How naked mole rats defy ageing
The naked mole rat (Heterocephalus glaber) is a small, hairless rodent native to East Africa famed for living up to about 37 years—nearly ten times longer than mammals of similar size. For years, scientists have wondered what molecular tricks these creatures use to keep their DNA intact as the years pass. A new study points to a surprising player: the molecule cGAS, known for its role in immune sensing, and how it interacts with the cell’s DNA repair machinery.
DNA damage accumulates as we age. Our cells rely on several repair pathways to fix breaks and stalled replication. When these processes falter, genomes become unstable, contributing to ageing and disease. A key constraint in many species is how repair pathways are regulated by signaling molecules that can both help and hinder the repair process.
The cGAS dilemma and a provocative twist in the naked mole rat
In humans and mice, cGAS detects foreign DNA and triggers immune responses. But it also tends to suppress homologous recombination, one of the cell’s primary DNA repair mechanisms. That suppression can increase genomic instability and potentially accelerate ageing and cancer risk. The question researchers posed: has the naked mole rat evolved changes in cGAS that prevent this suppression—or even convert cGAS into a helper for DNA repair?
A team led by researchers at Tongji University led a comparative investigation, analyzing cGAS genes and proteins from naked mole rats, humans, and mice. They then used precise genetic engineering to swap specific amino acids—protein building blocks—between species and observe the consequences for DNA repair.
Four amino acids and a repair boost
The central finding is striking: while human and mouse cGAS tends to hinder homologous recombination, naked mole rat cGAS enhances it. The trick lies in four amino acid substitutions in cGAS’s structure. These changes allow naked mole rat cGAS to stay bound to damaged DNA longer, rather than being tagged for destruction by ubiquitination. This prolonged binding appears to support the repair process rather than obstruct it.
In this context, naked mole rat cGAS acts as a facilitator, bringing together two key repair proteins—FANCI and RAD50—to accelerate homologous recombination. With this augmented repair activity, cells accumulate fewer signs of stress-induced ageing and genomic instability, painting a picture of why naked mole rats enjoy their remarkable longevity.
Implications for aging research and potential therapies
When the researchers introduced the same four amino acid substitutions into human cGAS, the molecule’s impact on DNA repair reversed: it stopped hindering the repair pathway and, in some models, appeared neutral or even beneficial. This demonstrates that a small set of evolutionary changes can flip the role of a regulatory protein from a detractor to a promoter of genome maintenance.
The study suggests that longevity could evolve not only through the improvement of repair enzymes themselves but also by reconfiguring regulators that were previously detrimental. In naked mole rats, evolution seems to have retooled cGAS to support genome integrity, aligning with the long-standing notion that robust DNA repair is central to delaying ageing.
What comes next for science and medicine
Experts unaffiliated with the study have called the findings provocative. If scientists could safely replicate, in humans or other species, the protective interaction between cGAS and DNA repair without compromising immune defense, it might open new routes for therapies targeting age-related decline. Potential approaches could involve drugs that modulate how cGAS binds to DNA or that adjust the balance between immune signaling and DNA repair to preserve genomic stability as we age.
A note on scope and limitations
While the results are promising, translating them into human therapies will require careful testing across species and contexts. Immune function, cancer risk, and other factors must be weighed as researchers explore whether similar cGAS remodeling could be safe and effective in people. Nonetheless, the naked mole rat study provides a compelling example of how small molecular tweaks, honed by millions of years of evolution, can yield big gains in cellular maintenance and longevity.
