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Resveratrol’s metabolic mechanism pinpointed?

Researchers from the US National Institutes of Health may have identified the ‘missing link’ that help explains how resveratrol influences metabolism.

The red wine compound may directly affect a signaling pathway controlled by a compound called cAMP (Cyclic Adenosine 3',5'-monophosphate), according to findings published in the journal Cell.

A direct effect on cAMP would influence the cascade of events associated with the pathway, particularly those that influence with energy regulation, cholesterol regulation, glucose uptake and insulin production, report researchers from the NIH, the University of California, Davis, The University of North Carolina, and four other research institutes around the world.

Resveratrol is often touted as the bioactive compound in grapes and red wine, and has particularly been associated with the so-called 'French Paradox'. The phrase, coined in 1992 by Dr Serge Renaud from Bordeaux University, describes the low incidence of heart disease and obesity among the French, despite their relatively high-fat diet and levels of wine consumption.

Other studies with only resveratrol have reported anti-cancer effects, anti-inflammatory effects, cardiovascular benefits, anti-diabetes potential, energy endurance enhancement, and protection against Alzheimer’s.

Longevity?

Interest in the compound exploded in 2003 when research from David Sinclair and his team from Harvard reported that resveratrol was able to increase the lifespan of yeast cells. The research, published in Nature, was greeted with international media fanfare and ignited flames of hope for an anti-ageing pill.

According to Sinclair’s findings, resveratrol could activate a gene called sirtuin1 (Sirt1 – the yeast equivalent was Sir2), which is also activated during calorie restriction in various species, including monkeys.

Since then studies in nematode worms, fruit flies, fish, and mice have linked resveratrol to longer lives. Other studies with only resveratrol have reported anti-cancer effects, anti-inflammatory effects, cardiovascular benefits, anti-diabetes potential, energy endurance enhancement, and protection against Alzheimer’s.

In an accompanying editorial in the journal, Ruth Tennen from Stanford University, Eriko Michishita-Kioi from the VA Palo Alto Health Care System, and Katrin Chua from Daiichi Sankyo Co in Japan note that the previous report that resveratrol directly activates Sirt1 appears to be an artifact of the tests used in those earlier studies.

The new study – led by Jay Chung from the US National Institutes of Health – indicates that the compound may work indirectly on Sirt1 by a direct effect on cAMP signaling.

Combining cell studies with data from experiments with mice, Chung and his co-workers showed that resveratrol inhibited the action of enzymes that degrade cAMP, thereby producing an increase in cAMP levels.

This subsequently led to an activation of a specific receptor that produced an increase in calcium ions, which activated a n enzyme called AMP-activated protein kinase (AMPK), a complex that “senses nutrient deprivation by sensing the AMP/ATP ratios”.

“Together, these data paint a detailed picture of how resveratrol activates AMPK and SIRT1 to produce metabolic benefits, with some interesting mechanistic and clinical implications. Resveratrol is thought to produce its health benefits by mimicking CR. D

In their editorial, Tennen, Michishita-Kioi, and Chua said that the new study provides “important insight into the mechanism by which resveratrol promotes metabolic health.

“But in the intensely controversial, complex, and rapidly evolving field of resveratrol and sirtuins, the identification of PDEs as the putative ‘missing link’ is certainly not the end of the story.”

Source: Cell
3 February 2012, Volume 148, Issue 3, Pages 421-433, doi: 10.1016/j.cell.2012.01.017
“Resveratrol Ameliorates Aging-Related Metabolic Phenotypes by Inhibiting cAMP Phosphodiesterases”
Authors: S-J. Park, F. Ahmad, A. Philp, K. Baar, T. Williams et al.

Editorial: Cell
3 February 2012, Volume 148, Issue 3, Pages 387-389, doi: 10.1016/j.cell.2012.01.032
“Finding a Target for Resveratrol”
Authors: R.I. Tennen, E. Michishita-Kioi, K.F. Chua

5 comments (Comments are now closed)

Resveratrol effects are dose dependent

The idea that a lower dose of resveratrol might have more pronounced beneficial effects is based upon one study, done by Dr Das, the discredited researcher, hired by sardi to undertake that study. It is now known that this scientists phonied up data in over 20 studies.

The reality is that virtually every other study, including human clinical trials, supports the conclusion that resveratrol benefits are proportional to dosage, up to at least 5,000mg, and probably higher.
In the Albert Einstein Medical School study using transmax resveratrol on pre diabetics it was shown that the improvements in blood glucose, insulin sensitivity and metabolic function observed at a dosage of 1,000 mg (2 transmax capsules), were all even greater at a dosage of 2,000mg. This was further evidenced in the Northumbria University study of cognition and brain blood flow in which 24 uni students were given one Bioforte capsule (250 mg) in the first trial phase, and 2 bioforte capsules in the second phase. Improvements in study parameters increased along an almost perfectly linear curve when the dosage was doubled. This trial will be repeated, using a much large study population and daily administration of the bioforte versue one time administration, beginning in March.

It is basically nonsense to postulate that the optimum dosage of resveratrol is only a fraction of that used in the majority of animal and human trials.

After over 6,000 trials and studies the consensus is coalescing around an optimum dosage level for humans of around 1,000mg daily.

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Posted by James
05 February 2012 | 18h38

Dosage

The comment titled "The dose is the poison" is rubbish. There is absolutely not peer-reviewed evidence to support this nonsense. The one study which possibly led to an indirect and quite ambiguous conclusion that higher doses, that is greater than 2,000 mg, may exhibit a reverse efficacy curve, was done by Dr Das, the researcher whose work was discredited recently due to data fraud and other ethical research violations. The sponsor of one of Dr. Das' studies happens to be the same person who authored the comment.

In reality it has been consistently and repeatedly established that the beneficial effects of resveratrol administration to animals is dose dependent, that is, the greater the dose up to at least 5,000mg daily, the greater the benefits.

In the Albert Einstein Medical School human trial, which recently passed peer review and was published in a major journal, it was shown that a dose of between 1,000 mg of transmax resveratrol, the supplement used in the majority of human clinical trials, was effective in improving both glucose tolerance and insulin sensitivity in human subjects. Increasing the dose to 2,000 mg (4 Transmax caps) was even more effective and did not result in adverse effects.

In the Northumbria Univ study of cognition and brain blood flow in which Bioforte resveratrol at doses of 1 capsule (250mg) and 2 capsules was used on a subject population of 24 uni students the same dose response curve was noted. In fact, in this study the brain blood flow increase was directly linerally proportional to the number of Bioforte capsules given to the subjects.

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Posted by James
05 February 2012 | 11h05

Resveratrol

what continues to astound me is the way resarchers and the media continue to mislead the public about the type of resveratrol they use in most "red wine" products. Even this study which has a graphic of grapes and wine and the illusion that the reservatrol is derived from grape seed extract is totally erroneous. The majority of products on the market use a resveratrol derived from knotweed.
I don't know how they are able to perpetuate such a lie.

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Posted by Margie
03 February 2012 | 22h36

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