Researchers at the University of Rochester expected that eliminating cGAS, a protein associated with inflammation, might help slow the aging process. Instead, they discovered the opposite: mice lacking the protein became more frail, developed increased inflammation, and had shorter lifespans.

The unexpected findings, published in Nature Aging, reveal that cGAS has two seemingly opposing functions. When it detects misplaced DNA in the cell’s cytoplasm, cGAS can activate the STING pathway and trigger inflammation. However, researchers found that cGAS also plays a protective role inside the cell nucleus by helping maintain chromatin, the structure that organizes DNA and keeps potentially harmful genetic elements under control.

In particular, cGAS helps suppress LINE1 elements, repetitive DNA sequences capable of copying themselves and inserting into other parts of the genome. As cells age, LINE1 activity can increase, producing DNA fragments that escape into the cytoplasm. The immune system may mistake this misplaced DNA for a sign of infection, triggering chronic inflammation.

When researchers removed cGAS from mice, LINE1 elements became more active, leading to greater amounts of DNA entering the cytoplasm and ultimately increasing inflammatory responses. This suggests that while cGAS can promote inflammation under certain conditions, it also helps prevent another important source of age-related inflammation.

Chronic inflammation is increasingly associated with aging and age-related diseases, including cancer, cardiovascular disease, and neurodegenerative disorders. The study therefore highlights the complexity of targeting the cGAS-STING pathway as a potential strategy for addressing age-related inflammation.

The researchers suggest that future therapies may need to take a more selective approach rather than simply blocking cGAS. Preserving its protective function within the nucleus while limiting its inflammatory activity elsewhere in the cell could offer a more effective strategy for reducing harmful inflammation without disrupting its beneficial role in maintaining cellular health.

Source: https://www.rochester.edu/newscenter/protein-cgas-sting-pathway-inflammation-aging-718912/