A few tiny molecular tweaks may explain why naked mole-rats live nearly ten times longer than similar species.
Researchers believe the key to the naked mole-rat’s remarkable lifespan may come down to small but significant differences in just four amino acids. A recent study found that evolutionary changes in cGAS, an enzyme in the innate immune system that detects DNA to trigger immune responses, may give these animals a superior ability to repair age-related genetic damage. In contrast, cGAS in other species, including mice and humans, can actually hinder DNA repair.
Despite their wrinkled, unremarkable appearance, the naked mole-rat (Heterocephalus glaber) is one of the longest-living rodents known, surviving for nearly 40 years, about ten times longer than other mammals of similar size. Interestingly, their genetic profile is more closely aligned with humans than with mice, making them a valuable subject for research into the molecular factors that promote longevity. One of the most important factors linked to a long life is the stability of an organism’s genome.
Still, scientists are only beginning to understand how naked mole-rats preserve the integrity of their DNA, especially through their unique repair systems that protect their cells from the ravages of time.
The Role of cGAS and DNA Repair
Homologous recombination (HR) is a critical DNA repair pathway, and defects in HR are linked to premature aging. In humans and mice, the DNA sensor cGAS (cyclic guanosine monophosphate–adenosine monophosphate synthase) can suppress HR repair, potentially promoting cancer and shortening lifespan.
Yu Chen and colleagues investigated whether cGAS similarly inhibits HR in long-lived naked mole-rats. Chen et al. found that, in naked mole-rats, four specific amino acid substitutions in mole-rat cGAS reduce ubiquitination and degradation, allowing the protein to persist for longer and at higher levels after DNA damage. This increased abundance strengthens interactions with key repair factors, FANCI and RAD50, thereby boosting HR repair.
Extending Lifespan Through Molecular Engineering
When cGAS was depleted from naked mole-rat cells, DNA damage accumulated. The authors further showed that fruit flies engineered to express human cGAS containing the four naked mole-rat–specific mutations lived longer than flies expressing unaltered human cGAS. The findings suggest that these specific evolutionary amino acid mutations in naked mole-rat cGAS not only enhance DNA repair but may also contribute directly to the extraordinary longevity of the species.
“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. “Further research will be required to establish the roles that cGAS may play in the nucleus in other organisms, both short- and long-lived, but the answer may be substantially more complex than originally predicted.”
Reference: “A cGAS-mediated mechanism in naked mole-rats potentiates DNA repair and delays aging” by Yu Chen, Zhixi Chen, Hao Wang, Zhen Cui, Kai-Le Li, Zhiwei Song, Lingjiang Chen, Xiaoxiang Sun, Xiaoyu Xu, Yixue Zhang, Li Tan, Jian Yuan, Rong Tan, Min-Hua Luo, Fang-Lin Sun, Haipeng Liu, Ying Jiang and Zhiyong Mao, 9 October 2025, Science.
DOI: 10.1126/science.adp5056
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