Doubts about the benefits of resveratrol have not been confirmed
Over the past decade, experts in the field of aging have been paying more and more attention to sirtuins, a group of proteins considered to protect various organisms, including mammals, from diseases associated with aging. Constantly accumulating scientific data indicate that a compound known as resveratrol and contained in grape skins, peanuts and berries increases the activity of one of the sirtuins – sirtuin-1 (SIRT1) – which prevents the development of various age–related diseases by stimulating the work of mitochondria - the energy centers of the cell, the efficiency of which decreases with aging the body.
Experiments on mice have shown that the use of resveratrol can double the physical endurance of these animals, as well as make them relatively resistant to the effects of obesity and aging. In addition, studies conducted on yeast, nematodes, bees, fruit flies and mice have demonstrated the ability of resveratrol to increase the lifespan of these organisms.
In 2006, scientists at Harvard University Medical School, working under the guidance of Professor David Sinclair, published the results of a study indicating that resveratrol increases the lifespan of mice. After that, they founded the company Sirtris Pharmaceuticals, whose activities are devoted to the development of pharmacological agents whose effectiveness would exceed the effectiveness of resveratrol. Currently, the company is already conducting several clinical studies of compounds that increase the activity of sirtuin-1.
However, despite the fact that numerous studies conducted by Sinclair's group and other scientists have brought additional evidence of the existence of a direct relationship between resveratrol and sirtuin-1, some experts in this field have expressed concern about the inconclusiveness of these results.
The stumbling block was the method of studying sirtuin-1 in the laboratory using a specific chemical label attached to the targets of this protein. The brightness of the fluorescence of the label increases with an increase in the activity of sirtuin-1. However, the label itself is a chemical compound synthesized artificially and does not exist in living nature. In 2010, an article was published, the authors of which claimed that the activation of sirtuin-1 under the action of resveratrol is just an artifact (a phenomenon caused by the influence of experimental methods on the process under study), reproduced exclusively in laboratory conditions. They also stated that the activity of sirtuin-1 in the body of mice was, at best, due to the indirect influence of resveratrol, and perhaps even a simple coincidence.
The appearance of this publication caused a debate around the mechanism triggered by resveratrol and its analogues. To get unambiguous answers to the questions that arose, Sinclair and his colleagues joined forces with employees of the US National Institutes of Health and Sirtris Pharmaceuticals.
Initially, they turned their attention to the problem of a fluorescent chemical label. When it was replaced with a substrate containing a residue of the amino acid tryptophan, which is part of the tissues of many organisms, the results of earlier experiments were reproduced in full – resveratrol and its analogues activated sirtuin-1 with the same success.
The next step was to find out the exact mechanism by which resveratrol activates sirtuin-1. To do this, the authors studied about 2,000 mutant forms of the gene encoding sirtuin-1, and found one variant that completely blocks the effects of resveratrol. At the same time, the mutation, which is a replacement of a single one of the 747 amino acids that make up the sirtuin-1 molecule, prevented the activation of the protein under the action of hundreds of molecules from the library compiled by Sirtris Pharmaceuticals employees, the activity of many of which significantly exceeds the activity of resveratrol.
Despite the fact that these experiments were conducted in laboratory conditions, they allowed the researchers to identify the exact location of the "gas pedal" that triggers sirtuin-1. To test their ideas in a living cell, they replaced the normal sirtuin-1 gene in muscle tissue and skin cells with its inert version. Experiments on such modified cells demonstrated the absolute immunity of their mitochondria to the action of resveratrol and its analogues, unlike normal cells, in which a significant increase in the activity of energy centers was recorded.
Synthetic analogue of resveratrol
binds to the sirtuin protein molecule.
According to the authors, the only rational explanation for the observed phenomenon is the ability of resveratrol to directly activate sirtuin-1. Moreover, the identification of the exact target of resveratrol on the sirtuin-1 molecule will allow the development of new compounds whose activity will far exceed the activity of the natural compound.
Article by B.P. Hubbard et al. Evidence for a Common Mechanism of SIRT1 Regulation by Allosteric Activators is published in the journal Science.
Evgeniya Ryabtseva
Portal "Eternal youth" http://vechnayamolodost.ru based on materials from Harvard Medical School:
New Study Validates Longevity Pathway.
11.03.2013