DNA damage may trigger harmful inflammation

The immune system protects the body by detecting and eliminating threats such as viruses. However, under certain conditions, it can mistakenly treat fragments of the body’s damaged DNA as foreign genetic material.

This false alarm can activate a prolonged immune response, causing chronic inflammation and damage to healthy tissue.

An international research team led by Dr. Marva Bergman and Professor Itamar Harel of the Hebrew University, in collaboration with Professors Yehuda Tzfati, Ido Ben-Ami of the Hebrew University and Sha’are Zedek Medical Center, and Professor Berenice Benayoun of the University of Southern California, found that this misguided immune response is a major driver of tissue degeneration in severe rapid-aging diseases.

When researchers reduced the immune response, they observed improvements across multiple biological systems.

Rethinking DNA damage in rapid-aging diseases

The study examined rare DNA damage repair syndromes, including ataxia telangiectasia (AT) and Bloom syndrome. In these conditions, the cellular systems responsible for repairing routine DNA damage do not function properly.

As damaged DNA accumulates throughout the body, it can contribute to genomic instability, neurodegeneration, increased cancer risk, and premature aging.

For decades, scientists primarily believed that unrepaired DNA was the main cause of cellular decline. The new findings suggest that the body’s response to this damage may be equally important.

“Our results show that the damage is not occurring in isolation,” Professor Harel said. “It’s the body’s response to that injury, an exaggerated chronic inflammatory response, that causes much of the degeneration.”

How cGAS turns damaged DNA into a false immune alarm

When DNA repair is disrupted, fragments of DNA can escape into the cell’s cytosol, the fluid-filled region outside the nucleus. There, they can activate cGAS, a molecular sensor that normally helps the body detect viral DNA.

Because cGAS cannot always distinguish foreign genetic material from fragments of the body’s own DNA, it may trigger persistent sterile inflammation. This type of inflammation occurs without an infection and can gradually damage tissues instead of protecting them.

The researchers identified another unexpected role for cGAS. In addition to activating inflammation, cGAS can move into the cell nucleus and directly interfere with DNA repair.

This means cGAS may contribute to degeneration in two ways: by promoting chronic inflammation and by disrupting the cellular mechanisms responsible for repairing damaged DNA.

Under normal conditions, cGAS is an important part of the body’s antiviral defenses. However, when DNA damage becomes severe, its activity may become harmful.

Reducing cGAS activity improved tissue function

To test whether suppressing this response could change disease progression, the researchers used a rapid-aging vertebrate model. This model allows scientists to study biological changes associated with aging over a relatively short period.

Reducing cGAS activity improved several key features of the disease, including neuroinflammation, tissue degeneration, and loss of fertility.

“We didn’t just slow the decline,” Dr. Bergman said. “We saw widespread recovery of tissue function, suggesting that the body can cope with more DNA damage than we had assumed if the inflammatory response is suppressed.”

The findings suggest that treating diseases caused by DNA damage may not require repairing every individual DNA lesion. Instead, future therapies could focus on controlling the body’s harmful inflammatory response to that damage.

Potential treatment strategies and limitations

Targeting the inflammatory response could offer a new approach for treating severe DNA repair disorders. Rather than attempting to repair all damaged genetic material, researchers may be able to reduce the tissue damage caused by the immune response that follows.

However, cGAS also plays an essential role in detecting viral infections. Completely blocking the pathway could therefore weaken antiviral immunity.

Future treatments will need to limit the damaging effects of cGAS while preserving its protective role in the immune system.

The discovery may also have implications beyond rare genetic diseases. Chronic inflammation and genomic instability are common features of many age-related conditions, raising the possibility that similar mechanisms contribute to more widespread forms of tissue degeneration.

What the findings mean for aging and long-term health

Other studies from the same research group are examining how fundamental biological programs, including the timing of reproduction and development, interact with aging and lifespan.

Together, this research supports a broader view of aging: biological systems that help organisms survive, grow, and reproduce early in life may also influence how long tissues remain healthy.

The researchers emphasize that reversing disease-related degeneration is not the same as slowing the fundamental rate of biological aging.

Still, the study marks a potential shift in how scientists understand DNA damage. The damage itself may be only part of the problem. The body’s response to that injury can also drive decline, and controlling that response could open new possibilities for treating severe degenerative diseases.