11 July 2008

What secrets of longevity do studies on model objects tell about (continued-2)

The role of Sirtuin family genes as potential longevity genes extends to mammals as well. The analogue of the yeast SIR2 gene, in particular, in rats and mice is the SIRT1 gene. The enzymatic activity of the protein encoded by it is similar to the activity of the product of the yeast SIR2 gene. The study of the Sirt1 protein in rodents made it possible to comprehensively characterize its participation in the regulation of life expectancy in mammals.

Firstly, its importance in the regulation of the process of apoptosis, which is known to be one of the important factors of aging, was demonstrated. The ability of the Sirt1 protein to increase the viability of mammalian cells is shown in a mutant Wallerian mouse line containing a gene duplication. Due to this mutation, the neurons of mutant animals are characterized by an increased ability to withstand stress, they have less frequent heart attacks and neurodegenerative disorders in a stressful environment. An increase in the content of Sirt1 protein in the body of animals prevents the launch of the apoptosis program. This effect is achieved indirectly through the regulation of the activity of proteins p53, FoxO and Ku70.

In addition, according to D. Milbrandt (2004, Washington University, St. Louis, USA), the mentioned mutation leads to an increase in the activity of the enzyme that catalyzes the formation of NAD, which, in turn, activates the Sirt1 protein. Moreover, the protective effect of the mutation on rodent neurons was comparable to the effect of the drug resveratrol when administered to wild-type animals (non-mutant by the SIRT1 gene). According to K. Neri (France), the prevention of the death of nerve cells in mice and worms is also achieved by using another modulator of Sirt1 activity - fisetin.

And finally, studies conducted by P. Pixerverom (Johns Hopkins University), confirmed that in mammals, as well as in lower organisms (yeast, worms, insects), there is a close relationship between caloric intake and the activity of the Sirt1 protein: an increase in the activity of the Sirt1 protein occurs in conditions of calorie deficiency when cells the liver increases the level of NAD. In the future, the Sirt1 protein changes the activity of other proteins and genes. At the same time, the proteins that Sirt1 acts on include one of the important transcription regulators PGC-1, which affects glucose metabolism in the cell.

Summing up the observations obtained suggested that the Sirt1 protein is one of the key regulators of metabolic processes in the liver, muscles and adipose tissue cells. Reacting to changes in the nature of nutrition and in the ratio of NAD and NADH, Sirt1 radically changes the transcription profile of genes in these tissues, coordinates the work of genes and metabolic pathways that affect the lifespan of the organism. At the same time, one of the hypotheses suggests the participation of Sirt1 in the regulation of the amount of stored fats in response to a change in the nature of nutrition. By controlling the amount of stored fats, he thereby determines the level of hormones secreted by fat cells, which sets the pace of aging of the body.

In addition, recent studies have shown that Sirt1 is involved in the regulation of insulin production and insulin-like growth factor 1 (IGF-1), these same molecules, in turn, regulate the production of Sirt1.

According to M. Mayo (University of Virginia, USA), Sirt1 suppresses the activity of the NF-kB protein complex, which is involved in triggering the inflammatory response accompanying diseases such as arthritis, arthrosis, asthma, cardiovascular diseases, neurodegenerative disorders. Many of these diseases are associated with old age. At the same time, it should be noted that calorie deficiency suppresses inflammatory processes in the same way as the modulator of Sirt1 activity - resveratrol.

Thus, the available data indicate that the expression of the SIRT1 gene is necessary for the regulation of aging processes in mammals. Of course, there can be a lot of causes of aging, and the deciphering of its mechanisms is still far from complete. But using the example of a variety of organisms, it is shown that aging can be slowed down by manipulating a limited number of regulators.

The genes of the Sirtuin family are evolutionarily ancient, they have been identified in yeast (unicellular yeast), leishmania (parasitic unicellular flagellates), roundworms, drosophila, mammals. In all of these species, these genes are responsible for life expectancy.

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