Sirtuins and resveratrol prolong life – is it too good to be true?
La Vie en Rouge
"Life in red": useful properties of red wine from the point of view of science – a myth or ...?
Valery Yudin, Weekly "Pharmacy""The measure of life is not in its duration, but in how you used it"
Michel de Montaigne
More than once we have heard or read about the positive effect of moderate consumption of dry red wine on human health. However, the provision on its therapeutic properties was known even at the dawn of human civilization – even then wine became a global socio-religious symbol associated with many advantages, including it was endowed with medicinal and magical properties.
Vicente Juan Masip (Vicente Juan Masip). The Last Supper. The 1560s. Prado Museum
The current popular opinion about the benefits of moderate wine consumption was first expressed by the father of medicine – Hippocrates. At the same time, the benefits of red wine in the prevention of cardiovascular diseases for the first time became the center of scientific research only relatively recently - after in 1992, French scientists Serge Renaud and Michel de Lorgeril published the results of a study in the journal "The Lancet", according to which the French there is a low mortality rate due to coronary heart disease, despite the same high fat intake as other Europeans and Americans, as well as despite the prevalence of other risk factors among them, including smoking. This phenomenon has been called the "French paradox", which scientists explain by the inherent French "Mediterranean diet", which includes a relatively large consumption of dry red wine (Renaud S., de Lorgeril M., 1992).
In 1997, the results of a Dutch epidemiological study showed that the level of coronary artery disease in elderly men is inversely proportional to their use of flavonoids, which are contained, among other things, in red wine (Hertog M.G., Feskens E.J., Kromhout D., 1997). Then, as a result of other studies, the antioxidant, hypocholesterolemic, cardioprotective, anticancer effect of red wine and/or biologically active substances included in its composition was shown or confirmed (Wu J.M., Wang Z.R., Hsieh T.C. et al., 2001; Das D.K., Maulik N., 2006; Das S., Santani D., Dhalla N.S., 2006; Das S., Das D.K., 2007; Penumathsa S.V., Maulik N., 2009).
Among such components, the flavonoid resveratrol was found, which has antioxidant properties and belongs to the class of biologically active substances – sirtuins.
Sirtuins (sirtuins; from the English Silent Information Regulator 2 (Sir2) proteins) – a class of enzymes found in all organisms, from bacteria to humans. It is assumed that sirtuins regulate the processes of aging, transcription, apoptosis and resistance to stress (for example, starvation) and are responsible for the lifespan of some organisms. The name Sir2 is applied to yeast (Saccharomyces cerevisiae), in which this enzyme was found, fruit flies Drosophila melanogaster and roundworms Caenorhabditis elegans. Similar proteins characteristic of other yeasts are called Hst1, and for humans – SIRT1
Resveratrol is contained in the skin and bones of grapes and it is from them that it gets into red wine during its maturation. In extreme conditions, this substance is produced not only by grapes, but also by many other plants. About 2 dozen other substances synthesized by plants in response to stress have similar properties. Five years ago, many researchers put forward or supported the hypothesis that this substance – resveratrol – can not only help us resist stress (fever, hunger), but also slow down the aging process, which will be discussed below (Fig. 1).
"Forever young, forever drunk"The beneficial properties of resveratrol are believed to be related to its ability to activate the enzyme Sir2 (from the English silent information regulator), which belongs to the group of sirtuins, which 10 years ago were associated with longevity.
It was then that biology professor Leonard P. Guarente from the Massachusetts Institute of Technology in Cambridge (USA) discovered that the lifespan of yeast when they add additional copies of the gene encoding the enzyme Sir2 is significantly higher than those that have a standard set of this gene (Kaeberlein M., McVey M., Guarente L., 1999). Four years later, David Sinclair, a postdoctoral fellow of the aforementioned Professor L. Guarente, published a paper in which he showed that resveratrol is able to activate sirtuins in yeast and thus increase their lifespan (Howitz K.T., Bitterman K.J., Cohen H.Y. et al., 2003). D. Sinclair further he continued his work on the study of this substance. With his research, he demonstrated that roundworms that fed on resveratrol had a half-increased life expectancy (Wood J.G., Rogina B., Lavu S. et al., 2004). At the same time, scientists were struck not so much by the similarity of the reactions of different organisms, as by the fact that this phenomenon was observed in an adult worm whose cells no longer divide and in which the replicative aging mechanism characteristic of yeast does not work.
A logical question arose: how does the gene encoding the Sir2 protein "work"?
"When you are silent, it is pleasant to listen to you..." The researchers found that this gene encodes an enzyme with unusual properties.
The DNA molecule in the cell is in a compact form: it is wound on "coils" formed by histones (nuclear proteins necessary for the assembly and packaging of DNA strands into chromosomes; there are five types of histones called H1, H2A, H2B, H3, H4 and H5 – Fig. 2).
With the activation of DNA transcription, histone acetylation occurs under the action of the enzyme histone acetyltransferase (English histone acetyltransferases - HAT). Acetyl groups attached to histones act as "chemical labels", with the help of which the desired DNA packing density is maintained: acetylation of histones introduces a negative charge on their surface, which leads to repulsion of histones from each other. As a result, the previously closed DNA becomes available to transcription enzymes. If part of these "tags" are removed, then the DNA is wound too tightly on the histone "coil", and the enzymes that ensure the isolation of ring ribosomal DNA (rDNA) responsible for the synthesis of ribosome components from it are blocked. Sections of DNA in such a super-dense state are called silent because none of their genes can be activated.
Scientists have found out that the Sir2 protein is one of the enzymes that cleaves acetyl groups from histones and thus participates in maintaining genes in a "silent" state. This enzyme is active only in the presence of the coenzyme nicotinamide adenine dinucleotide (nicotinamide adenine dinucleotide - NAD+), which is involved in most metabolic processes. And, consequently, the relationship between the nature of nutrition and aging was also found.
Chewing less means living longer? Perhaps someone will be surprised, however, scientists believe that life expectancy directly depends on the amount of calories consumed.
The restriction regime usually consists in reducing the amount of food consumed by 30-40% compared to what is considered the norm for this species. Absolutely all living creatures – from rats and mice to dogs and primates – not only live longer on such a diet, but also have a better state of health: the incidence of many diseases, including cancer, diabetes mellitus and neurodegenerative disorders, is decreasing. However, reproductive abilities, the researchers note, weaken at the same time.
Scientists have long believed that with a reduced amount of food consumed, the metabolism slows down, and with it the amount of toxins formed during this process, by-products of the digestive process, decreases. Today, this point of view is recognized as erroneous – a low-calorie diet does not slow down the metabolism of either mammals or lower organisms. On the contrary, according to D. Sinclair and L. Guarente, there is an acceleration and a change in metabolism. Calorie deficiency is the same biological stress factor as lack of food, which turns on the body's defense systems, mobilizing them to fight for survival. In mammals, the efficiency of cellular repair and energy production systems changes, and apoptosis (programmed cell death) is delayed.
In experiments on yeast, it was found that nutrient deficiency triggers mechanisms that increase the enzymatic activity of Sir2, one of which activates energy production and forms NAD+ as a by–product (which activates Sir2) and simultaneously reduces the level of its antagonist - the reduced form of nicotinamide adenine dinucleotide (NADH), which inactivates Sir2. Obviously, by changing the NAD+/NADH ratio in the cell, it is possible to influence the activity of Sir2, and, consequently, the lifespan.
Don't take it, Lord, for drunkenness – take it for medicineIn 2007, D. Sinclair and Sirtris Pharmaceuticals Inc., a biopharmaceutical company that D. Sinclair founded together with venture capitalist Christoph Westphal in Cambridge (Massachusetts, USA) to develop sirtuin activators, received a large number of low–molecular compounds after screening, among which mammalian sirtuin activators were searched for – SIRT1.
The results of this study were published in the journal "Nature" (Milne J.C., Lambert P.D., Schenk S., 2007). The researchers found three substances (SRT1720, SRT2183, SRT1460), whose activity in relation to the activation of this enzyme was more than 1 thousand. times more powerful than resveratrol (Milne J.C., Lambert P.D., Schenk S. et al., 2007). In addition, one of the discovered substances showed the ability to increase insulin sensitivity in obese mice and rats, thus suggesting the possibility of using these new substances in the treatment of type II diabetes mellitus. Less than a year later, at the end of April 2008, the British multinational pharmaceutical company GlaxoSmithKline plc acquired Sirtris Pharma for 720 million US dollars. Two of the company's drugs are currently undergoing phase II clinical trials – the first for the treatment of cancer and both for the treatment of type II diabetes mellitus.
Between the first and second… However, optimism about the potential properties of these substances was somewhat overshadowed over time by reports of research results, according to which resveratrol does not directly activate SIRT1, but is active only by being covalently bound to a fluorophore – this conjugate was determined during previous screenings, and also showed efficacy in increasing the activity of SIRT1 in previous studies (Kaeberleina M., McDonaghc T., Heltweg B.
et al., 2005; Beher D., Wu J., Cumine S. et al., 2009). And the results of the study, published on January 8 this year in the journal of Biological Chemistry, caused even more disagreement between those who believe in the unique properties of resveratrol and those who think it is "too good to be true" (Pacholec M., Chrunyk B.A., Cunningham D. et al., 2010).
Currently, researchers led by biochemist Kay Ahn from the Department of Cardiovascular, Metabolic and Endocrine Diseases and Structural Biology of the Pfizer Global Research and Development Laboratory of the American corporation Pfizer Inc. have confirmed that the molecules isolated by scientists "Sirtris Pharma" do not directly activate SIRT1 unless they form conjugates with fluorophores (Pacholec M., Chrunyk B.A., Cunningham D. et al., 2010).
"There are no failed experiments, there are experiments with an unexpected end"
(Richard Buckminster)Despite this "embarrassment", L. Guarente, who is currently a scientific consultant for Sirtris Pharma, believes that such results of recent studies should not upset or cause concern.
Although the substances synthesized by his company are able to "work" in vitro and only in the form of fluoroforconjugated peptides, however, the situation is completely different in vivo, he says. Thus, the journal "Nature", among others, published the results of studies according to which the activity of the enzyme SIRT1 was higher in cell culture and in animal models after the introduction of substances found by "Sirtris Pharma". In addition, resveratrol had no effect on the lifespan of yeast that lacked the gene encoding the enzyme Sir2, thereby indicating that the activity of this enzyme depends on the presence of this gene (Howitz1 K.T., Bitterman K.J., Cohen H.Y. et al., 2003).
At the same time, according to a statement made by GlaxoSmithKline, the results of K. Ahn's study exclude any possibility of direct activation of SIRT1 outside the experiment in vitro. However, there are still those who are not deterred by these results. Another former employee of L. Guarente's laboratory, Brian Kennedy, who is currently an employee of the University of Washington in Seattle, points out that the results of studies on cell cultures are quite difficult to interpret, especially because resveratrol is believed to interact with many enzymes. B. Kennedy, who in 2005 became the first of those who reported that resveratrol activates SIRT1 only in vitro and only when conjugated with fluorophores, believes that resveratrol does not show specificity, but can still be effective in vivo. It remains only a mystery what exactly activates this process-the target and it is unlikely that SIRT1 is the key target.
Woe from wine In the second part of his last study, K. Ahn also tried to reproduce the results obtained in the Sirtris Pharma laboratory on lowering blood glucose levels in obese mice.
At the same time, the result was deplorable – several of these mice even died, despite receiving the same dose of SRT1720, SRT2183, SRT1460 and resveratrol, which was indicated in an article published in Nature. However, K. Ahn hastened to emphasize that experiments conducted in vivo by different researchers may differ somewhat from each other. "In our case," he noted, "we have not observed favorable effects, but we do not want to make far–reaching conclusions based on these results."
One of the reasons for such a discrepancy in the results, D. Sinclair believes, is that K. Ahn and his colleagues did not have complete information about the characteristics of the substances under study, which they synthesized themselves for their research. Thus, he believes, it is impossible to know for sure how pure these substances were and in general whether they are the same ones that were synthesized by scientists from Sirtris Pharma. And the fact of the death of experimental animals, D. Sinclair believes, indicates that, probably, the substances were not sufficiently purified.
Those who are skeptical about the results obtained earlier by D. Sinclair continue to doubt. Enthusiasm for the activators of sirtuins synthesized by Sirtris Pharma and resveratrol was premature, – says Richard Miller, an employee of the geriatric Center of the University of Michigan (University of Michigan Geriatrics Center) in Ann Arbor (Michigan, USA), who found that the activation of metabolism increases the life expectancy of mammals (Harrison D.E., Strong R., Sharp Z.D., 2009). These substances, he believes, may well have a positive effect on health, but the very first results do not seem convincing enough, and all subsequent facts suggest that the system will be much more complex than it might have seemed before.
However, the growing number of studies demonstrating the beneficial effects of sirtuins and resveratrol does not contribute to scientists rushing to write off newly discovered substances from the accounts. "If I were asked to list the ten proteins that deserve the most attention in connection with the aging of mammals, then sirtuins would be on this list," says R. Miller. "The only thing is, they wouldn't be at the top of the list."
...As one character from the movie "Carnival Night" said, "is there life on On Mars, is there no life on Mars is unknown to science." Perhaps, for the time being, science cannot say for sure about the benefits of wine either: is there "life" in red, is there "life" in red ... But anyway, we will appreciate it first of all for its rich bouquet and taste. The main thing is not to forget Avicenna's advice: "Wine is our friend, but guile lives in it: you drink a lot – poison, you drink a little – medicine."
Portal "Eternal youth" http://vechnayamolodost.ru10.02.2010