the role of DNA repair highlighted in mice

Aging can be defined as a loss of function of cells and organs that gradually fulfill their role less well. A number of hypotheses have been put forward to explain it: accumulation of mutations in DNA; shortening of the ends of the chromosomes, the telomeres, over cell divisions; stress related to oxygenated molecules in cells; reduced ability of stem cells to renew themselves; multiplication of cells that have entered senescence, sometimes referred to as “zombies”… But it often remains difficult to know whether, beyond the correlations, we can speak of causality.

In an article published in the journal Cell dated January 19David Sinclair (Harvard Medical School) and his colleagues take the plunge: “Loss of epigenetic information is a cause of aging in mammals”, they write in the title of their study. To understand what they mean by this, we must first define epigenetics, a tricky term that covers different realities depending on the currents of research. Historically, it designates the influence of the environment in the broad sense on the expression of genes, the acquired versus the innate, which can resonate over several generations. It is now a question of the mechanisms that cause the same genetic heritage, present in each of our cells, to be expressed differently as we develop, in the specialized cells of our organs and tissues.

In the mind of David Sinclair, epigenetics is superimposed on the genetic code, and designates a kind of ” software “ written in chromatin, this complex structure associating proteins and RNA with the DNA of our chromosomes, which is involved in the expression of genes and their repair. Starting from the observation that certain senescent cells do not show an accumulation of mutations in the DNA and that, conversely, high mutation rates do not necessarily result in premature aging, he has been digging since the 1990s “epigenetics”, first explored in yeast.

Chromatin disorganization

This time, it is on the mouse that he supports his demonstration. With his colleagues, he created a line of mice in which a small number of breaks in the double helix of their DNA could be induced for a given period. These breaks temporarily activate the DNA repair system, which apparently did its job well since the analysis of the mice then showed that their genome had not retained any trace of the damage. On the other hand, in the following months, these rodents showed accelerated aging compared to a control group: graying, loss of muscle tone and memory, etc. The American researchers hypothesize that the price to pay for the activation of the DNA repair system is a disorganization of the chromatin, to which they link a loss of cellular identity. As if tissue differentiation were eroded, while the genetic code is intact.

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