Determinants of age-induced hearing loss and reversal strategies

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Abstract Presbycusis or age-related hearing loss (ARHL) represents the most prevalent sensory deficit. It begets social isolation and depression. We hypothesize that aging auditory neurons undergo cellular, and structural changes, resulting in demyelination and selective neuronal subtypes loss. The ensuing plasticity produces profound neural network re-wiring and aberrant functional plasticity along the auditory pathway. These predicted changes' progressive nature requires systematic analyses of the ARHL mechanism at different auditory pathway hubs, which can only be achieved through a joint collaborative effort. Motivated by this public health challenge, we have designed a collaborative multiscale study that addresses the aging auditory system's successive mechanisms. The clinical and translational outcomes of our findings promise to be vast. The overarching hypotheses are tested in three Projects, using resources and tools from four Cores. The investigative team consists of experts from genetic to physiology and imaging and analytical chemistry. Three projects (P1-3) are served by four Cores (A-D). Core A is for administrative oversight and organization of the Cores and Projects. The team includes Drs. Yamoah (Project 1), Xie (Project 2), Maria-Rubio/Williamson (Project 3), Yamoah (Core A), Yamoah/Lee (Core B), Fritzsch/Perkins (Core C), and Zhu (Core D). Together, they will determine the mechanisms of ARHL of sensory and neural etiology. The team has worked together synergistically and productively. The projects focus on critical centers of the auditory pathways recognized for the coding and processing of sound information. They include the primary auditory neurons (AN; P1), cochlear nuclei (CN; P2-3), superior olivary complex (SOC; P2-3), and auditory cortex (ACtx, P3). We use genetic, optogenetics, and pharmacogenetic mouse models (Core B). We employ structural analyses (Core C) and differential proteomic analyses of young-and aged-auditory neurons to uncover biomarkers (Core D). Integration of the program ensures outcomes that are overwhelmingly greater than the sum of the individual components. Identification of ARHL biomarkers is likely to pave the way for effective treatment strategies.