Another touch to the connection of fasting with life expectancy
Scientists at the University of Washington, working under the guidance of Doctors Brian Kennedy and Matt Kaeberlein, have deciphered additional details of the mechanisms by which calorie restriction slows down the aging process. In experiments on yeast, the authors found a relationship between the activity of ribosomes – organelles that provide protein synthesis in cells – and a specialized protein Gcn4 involved in the expression of genetic information, with mechanisms associated with the body's response to starvation and aging processes.
According to the results of earlier studies, the life-prolonging effects of a starvation diet are partially mediated by the functioning of the TOR enzyme. TOR (target of rapamycin) got its name because it is the object of exposure to the immunosuppressant rapamycin, which blocks its regulatory functions. This protein, present in the body of plants, animals and humans, regulates the processes of cellular metabolism and energy exchange and is responsible for cell growth. In response to the restriction of the nutritional value of the diet, the activity of the TOR-mediated signaling mechanism in the body decreases. One of the side effects of this is a decrease in the rate of synthesis of new proteins.
Scientists studied a large number of different yeast strains characterized by a low level of protein synthesis, and found various mutations of ribosomal proteins, some of which increased the lifespan of organisms. The researchers set out to determine the localization of such mutant proteins in one of the structural subunits of the ribosome.
The ribosome consists of large and small subunits, and it was not difficult for researchers to notice that in long-lived yeast strains mutations occurred exclusively in the large subunit.
Treatment of cells with the drug diazaborine, which specifically disrupts the synthesis of a large ribosome subunit, increased their lifespan by 50% compared to control cells. Using a set of genetic tests, the authors demonstrated that the destruction of large ribosome subunits increased life expectancy through a mechanism associated with calorie restriction – the enzyme-mediated TOR signaling pathway.
Thus, the researchers found that the effects of calorie restriction, a decrease in the activity of the TOR-mediated signaling mechanism and a decrease in protein synthesis are linked in one genetic scheme. However, the relationship between aging processes and the reduced ability of ribosomes to translate (protein synthesis) remained unclear.
The authors decided to analyze the possible involvement in this mechanism of the Gcn4 protein, a transcription factor involved in the transfer of genetic information from DNA to matrix RNA. This protein is activated when there is insufficient intake of amino acids into the cell.
If the ribosome does not work at full capacity, the efficiency of synthesis of most proteins decreases, but at the same time the synthesis of Gcn4 protein increases. Scientists have observed this paradox in long-lived yeast cells with mutations of proteins of the large ribosome subunit.
Experiments with various yeast strains have shown that suppression of Gcn4 synthesis prevents an increase in life expectancy under starvation conditions, and this effect is more pronounced in strains characterized by initially increased Gcn4 synthesis.
The increased production of Gcn4 in the cells of long-lived yeast strains in combination with its need for an increase in life expectancy associated with fasting makes this protein an important factor in the mechanism of life extension that has been actively studied recently.
To date, scientists do not know whether Gcn4 plays a similar role in other organisms, but they emphasize that in worms, flies, mice and humans, the regulation of the functioning of Gcn4 protein analogues is carried out in the same way as in yeast.
The role of the TOR protein and translation (protein synthesis by ribosomes in accordance with the information recorded in the matrix RNA) in the aging process remained unchanged during evolution in a large number of different species, so the authors suggest that the functioning of the Gcn4 protein also remained unchanged. They plan to test this hypothesis in the near future.
It is obvious that the TOR-mediated signaling mechanism is one (perhaps the most important) of the components of the mechanism that provides the beneficial effects of caloric restriction on the diet. However, its use as a therapeutic target is fraught with the development of negative side effects. The authors believe that the more detailed the functioning of this mechanism is studied, the more chances there will be to identify optimal therapeutic targets for the treatment of aging-associated diseases.
Evgeniya Ryabtseva
Portal "Eternal youth" www.vechnayamolodost.ru based on the materials of the University of Washington
22.04.2008