Scientists have uncovered how naked mole-rats achieve exceptional longevity through subtle changes in a key immune protein. These mutations in the enzyme cGAS improve DNA repair, potentially explaining why the rodents live up to 40 years. The findings, tested in fruit flies, suggest broader implications for understanding aging.
Naked mole-rats (Heterocephalus glaber), despite their wrinkled appearance, live up to 40 years—about ten times longer than most rodents of similar size. Their genetic blueprint is closer to humans than to mice, making them valuable for longevity research. A study published in Science reveals that four amino acid substitutions in their version of cGAS, an enzyme in the innate immune system that detects DNA and triggers defenses, play a crucial role in this resilience.
In humans and mice, cGAS interferes with homologous recombination (HR), a vital DNA repair pathway that prevents genome instability, aging, and cancer when functioning properly. However, the naked mole-rat's cGAS avoids this issue. The mutations reduce the protein's tagging for degradation, allowing it to stay active longer and accumulate after DNA damage. This enables stronger interactions with repair proteins like FANCI and RAD50, bolstering HR efficiency.
Researchers led by Yu Chen found that removing cGAS from naked mole-rat cells sharply increased DNA damage, confirming its protective function. To test broader applicability, they engineered fruit flies with the same four mutations in human cGAS; these flies lived longer than those with the normal enzyme.
"The findings from Chen et al. describe an unexpected role for naked mole-rat cGAS in the nucleus that influences longevity," write John Martinez and colleagues in a related Perspective. They note that further research is needed to explore cGAS's nuclear roles in other organisms, both short- and long-lived. The study, detailed in Science (2025; 390 (6769)), offers insights into how evolution tweaks biology to combat aging.