University of Rochester researchers show that mice genetically modified to have a gene (HAS2) from long-lived naked mole rats exhibit longer lifespans, lower cancer rates, and reduced frailty.
Naked mole rats are rodents that are about the size of a mouse with a key difference, aside from having no fur — they’re extremely long-lived — reaching ages of around 40 years old. For comparison, lab mice live an average of about three and a half years. To explain their extensive lifespans, researchers have sought to pinpoint how naked mole rats evade the onset of age-related diseases like cancer. In doing so, they’ve identified a form of gelatinous substance called hyaluronan, which has anti-inflammatory and anticancer properties. Now, the question of whether the benefits of the naked mole rat’s abundant levels of this form of hyaluronan — called high molecular mass hyaluronic acid (HMM-HA) — can be exported to other species has recently drawn attention.
Published in Nature, Gorbunova and colleagues from the University of Rochester show that genetically modifying mice to harbor an enzyme that produces HMM-HA extends their lifespan. The researchers go on to show that increasing HMM-HA reduces the prevalence of cancer. Additionally, the nmrHAS2 gene improves the healthspan of mice by countering physiological dysfunction, as measured with a frailty score. These findings provide the first evidence that genes from long-lived species can be exported to other species, perhaps conferring benefits to humans one day.
To find whether naked mole rat HMM-HA influences longevity, Gorbunova and colleagues used mice with a gene for an enzyme that synthesizes naked mole rat HMM-HA — the nmrHAS2 gene — inserted into their DNA. The mice with this genetic modification — nmrHAS2 mice — exhibited significantly increased naked mole rat HMM-HA in organs such as the muscle, kidney, and intestines, confirming that the gene increases HMM-HA. The researchers then measured how long the nmrHAS2 mice lived and found that they displayed a 4.4% and 12.2% increase in median and maximum lifespan, respectively. These breakthrough findings show that a longevity gene from one mammal can be transferred to another species of mammal for lifespan extension.
Since cancer is one of the key age-related conditions that HMM-HA works against in naked mole rats to make them live longer, the Rochester-based researchers measured its impact on cancer in nmrHAS2 mice. They found that old nmrHAS2 mice exhibited a significant 34% reduction in cancer development during the mice’s lifetimes. These results suggest that the HMM-HA anticancer benefits found in naked mole rats can be exported to mice.
Because increasing healthspan — the amount of time spent living in a healthy state — is a primary aspect of improved aging, Gorbunova and colleagues measured an indicator of healthspan, the frailty index score, in mice with the gene insertion. While frailty index scores jumped drastically in aged mice without the gene insertion, old nmrHAS2 mice showed remarkably lower frailty index scores than their age-matched counterparts. These data show that old mice with the naked mole rat gene insertion physically deteriorate at a reduced rate compared to those without the insertion, thus enhancing healthspan.
“It took us 10 years from the discovery of [HMM-HA] in the naked mole rat to showing that [HMM-HA] improves health in mice,” Gorbunova says in a press release. “Our next goal is to transfer this benefit to humans.”
The study’s findings showing that a longevity-promoting molecule like HMM-HA from naked mole rats can be exported to other species to extend life- and healthspan have researchers wondering how to implement benefits for aging humans. Gorbunova and colleagues have two ideas regarding how to implement these findings for human gain. They aim to slow the degradation of HMM-HA in the human body, which circulates at about 1/5th the level as that in naked mole rats. Alternatively, they seek ways of increasing human HMM-HA synthesis.
“We already have identified molecules that slow down hyaluronan degradation and are testing them in pre-clinical trials,” says Seluanov, an author of the study, in a press release. “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.”
Hyaluronan is available over the counter as a skin hydrating solution or as an oral supplement. Whether the hyaluronan present in these skin applications and capsules contains significant amounts of high molecular mass hyaluronan abundant in naked mole rats isn’t likely. Bottles with supposed skin-rejuvenating hyaluronan say they combine low, medium, and high molecular mass forms of hyaluronan. Still, the ratio of high molecular mass hyaluronan compared to low and medium molecular mass hyaluronan isn’t defined, and the low molecular mass forms have been shown to contribute to inflammation and cancer spreading (metastasis). Along those lines, applying over the counter hyaluronan to the skin isn’t likely to confer the same longevity-related benefits described in this study, especially since the gelatinous substance isn’t absorbed into organs like the muscle, kidney, or intestines.
The hyaluronan capsules, on the other hand, contain solely low molecular mass hyaluronan. Since the low molecular mass hyaluronan may contribute to inflammation and isn’t the same as the high molecular mass hyaluronan shown to confer longevity-related benefits in the study, the supplements likely don’t extend longevity or reduce frailty. Perhaps supplements available in the future will include higher concentrations of high molecular mass hyaluronan to potentially work against aging.
Model: Transgenic C57BL/6 mice with inserted nmrHas2 gene