Age-related hearing loss persisted in mice that had demonstrated improved healthspan, reduced inflammaging and extended lifespan following expression of the naked mole-rat transgene for hyaluronan synthase 2

Vollständiger Abstract

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Background Approximately one in three adults aged 65–74 years reports hearing difficulty, including age-related hearing loss (AHL, presbycusis). The C57BL/6 mouse is widely used in preclinical AHL research because it develops AHL relatively early. Calorie restriction (CR) attenuates AHL and improves healthspan and longevity in this strain. A recently developed transgenic C57BL/6 mouse expressing naked mole-rat hyaluronan synthase 2 ( nmrHas2 ), which produces very high molecular mass hyaluronan (vHMM-HA), also exhibits improved healthspan, reduced inflammaging, and increased longevity. Therefore, we evaluated nmrHas2 mice for evidence of alleviated AHL. Objective To determine whether AHL is attenuated in nmrHas2 mice . Methods This study supplemented a larger investigation of nmrHas2 and female reproductive aging. Tamoxifen administered at 1 month induced ubiquitous nmrHas2 expression in nmrHas2+ females; nmrHas2− controls received tamoxifen or vehicle. Auditory brainstem response (ABR) testing was performed approximately 2 weeks before mice reached 3 or 12 months of age. Cochleae and reproductive tissues were collected following euthanasia approximately 2 weeks later. Results ABR thresholds to clicks and six tones (4–32 kHz) showed marked hearing loss from 3 to 12 months of age in both nmrHas2+ mice and controls, with no evidence that nmrHas2 attenuated AHL. Cochlear nmrHas2 expression in nmrHas2+ mice was confirmed by quantitative RT-PCR. Conclusion Ubiquitous nmrHas2 expression did not attenuate AHL in C57BL/6 mice despite previously reported benefits for other aging phenotypes. These findings contrast with CR, suggesting that vHMM-HA and CR influence aging through distinct mechanisms.