New twist in aging science: naked mole rats and DNA repair
The naked mole rat (Heterocephalus glaber) is not just famous for living up to about 37 years—nearly ten times longer than mammals of similar size. A groundbreaking study published in Science reveals a surprising mechanism behind this longevity: four amino acid changes in a key DNA-sensing protein, cGAS, flip its role from hindering DNA repair to actively promoting it. This shift helps naked mole rats maintain genome integrity as they age.
cGAS: from immune alarm to DNA repair partner
In humans and mice, the enzyme cyclic GMP-AMP synthase (cGAS) detects foreign DNA and triggers immune responses. But it also tends to suppress a central DNA repair pathway known as homologous recombination (HR). The result can be accelerated cellular ageing and a higher cancer risk due to genome instability. The big question: could naked mole rats have evolved cGAS to avoid this trade-off?
A team led by researchers at Tongji University set out to answer this by comparing the cGAS genes and proteins across species and testing the effects of specific amino acid changes. Through genetic engineering, they swapped a few amino acids between naked mole rats, humans, and mice and studied the consequences in cells, fruit flies, and mice.
Four amino acids reshape cGAS’s role
The researchers identified four amino acid substitutions in naked mole rat cGAS that alter how the protein behaves after DNA damage. In naked mole rats, these substitutions allow cGAS to stay bound to DNA longer following a break, preventing the protein from being marked for degradation by ubiquitination. Far from being a passive immune sensor, naked mole rat cGAS then acts as a facilitator of DNA repair.
With cGAS maintaining a stable DNA association, the repair proteins FANCI and RAD50 are better organized to execute homologous recombination quickly and accurately. The net effect is fewer DNA breaks persisting in cells and a reduction in stress signals associated with ageing.
From discovery to age lab implications
When the same four amino acids were introduced into human cGAS, the molecule’s interference with HR resurfaced, underscoring the evolutionary specificity of the naked mole rat adaptation. This demonstrates that longevity can evolve not only by enhancing repair enzymes but also by weakening regulators that hinder repair.
Independent experts note the broader potential: if scientists can safely translate this mechanism to other species, including humans, they might unlock new therapies aimed at preserving genome integrity with age. One avenue is pharmacologically tuning cGAS’s interaction with DNA to boost repair pathways while maintaining essential immune functions.
Why this matters for aging and disease
Genome stability is a cornerstone of healthy ageing. Accumulating DNA damage drives cellular senescence, tissue dysfunction, and cancer. The naked mole rat’s exceptional longevity has long inspired researchers to explore how its cells resist damage, but unraveling the cGAS–HR connection adds a fresh layer to the story. By showing that a few precise protein tweaks can rewire a regulatory circuit, the study offers a concrete blueprint for age-related interventions.
Looking ahead
Future work will explore how safely translating these findings could influence human ageing and disease prevention. Any therapeutic strategy would need to preserve cGAS’s primary role in immune defense while gently tuning its interaction with DNA repair processes.
