The molecule that lets naked mole rats live 41 years, and what Rochester did with it

Roughly the size of a cocktail sausage, almost entirely blind, with skin the texture of a wrinkled thumb — the naked mole rat does not age the way most mammals do.

Captive specimens have reached 41 years. By body-mass scaling, a rodent that size should live about six. Cancer develops at a fraction of the rate seen in mice. Mortality risk stays flat across most of adult life, defying the Gompertz law of accelerating death that governs virtually every other mammal studied. Biologists have been probing this anomaly since the 1980s, and one explanation centres on a molecule already present in human bodies: hyaluronic acid.

In August 2023, a team led by Vera Gorbunova and Andrei Seluanov at the University of Rochester published findings in Nature showing that transplanting the naked mole rat’s enhanced hyaluronan-production gene into ordinary mice extended their lives, cut cancer rates sharply, and damped inflammatory markers across multiple tissues. Three years on, the Rochester group’s pre-clinical program has expanded considerably — but the paper that launched it deserves its own reckoning.

What HMW-HA is, and why naked mole rats make so much of it

Hyaluronic acid is a long-chain sugar polymer found throughout the extracellular matrix of most animals, including humans. Connective tissue retains water with it, joints are lubricated by it, and the structural scaffolding that holds cells in place depends on it. Molecular weight governs much of its behavior. Human hyaluronic acid typically runs from around 100 kilodaltons to a few megadaltons. The mole rat’s version reaches 6 to 12 megadaltons — an unusually high upper end the Rochester lab first documented in a 2013 Nature paper.

Part of this difference traces back to the sheer volume the animal produces. Mole rat tissues carry roughly ten times the HMW-HA concentration found in mice. Takasugi and colleagues, writing in Nature Communications in 2020, showed that this form of the polymer has superior cytoprotective properties: it shields cells from chemical stress more effectively than shorter-chain versions found in mice or humans, and dampens inflammatory signaling in ways the lower-weight forms cannot.

The gene driving this difference is hyaluronan synthase 2, abbreviated Has2. In naked mole rats, Has2 appears to have evolved to run at a higher rate than in other rodents. Documenting that difference was the easy part. Testing whether it could be moved to another species took, by Gorbunova’s own accounting, a decade.

Transferring the gene into mice

Zhihui Zhang led the 2023 paper alongside Tian, Lu, Seluanov, and Gorbunova. Their transgenic mice carried the naked mole rat version of Has2 under the control of the mole rat’s own promoter sequence — a deliberate choice. Retaining the original promoter meant the transgene would operate in the same biological context as in its source animal, rather than firing at maximum output regardless of cellular conditions.

Lifespan data came from 84 transgenic mice and 91 controls tracked across their full natural lives. Median survival in the nmrHas2 group extended by approximately 4.4%. Modest-sounding. But cancer incidence told a different story: roughly 80% of old control mice developed spontaneous tumors; among nmrHas2 mice, about 40% did. Cutting cancer incidence in half from a single transgene is not a trivial result in mouse longevity research, by any standard.

Healthspan data added depth. Tissue inflammation markers declined in the liver and intestine. Gut microbiome composition shifted toward patterns associated with younger animals. P16 expression — a standard molecular marker of cellular senescence — was measurably lower in transgenic mice at comparable chronological ages. Multiple hallmarks of aging moved in concert, not in isolation.

“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.

Before this result, the assumption in aging research was that adaptations in extreme longevity outliers were too idiosyncratic to replicate elsewhere. Naked mole rats share a common ancestor with mice roughly 70 million years back. That an NMR gene could work in mouse physiology at all, let alone produce benefits across multiple systems, was itself a non-obvious finding.

What inflammation has to do with it

HMW-HA’s potential influence on lifespan runs through its relationship with immune signaling. Short hyaluronic acid fragments — the lower-weight polymers produced by normal tissue turnover and degradation — can trigger inflammatory cascades. These fragments bind to pattern-recognition receptors on immune cells that evolved to detect tissue damage. During aging, those receptors fire persistently without any wound to address.

Very-high-molecular-weight HA breaks apart less readily. At elevated concentrations, it appears to suppress this background inflammation rather than feed it. Inflammaging — the chronic, subclinical immune activation associated with cellular aging — ranks among the better-supported mechanistic explanations for why biological systems deteriorate over time without a discrete initiating pathology. The HMW-HA pathway is a plausible target.

Takasugi and colleagues addressed this mechanistic question directly in 2020, comparing molecular-weight variants at matched concentrations. The NMR form outperformed human and mouse HA on every cytoprotective measure tested. That is the foundation the 2023 mouse lifespan paper builds on.

What it does not do

Complications exist. A 2021 paper in Scientific Reports measured NMR hyaluronic acid at a maximum of roughly 2.5 megadaltons — well below the 6-12 MDa range the Rochester group reported in 2013. Methodological differences in extraction or tissue sourcing likely explain some of that gap, but no reconciliation has appeared in the literature. Because the molecular weight figure is central to any pharmacological replication strategy, the discrepancy matters: a formulation that can’t reach the high-weight range probably won’t produce the cellular effects.

More concrete is the hearing loss data. A 2025 preprint posted to bioRxiv found that nmrHas2 transgenic mice showed no protection against age-related hearing loss. That’s a specific, measurable null result in a validated model — and it’s informative. The HMW-HA pathway doesn’t appear to globally reset an aging program. Protection concentrates in tissues with dense extracellular matrix; others go unaffected.

That selectivity matters for anyone drawing conclusions about human longevity. Tissue-specific protection is not the same as systemic life extension, and every downstream clinical question about what this pathway can accomplish depends on where the boundary falls.

Oral HA supplements are a different story

Readers familiar with the supplement market will notice an obvious question. Hyaluronic acid capsules are sold for joint comfort and skin hydration. Does any of this research validate those products?

No. The Rochester mice expressed nmrHas2 throughout their full lives, generating HMW-HA locally within their own tissues at a genetically elevated rate. Oral supplements are broken down during digestion; the polymer doesn’t reach peripheral tissues intact in any form comparable to endogenous production. Small human trials have reported some systemic absorption of orally delivered HA, but none have shown it reproduces the cellular-level HMW-HA accumulation the mouse study required.

The mechanism is genetic, not dietary. Treating these as equivalent categories would require a substantially longer chain of evidence than currently exists. The same skepticism applies to any marketing claim that invokes naked mole rat research as validation for a supplement.

The pharmacological route the Rochester team is pursuing

Gene therapy is not where the lab is directing its translational efforts. The approach the Rochester team has publicly described is pharmacological: identifying small molecules that inhibit the enzymes responsible for breaking down hyaluronic acid. The reasoning is that slowing HA degradation would let the body’s own polymer accumulate at higher molecular weights and concentrations, without requiring any genetic modification.

One compound under investigation is delphinidin, an anthocyanin concentrated in dark berries and red grapes. Pre-clinical work shows it inhibits TMEM2 and HYBID, two hyaluronidases involved in HA degradation. Seluanov described the state of the work at the time of the 2023 publication: “We already have identified molecules that slow down hyaluronan degradation and are testing them in pre-clinical trials. We hope that our findings will provide the first, but not the last, example of how longevity adaptations from a long-lived species can be adapted to benefit human longevity and health.”

A $22 million ARPA-H PROSPR award announced in February 2026 is backing this broader program. The HMW-HA inhibitor work is one strand alongside other NMR-derived research threads at Rochester.

Rapamycin, caloric restriction, and what makes this different

To be clear about scale: a 4.4% median lifespan extension is not where the Has2 story earns its interest. Rapamycin, dosed appropriately in male mice, has extended median survival by 10 to 15%. Caloric restriction under controlled conditions can push that to 20 to 40%. The nmrHas2 transgene is smaller by those comparisons.

What sets it apart is the mechanism and the cancer data. Rapamycin acts on mTOR signaling; caloric restriction works partly through nutrient-sensing pathways and metabolic reprogramming. The HMW-HA pathway acts primarily through extracellular matrix remodeling and the suppression of chronic inflammation. These aren’t competing approaches. Cancer incidence falling from 80% to 40% is a finding that neither rapamycin nor caloric restriction reliably produces in the standard mouse model — and from a clinical standpoint, that may be the more consequential number.

A 2025 paper in Science by Yu Chen and colleagues identified another NMR adaptation worth watching: a variant of the cGAS enzyme that boosts DNA repair at the cellular level, slowing molecular aging through a third distinct route. What the Rochester body of work is revealing is that the naked mole rat’s exceptional longevity isn’t a single trick. It’s layered, and several of those layers appear exportable.

Has2 was the first to pass that test under controlled experimental conditions. No treatment follows directly from the mouse result. But demonstrating that a longevity mechanism from one mammalian species can be transplanted into another — and produce measurable, multi-system benefits — wasn’t a given before 2023. That proof of principle is what makes the work worth taking seriously on its own terms.

References

1. Zhang Z, Tian X, Lu JY, Seluanov A, Gorbunova V. Increased hyaluronan by naked mole-rat Has2 improves healthspan in mice. Nature 621:578-584. 2023. https://doi.org/10.1038/s41586-023-06463-0
2. Tian X, Gorbunova V, Seluanov A. High-molecular-mass hyaluronan mediates the cancer resistance of the naked mole rat. Nature 499:346-349. 2013. https://doi.org/10.1038/nature12334
3. Takasugi M, Tombline G, Seluanov A, Gorbunova V. Naked mole-rat very-high-molecular-mass hyaluronan exhibits superior cytoprotective properties. Nature Communications 11:2376. 2020. https://doi.org/10.1038/s41467-020-16050-w
4. Chen Y, Mao Z. A cGAS-mediated mechanism in naked mole-rats potentiates DNA repair and delays aging. Science 386(6724):eadp5056. 2025. https://doi.org/10.1126/science.adp5056