SIRT1 protects cochlear hair cell and delays age-related hearing loss via autophagy.

Age-related hearing loss (AHL) is typically caused by the irreversible death of hair cells (HCs). Autophagy is a constitutive pathway to strengthen cell survival under normal or stress condition. Our previous work suggested that impaired autophagy played an important role in the development of AHL in C57BL/6 mice, although the underlying mechanism of autophagy in AHL still needs to be investigated. SIRT1 as an important regulator involves in AHL and is also a regulator of autophagy. Thus, we hypothesized that the modulation between SIRT1 and autophagy contribute to HC death and the progressive hearing dysfunction in aging. In the auditory cell line HEI-OC1, SIRT1 modulated autophagosome induction because of SIRT1 deacetylating a core autophagy protein ATG9A. The deacetylation of ATG9A not only affects the autophagosome membrane formation but also acts as a sensor of endoplasmic reticulum (ER) stress inducing autophagy. Moreover, the silencing of SIRT1 facilitated cell death via autophagy inhibition, whereas SIRT1 and autophagy activation reversed the SIRT1 inhibition media cell death. Notably, resveratrol, the first natural agonist of SIRT1, altered the organ of Corti autophagy impairment of the 12-month-old C57BL/6 mice and delayed AHL. The activation of SIRT1 modulates the deacetylation status of ATG9A, which acts as a sensor of ER stress, providing a novel perspective in elucidating the link between ER stress and autophagy in aging. Because SIRT1 activation restores autophagy with reduced HC death and hearing loss, it could be used as a strategy to delay AHL.