Removing an inflammation-linked protein makes aging worse

Researchers at the University of Rochester thought that shutting down a protein linked to inflammation might help slow aging. Instead, they found the opposite: Without the protein, mice became frailer, experienced more inflammation, and had shorter lifespans.

The unexpected result reveals that the protein, called cGAS, has two seemingly opposing roles. It can trigger inflammation when it detects DNA in the wrong place inside a cell. But researchers discovered it also helps prevent another source of the chronic inflammation associated with aging and age-related diseases.

The findings, published in Nature Aging, could have implications for developing treatments and therapies designed to target age-related inflammation.

“We thought that getting rid of cGAS would be beneficial because of its role in inflammation, but instead we found that it made animals age faster,” says Vera Gorbunova, the Doris Johns Cherry Professor in the Department of Biology and codirector of the Rochester Aging Research (RoAR) Center and the Upstate NY Comparative Biology of Aging Nathan Shock Center.

cGAS: A protein with two jobs

Researchers have long known that cGAS plays a role in inflammation. When the protein detects DNA in the cytoplasm—the fluid-filled area outside a cell’s nucleus—it can activate an inflammatory protein called STING. Together, cGAS and STING form part of a cellular defense system known as the cGAS-STING pathway.

Because chronic activation of this pathway has been linked to aging and inflammation, researchers have been exploring whether blocking cGAS-STING could help reduce age-related chronic inflammation and preserve health as people grow older.

But when Gorbunova and her team removed cGAS from mouse models, they discovered another side of the protein.

Inside the cell’s nucleus, cGAS helps maintain chromatin, the tightly organized structure that packages the cell’s DNA. By keeping certain stretches of DNA tightly packed and inaccessible, chromatin helps suppress genetic elements called LINE1s.

Without cGAS, the researchers found, those normally suppressed elements become more active. That can lead to more LINE1-derived DNA entering the cytoplasm, where the cell can mistake it for a sign of danger and trigger inflammation.

In other words, cGAS has two seemingly opposing jobs. Outside the nucleus, it can act as an alarm system that detects misplaced DNA and activates inflammation. Inside the nucleus, cGAS helps prevent some of that potentially inflammatory DNA from being produced in the first place.

What is inflammation—and what causes it?

Inflammation is the body’s natural immune response to injury or infection. In a young, healthy body, inflammation is an important short-term defense mechanism. But when inflammation persists, it can damage cells and tissues.

As people age, inflammation becomes more persistent and is associated with many diseases that become more common with age, including cancer, cardiovascular disease, and neurodegenerative disorders.

“Reducing harmful, persistent inflammation may potentially reduce some of the cellular damage that contributes to disease and loss of function as we age,” says Andrei Seluanov, a Dean’s Professor of Biology at URochester and a coauthor of the study.

One source of inflammation lies within our own DNA.

Much of human DNA consists of genetic sequences that do little more than propagate themselves in their hosts. Among them are transposable elements called LINE1s, which can copy themselves and insert those copies elsewhere in the genome.

Cells have several ways of keeping transposable elements switched off. But previous research from Gorbunova’s lab has shown that LINE1s become more active with aging and can contribute to chronic inflammation.

When LINE1s become active, they can produce DNA that escapes into the cytoplasm. There, the cell can mistake the DNA for an invading threat—much as it would a virus—and launch an inflammatory response.

The new findings show that cGAS, despite its own role in triggering inflammation, also helps keep this process in check.

Rethinking therapies for aging

The findings present a challenge for scientists investigating ways to target cGAS to combat age-related inflammation. Eliminating or blocking cGAS might shut down one source of inflammation. But doing so could also remove one of the cell’s defenses against another.

“Rather than simply turning off the protein, future therapies may need to preserve its protective role in the nucleus while blocking its inflammatory activity elsewhere in cells,” Gorbunova says.