The missing link between resveratrol and sirtuin
Resveratrol is synthesized by many plants, but it is usually associated with red wine, since the largest amount of it is contained in the peel of red grapes. This compound has attracted a lot of attention after researchers demonstrated that it activates a mechanism that increases the lifespan of different organisms, as well as its ability to prevent weight gain and the development of diabetes in mice kept on a fat-rich diet.
Several scientists involved in the study of resveratrol have founded the biotech company Sirtris, whose goal is to combat age-related diseases, including diabetes. In 2008, the international pharmaceutical giant GlaxoSmithKline bought Sirtris for 720 million US dollars.
The name Sirtris comes from the name of a family of sirtuin proteins that play an important role in the aging process, since the founders of the company were convinced that the activation of the sirtuin 1 protein (Sirt1) is at least partially at the heart of the action of resveratrol, and found several substances that stimulate the work of sirtuin much more effectively than resveatrol.
However, subsequently, another group of researchers expressed doubts about the correctness of this mechanism of action and provided evidence in favor of the fact that resveratrol does not activate sirtuin 1 directly, and earlier results are an artifact of the method used to assess the activity of the protein. If this is indeed the case, work on the identification and improvement of drugs with an effect similar to that of resveratrol will inevitably face serious difficulties.
It seems that researchers at the US National Institutes of Health, working under the leadership of Dr. Jay H. Chung, have finally managed to find the missing link in the resveratrol story. They demonstrated that resveratrol does not really have a direct activating effect on sirtuin 1, but rather inhibits certain types of enzymes belonging to the phosphodiesterase family and involved in the regulation of cell energy metabolism.
The prerequisite for the new study was the observation made by the authors, according to which the enzyme AMP-dependent kinase is required to manifest the effects of resveratrol. This was completely inconsistent with the hypothesis that resveratrol directly interacts with sirtuin 1.
The researchers methodically tracked the metabolic activity of cells treated with resveratrol and found that its main target is the enzyme phosphodiesterase-4 (PDE4) in skeletal muscle cells. Inhibition of this enzyme under the action of resveratrol triggers a cascade of biochemical reactions in the cell, the result of one of which is the activation of sirtuin 1.
To confirm the ability of resveratrol to bind to phosphodiesterase molecules and suppress the activity of this enzyme, researchers injected mice with rolipram, a drug known to have an inhibitory effect against phosphodiesterase–4. The result was the reproduction of all the beneficial effects of resveratrol, including the prevention of obesity caused by excessive nutrition, improving glucose tolerance and increasing physical endurance.
Dr. Zhong notes that in its natural form resveratrol interacts not only with phosphodiesterases, but also with many other proteins. Therefore, when used, especially for a long time, as a drug, it can have unknown side effects to date. He also adds that the content of resveratrol in wine and other foods is not so high as to have any beneficial or harmful effect on health. The dosage of resveratrol used in conducting convincing clinical studies was approximately 1 g per day, which corresponds to the amount of the compound contained in about half a cubic meter of red wine.
The results of the latest study also indicate that selective phosphodiesterase-4 inhibitors can have positive effects attributed to resveratrol without the potential toxicity associated with the interaction of this compound with other proteins. One of the well-known phosphodiesterase-4 inhibitors, roflumilast, has already been approved by the US Food and Drug Administration as a treatment for chronic obstructive pulmonary disease.
In any case, the results indicate that the effects of resveratrol are much more complex than previously thought. Therefore, it is necessary to conduct carefully planned and controlled studies devoted to the study of the mechanisms of action of this promising compound.
Article by Park et al. Resveratrol Ameliorates Aging-Related Metabolic Phenotypes by Inhibiting cAMP Phosphodiesterases published in the journal Cell.
Evgeniya Ryabtseva
Portal "Eternal youth" http://vechnayamolodost.ru based on the materials of the National Institutes of Health:
NIH study uncovers probable mechanism underlying resveratrol activity.
03.02.2012