Scientists believe that the remarkable longevity of naked mole-rats may be tied to subtle changes in just four amino acids. A recent study found that small evolutionary mutations in cGAS — an enzyme in the innate immune system that detects DNA and triggers immune defenses — could make these animals better at repairing age-related genetic damage. In contrast, the same enzyme in mice and humans can actually hinder DNA repair.
Despite their wrinkled, almost alien appearance, naked mole-rats (Heterocephalus glaber) are extraordinary among rodents, living up to 40 years, or about ten times longer than most animals their size. Surprisingly, their genetic blueprint is closer to humans than to mice, making them an important species for studying how organisms maintain health over long lifespans. One crucial element of longevity is the ability to preserve genome stability. Yet how naked mole-rats manage to keep their DNA so resilient has remained largely unclear.
How Naked Mole-Rats Protect Their DNA
A key process involved in maintaining DNA integrity is homologous recombination (HR), a pathway that repairs genetic breaks. When this process fails, it can accelerate aging and increase the risk of cancer. In humans and mice, the DNA-sensing enzyme cGAS (cyclic guanosine monophosphate-adenosine monophosphate synthase) is known to interfere with HR repair, which can lead to genome instability and a shorter lifespan.
To understand whether naked mole-rats have found a way around this limitation, Yu Chen and colleagues examined how their version of cGAS behaves. The researchers discovered that four amino acid substitutions in the naked mole-rat’s cGAS reduce the protein’s tagging for degradation, allowing it to remain active longer and accumulate after DNA damage. This stability enables the enzyme to interact more effectively with important DNA repair proteins, including FANCI and RAD50, strengthening the HR repair process.
Evolutionary Mutations That Extend Life
When the scientists removed cGAS from naked mole-rat cells, the amount of DNA damage sharply increased, confirming the enzyme’s protective role. Even more strikingly, fruit flies genetically engineered to carry the same four naked mole-rat-specific mutations in human cGAS lived longer than flies with the normal version of the enzyme.
These findings suggest that just a few precise molecular tweaks may help explain why naked mole-rats live so long. The mutations appear to turn cGAS from a potential inhibitor into a powerful ally of DNA repair, offering the animals a natural mechanism to combat the effects of aging.
A New Clue in the Search for Longevity
“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.”
