Another mechanism of aging
Among the causes of aging, scientists have found double-strand breaks in DNA
MIPT Press Service
A scientific group of Russian cytologists and gerontologists, as a result of joint experimental work, revealed a pattern that clarifies the cellular mechanisms of human aging and indicates new ways to find a possible "cure for old age". In particular, scientists have found a correlation between the age of cell donors and the number of double–strand breaks in the DNA of fibroblasts - cellular elements of human skin. The work was published in the journal Aging (Zorin et al., Spontaneous yH2AX foci in human dermal fibroblasts in relation to proliferation activity and aging).
Scientists from the Moscow Institute of Physics and Technology, the Institute of Human Stem Cells, the A. I. Burnazyan Federal Medical Biophysical Center, the N. M. Emanuel Institute of Biochemical Physics of the Russian Academy of Sciences, the N. N. Semenov Institute of Chemical Physics of the Russian Academy of Sciences, the N. N. National Medical Research Center of Oncology participated in the study. Blokhin, the National Medical Research Center for Rehabilitation and Balneology of the Ministry of Health, the Institute of Biology of the Komi Scientific Center of the Ural Branch of the Russian Academy of Sciences, the V. A. Engelhardt Institute of Molecular Biology of the Russian Academy of Sciences and the Institute of Cell Biophysics of the Russian Academy of Sciences.
The ideas about the causes and mechanisms of biological aging, to which most gerontologists of the world are inclined, are somehow based on the hypothesis of the accumulation of various genetic disorders in the cells of the body with age. In particular, those that reduce the ability of cells to repair (repair) critical DNA damage. The authors studied these processes using the example of so–called fibroblasts - cellular elements of connective tissue located in the middle layer of the skin. Comparing many indicators of fibroblasts obtained from donors of different ages, scientists revealed the degree of influence of certain cellular processes on the mechanisms of aging of the body.
In particular, they found that such an important indicator as the proliferative activity of cells (the ability to grow biological tissue by cell division) retains an almost constant value with age. Fibroblasts obtained from a 70-year-old donor have almost the same proliferative activity as in a 20-year-old boy. The same applies to most other biological indicators, on which "suspicion" falls first. The same indicators that really shed light on the mechanisms of aging were found only among the very subtle and difficult to determine.
"We were looking for a connection between the age of a person and his skin with the accumulation of critical DNA damage of a special kind in fibroblasts, the so–called double-strand breaks," says Andreyan Osipov, Professor of the Russian Academy of Sciences, Senior Researcher at the Laboratory for the Development of Innovative Medicines at MIPT. – As markers of double-stranded DNA breaks in human cells, radiobiologists use foci of phosphorylated histone yH2AX, which are formed in chromatin regions adjacent to the double-stranded break. However, no one has been able to find a correlation between the number of these foci in actively proliferating cells with human age until now."
The fact is that in the populations of proliferating cells that most scientists work with, there are usually cells at different stages of the cell cycle.
The procedure of cell division in the most general form resembles the process of reproduction of macroorganisms. First of all, the cell needs to prepare for reproduction: this stage is called interphase. It is divided into the following components, traditionally denoted by Latin letters and numbers: G0 – the "rest" phase. The cell just lives and is not going to divide yet. At this phase, it is called "resting" or "resting"; G1 – the synthesis of cellular components begins; S – the most interesting phase in the context of this work: synthesis (replication) occurs here DNA of the cell nucleus; G2 – preparation for mitosis – and, finally, mitosis proper, the division of a cell into two new ones.
A certain part of the cells is at the stage of DNA synthesis, in the so-called S-phase. At this phase, a lot of double-strand breaks are formed, which are then correctly repaired. Therefore, if in such circumstances the rupture markers are analyzed, then it is possible to detect a correlation only with cellular proliferative activity. And she, as it was said, does not depend on the age of the donor at all.
"Our idea was to separate resting cells from proliferating ones and count their foci separately," continues Andreyan Osipov. "It was possible to do this with the help of the cell division marker Ki67."
As a result, for the first time in the world, our scientists have discovered a completely clear and unambiguous dependence of the number of double-strand breaks in resting skin fibroblasts on the age of donors.
The detection of this dependence allows, in particular, to admit the possibility of creating a method of anti-aging therapy based on increasing the efficiency of repair of double-strand breaks. It may be possible to achieve this with the help of genetic engineering methods or the selection of chemical compounds that affect the relevant processes.
"We have confirmed the leading role of double–strand breaks in cellular aging," says Andreyan Osipov.
"In addition, the data we have obtained opens up opportunities for the development of new therapeutic procedures and pharmacological correction for individuals with impaired signal transmission processes in the cellular repair pathways of double–stranded DNA breaks," he added Sergey Leonov, Head of the Laboratory for the Development of Innovative Medicines at MIPT
The further direction of the team's work, according to him, is the study of the mechanisms of repair of this type of damage using various test effects – for example, ionizing radiation.
The work was supported by the Russian Science Foundation and the Ministry of Education and Science of the Russian Federation.
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