Naked mole-rats are well known for both their wrinkly appearance and for their unexpectedly long lives. The source of this extended lifespan has been under scrutiny for decades. While many rodents are relatively short-lived—mice tend to live approximately four years—naked mole-rats can live nearly 10 times as long. Further, as different as they seem from the outside, the genetics of naked mole-rats are more similar to humans than the oft-used mouse model. This makes them especially useful for studying the underlying genetics behind their longevity and the possible applicability to human longevity understanding.
Current research into the genetics behind the longevity of naked mole-rats suggests that they have an enhanced ability to maintain DNA integrity through repair mechanisms, though the process by which this occurs is not well understood.
A team of researchers in China has determined how to identify the genetic basis for the naked mole-rats’ longevity and has published their recent findings in Science in a paper entitled, “A cGAS-mediated mechanism in naked mole-rats potentiates DNA repair and delays aging.”
Aging is often associated with poor or declining ability of the DNA to be repaired correctly or efficiently. One critical repair pathway for DNA is homologous recombination (HR), which when the process is defective, is linked to premature aging. Previous studies have shown that the DNA sensor cyclic guanosine monophosphate–adenosine monophosphate synthase (cGAS) can suppress HR in humans and mice, so the researchers aimed to determine the function of cGAS in naked mole-rats.
“Our work provides a molecular basis for how DNA repair is activated to contribute to the exceptional longevity during evolution in naked mole-rats,” the authors wrote.
Using a panel of assays, the researchers assessed the interaction between naked mole-rat cGAS, damaged DNA, and other HR factors, including RAD50 and FANCI. In their paper, they “demonstrated that FANCI promoted chromatin recruitment of RAD50, thereby potentiating HR repair.”
Fruit flies with naked mole-rat cGAS had increased lifespan along with reduced organ deterioration. In aged mice, AAV delivery of the naked mole-rat cGAS “reduced frailty, attenuated hair graying, lowered circulating levels of IgG and interleukin-6, and decreased cellular senescence markers in multiple tissues.”
The team identified that the difference between naked mole-rat cGAS and human and mouse cGAS was a mere four amino acids. Changing the amino acid residues in the naked mole-rat sequence removed the protective function of cGAS on HR repair mechanisms.
Combined, this study suggests that the small sequencing changes in naked mole-rat cGAS may have a big impact on longevity. While its function in humans and mice is one of suppressing DNA repair, in naked mole-rats, it enhances repair mechanisms and has shown evidence suggesting the improved DNA repair mechanisms may positively impact health and longevity.
“These findings support the notion that efficient DNA repair decelerates the aging process and raise the possibility that targeting cGAS to enhance DNA repair could provide an intervention strategy for promoting longevity,” concluded the authors.
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