cGAS knockout in killifish: fewer senescence signs, no lifespan gain
Knocking out cGAS in turquoise killifish reduced cellular senescence markers in kidneys and fin cells but did not extend lifespan across 149 fish; in mice, the same deletion shortened life.
Turquoise killifish, a short-lived fish whose entire lifespan can be tracked in a single lab strain, showed fewer signs of cellular senescence when cGAS was knocked out, but the survival curve did not shift. The paper appeared in EMBO Reports on 9 September.
cGAS detects DNA outside the cell nucleus and triggers inflammatory signaling. Killifish have two genes similar to cGAS. The authors found that one, cGASa, activates immune genes, and used CRISPR to delete it. In the first hours after irradiation, fin-derived cells from knockout fish had higher levels of γH2AX, a marker of DNA damage. Nine days later, fewer cells showed signs of stable cell-cycle arrest (SA-β-gal), and more incorporated EdU, a marker of DNA synthesis. Kidneys of old fish followed the same pattern: SA-β-gal staining covered a smaller area of the kidney tubules, while markers of cell division (EdU and PCNA) were more frequent. The intestine did not show these differences; the two tissues responded differently to the gene's deletion.
The team tracked 70 knockout fish and 79 controls. Median lifespan was 150.5 days in knockouts versus 143 days in controls; maximum was 215 and 213 days respectively. Survival analysis found no statistically significant difference, either across the full cohort or when comparing by sex.
In a separate mouse experiment, complete loss of cGAS reduced median lifespan from 2.01 to 1.64 years. In killifish, the same genetic intervention changed cellular and kidney markers while leaving the survival curve unchanged.
The killifish cGAS paper is a clean, current example of the senescence-marker-vs-lifespan gap: tissue markers shifted, survival did not. The Eternal Search Cellular Senescence page is the natural entry point for readers who want to understand what the measured endpoints actually represent, making it the right concept page to anchor the post.