Wednesday, December 29, 2010

new resveratrol revelations

What a year it has been for resveratrol, the polyphenol molecule from red wine. Last year at this time it was the toast of the town, having been credited with triggering a metabolic change leading to increased lifespan in experimental models, then catapulted into the limelight as a potential cancer cure with clinical trials under the auspices of pharma giant GlaxoSmithKline. Sales of resveratrol supplements were skyrocketing, with audacious claims about weight loss, brain power, and longevity, never mind that none of this had been proven in humans. But with the new year came new controversy. Two of Glaxo’s competitors, Pfizer and Amgen, published their own studies on resveratrol, concluding that the longevity effect was false, an artifact of the testing method. What few clinical trials there are in humans revealed that it is poorly absorbed and doesn’t last very long in the body anyway. Then in November Glaxo abruptly announced the suspension of the clinical trial and all further development of their flagship resveratrol derivative, SRT501. Supplement sellers started to look more and more like snake oil peddlers, while enthusiasm began to fade in the scientific community.

Despite these setbacks, progress on the basic science front continues to reveal interesting properties of resveratrol. One line of research looks at extending lifespan of cells not through metabolic change but by repairing the caps on DNA strands that are clipped each time the cell divides. These caps, called telomeres, are sequences on the ends of the chromosomes that prevent unraveling with the replication cycle; with each division they shorten, limiting the number of times the cycle can repeat and therefore the lifespan of the cell. Cell types that require constant replenishment, such as skin and the linings of blood vessels, show their age more than others as they lose the ability to replicate. But cancer cells have figured out how to by pass this limitation and become immortal by rebuilding telomeres with an enzyme called telomerase. Control telomerase and you harness cellular immortality, and it appears resveratrol may provide the key.

The source of new cells is what are called progenitor cells, which in turn trace their lineage to stem cells. A recent study enticingly called “Immortalization of epithelial progenitor cells mediated by resveratrol” outlines the mechanism by which resveratrol pulls this off in skin cells. There is a lot that remains to be deciphered about this but it looks promising. Another paper reported on the role of resveratrol in reducing senescence of the progenitor cells that replace blood vessel lining, an important step in countering atherosclerosis, by activating telomerase. Just as important though is that resveratrol uses the same metabolic pathways to slow the growth of cancer cells.

Such is the state of affairs with resveratrol: exciting new findings on the leading edge of biomedical research, while verification of its use in clinical medicine seems ever farther off. All I can say is stay tuned.

1. Pearce VP, Sherrell J, Lou Z, Kopelovich L, Wright WE, Shay JW. Immortalization of epithelial progenitor cells mediated by resveratrol. Oncogene 2008 Apr 10;27(17):2365-74.
2. Xia L, Wang XX, Hu XS, Guo XG et al. Resveratrol reduces progenitor endothelial cells senescence through activation of telomerase activity by Akt-dependent mechanisms. Br J Pharmacol 2008 Oct;155(3):387-94.
3. Lanzilli G, Fuggetta MP, Tricarico M, Cottarelli A et al. Resveratrol down-regulates the growth and telomerase activity of breast cancer cells in vitro. Int J Oncol 2006 Mar;28(3):641-8.
4. Fuggetta MP, Lanzilli G, Tricarico M, Cottarelli A et al. Effect of resveratrol on proliferation and telomrease activity of human colon cancer cells in vitro. J Exp Clin Cancer Res 2006 Jun;25(2):189-93.

Monday, December 13, 2010

Believe in wine

Believing in Santa Claus may not be a scientifically tenable position, but it does come with benefits. As children reach the age where suspicions arise as to the veracity of the notion of a jolly visitor bearing gifts in the night, they come to understand that it is in their best interest to play along. In the case of wine, the science may be on more solid footing as to the benefits of moderate consumption, but what people believe does not always align with the facts here either. That is why it is encouraging to see recent survey data that people are finally acknowledging the connection between wine and health, even if there are still some areas of uncertainty.

London-based Mintel research recently released the results of a survey finding that some 85% of drinkers believe that wine in moderation is good for overall health, while wine drinkers hold that red wine is good for the heart. On the other hand, half of those attribute the same benefits to white wine. Given white wine’s relative lack of the polyphenol antioxidants that red wine has (extracted from the skins and seeds during fermentation of the whole grape), white is probably given more credit than it deserves here, but it is a least a step in the direction of healthy drinking. Some confusion is to be allowed here though since the degree to which red is better depends a lot on what health parameters are being studied, not to mention effects of beer or spirits consumption.

What the report didn’t evaluate is the level of penetration of knowledge about wine’s other benefits. One of the more difficult jobs that wine and health educators have is overcoming the assumption that heart health is the whole story. Sure, it’s the French paradox, I get it, people say. But that is only the beginning of a story whose conclusion is nowhere in sight. For example, every major epidemiologic survey on factors associated with Alzheimer’s disease has found the lowest incidence in wine drinkers, but we rarely hear anything about that. The other misconception out there is that it’s all about the polyphenols, so we just need to take a pill and skip the alcohol. Supplement marketers regularly claim that their brand has “all the benefits of wine” which is a misnomer because alcohol in the right amounts is also healthy (improves the high-density to low-density cholesterol ratio, among other good things.)

Another thing the Mintel report found was that people plan to drink more wine this holiday season, and that overall wine consumption is trending upward over the long-term. As for me, I believe that is a good thing. Cheers to all and best wishes for a good bottle from Santa.

Friday, December 3, 2010

Glaxo pulls the plug on resveratrol drug: end of the line?

Resveratrol, the antioxidant molecule from red wine (along with miniscule amounts from some berries and the non-edible parts of the peanut plant), took the world by storm a few years back when it was announced that it could trigger a specific metabolic change associated with significant lifespan extension. Though the phenomenon was only found at first in some strains of yeast under certain conditions, it was believed to work by activating an enzyme system known as sirtuins, which in turn control the switching on and off of genes associated with longevity and a range of diseases of aging. The potential for resveratrol-based compounds caught the attention of pharma giant GlaxoSmithKline, which acquired the rights to it for US $720 million in 2008. But this week Glaxo announced the suspension of all development of their product, known as SRT501, citing concerns about complications in a clinical trial for the blood cancer multiple myeloma. Many now wonder whether resveratrol has gone from darling to dud in only 2 short years.

Meanwhile, sales of resveratrol supplements, based on the naturally occurring and non-patentable molecule, have soared in recent years. Purveyors openly tout it as a “fountain of youth in a pill” and a miracle weight loss solution. Some advocates of natural healing are openly celebrating Glaxo’s failure, accusing them of greedily hijacking a perfectly good natural cure in the name of corporate greed by developing synthetic (and patentable) variations. Pfizer and Amgen have both weighed in recently with scientific publications casting doubt on the ability of resveratrol and its derivatives to activate sirtuins at all, pointing to evidence that the testing method was an artifact leading to false positive results. Is this the end of the road for resveratrol?

There’s support for both arguments, but don’t mark your calendars just yet for resveratrol’s funeral. For one, the natural molecule has a wide range of interesting capabilities, at least in lab studies. Clinical trials are ongoing and much remains to be learned about whether this translates to verifiable benefits in humans. (One thing that appears unlikely is the lifespan extension phenomenon via sirtuin activation, as it has not been found in mammals.) Glaxo was careful to point out that other resveratrol derivatives are being studied, and the point of synthesizing variations on the molecule is to find more potent versions with specifically targeted actions. (See the full quote below.) And without the prospect of return on investment, there is little funding available for studying the natural version. Until more results are in, my suggestion is to bear in mind that the whole thing started with red wine, which does confer longer life on average for moderate regular consumers, along with higher quality of life.

From Glaxo: ”We are focusing our efforts now on more selective SIRT1 activator compounds that have no chemical relationship to SRT501 and more favorable drug-like properties. Currently we have two of these latest generation compounds (SRT2104 and SRT2379) in several exploratory clinical trials.”