Upregulation of the Ca_v1.3 channel in inner hair cells by interleukin 6-dependent inflammaging contributes to age-related hearing loss

Age-related hearing loss (AHL) is the most common sensory disorder amongst the older population. Inflammaging is a ≈chronic low-grade inflammation that worsens with age and is an early sign of AHL; however, the underlying mechanisms remain unclear. We used electrophysiological and genetic approaches to establish the importance of interleukin 6 (IL-6)-dependent inflammation in AHL. Elevated IL-6 in the cochlea enhanced Ca_v1.3 calcium channel function in the inner hair cell (IHC) synapse in mice with AHL. IL-6 upregulated the Ca_v1.3 channel via the Janus kinase-mitogen activated kinase pathway, causing neurotransmitter excitotoxicity and synapse impairment; IL-6 deficiency or the administration of a Ca_v1.3 channel blocker attenuated this age-related damage, and rescued hearing loss. Thus, IL-6-dependent inflammaging upregulated the Ca_v1.3 channel in IHCs, contributing to AHL. Our findings could help the comprehensive understanding of inflammaging's effects on AHL, aiding in early intervention to protect against hearing decline.