Scientists have found that the cGAS protein in naked mole rats, a famously long-lived species, boosts DNA repair, while the human version tends to hamper it. The difference boils down to just four amino acids [1].
DNA repair and cGAS
Despite their unassuming appearance, naked mole rats (NMRs) are stars in the longevity field. These animals can live up to about 40 years in captivity, which is ten times more than any comparably sized rodent. Scientists have been studying NMR biology for years, looking for the adaptations that drive their unique longevity. Previous studies have shown that NMRs produce unique (and apparently improved) versions of some proteins [2].
In this study, a team of scientists from China focused on how a protein called cGAS works in NMRs. This protein is most known as a part of the inflammatory cGAS-STING pathway. The role of cGAS is to sniff out foreign DNA in the cytosol, which can indicate viral or bacterial infection, and send the alarm signal down the chain, eventually triggering the expression of several inflammatory genes.
Interestingly, cGAS also accumulates in the nucleus, where it binds DNA wrapped around histones (nucleosomes). This likely serves to prevent cGAS from being triggered by the cell’s own DNA (autoreactivity), especially during cell division (mitosis) [3]
However, when in the nucleus, chromatin-bound cGAS influences DNA repair processes. In species like mice and humans, nuclear cGAS impairs homologous recombination, which is one of the cell’s ways to fix DNA breaks.
As slower DNA repair is linked to genomic instability, aging, and disease, this seems to pose a disadvantage. This might be partly a harmful byproduct of cGAS being stuck to the histones and partly a useful evolutionary adaptation. In a Perspective article, which accompanies the paper, John Martinez and colleagues note that “preliminary data from genetically modified mice lacking cGAS show derepression of transposable elements – ‘jumping genes’ that can move from one location of the genome to another – that ultimately leads to increased inflammatory signaling and a shortened life span.” [4]
The NMR version does the opposite
The discovery at the heart of this study is that in NMRs, nuclear cGAS has the opposite effect: it promotes homologous recombination by sticking to the chromatin for longer.
When DNA snaps, the cell needs to bring in the right repair crew in the proper order. Lingering around the break a little longer allows cGAS in NMRs to act as a temporary docking platform, facilitating the recruitment and anchoring of the proteins involved. By serving as a short-lived scaffold at the break, NMR cGAS facilitates accurate DNA repair.
The researchers discovered that the difference in function was due to just four amino acids near one of the protein’s tails. These four positions act like a toggle, which the team proved with a series of “mix-and-match” experiments. With the NMR version of the sequence installed, human cGAS stopped dampening repair. Conversely, replacing these four residues with the human version caused the pro-repair effect to disappear.
The team built transgenic fruit flies that express enzymatically inactive cGAS variants to isolate the repair role without the inflammatory part. In middle-aged flies, NMR cGAS improved gut barrier integrity, curbed age-related gut stem-cell overgrowth, boosted climbing ability, and extended lifespan. Swapping the four key residues erased these gains.
The researchers then delivered NMR cGAS, or a 4-residue mutant control, using viral vectors into 17-month-old male mice and checked outcomes two months later. The NMR cGAS group scored better on a standard frailty index, showed healthier hair and skin with fewer gray hairs, and had less of the circulating inflammation markers IgG and IL-6. Tissue analyses showed a similar picture, with lower senescence and DNA damage markers.
We’re not there yet
“The findings from Chen et al. describe an unexpected role for naked mole-rat cGAS in the nucleus that influences longevity,” wrote Martinez and colleagues. “Further research will be required to establish the roles that cGAS may play in the nucleus in other organisms, both short- and long-lived, but the answer may be substantially more complex than originally predicted.”
“This study underscores the importance of analyzing longevity adaptations in naturally long-lived animals,” Vera Gorbunova from the University of Rochester, a longtime NMR researcher and a co-author of the Perspective article, told Lifespan News. “Such studies reveal novel strategies that would not be found in short-lived laboratory species. Additionally, this study demonstrates that enhanced DNA double-strand break repair is required for longevity.”
While replacing human proteins with “superior” versions from long-lived species might seem enticing, scientists will probably have to proceed with caution, given how uniquely tuned every organism is. It might be a while before we have proteins borrowed from NMRs, bats, and bowhead whales in our bodies.
Literature
[1] Chen, Y., Chen, Z., Wang, H., Cui, Z., Li, K. L., Song, Z., … & Mao, Z. (2025). A cGAS-mediated mechanism in naked mole-rats potentiates DNA repair and delays aging. Science, 390(6769), eadp5056.
[2] Zhang, Z., Tian, X., Lu, J. Y., Boit, K., Ablaeva, J., Zakusilo, F. T., … & Gorbunova, V. (2023). Increased hyaluronan by naked mole-rat Has2 improves healthspan in mice. Nature, 621(7977), 196-205.
[3] Volkman, H. E., Cambier, S., Gray, E. E., & Stetson, D. B. (2019). Tight nuclear tethering of cGAS is essential for preventing autoreactivity. Elife, 8, e47491.
[4] Martinez, J. C., Seluanov, A., & Gorbunova, V. (2025). Longevity steps on the cGAS. Science, 390(6769), 126-127.
View the article at lifespan.io
