PROJECT SUMMARY/ABSTRACT – PROJECT 3 Determining the mechanisms and site(s) of pathologies involved in age-related hearing loss is challenging as they likely reflect a lifetime of environmental exposures, differences in susceptibility and co- morbidities, and complex genetic factors. These individual differences may contribute to the large variation in audiometric profiles and suprathreshold auditory function seen in older adults. In our Center, classification of metabolic and sensory presbyacusis phenotypes is based on animal models linking specific cochlear deficits to audiometric profiles, and has resulted in four cochlear-based phenotypes. Project 3 will refine these phenotypes by developing and validating physiologic measures that predict cochlear and auditory nerve pathology in older adults. Aim 3.1 tests the hypothesis that outer hair cell and cochlear lateral wall deficits differentially contribute to sensory versus metabolic presbyacusis. Experiments in Aim 3.1 incorporate metrics related to outer hair cell and stria vascularis function to predict cochlear pathologic site(s) and determine the extent to which patterns of pathology are consistent with estimates of sensory and metabolic hearing loss. Aim 3.2 examines auditory nerve structure and function to test the hypothesis that changes in auditory nerve activity result in unique and additive effects in auditory function of older adults. By using similar physiologic assessments, experiments in Project 1 and Project 2 will provide a means to validate Project 3 results in mouse models where the mechanisms and anatomical pathology are well defined. A significant advancement in the characterization of underlying cochlear and neural pathologies of presbyacusis is crucial in developing and testing new treatments as they become available, by appropriately assigning participants in clinical trials, and in determining the best course of intervention for an individual. Moreover, individual differences in pathophysiology identified in Project 3 are hypothesized to have differential effects on cortical representation of speech and suprathreshold auditory processing, assessed in Project 4.