The focus of this research is age-related hearing loss (presbycusis). Currently, more than 28 million Americans have impaired hearing and approximately 75% of these persons are over the age of 55. The prevalence of presbycusis will increase substantially with the aging of the population. To meet the challenges of this most common chronic condition of aging, improved diagnostic methods, treatment approaches, and prevention strategies will be of great importance. To meet these objectives, four research projects are proposed. Project 1 assesses age-related changes in human cochlear and neural function related to metabolic, sensory, and neural pathologies. Project 2 examines the impact of metabolic and sensory presbycusis and aging on brain structure and functional networks that support speech recognition. Project 3 identifies genetic variations causing an increased susceptibility to age-related hearing loss using DNA samples from older adults in our study and defines their pathological consequences in human temporal bones. Project 4 studies adult stem cell dependency on the cochlear extracellular matrix (ECM) microenvironment using animal models of metabolic presbycusis and ECM deficiency, and observations of cochlear tissues from human temporal bones. A central goal is to relate changes observed in animal models of metabolic presbycusis to declines in hearing in older humans. In parallel with this goal, results from the large battery of tests obtained from participants in our longitudinal study (Human Subjects Core) will be analyzed to further define and validate phenotypes of age-related hearing loss. Thus, four interrelated research projects, supported by large numbers of well-characterized human subjects and a detailed database of cross-sectional and longitudinal data, form a cohesive program that addresses fundamental questions on human presbycusis. The Clinical Research Center is unique in several respects, including its 25-year longitudinal study of hearing in older persons, the diversity of basic, translational, and clinical approaches, and its focus on a disorder that contributes to poor communication abilities and reduced quality of life for millions of older adults.