Unraveling a Longevity Secret: cGAS in Naked Mole-Rats
For decades, naked mole-rats have puzzled scientists with their unusually long lifespans and robust genome maintenance. Reaching nearly 40 years in the wild, they outlive many rodents of similar size. A new line of inquiry suggests that subtle changes in a single enzyme of the innate immune system—cGAS—may be a key to their remarkable DNA repair and, by extension, their longevity.
cGAS: Sensing DNA, Shaping Repair
In many mammals, the enzyme cyclic GMP-AMP synthase (cGAS) detects cytosolic DNA and triggers immune responses. In humans and mice, cGAS can actually suppress homologous recombination (HR), a crucial DNA repair pathway that fixes double-strand breaks with high fidelity. Suppression of HR is a double-edged sword: it can help elicit immune defenses but may compromise genome integrity over time, potentially contributing to aging and cancer risk.
The four amino acids that may matter
Researchers led by Yu Chen examined naked mole-rats and found four specific amino acid substitutions in the mole-rat version of cGAS. These substitutions appear to reduce the enzyme’s ubiquitination and subsequent degradation, allowing cGAS to persist longer and at higher levels after DNA damage. The result is a stronger partnership with key DNA repair factors, notably FANCI and RAD50, thereby boosting HR repair in naked mole-rat cells.
By preserving cGAS in the nucleus and enhancing its interactions with repair proteins, the naked mole-rat can more effectively mend DNA lesions that accumulate with age. This stands in contrast to the typical role of cGAS in other species, where its activity can dampen HR and potentially escalate genome instability if misregulated.
Evidence across species strengthens the case
Functional experiments showed that depleting cGAS from naked mole-rat cells leads to an accumulation of DNA damage, underscoring its protective role in this species. In an intriguing cross-species experiment, fruit flies engineered to express human cGAS carrying the four naked mole-rat mutations lived longer than flies with wild-type human cGAS. While not a direct reproduction of mammalian biology, these results hint that the four mutations can modulate DNA repair and influence lifespan-related traits beyond the naked mole-rat.
Implications for aging research
The study adds a new dimension to our understanding of longevity: evolution may tune core DNA-sensing enzymes to favor repair over damage accumulation. If the naked mole-rat’s cGAS profile promotes genome stability without triggering harmful inflammatory responses, similar strategies could be explored for aging interventions in other species. The findings also encourage a nuanced view of cGAS—an enzyme traditionally linked to immune defense—highlighting its potential roles inside the nucleus related to maintenance of DNA integrity.
What remains to be learned
As with many groundbreaking discoveries, several questions remain. How do these four substitutions affect cGAS’s broader immune signaling in naked mole-rats? Do similar mutations exist in other long-lived species, and could they be leveraged safely in humans? The researchers call for broader studies to map the nuclear functions of cGAS across species and to determine how these dynamics influence aging, cancer risk, and overall organismal health.
Looking ahead
While this work does not yet translate into a therapy, it opens a promising avenue: tweaking DNA repair pathways via evolution-informed protein changes might help extend healthspan. As scientists continue to decode the naked mole-rat’s genome maintenance toolkit, cGAS may emerge as a central node where immunity and genome stability intersect to shape longevity.
