Rejuvenated fibroblasts have refuted the mitochondrial theory of aging
Japanese researchers from the University of Tsukuba, working under the guidance of Professor Jun-Ichi Hayashi, in experiments on human cell cultures have demonstrated the ability to delay and even reverse the aging process. They also found that the regulation of the activity of two genes involved in the production of glycine, the smallest and simplest of amino acids, partly determines some characteristics of aging.
The authors made their discovery as part of a study aimed at clarifying a number of contradictory points of the currently popular mitochondrial theory of aging. According to this theory, age-related mitochondrial defects are caused by the accumulation of mitochondrial DNA mutations.
Violation of mitochondrial function is one of the main characteristics of aging of representatives of many species, including humans. This is mainly due to the fact that mitochondria are the energy centers of the cell, producing energy as a result of a process known as cellular respiration. Damage to mitochondrial DNA leads to changes in the sequence of its nucleotides and, accordingly, to disruption of the functions of proteins encoded in these genes. The accumulation of such changes is associated with a decrease in life expectancy and the premature development of age-related manifestations, such as a decrease in body weight and hair density, curvature of the spine and osteoporosis.
However, the growing number of conflicting data has raised doubts among experts about the reliability of this theory. In particular, the authors conducted a number of interesting studies, the results of which indicate that age-associated mitochondrial defects are not associated with the accumulation of DNA mutations, but with another form of genetic regulation.
The object of the study was the mitochondrial function of human fibroblasts isolated from the skin of young (from the embryo stage to 12 years) and elderly (aged 80-97 years) people. The authors compared the activity of mitochondrial respiration and the amount of mitochondrial DNA damage in the cells of these two groups. They expected to see a decrease in respiratory activity and an increase in the amount of DNA damage in the cells of the older age group. But, although the elderly were indeed characterized by a decrease in the activity of mitochondrial respiration, it turned out that the amount of damage to mitochondrial DNA does not depend on age. This led the researchers to the idea that another form of genetic regulation – epigenetic mechanisms - may be responsible for the age-related changes observed in mitochondria.
Epigenetic regulation implies a change in the physical structure of DNA due to the addition of chemical structures, which leads to the activation or blocking of gene activity. Unlike mutations, such changes do not affect the DNA sequence. If the proposed theory is correct, genetic reprogramming of cells into a state similar to that of embryonic stem cells should remove all epigenetic changes in mitochondrial DNA.
To test this hypothesis, the authors reprogrammed human fibroblasts of young and elderly people into the state of embryonic stem cells. Subsequently, these cells were transformed into fibroblasts again and the respiratory function of their mitochondria was analyzed. It seemed incredible, but the manipulation completely eliminated the age-related defects. The levels of respiratory function of all obtained fibroblasts, regardless of the age of the person from whose skin the original cells were isolated, were comparable to the level of respiratory function of embryonic fibroblasts. This confirmed the assumption of the authors, according to which the aging process of mitochondria is regulated not by mutations, but by epigenetic mechanisms.
The subsequent search for genes whose epigenetic regulation of activity can lead to the development of age-related mitochondrial defects led them to two genes, CGAT and SHMT2, regulating the production of the amino acid glycine in mitochondria. Experiments have shown that changes in the activity of these genes can induce the appearance of mitochondrial damage or restore the functionality of these organelles in cultured fibroblasts. Moreover, the addition of glycine to the culture medium of a line of fibroblasts isolated from the skin of a 97-year-old man restored their respiratory function within 10 days.
In general, the data obtained by the authors indicate that, contrary to the mitochondrial theory of aging, epigenetic regulation is the cause of age-related disorders of the respiratory function of mitochondria grown in fibroblasts culture. Scientists have yet to find out whether epigenetic regulation can control the aging of the human body and whether glycine-containing dietary supplements can give "new life" to an aging population of mitochondria.
Article by Osamu Hashizume et al. Epigenetic regulation of the nuclear-coded GCAT and SHMT2 genes confers human age-associated mitochondrial respiration defects is published in the journal Nature Scientific Reports.
Evgeniya Ryabtseva
Portal "Eternal youth" http://vechnayamolodost.ru
27.05.2015