Scientists have identified the mechanism of accelerated aging in genetic diseases

Excessive activity of the cGAS immune sensor can increase inflammation and tissue damage in rare hereditary diseases associated with impaired DNA repair. In experiments on short-lived fish, suppression of this mechanism reduced inflammation in the brain, cellular aging in the liver, and disorders of the reproductive system. The article "Izvestia" explains why the immune system takes fragments of its own DNA as a sign of infection and whether this mechanism can be used to create new treatment methods.

How DNA Damage Triggers Inflammation

DNA in cells regularly gets damaged, for which there is a special repair system. In some rare hereditary diseases, including ataxia-telangiectasia and Bloom's syndrome, this system is disrupted. Damage accumulates, genome instability occurs, and patients are at increased risk of degenerative changes and cancer.

For a long time, it was believed that the deterioration of tissues was primarily due to DNA damage itself. The new work shows that additional harm can be caused by the body's reaction to these disorders.

Fragments of damaged DNA can escape from the nucleus into the cytoplasm, the internal environment of the cell. There they are detected by the cGAS enzyme, which normally helps to recognize the genetic material of viruses and trigger an innate immune response.

However, cGAS is not always able to distinguish foreign DNA from its own. As a result, it can mistake parts of the damaged genetic material of a cell for a sign of infection and cause prolonged aseptic inflammation, that is, an inflammatory reaction without a virus or other pathogen.

How scientists tested the role of cGAS

An international team led by Marva Bergman and Itamar Harel from the Hebrew University of Jerusalem used African turquoise killifishes, short—lived vertebrates used in the study of aging and age-related changes.

Researchers have created genetically modified fish with signs of ataxia-telangiectasia and Bloom's syndrome. Then, in the ataxia-telangiectasia model, they disabled the cgas gene to test whether the immune response was just a consequence of DNA damage or was itself involved in the development of disorders.

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Suppression of cGAS partially reduced several manifestations of the disease at once. In fish, inflammation in the cerebellum decreased, signs of aging of liver cells decreased, and the condition of germ cells improved. The results showed that the tissues could retain some of their functions, although the original genetic disorders and DNA damage were not corrected.

According to her, the body is able to tolerate more DNA damage than previously thought if an excessive inflammatory reaction can be contained.

Why cGAS can enhance damage in two ways

The scientists also found that the role of cGAS is not limited to triggering inflammation. The enzyme is able to penetrate into the cell nucleus and influence the processes of DNA repair and the organization of chromatin, a complex of DNA and related proteins.

After disabling cgas, fish have fewer micronuclei, small structures that may contain damaged or incorrectly distributed parts of chromosomes. The researchers also recorded an improvement in the integrity of telomeres located at the ends of chromosomes and a partial restoration of the structure of tightly packed chromatin.

Thus, cGAS can enhance disorders in two ways at once: to support chronic inflammation in the cytoplasm and to interfere with the preservation of genome stability inside the nucleus. The authors called it a context-dependent enhancer of pathological processes in chronic DNA damage.

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Can the discovery be used to treat people?

The results point to a potential new approach to the treatment of rare DNA repair syndromes. Instead of trying to fix every damage to the genetic material, it is possible to influence the body's overreaction, which increases tissue degeneration.

However, cGAS cannot be completely blocked. This enzyme is necessary to protect against viruses, and in healthy fish, disabling it, on the contrary, increased genome instability and pathological changes. Therefore, possible therapy should selectively reduce the harmful activity of the mechanism without depriving the body of normal antiviral protection.

The work is of a preclinical nature: experiments were conducted on fish, but the safety and effectiveness of exposure to cGAS in humans have not been studied. The results also do not mean that scientists have managed to slow down normal human aging. We are talking about reducing the manifestations of severe hereditary disorders in the experimental model.

The authors believe that in the future, cGAS and related signaling pathways can be considered as potential targets for drugs against diseases accompanied by chronic DNA damage. To do this, it is necessary to determine how to weaken the pathological reaction, while maintaining the necessary work of the immune system.