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.
The Clinical Research Center leverages the multidisciplinary and wide-ranging expertise in each project, and the wealth of information available in the human subject database, to generate new knowledge on the high prevalence public health problem of age-related hearing loss. Our goals are to reduce its prevalence, slow its progression, and develop new prevention, diagnostic, and treatments strategies to improve communication and quality of life of older adults. Subproject 1 Defining Phenotypes of Age-Related Hearing Loss Lead Investigator: Judy R. Dubno, Ph.D. DESCRIPTION (provided by applicant): The complex genetic and environmental factors affecting human hearing over the lifespan contribute to a large variation in audiometric profiles and suprathreshold measures of auditory function. As a result, determining mechanisms of age-related hearing loss in older adults is challenging because genetic, age, noise history, injury, disease, medication, diet, and other factors can work independently and jointly to alter human auditory function. Although morphologic findings from older humans are limited to postmortem data, experimental procedures with animals of known heredity can disrupt specific cochlear systems, model certain pathologic conditions, and introduce or minimize environmental exposures, while measuring subsequent changes in auditory function. Consistent with results from animal models linking audiometric profiles to specific cochlear pathologies, such as metabolic or sensory loss, audiograms from the Clinical Research Center's human subject database (Core B) were classified into four audiometric phenotypes, which provided a means to characterize the pathophysiology of hearing loss in older humans. Audiometric phenotypes determined using supervised machine learning classifiers were consistent with expected demographic and noise history patterns that segregate with patterns of hearing loss. Project 1 will refine and further validate these phenotyping methods using suprathreshold measures of cochlear and neural function beyond the audiogram that characterize metabolic and sensory presbyacusis, and the additive effects of morphologic and functional neural loss. To meet this goal Aim 1.1 tests the hypothesis that older adults with metabolic and sensory presbyacusis differ in cochlear nonlinearities and lower frequency suprathreshold auditory function. Aim 1.2 tests the hypothesis that changes in auditory nerve activity result in unique and additive effects in older adults with metabolic and sensory presbyacusis. Thus, Project 1 will assess age- related changes in auditory function related to metabolic, sensory, and neural pathologies and link findings to Project 2, focused on central auditory and cortical changes, and to translational Projects 3 and 4, which will determine the genetic and cellular mechanisms of age-related hearing loss using humans and human tissue. With these approaches, morphologic and physiologic changes characterizing metabolic, sensory, and neural presbyacusis provide a framework for assessing and interpreting age-related changes in human auditory function. PUBLIC HEALTH RELEVANCE: Knowledge of the variations in pathophysiology underlying human age-related hearing loss may dictate different diagnostic test batteries, hearing-aid fitting algorithms, auditory-training regimens, and recommendations for communication strategies. This new information will lead to better diagnosis and treatments for this high-prevalence public health concern, and improved communication and quality of life for millions of older adults.
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