Disabling the cellular DNA sensor cGAS reduced signs of aging in killifish without extending their lifespan

Disabling the cellular DNA sensor cGAS reduced signs of aging in killifish without extending their lifespan

A study published on 9 September in EMBO Reports examined turquoise killifish, a short-lived fish whose entire lifespan can be followed in a single laboratory strain.

cGAS detects DNA outside the cell nucleus and triggers inflammatory signaling. The authors first tested which of the fish's two similar genes functions as cGAS. They found that cGASa produced the signaling molecule cGAMP and activated immune genes, then used CRISPR to knock out that gene.

During the first hours after irradiation, fin-derived cells from fish lacking cGAS had more γH2AX, a marker of DNA damage. Nine days later, fewer cells showed SA-β-gal, one indicator of stable cell cycle arrest, and more cells incorporated EdU, a marker of DNA synthesis. Thus, the stronger DNA damage signal was accompanied by fewer cells in stable cell cycle arrest.

The same pattern appeared in the kidneys of old fish: SA-β-gal staining covered a smaller area of the kidney tubules, while EdU and PCNA, another marker of cell division, were more frequent. These differences were absent in the intestine, indicating that the two tissues responded differently.

The authors then measured lifespan in 70 knockout fish and 79 control fish. Median lifespan was 150,5 days in fish lacking cGAS and 143 days in controls; maximum lifespan was 215 and 213 days, respectively. Survival with age did not differ statistically, either across the full cohort or when males and females were compared separately.

In a mouse experiment, complete loss of cGAS reduced median lifespan from 2,01 to 1,64 years. In killifish, the same genetic intervention changed several cellular and kidney markers while leaving the survival curve unchanged.