Naked mole rat longevity gene extends mouse lifespan — Rochester team transfers HMW-HA pathway

Ten years ago, Xiao Tian and the Gorbunova-Seluanov laboratory at University of Rochester found something they couldn’t explain. Naked mole rats live more than four decades, far longer than other rodents. They were producing a form of hyaluronic acid so massive it barely registered on standard laboratory equipment. Polymer chains of six to twelve megadaltons accumulated in the animals’ skin, organs, and extracellular matrix. Human and mouse tissues typically contain chains only a fifth that size. Tian extracted the enzyme responsible, hyaluronan synthase 2, from the naked mole rat genome. He showed that removing it made the animal’s cells vulnerable to malignant transformation. The question that followed: would that cancer resistance mechanism work in short-lived mammals?

Vera Gorbunova, co-director of the Rochester Aging Research Center, describes what followed. “It took us 10 years from the discovery of HMW-HA in the naked mole rat to showing that HMW-HA improves health in mice,” she said in a University of Rochester news release. “Our next goal is to transfer this benefit to humans.”

In a Nature paper published this August, Zhihui Zhang and colleagues reported that genetically engineering mice to overexpress the naked mole-rat version of Has2 extended lifespans. Medians increased by 4.4 percent. Maximum lifespans stretched 12.2 percent longer. Females lived 9 percent longer on median; males showed a 16 percent extension in maximum lifespan. These gains are modest, but they demonstrate something new: a longevity mechanism evolved naturally in one mammal can function in another.

The cancer numbers shifted as well. Incidence dropped from 70 percent in control mice to 57 percent in the engineered group. The gap widened in the oldest animals. Among mice older than 27 months, cancer rates fell to 49 percent in the genetically modified group compared to 83 percent in controls. Healthspan improved beyond cancer data. Mobility, inflammation control, and gut barrier function all showed changes. The transcriptome signatures of engineered mice shifted toward patterns seen in longer-lived species. Inflammation markers declined across multiple organs.

Why does very-long-chain hyaluronic acid produce these effects? Hyaluronic acid chains trigger opposite cellular responses depending on their size. Long chains act as anti-inflammatory signals. Short fragments from chain breakdown turn pro-inflammatory and can promote tumor growth. The engineered mice produced more protective long-chain hyaluronan and fewer inflammatory fragments.

The long chains bind the CD44 receptor and suppress protein interactions that drive cell stress pathways. Very-high-molecular-mass hyaluronan prevents CD44 from forming complexes that activate p53. High-molecular-weight hyaluronan promotes those interactions instead. Polymer length determines the outcome.

A 2020 Nature Communications study clarified this mechanism. Researchers showed that hyaluronan above 6.1 megadaltons protects cells from stress better than shorter forms. Very-long-chain hyaluronan suppresses CD44 protein interactions that high-molecular-weight hyaluronan promotes. Naked mole rats carry six to twelve megadalton hyaluronan, so the protective signal dominates. Humans and mice rarely exceed two megadaltons, so the balance tilts toward more inflammation and less stress resistance.

Translation to humans faces challenges. Rochelle Buffenstein, a comparative biologist who has studied naked mole rats for decades, questions whether mouse models predict human responses for this type of intervention. Mouse aging operates on a compressed timescale with different reproductive strategies and selective pressures than human aging. Naked mole rats evolved longevity in subterranean environments with specific respiratory challenges and social structures that don’t map to human experience.

Regulators are also concerned. The Norwegian Scientific Committee for Food and Environment reviewed hyaluronic acid supplements in 2020 and flagged gaps in safety data beyond 12-month trials. Hyaluronic acid circulates through multiple organ systems and participates in immune signaling, wound healing, and stress responses. Inhibiting the enzymes that break it down could have cumulative effects that appear years later. Molecules persisting longer in circulation change the safety profile.

Andrei Seluanov, who co-led the Rochester study, sees a different bottleneck. The team identified small molecules that slow hyaluronan degradation and is testing them in pre-clinical models. The difficulty lies in finding the right balance. Degradation inhibitors must preserve long chains without allowing uncontrolled accumulation. They must avoid autoimmune and cardiovascular side effects seen in some hyaluronic acid therapeutics. They must maintain sufficient turnover so the extracellular matrix doesn’t stagnate.

Manufacturing presents another obstacle. Very-high-molecular-mass hyaluronan above six megadaltons is difficult to produce at scale. Commercial hyaluronic acid for cosmetic and medical applications typically tops out in the two-to-three megadalton range. Scaling to consistent six-to-twelve megadalton lengths while maintaining purity is an unsolved engineering problem at clinical grade. Enzymes producing these chains generate heterogeneous products. Quality control becomes harder as molecular weight increases. Regulatory pathways don’t clearly account for polymers this large.

Rochester plans human translation. One approach targets degradation inhibitors that let endogenous hyaluronic acid persist longer without breaking into inflammatory fragments. This likely faces the clearest regulatory path if safety data hold up. Gene therapy or tissue engineering could transplant the naked mole-rat Has2 sequence into specific cell types. That delivers the mechanism more directly but introduces genetic modification complexity. A third option would develop stable very-high-molecular-mass hyaluronan formulations for direct delivery, though tissue distribution and dosage frequency raise questions.

The financial calculus differs across paths. Degradation inhibitors offer the conventional pharmaceutical model with oral or injectable small molecules and established precedents. Direct hyaluronic acid delivery faces questions about whether polymers reach target organs intact. Gene therapy requires enormous upfront cost and raises permanent modification concerns. Venture capital has begun funding longevity startups pursuing hyaluronan-related approaches, but business models remain speculative.

A broader question: do naked mole-rat longevity mechanisms transfer cleanly? Their extended lifespans evolved under selective pressures absent in laboratory mice. Subterranean colonies experience chronic hypoxia, hypercapnia, and tightly regulated social structures that shape disease exposure. Reproductive strategies involve overlapping generations and specialized castes. A single gene transfer captures one piece of that evolutionary puzzle. Other naked mole-rat longevity adaptations may interact with Has2 in ways that don’t translate. The system evolved as a package.

Rochester researchers frame their work as proof of principle. “Our study provides a proof of principle that unique longevity mechanisms that evolved in long-lived mammalian species can be exported to improve the lifespans of other mammals,” Gorbunova said. Whether that principle survives the trip from mouse to clinic will determine if the decade-long journey from naked mole-rat tissue to transgenic mouse started a longer translational story or reached a dead end.

References

1. Tian X, Azpurua J, Hine C, et al. High-molecular-mass hyaluronan mediates the cancer resistance of the naked mole-rat. Nature. 2013;498:346-349. https://doi.org/10.1038/nature12234
2. Zhang Z, Tian X, Lu JYY, et al. Increased hyaluronan by naked mole-rat Has2 improves healthspan in mice. Nature. 2023;620:389-395. https://doi.org/10.1038/s41586-023-06463-0
3. Takasugi M, Seluanov A, Gorbunova V. Naked mole-rat very-high-molecular-mass hyaluronan exhibits superior cytoprotective properties. Nat Commun. 2020;11:3067. https://doi.org/10.1038/s41467-020-16050-w