D-galactose administration via semicircular canal induces accelerated cochlear aging: A novel model of oxidative stress-mediated presbycusis.

Age-related hearing loss (ARHL) is a progressive, bilateral sensorineural impairment with significant socio-psychological consequences. Current ARHL models (natural aging or systemic D-galactose (D-gal) injection) face limitations: prolonged timelines, high variability, and inconsistent D-gal protocols. To concentrate aging pathology within the peripheral auditory system, we developed a novel accelerated cochlear aging model by targeted delivery of D-gal via the posterior semicircular canal. This approach aimed to concentrate aging pathology within the peripheral auditory system. Auditory brainstem response testing was employed to assess murine hearing thresholds for determining optimal D-gal concentration and exposure duration. Results demonstrated that by post-administration day 14, the D-gal-H group exhibited pronounced auditory characteristics consistent with ARHL. Morphological staining further revealed significant outer hair cells loss and ribbon synapses degeneration. Concurrently, immunohistochemical analysis of 4-HNE and 8-OHdG showed elevated oxidative stress levels in the stria vascularis, spiral ganglion cells, and inner hair cells of D-gal-treated groups. Substantial alterations in aging-associated proteins were also observed. Mitochondrial membrane potential assessment indicated significant depolarization in treated cochleae. Accordingly, we established a rapid, targeted, and pathologically validated model of cochlear aging, which provides a valuable tool for investigating the mechanisms underlying peripheral auditory aging.