Rapamycin ameliorates age-related hearing loss in C57BL/6J mice by enhancing autophagy in the SGNs.

Autophagy plays a pathogenic role in neurodegenerative disease. However, the involvement of autophagy in the pathogenesis of age-related hearing loss (ARHL) remains obscure. Naturally aged C57BL/6J mice were used to identify the role of autophagy in ARHL, and rapamycin, a mammalian target of rapamycin (mTOR) inhibitor, was administered for 34 weeks to explore the potential therapeutic effect of rapamycin in ARHL. We found that the number of autophagosomes and the expression of microtubule-associated protein 1 light chain 3B (LC3B) decreased as the mice aged. The expression of autophagy-related (Atg) proteins, including Beclin1 and Atg5, and the ratio of LC3-II/I was reduced in aged mice, while mTOR activity in aged mice gradually increased. Rapamycin improved the auditory brainstem response (ABR) threshold (at 8, 12, and 24 kHz). Further exploration demonstrated that spiral ganglion neuron (SGN) density was enhanced in response to administration of rapamycin. The rate of apoptosis in the basal turn SGNs was decreased, whereas autophagy activity was increased in the experimental group. Meanwhile, mTOR activity in the experimental group was decreased. Our findings indicate that age-related deficiency in autophagy may lead to increased apoptosis of aged SGNs. Rapamycin enhances autophagy of SGNs by inhibiting mTOR activation, resulting in amelioration of ARHL. Therapeutic strategy targeting autophagy may provide a potential approach for treating ARHL.