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

Studies on model objects have revealed a whole family of genes that affect the lifespan of various organisms. Thus, the Sirtiun family genes provide life extension due to an increase in the number of copies or hyperactivation of the products encoded by them. The SIR2 gene belongs to the members of this family and was discovered in studies, it would seem, on a completely unsuitable object – on unicellular yeast fungi.

Screening of yeast colonies made it possible to identify long-lived yeasts that were capable of significantly more divisions. The search for genes that endow the body with such a remarkable property was successful, and such mutations were found. In these mutants, the enzyme controlled by the SIR2 gene was concentrated near the region of the yeast genome with repeating sequences responsible for yeast ribosomes (the so-called "cellular factories" for protein assembly). This area is called ribosomal DNA (rDNA), and contains about a hundred such repeats. Further studies have shown that the aging of maternal yeast cells is associated with the instability of this particular region – rDNA. Some redundant copies of rDNA are isolated from yeast chromosomes in the form of ring elements, which are called ERC – extrachromosomal rDNA circles (extra-chromosomal ring rDNA). ERC replicates simultaneously with chromosomal DNA, but during cell division remains in the nucleus of the original cell. Excessive accumulation of ERC leads to cell death. However, if additional copies of the SIR2 gene are introduced into the yeast cell, the formation of ERC is suppressed. By forcing a vulnerable region of the genome to curl more tightly, Sir2 protects it from cutting out rDNA and thereby affects the cell's lifespan, increasing it by 30%. These studies have indicated the existence of a replicative aging mechanism in yeast.

But does this gene matter in the life of multicellular? Modern methods of genetic engineering made it possible to introduce copies of the SIR2 gene into nematode cells (roundworms), and the results were amazing – the worm lived not one, but one and a half of the required life span. And this phenomenon was observed in an adult worm whose cells were no longer dividing.

What properties of the enzyme encoded by the SIR2 gene made the worm long-lived? The fact that Sir proteins (from the English silent information regulator) are involved in the maintenance of genes in a silent state was known before. This feature is determined by the fact that Sir enzymes are able to influence the nature of DNA stacking in the chromosome. The DNA and proteins (histones) that make up the chromosome are stacked in the form of so-called nucleomes. As a result, the chromosome resembles a string of beads, in which long strands of DNA are wound, as on bobbins, on histone molecules that make up the core of the nucleosome. At the same time, DNA packing density is of great importance, which is determined by the peculiarities of the chemical structure of histones. In particular, the presence of acetyl groups in histones maintains the desired packing density. So, Sir2 belongs to the group of enzymes that cleave acetyl groups from histones. As a result, a super-dense packaging is formed, i.e. the DNA strand is wound too tightly on the histone core, and the enzymes that isolate ring RDNAS from the chromosome are helpless.

Further research allowed us to bridge the purely genetic interpretation of life expectancy and aging to metabolism. The conjugation of the work of the Sir2 enzyme controlled by the SIR gene and a small NAD molecule involved in many metabolic processes in the cell was established. It was found that in yeast, the change in Sir2 activity depends on the ratio of the oxidized (NAD) and reduced form (NAD-H). [NAD – nicotinamide-adenine-dinucleotide is a coenzyme acting as a hydrogen acceptor in redox reactions in the electron transport chain during cellular respiration; its effect is weakened by the reduced form of the NADH coenzyme.]

The possibility of regulating the activity of the Sir2 protein has been established at various sites. Thus, the lack of nutrients in the medium led to an increase in the enzymatic activity of Sir2 in yeast, and as a result of exposure to such moderate stress, the lifespan of yeast cells increased by 30%. The activity of the protein in question can also be changed with the help of modulators. One of them is resveratrol. In extreme conditions, it is produced by many plants, and is also found in red wines. Its presence in the culture medium where yeast grows, the introduction of worms and fruit flies into the body increases their life expectancy by 30%. Fruit flies treated with resveratrol lived longer and at the same time retained fertility, which was often lost with a calorie deficit. If hyperproduction of Sir2 protein was observed in fruit flies, then neither resveratrol nor calorie deficiency gave any additional effect.

Thus, genetic studies of the function of the SIR2 gene on model unicellular and invertebrate multicellular objects indicated the presence of a certain relationship between the genetic regulation of life expectancy, the level of metabolic activity and caloric intake. The next task is to assess the significance of this gene for mammals.