible anti-aging properties.  The resveratrol site of the Linus Pauling Institute, is a good source of information on all aspects of the substance with 109 literature citations but appears not to be up-to-date since no citations subsequent to 2006 are listed. The Wikipedia article on resveratrol is also a good general information source but appears also not to be completely current. 

Bioavailability of resveratrol is low because it is rapidly metabolized and eliminated.  “–much of the basic research on resveratrol has been conducted in cultured cells exposed to unmetabolized resveratrol at concentrations that are often 10-100 times greater than peak concentrations observed in human plasma after oral consumption (ref)(ref)(ref).”   Therefore, conclusions of such studies may not be applicable even for people who take large amounts of supplementary resveratrol. New micronized forms of resveratrol and sublingual tablets may increase bioavailability(ref)(ref).  Resveratrol appears to exercise few side effects even at large dose levels(ref)(ref).  Since effects may vary widely by individual depending on genetic makeup, however, it is appropriate to exercise caution with large doses. 

Example health benefits of resveratrol 

·        Studies have included looking at resveratrol’s actions in leukemia and in colon, stomach, pancreatic, esophageal, intestinal, and breast cancers, both from preventative and therapeutic viewpoints.  “Although resveratrol can inhibit the growth of cancer cells in culture and in some animal models, it is not known whether high intakes of resveratrol can prevent cancer in humans(ref).” See the discussion and citations here. Multiple forms of biological activity against cancers can be involved. For example, resveratrol might prevent cancer by inhibiting  the expression of certain cytochrome p450 enzymes(ref).   To find recent and current publications related to resveratrol and cancer, I suggest doing a search on “cancer resveratrol” in PubMed.org.

·        “Resveratrol has been found to exert a number of potentially cardioprotective effects in vitro, including inhibition of platelet aggregation (47, 48, 68), promotion of vasodilation by enhancing the production of NO (46, 69) and inhibition of inflammatory enzymes (34, 70, 71). However, the concentrations of resveratrol required to produce these effects are often higher than those that have been measured in human plasma after oral consumption of resveratrol (7)(ref).”  There is an impressive number of current and recent publications related to resveratrol and cardiovascular issues as can be found by doing a search on “cardiovascular resveratrol” in PubMed.org. 

·        Numerous studies indicate that resveratrol might be be useful in control of obesity and diabetes.  A March 2010 publication Resveratrol, obesity and diabetes states “It is well established that resveratrol exerts beneficial effects in rodents fed a high-calorie diet. In some studies, resveratrol was reported to reduce body weight and adiposity in obese animals. The action of this compound involves favourable changes in gene expressions and in enzyme activities. The accumulating evidence also indicates the benefits of resveratrol in diabetes and diabetic complications. It is known that resveratrol affects insulin secretion and blood insulin concentration. In animals with hyperinsulinemia, resveratrol was found to reduce blood insulin. Moreover, numerous data indicate that in diabetic rats, resveratrol is able to reduce hyperglycemia.”

·        “In November 2008, researchers at the Weill Medical College of Cornell University reported that dietary supplementation with resveratrol significantly reduced plaque formation in animal brains, a component of Alzheimer and other Neurodegenerative diseases.^[23] In mice, oral resveratrol produced large reductions in brain plaque in the hypothalamus (-90%), striatum (-89%), and medial cortex (-48%) sections of the brain. In humans it is theorized that oral doses of resveratrol may reduce beta amyloid plaque associated with aging changes in the brain(ref).”

·        Re. resveratrol and bone loss see these articles.  Re. resveratrol and prostate function see these articles.  Re. resveratrol and stroke see these articles.  Re. resveratrol and cataracts see these articles.  Re resveratrol and its anti-viral activities see these articles. 

The main messages up to this point are: 

·        Resveratrol appears to offer a wide range of potential health benefits based on biochemical, cell-level and in some cases, small-animal studies.  Except for bioavailability, it appears to be an amazing supplement.

·        It is unclear as to whether taking the usual doses of commercial resveratrol supplements lead to any of these benefits, however, first because of absence of any clinical studies on humans, and second because of resveratrol’s low bioavailability profile. 

Resveratrol activating SIRT1 

SIRT1, you will recall is the evolutionary-conserved gene activated by calorie restriction that, when activated, provides health and life extension in a number of lower species.  The SIRT1 protein is the most interesting member of the sirtuins, protein deacetylases. I have discussed aspects of SIRT1 in several blog posts and cited this current review of 10 years of research in sirtuins by Leonard Guarante and a colleague. 

In the course of these discussions, I have in keeping with the literature repeatedly asserted that resveratrol activates SIRT1.  I have also provided multiple literature citations to back up this assertion.   The blog post SIRT1, mTOR, NF-kappaB and resveratrol and this 2010 publication, for example, indicates how resveratrol inhibits mTOR signaling while activating SIRT1 showing a linkup between the mTOR “shortivity” pathway and the SIRT1 “longevity” pathway.  This article suggests a linkup between TXNIP, another “shortivity” pathway,  and the SIRT1 “longevity” pathway.   

I repeat a couple of paragraphs here from my blog post Visit with Leonard Guarante which are directly relevant to the present discussion.  “The work of Guarante and his colleagues has led to the identification of  resveratrol as an activator of SIRT1 and later to the establishment of Sirtris Pharmaceuticals, a company devoted to the discovery of small-molecule activators of sirtuins that could address diseases of aging.   Reported in the Sirtris web site, “A long-term study of middle-aged mice shows resveratrol improves health and mimics some benefits of dietary restriction(ref).”

“David Sinclair, a key player in sirtuins research at Harvard and founder of Sirtris, originally came from Australia to work at MIT in Guarante’s lab.   Leonard is on the Board of Sirtris which has been acquired by GlaxoSmith Kline (GSK).  The 2007 publication Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes by Sinclair and other Sirtris-affiliated  authors is one of a number of publications relating SIRT1 to type 2 diabetes.  “Resveratrol, a polyphenolic SIRT1 activator, mimics the anti-ageing effects of calorie restriction in lower organisms and in mice fed a high-fat diet ameliorates insulin resistance, increases mitochondrial content, and prolongs survival^10–14   Here we describe the identification and characterization of small molecule activators of SIRT1 that are structurally unrelated to, and 1,000-fold more potent than, resveratrol. These compounds bind to the SIRT1 enzyme—peptide substrate complex at an allosteric site amino-terminal to the catalytic domain and lower the Michaelis constant for acetylated substrates. In diet-induced obese and genetically obese mice, these compounds improve insulin sensitivity, lower plasma glucose, and increase mitochondrial capacity. In Zucker fa/fa rats, hyperinsulinaemic-euglycaemic clamp studies demonstrate that SIRT1 activators improve whole-body glucose homeostasis and insulin sensitivity in adipose tissue, skeletal muscle and liver. Thus, SIRT1 activation is a promising new therapeutic approach for treating diseases of ageing such as type 2 diabetes(ref).” 

Sirtris currently has four SIRT1 activator substances in Phase IIa clinical trials(ref).  Phase I safety and dose trials of SRT2104 are complete.  The substances are identified as SRT2104, SRT2379 and SRT501.  Trials relate to metabolic disease (Type 2 Diabetes), inflammation, cardiovascular disease and oncology.”

The April 2009 paper Sirtuin activators summarized the most-accepted view of the situation at the time of its publication “CONCLUSIONS: To date, resveratrol is the most potent natural compound able to activate SIRT1, mimicking the positive effect of calorie restriction. Resveratrol might help in the treatment or prevention of obesity and in preventing the aging-related decline in heart function and neuronal loss. As resveratrol has low bioavailability and interacts with multiple molecular targets, the development of new molecules with better bioavailability and targeting sirtuin at lower concentrations is a promising field of the medicinal chemistry. New SIRT1 activators that are up to 1000 times more effective than resveratrol have recently been identified. These improve the response to insulin and increase the number and activity of mitochondria in obese mice. Human trials with a formulation of resveratrol with improved bioavailability and with a synthetic SIRT1 activator are in progress.”  The new “1000 times more effective” SIRT1 activators referred to here are the molecules developed by and being tested by Sirtris.As written in a February 2010 Special Report in Gen Sirtuins: Antiaging Medicines or Marketing? – “A large body of basic research does indeed support the nomination of SIRT1 activators as antiaging drugs. SIRT1 activation has profound metabolic effects: It regulates glucose or lipid metabolism through its deacetylase activity for over two dozen known substrates and has a positive role in the metabolic pathway through its direct or indirect involvement in insulin signaling. It also stimulates glucose-dependent insulin secretion from pancreatic β cells and directly stimulates insulin-signaling pathways in insulin-sensitive organs. SIRT1 also reportedly influences adiponectin secretion, inflammatory responses, gluconeogenesis, and levels of reactive oxygen species, which together contribute to the development of insulin resistance.” 

The dissenting publications 

Two dissenting publications appeared recently, ones that challenge whether resveratrol or any of the Sirtris small-molecule activators actually activate SIR1 Also indirectly challenged is whether Sirtris has a sound platform of drug candidates with which to succeed.   

The October 2009 paper Resveratrol is Not a Direct Activator of SIRT1 Enzyme Activity in the journal Chemical Biology and Drug Design  is by a group of authors associated with Amgen Inc.  The researchers claimed that the activation of SIRT1 observed by Sinclair and his colleagues and reported in the publication Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes was not real but was an artifact of the use of a high-throughput in vitro fluorescence polarization assay.  The Amgen authors write “Here, we show that: (i) the Fluor de Lys-SIRT1 peptide is an artificial SIRT1 substrate because in the absence of the covalently linked fluorophore the peptide itself is not a substrate of the enzyme, (ii) resveratrol does not activate SIRT1 in vitro in the presence of either a p53-derived peptide substrate or acetylated PGC-1alpha isolated from cells, and (iii) although SIRT1 deacetylates PGC-1alpha in both in vitro and cell-based assays, resveratrol did not activate SIRT1 under these conditions.” 

The second dissenting paper SRT1720, SRT2183, SRT1460, AND RESVERATROL ARE NOT DIRECT ACTIVATORS OF SIRT1 was published in January 2010 in the Journal of Biological Chemistry.  Several of the co-authors are associated with Pfizer.  SRT1720, SRT2183 and SRT1460 were earlier reported by Sirtris to be SIRT1 activators.  This is a highly technical paper where the researchers developed their own assay approach.  “These data demonstrate that neither the Sirtris series nor resveratrol would serve as useful  pharmacological tools due to their highly promiscuous profiles. – Our results show that the Sirtris series of compounds and resveratrol have little or no effect on SIRT1 activity even with these two full length protein substrates. — In summary, our detailed assessment of the Sirtris series and resveratrol involving several biochemical assays with native substrates and biophysical studies employing NMR, SPR, and ITC demonstrate that these compounds are not direct SIRT1 activators. We also demonstrated that SRT1720 does not show beneficial effects in a rodent diabetes model, which is in contrast to that previously reported (26). The broad selectivity assessment against over 100 targets including receptors, enzymes, ion channels, and transporters show that the Sirtris series and resveratrol are highly promiscuous and would not serve as useful pharmacological tools for studying SIRT1 pathways. In the literature, resveratrol has been widely referred to as a “SIRT1 activator” (For selected recent references, see 40-44) and routinely used to “activate” SIRT1 in variouscellular assays, with only a few questioning the original study that reported its ability to activate SIRT1 in an artificial substrate-based fluorescent assay (28,29,39,45). Likewise, the Sirtris compounds have been referred to as “SIRT1 activators” in recent publications (46-48). Our present data are significant for the field as we provided strong evidence that neither the Sirtris series nor resveratrol are direct SIRT1 activators.” 

Where am I in all this? 

First of all, I am skeptical of the skeptics.  This paper by the Pfizer people appears to condemn resveratrol along with the Sirtris small-molecule compounds for two reasons: 1.  It does not really directly activate SIRT1, and 2.  It is biochemically highly “promiscuous,”  making it a kind of biochemical whore.  Even if point 1. Were correct, what about the very large number of publications (hundreds) from researchers around the world written over nearly two decades documenting the positive health benefits of resveratrol quite independently of whether it has any SIRT1 action?  Did all of those researchers miss seeing or overlook the promiscuity?  Were they carried away by resveratrol’s sexiness?  Perhaps, but I have trouble believing that.   And, if resveratrol were indeed so promiscuous, why does it seem to have so few negative side effects and so many positive effects?   

And as far as resveratrol and SIRT1 are concerned, I would ask the question “If resveratrol does not activate SIRT1, then why does it seem to provide so many of the same health benefits that would be expected from activating SIRT1?” 

Second, the stakes involved are big.  If the Sirtris small molecules turn out to be worthless, then just what will have GSK gotten for the $720 million they paid for Sirtris?  If the original studies done at MIT and Harvard and Sirtris on SIRT1 activation are based on faulty science, what will be the result on the reputations of the key scientists and laboratories involved?  

Third, the results of the Sirtris clinical trials should tell a lot.  If one of the substances turns out to be a blockbuster, this should send the SIRT1 activator skeptics scampering.  If all the Sirtris substances fizzle, then perhaps the rival skeptics are in part right.  But even if all the proprietary Sirtris SIRT1 activators fizzle as drugs, that still won’t explain all the positive research results on health benefits of good old resveratrol. 

Finally, being just an individual, I have no personal desire to get anywhere near the middle of a knife fight between pharmaceutical and biotech giants like Pfizer, GSK and Amgen and research institutions like Harvard and MIT. 

Please see the medical disclaimer for this blog.