Tuberous sclerosis complex-mediated mTORC1 overactivation promotes age-related hearing loss.
The underlying molecular mechanisms of age-related hearing loss (ARHL) in humans and many strains of mice have not been fully characterized. This common age-related disorder is assumed to be closely associated with oxidative stress. Here, we demonstrate that mTORC1 signaling is highly and specifically activated in the cochlear neurosensory epithelium (NSE) in aging mice, and rapamycin injection prevents ARHL. To further examine the specific role of mTORC1 signaling in ARHL, we generated murine models with NSE-specific deletions of Raptor or Tsc1, regulators of mTORC1 signaling. Raptor-cKO mice developed hearing loss considerably more slowly than WT littermates. Conversely, Tsc1 loss led to the early-onset death of cochlear hair cells and consequently accelerated hearing loss. Tsc1-cKO cochleae showed features of oxidative stress and impaired antioxidant defenses. Treatment with rapamycin and the antioxidant N-acetylcysteine rescued Tsc1-cKO hair cells from injury in vivo. In addition, we identified the peroxisome as the initial signaling organelle involved in the regulation of mTORC1 signaling in cochlear hair cells. In summary, our findings identify overactive mTORC1 signaling as one of the critical causes of ARHL and suggest that reduction of mTORC1 activity in cochlear hair cells may be a potential strategy to prevent ARHL.
['Fu|Xiaolong|X|', 'Sun|Xiaoyang|X|', 'Zhang|Linqing|L|', 'Jin|Yecheng|Y|', 'Chai|Renjie|R|', 'Yang|Lili|L|', 'Zhang|Aizhen|A|', 'Liu|Xiangguo|X|', 'Bai|Xiaochun|X|', 'Li|Jianfeng|J|', 'Wang|Haibo|H|', 'Gao|Jiangang|J|']
D000375:Aging D000818:Animals D005260:Female D006198:Hair Cells, Auditory D034381:Hearing Loss D008297:Male D000076222:Mechanistic Target of Rapamycin Complex 1 D051379:Mice D018345:Mice, Knockout D018384:Oxidative Stress D000076223:Regulatory-Associated Protein of mTOR D015398:Signal Transduction D000077004:Tuberous Sclerosis Complex 1 Protein
Aging Neurodegeneration Neurological disorders Neuroscience