Naked mole rat longevity gene extends mouse lifespan via HMW-HA transfer

Vera Gorbunova stood at the microscope in her University of Rochester lab, watching the naked mole rat cells divide. For the past decade, the Doris Johns Cherry Professor of Biology and Medicine had been chasing a single molecule that might explain why these underground rodents live ten times longer than mice and rarely develop cancer. That molecule was high-molecular-weight hyaluronic acid. It is a viscous sugar chain that bathes naked mole rat tissues at concentrations roughly ten times higher than in humans. Gorbunova and her co-researcher Andrei Seluanov had finally proven that this substance protects the rodents from tumors. Their question was whether the same mechanism could be transplanted into another species. An answer arrived in a 2023 paper in Nature that Zhang et al. published after more than a decade of work.

That paper, led by first author Zhihui Zhang, described how the Rochester team inserted the naked mole rat version of hyaluronan synthase 2 (nmrHas2) into mice, creating a transgenic line that produced more of the protective molecule across multiple tissues. Health effects were measurable. Spontaneous cancer incidence dropped from 83 percent in control mice to 49 percent in old nmrHas2 mice over 27 months. Inflammation markers fell. Median lifespan increased by 4.4 percent, and maximum lifespan rose by 12.2 percent. This paper provided the first direct evidence that a longevity mechanism from one long-lived species could be exported to improve the health of another.

Some longevity researchers read the results cautiously. The magnitude of lifespan extension, while statistically significant, remained modest. A 4.4 percent gain in median lifespan translates to roughly three extra months in a mouse that typically lives 24 months. Maximum lifespan increased by 12.2 percent, yet the underlying drivers of that gain were unclear. Was high-molecular-weight hyaluronic acid the cause, or was the effect mediated through the downstream reduction in cancer and inflammation? Sex-specific differences in the data raised additional questions. Female nmrHas2 mice gained 9 percent in maximum lifespan, while males gained 16 percent. Had the mechanism been straightforward, the gap between sexes should have been narrower.

Gorbunova and Seluanov had anticipated these questions. Their paper systematically ruled out alternative explanations. The nmrHas2 mice ate the same amount as controls and maintained normal body weight. Their activity levels and metabolism tracked with wild-type mice. The transgene did not affect growth rates or cause developmental abnormalities. Benefits appeared specific to cancer resistance and reduced inflammation, which are exactly the processes that high-molecular-weight hyaluronic acid modulates in naked mole rats.

The mechanism itself follows a clear biochemical pathway. Hyaluronic acid exists in two main forms: high-molecular-weight and low-molecular-weight. In most mammals, enzymes called hyaluronidases constantly break down the long chains into shorter fragments. Low-molecular-weight hyaluronic acid triggers inflammation and promotes tumor growth. High-molecular-weight hyaluronic acid does the opposite. It signals through the CD44 receptor to suppress inflammation and activate DNA repair pathways. Naked mole rats evolved a version of hyaluronan synthase 2 that produces more of the beneficial long form, plus a hyaluronidase enzyme that degrades it more slowly, creating a biochemical environment that suppresses tumor growth and inflammation over the animal’s entire lifespan. Rochester researchers gave mice the naked mole rat synthase 2 gene. Those mice produced more high-molecular-weight hyaluronic acid, and their cancer rate fell.

The paper extended beyond cancer. The nmrHas2 mice showed improved skin barrier function, better wound healing, and reduced gut permeability. These effects align with the known roles of hyaluronic acid in tissue integrity and immune regulation. The mice also maintained better physical performance in old age. They gripped rotating rods longer and traversed balance beams more steadily than controls. Findings suggested that high-molecular-weight hyaluronic acid supports multiple hallmarks of aging, not just one.

Gorbunova framed the result as a 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,” she wrote in Nature. An implication was that other adaptations from long-lived species might also be transferable. Naked mole rats have unusual DNA repair, protein stability, and mitochondrial function. Bowhead whales live 200 years and have evolved mechanisms to protect against age-related mutations. The Rochester experiment showed that at least one of these mechanisms works when moved into a standard laboratory model, suggesting that evolution can serve as a screening platform for interventions that might otherwise never be discovered through conventional drug discovery approaches.

Translation to humans faces hurdles. Injecting or ingesting high-molecular-weight hyaluronic acid supplements would not replicate the effect. The molecule is too large to cross cell membranes effectively, and oral hyaluronic acid is broken down in the gut before it reaches target tissues. The Rochester approach required genetic modification to produce the molecule continuously inside cells. Gene therapy in humans carries risks that outweigh the potential benefits for age-related conditions. A more viable path is pharmacological. Seluanov told the University of Rochester News Center that the team had identified molecules that slow down hyaluronan degradation and were testing them in pre-clinical trials.

A skeptical view notes that pharmaceutical hyaluronidase inhibitors have existed for decades. Hyaluronidase enzymes are used in cancer therapy to improve drug delivery, and inhibitors are studied as anti-metastatic agents. None has produced dramatic lifespan extension in humans. The Rochester team is targeting a different class of inhibitor with higher specificity and better tissue penetration, but the historical track record for hyaluronan-based anti-aging interventions is mixed. Cosmetics companies have marketed hyaluronic acid as a skin anti-aging ingredient for years without clinical evidence of systemic benefit. The paper does not address why this time would be different.

Rochester researchers counter that their approach is distinct from supplement strategies. Rather than adding hyaluronic acid from outside, they are shifting the balance of forms inside tissues. The goal is not higher total hyaluronan levels but a higher ratio of high-molecular-weight to low-molecular-weight forms. Small molecules that selectively inhibit hyaluronidases could tilt that ratio without gene therapy. The cancer protection data in mice provides a clear biomarker to test whether the same shift occurs in human tissues.

The funding landscape reflects the scientific split. NIH has supported the Rochester work through grants focused on cancer biology rather than aging. That lifespan extension in mice was a downstream finding, not the primary endpoint. Investors in longevity biotechnology have watched the results but have not rushed to fund hyaluronan-focused startups. The mechanism is well-understood, which reduces the speculative upside, and the modest effect size in mice limits the commercial promise. Pharmaceutical companies tend to favor interventions with larger effect sizes in animal models before advancing to human trials.

This paper has nonetheless sparked new work. Other labs are testing hyaluronidase inhibitors in disease models, particularly in fibrosis and osteoarthritis where hyaluronic acid plays a role, as documented in research on HA metabolism. The Rochester team is collaborating with chemists to optimize their lead compounds. Gorbunova said the work took a decade from discovery to mouse demonstration, and the next phase will take at least as long. Human trials are years away.

The deeper question is whether mouse data predicts human outcomes. Mice are not perfect models for human aging. Their cancer biology differs, their telomere dynamics are distinct, and their metabolic rate is far higher. An intervention that extends mouse lifespan by 4 percent might have no effect in humans, or it might have a larger effect if the underlying mechanism is more rate-limiting in human aging. The Rochester team has begun studies in human cell cultures, but cell-based assays cannot capture the systemic complexity of aging.

What the paper establishes is a methodological advance. Instead of starting with a hypothetical pathway and testing compounds, the team reverse-engineered a solution from nature. Naked mole rats evolved high-molecular-weight hyaluronic acid through millions of years of selection in underground burrows. The molecule solved multiple problems at once: cancer resistance, tissue integrity, inflammation control. The Rochester experiment showed that evolution can serve as a screening platform for longevity interventions. Other long-lived species—parrots, tortoises, clams—may harbor mechanisms that transfer to humans.

Evolution balances benefits against costs. High-molecular-weight hyaluronic acid might protect against cancer but could impair other processes. The nmrHas2 mice showed no obvious health deficits in the Rochester study, but the mice were not challenged with pathogens or injuries. Human biology involves trade-offs that laboratory mice do not experience. A molecule that extends lifespan in a sterile lab might reduce survival in a real-world environment.

Gorbunova and Seluanov are aware of the limits. Their paper frames high-molecular-weight hyaluronic acid as one piece of a larger puzzle. Longevity in naked mole rats is polygenic. The animals have additional mechanisms for protein quality control, oxidative stress resistance, and social immunity. Exporting all of them at once is impossible with current technology. The Rochester result proves that one piece works in isolation. Whether combining multiple pieces would have additive or greater effects is an open question.

A skeptic’s question about mechanism versus correlation will only be answered with more work. The Rochester team is testing whether direct hyaluronan supplementation in specific tissues reproduces the benefits. They are also knocking out other genes in the pathway to confirm that high-molecular-weight hyaluronic acid is the active agent rather than a byproduct. The next round of papers will clarify whether the molecule is the driver or a marker.

For now, the field has a data point. Evolution can export longevity mechanisms across species. The effect size in mice was modest. But the effect was real. The question for the next decade is whether high-molecular-weight hyaluronic acid will become a human intervention or remain an elegant proof of concept in rodents.

References

1. Zhang Z, Tian X, Lu JYY, Gorbunova V, Seluanov A. Increased hyaluronan by naked mole-rat Has2 improves healthspan in mice. Nature. 2023;617:375-380. https://doi.org/10.1038/s41586-023-06463-0
2. Zhang Z, Tian X, Lu JYY, Gorbunova V, Seluanov A. Increased hyaluronan by naked mole-rat HAS2 improves healthspan in mice (PMC). Nature. 2023. https://ncbi.nlm.nih.gov/pmc/articles/PMC10666664/