Introduction: A Tiny Rodent with Remarkable Longevity
The naked mole rat (Heterocephalus glaber) is a small, hairless rodent native to East Africa famed for living up to 37 years—almost ten times longer than mammals of similar size. Researchers have long suspected that its longevity stems from genetic and cellular strategies that protect DNA, the blueprint of life, from accumulating dangerous damage as the animal ages.
cGAS: A Double-Edged Sword in DNA Surveillance
One molecule central to this story is cyclic GMP-AMP synthase (cGAS). In humans and mice, cGAS is a guardian against foreign DNA, such as viral genomes, triggering immune responses. But it also dampens one of the body’s principal DNA repair pathways, homologous recombination (HR). That unintended suppression can speed up genome instability, ageing, and cancer risk in these species.
The Four Substitutions That Flip the Script
A new study led by researchers from Tongji University and published in Science examined whether naked mole rats have evolved cGAS to avoid hindering DNA repair—perhaps even to boost it. The team compared the cGAS genes and proteins from naked mole rats with those of humans and mice. By swapping specific amino acids (the building blocks of proteins) between species, they tested how these changes influenced DNA repair in cells, fruit flies, and mice.
The researchers uncovered a striking finding: in humans and mice, cGAS interferes with HR, but in naked mole rats it actually enhances DNA repair. Four precise amino acid substitutions in naked mole rat cGAS alter its behavior: after DNA damage, cGAS tends to stay bound to DNA longer, avoiding rapid ubiquitination and degradation. This persistent DNA binding enables cGAS to recruit and assemble the repair partners FANCI and RAD50 more efficiently, accelerating homologous recombination and improving genome maintenance.
Mechanistic Insight: How the Four Changes Work
With these four substitutions, naked mole rat cGAS remains attached to damaged DNA long enough to orchestrate repair. By avoiding ubiquitination, the protein is not removed prematurely, allowing it to serve as a scaffold that brings together FANCI and RAD50—two critical components of the HR machinery. The net effect is faster and cleaner repair of DNA breaks, reducing cellular stress and slowing the onset of ageing signals at the cellular level.
Implications Across Species
When the four amino acid changes were introduced into human cGAS, the molecule no longer impeded DNA repair. This cross-species experiment demonstrates that longevity-advancing DNA repair can evolve not just through more active repair enzymes, but also by transforming regulatory proteins that previously hindered repair. The naked mole rat’s cGAS effectively re-wired immune surveillance to support genome integrity and long life.
Why This Matters for Ageing and Therapies
The discovery reinforces a central idea in ageing research: efficient DNA repair is a core defense against ageing. It also reveals a path to potential therapies. If scientists can safely mimic or regulate this cGAS-DNA interaction in humans, they might improve genome stability without suppressing immune defenses. Future medicines could aim to adjust how cGAS interacts with DNA, balancing immune sensing with robust DNA repair to promote healthy ageing.
Looking Ahead: Cautious Optimism
Independent experts caution that translating these findings to humans will require careful navigation of the immune roles of cGAS. Any therapy must preserve antiviral defenses while enhancing genome maintenance. Still, the study provides a compelling molecular explanation for naked mole rats’ exceptional longevity and opens new avenues for age-related research and interventions.
