The discoverer of the role of sirtuins in aging comments on the latest data
In the early 90s of the last century, Professor Leonard Guarente of the Massachusetts Institute of Technology found that sirtuin class proteins, which are part of the organisms of almost all animals, protect yeast from the harmful effects of the aging process. Subsequently, similar conclusions were made with respect to many other organisms.
In 2003, David Sinclair, who worked in the Guarente laboratory after receiving his PhD, demonstrated that the resveratrol compound, which is part of the peel of red grapes and, accordingly, red wine, also has the ability to resist the harmful effects of aging. After that, many researchers tried to understand the relationship between sirtuins, resveratrol and aging. More recently, Sinclair, currently a professor at Harvard University Medical School, and his colleagues for the first time managed to obtain convincing evidence that the action of resveratrol and its analogues is based on the direct activation of sirtuins.
In this article, Professor Guarente, who is an unsurpassed expert in this field, expresses his opinion on the significance of the new data obtained by Sinclair.
Question: The opinions of experts regarding the ability of resveratrol to slow down the aging process through the activation of sirtuins have diverged. What is the basis of these disagreements?
Answer: About 10-15 years ago, we and other researchers formulated three characteristics of sirtuins that were considered confirmed at that time. One of them was the ability to regulate the speed of the aging process; the second was the involvement in the mechanisms mediating the positive effects of a low–calorie diet; and the third was the ability to be activated by the action of small molecules such as resveratrol. Over the next decade, all these provisions were questioned in one way or another. A few years ago, an article appeared in the press, the essence of which is that the described compounds do not have the action attributed to them. However, in recent years, all the initial statements, one after another, have been confirmed.
As for resveratrol and its analogues, there are three systems of views. According to one of them, these compounds have no effect on sirtuins, and their effects are due to antioxidant properties. The second is that these compounds actually activate sirtuin-1 (the main mammalian sirtuin) in cells, but this is an indirect effect of some other mechanism triggered by them. The third and last of the possible options is the ability of resveratrol to directly affect the sirtuins.
Some experts doubt the validity of the latter statement, since most of the small molecules used as drugs inhibit enzymes, and do not activate their work. It is easy enough to imagine a small molecule interacting with an enzyme molecule and blocking its activity, whereas opposite situations are much less common. Therefore, many people tend to believe that resveratrol and its analogues are not capable of such a thing in a living cell, but act by triggering some other mechanisms.
Question: How do the results of the new study help to understand this issue?
Answer: I believe that the described observations are extremely difficult to interpret otherwise than as a direct activation under the action of a compound. The most convincing of the evidence presented in the article is the fact that the substitution of one amino acid (glutamine for lysine), which has no effect on the enzymatic activity of sirtuin-1, makes it absolutely immune to the effects of resveratrol. The authors also tested several of the synthetic analogues of resveratrol developed after the discovery of its effect on sirtuin, with a similar result.
They also created cells expressing the enzyme sirtuin-1 with the described substitution of one amino acid. Cells expressing a normal enzyme reacted to resveratrol with real biological changes, such as activation of mitochondria, which is one of the known manifestations of the action of sirtuin-1, whereas cells with a mutant form of the enzyme did not respond to resveratrol.
Thus, if we compare the results of experiments conducted "in vitro" and in living cells, in combination they are convincing evidence that the tested compounds, including resveratrol, have the ability to directly affect sirtuin-1, increasing its activity.
Question: What are the potential positive effects of taking drugs that have the effects of resveratrol?
Answer: We are of the opinion that aging is a component of many diseases or conditions, such as diabetes mellitus, Alzheimer's disease and arthritis. As a rule, they develop in the later stages of life. The idea is that if you can influence a molecule that can control the aging process, you can control the development of diseases. There is a lot of genetic data obtained in experiments on mice, indicating that sirtuin-1 can be activated through genetic mechanisms and that this protects the body from age-related diseases. Therefore, it is logical to assume that any compound capable of activating sirtuin-1 may be useful in the fight against these diseases.
The result of the fundamental work carried out 10 years ago by Sinclair and Hovitz was the identification of resveratrol and other natural compounds belonging to the class of plant polyphenols. This prompted the biotechnology industry to develop artificial products whose activity would exceed the activity of natural analogues. To date, the number of such compounds totals several hundred. The most promising of them are already undergoing clinical trials as means to protect the body from age-related diseases.
Drug developers always want to know exactly what their targets are, so the proof that resveratrol and, more importantly, experimental drugs being developed for clinical use directly affect sirtuin-1 gives the green light to continue working in this direction.
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 the materials of the Massachusetts Institute of Technology:
3 Questions: MIT biologist on new resveratrol study.
14.03.2013