TRANSLATIONAL AND COMPUTATIONAL APPROACHES TO UNDERSTANDING AND MITIGATING AGE-RELATED CENTRAL NERVOUS SYSTEM DECLINE

Abstract

Brain aging is a complex biological phenomenon characterized by the progressive dysregulation of multiple biological processes that lead to tissue dysfunction, cognitive decline, and neurodegeneration. Although the causes and effects of brain aging have been extensively studied, exactly how this multi-faceted process initiates and progresses is incompletely understood. Additionally, as brain aging predisposes individuals to multiple neurodegenerative diseases, understanding this complex process is an extremely important research priority. The studies detailed throughout this dissertation investigate: 1) mechanisms of aging that precede and contribute to neurodegeneration; and 2) novel therapeutics aimed at targeting and ameliorating brain aging. Guided by my mentoring team, I investigated these topics through various experimental models and datasets across three major studies. First, I examined transposable element dysregulation in the most active immune cell type in the aging brain (microglia). Second, I tested a naturally occurring bioactive compound (apigenin) for its protective effects against age-related functional declines, age-related neurodegeneration, and Alzheimer’s disease-relevant proteotoxicity while attempting to address the discrepancies in the literature regarding the biological mechanisms involved. Conversely, I also investigated fine particulate matter from wildfire smoke for its effects on age-related decline. Finally, I examined the impact of circulating systemic age-related proteins for their impact on blood-brain-barrier integrity. All of these studies focused on either emerging upstream causes of brain aging and neurodegeneration or novel therapeutics that could potentially target and mitigate age-related decline and improve resilience to disease. Collectively, this work may serve as a foundation for future studies examining mechanisms of brain aging, neurodegeneration, and disease.