Naked mole-rats, a long-lived species, perfectly embody the idea of "when one door closes, another opens."
They may be unattractive, start "working" right after birth, and lack reproductive rights (only the queen can reproduce)—but they are extraordinarily long-lived! Not only do they show little signs of aging throughout their lives, but they also have a lifespan of up to 37 years. Their other "superpowers" include being virtually cancer-resistant, almost pain-insensitive, and able to survive long periods of hypoxia.
Figure Note: Humans, are you envious?
Compared to mice—similar in size but with a lifespan of only about 3 years—naked mole-rats’ lifespan (10 to 12 times longer) is like a goldmine of anti-aging secrets for researchers.
For years, scientists have explored the mysteries behind their longevity. Now, a groundbreaking study published in the top international journal Science by a team from Tongji University [1] has revealed a surprising answer: Naked mole-rats simply modified a protein that everyone has, reversing its function by 180 degrees—from "accelerating aging" to "promoting longevity"—and significantly reversing the aging process. Who wouldn’t be tempted by that?
1. One Protein, Two Fates
Researchers found that the secret to naked mole-rats’ longevity may lie in targeting a core cause of aging: the accumulation of DNA damage.
Our genome is constantly under attack from external stimuli and internal errors, so cells have evolved a DNA repair system. Among these mechanisms, homologous recombination repair (HR) is responsible for fixing DNA double-strand breaks (DSBs)—the most common and damaging type of DNA damage.
HR is a precise and efficient repair mechanism. Simply put, it works like "patching": when a DNA double-strand break occurs, the HR system finds a "DNA patch" (a matching segment on the sister chromatid) at the break site, and accurately repairs the DNA "wound."
Figure Note: One step in the homologous recombination repair process (Single-stranded DNA invades the homologous double strand, displacing one strand to form an extended D-loop structure).
However, one molecule hinders this process significantly: cGAS (cyclic GMP-AMP synthase).
cGAS acts as an immune sensor in cells, recognizing abnormal DNA in the cytoplasm and triggering immune responses to fend off potential pathogens. While it functions well in the cytoplasm, it becomes a problem once it enters the nucleus.
When DNA double-strand breaks occur in the nucleus, cGAS quickly rushes to the damage site and "tries to help but only makes things worse": it not only interferes with the formation of key repair complexes but also binds to the damage site, preventing real repair proteins from acting—seriously slowing down HR repair [2].
So, how to solve this "unhelpful teammate" (cGAS)? Researchers discovered that naked mole-rats—endowed with exceptional genomic stability and longevity—are skilled at resolving this issue, thereby gaining a significant lifespan advantage.
2. Is Your cGAS Different from Mine?
The study found that naked mole-rats’ secret is not preventing cGAS from entering the nucleus or eliminating its nuclear function, but rather "reforming" it to work for good!
For example, while human nuclear cGAS inhibits HR-mediated DNA repair, naked mole-rat nuclear cGAS greatly enhances the efficiency of HR repair.
How do naked mole-rats achieve this magical function reversal?
Through comparison, researchers found that naked mole-rat cGAS differs from human cGAS by only 4 key amino acid substitutions: S463, E511, Y527, and T530. These four "critical tweaks" brought about two transformative changes to cGAS.
Figure Note: Effects of 16 single amino acid mutations on relative HR repair efficiency (P<0.0001 for the 4 key mutations).
Change 1: Gained "Long-Duration Stay" Ability
In the human nucleus, cGAS bound to DNA break sites is recognized by the enzyme TRIM41, which attaches a special ubiquitination tag. This tag marks cGAS for removal from chromatin by the p97 protein complex—preventing cGAS from lingering at break sites and delaying repair [3].
However, the 4 amino acid mutations in naked mole-rat cGAS make it nearly impossible for TRIM41 to tag it. As a result, naked mole-rat cGAS can remain at DNA damage sites for far longer than human cGAS.
Figure Note: Thirty minutes after DNA damage, the amount of naked mole-rat cGAS bound to chromatin was much higher than that of human cGAS. The 4-amino-acid mutant (4mut) reversed this phenomenon.
Change 2: Gained the Ability to "Recruit Repair Teams"
The same 4 amino acid changes not only give cGAS a "long-duration stay" ability but also enhance its binding affinity to key repair factors FANCI and RAD50—transforming it from a repair obstacle into a "scaffold" that brings repair proteins together.
Figure Note: Naked mole-rat cGAS showed increased binding ability to FANCI and RAD50 (IP/Input ratio: 4.26 ± 0.68 for the complex, vs. 1 for controls).
Researchers confirmed this mechanism with reverse experiments:
- When the 4 amino acids of naked mole-rat cGAS were mutated back to the human version, its repair-promoting ability disappeared.
- Conversely, mutating the corresponding sites in human cGAS to match the naked mole-rat version gave it repair-promoting ability.
Figure Note: Reverse modification of the 4 amino acids successfully reversed cGAS’s ability to promote or inhibit HR repair (P<0.0001 for both experiments).
In short, by changing just 4 amino acids in cGAS, naked mole-rats fixed the "flaw" in human cGAS. This raises a question: If we learn from naked mole-rats and modify these 4 amino acids, can we enhance DNA repair and even extend lifespan?
3. Is This Longevity "Cheat Code" Effective?
While the idea is promising, human clinical applications are still far off. So researchers first tested it in fruit flies and mice.
3.1 Fruit Fly Experiments: 30% Lifespan Extension
Fruit flies expressing naked mole-rat cGAS showed a significant ~30% extension in maximum lifespan. They also had healthier intestinal function and regeneration, and better climbing ability and speed.
Figure Note: Naked mole-rat cGAS significantly extended fruit fly lifespan, improved intestinal health in old flies, and enhanced motor function (P<0.05 for all key comparisons vs. controls).
3.2 Old Mouse Experiments: Visible Rejuvenation
Next, researchers verified the effect in 17-month-old mice (equivalent to 50–60 years old in humans). Two months after injecting naked mole-rat cGAS into old mice via a safe vector, the mice showed visible signs of rejuvenation:
- Their previously gray, sparse fur became black and dense.
- Their skin became healthier, with faded age spots.
- Their frailty index decreased significantly, and they were more active.
Figure Note: Mice injected with naked mole-rat cGAS had lower frailty indexes and less gray fur (P=0.0281 for frailty index, P=0.0043 for gray fur vs. controls).
At the tissue level, the mice had significantly fewer senescence markers (SA-β-gal-positive areas) in vital organs like the liver and kidneys—indicating effective clearance of senescent cells.
Figure Note: Senescence marker SA-β-gal staining in the liver was significantly reduced (blue areas represent senescent cells; P=0.0043 vs. controls).
Blood tests showed that senescence-related inflammatory factors decreased by nearly 40%, including significant reductions in immunoglobulin G (IgG) and interleukin-6 (IL-6) levels.
Figure Note: Levels of inflammatory factors (IgG and IL-6) in the blood decreased significantly (P<0.05 for both vs. controls).
Critically, when the 4 key amino acids of naked mole-rat cGAS were mutated back to the human version, all these anti-aging effects disappeared. There is no doubt that these 4 amino acid differences give naked mole-rat cGAS its amazing anti-aging ability.
4. Broader Insights from Long-Lived Species
Evolutionary outcomes are full of surprises: Naked mole-rats evolved a unique cGAS protein, gaining stronger HR repair ability to resist aging.
Across nature, "strong DNA repair ability" seems to be a common trait among long-lived species:
- Greenland sharks (lifespan >400 years) have powerful genome maintenance capabilities.
- Arctic clams (lifespan >500 years) show extremely high tolerance to oxidative stress-induced DNA damage [4].
- North American beavers (lifespan up to 50 years) have higher activity of the DNA repair protein SIRT6 [5].
In short, these species have evolved more efficient DNA damage repair systems than their shorter-lived relatives.
Of course, naked mole-rats’ longevity is not due to this single advantage. Previous studies found that they produce ultra-high-molecular-weight hyaluronan (hyaluronic acid), which gives them exceptional tissue elasticity and cancer resistance [6]. They also have extremely high fidelity in protein synthesis, ensuring long-term stable protein function [7].
We look forward to uncovering more clues from the evolutionary wisdom of long-lived species, so that we can adapt these insights to significantly extend human lifespan.
Research Team & Funding
- Corresponding Authors: Prof. Zhiyong Mao (School of Life Sciences and Technology / Affiliated Obstetrics and Gynecology Hospital, Tongji University), Assoc. Prof. Ying Jiang
- First Authors: Dr. Yu Chen (Assistant Professor), Graduate Student Zhixi Chen
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Funding Sources:
National Natural Science Foundation of China (NSFC) Project 82225017;National Key R&D Program of China (2022YFA1103700).
- Supporting Researchers: Prof. Haipeng Liu, Prof. Fanglin Sun, Prof. Jian Yuan (Tongji University); Prof. Minhua Luo (Wuhan Institute of Virology, CAS); Assoc. Prof. Rong Tan (Central South University); Assoc. Prof. Li Tan (Fudan University).
References
[1] Chen, Y., Chen, Z., Wang, H., Cui, Z., Li, K.-L., Song, Z., et al. (2025). A cGAS-mediated mechanism in naked mole-rats potentiates DNA repair and delays aging. Science, 390(6769), eadp5056. https://doi.org/10.1126/science.adp5056[2] Zhang, H., Jiang, L., Du, X., Qian, Z., Wu, G., Jiang, Y., & Mao, Z. (2024). The cGAS-Ku80 complex regulates the balance between two end joining subpathways. Cell Death & Differentiation, 31(6), 792–803. https://doi.org/10.1038/s41418-024-01296-4[3] Chen, Y., Chen, Z., Wang, H., et al. (2025). A cGAS-mediated mechanism in naked mole-rats potentiates DNA repair and delays aging. Science, 390(6769), eadp5056. https://doi.org/10.1126/science.adp5056[4] Ungvari, Z., Ridgway, I., Philipp, E. E. R., et al. (2011). Extreme Longevity Is Associated With Increased Resistance to Oxidative Stress in Arctica islandica, the Longest-Living Non-Colonial Animal. The Journals of Gerontology: Series A, 66A(7), 741–750. https://doi.org/10.1093/gerona/glr044[5] Tian, X., Firsanov, D., Zhang, Z., et al. (2019). SIRT6 Is Responsible for More Efficient DNA Double-Strand Break Repair in Long-Lived Species. Cell, 177(3), 622–638.e622. https://doi.org/10.1016/j.cell.2019.03.043[6] Takasugi, M., Firsanov, D., Tombline, G., et al. (2020). Naked mole-rat very-high-molecular-mass hyaluronan exhibits superior cytoprotective properties. Nature Communications, 11(1), 2376. https://doi.org/10.1038/s41467-020-16050-w[7] Azpurua, J., Ke, Z., Chen, I. X., et al. (2013). Naked mole-rat has increased translational fidelity compared with the mouse, as well as a unique 28S ribosomal RNA cleavage. Proceedings of the National Academy of Sciences, 110(43), 17350–17355. https://doi.org/10.1073/pnas.1313473110