Expression of the naked mole-rat transgene for Has2 improved health span in C57Bl/6 mice, but it did not attenuate age-related hearing loss.

Abstract

The naked mole-rat (NMR) is renowned for being the longest-lived rodent, with a maximum lifespan of over 40 years. This exceptional longevity has been attributed to increased cytoprotective signaling, which has been partially ascribed to a major component of the NMRs extracellular matrix hyaluronan (HA), which has an unusually large molecular mass in this species. The HA molecular mass in the NMR is five to six times greater than in mice and humans. Mice expressing the transgene for NMR HA synthase 2 (nmrHas2), which is the enzyme that produces very high molecular mass HA (vHMM-HA), had improved health outcomes at an advanced age, such as improved mobility, grip strength, and reduced inflammation. Calorie restriction (CR) similarly improves healthspan in mice, and CR has also been shown to attenuate age-related hearing loss (AHL). Specifically, CR mitigates the effects of a single-nucleotide polymorphism (SNP) in the cadherin 23 (Cdh23) gene, which encodes a protein required for the stability of stereocilia on cochlear hair cells in mice and humans. Therefore, we hypothesized that AHL would be attenuated in nmrHas2+ mice. We performed auditory brainstem response testing on 3-month and 12-month-old mice with (nmrHas2+) and without (nmrHas2-) the NMR transgene. We observed AHL at 12 months of age in both nmrHas2+ and nmrHas2-mice, and AHL was not attenuated by nmrHas2 expression. This suggests that the cytoprotective effects of vHMM-HA work through a different pathway from CR, at least with respect to the inner ear.