Urinary Symptoms and Incontinence in Aging Reflect Loss of Lower Urinary Tract Resilience

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ABSTRACT A geroscience approach to urinary symptoms requires knowledge about the mechanisms that normally ensure bladder control homeostasis/allostasis and how they are impacted by aging, yet these remain largely undiscovered. My general hypothesis is that the aging bladder phenotype is the expression of decline of multifaceted mechanisms needed to achieve adaptive control over what the brain “knows” about bladder content. Discovering these adaptive mechanisms and systems, and how they are impacted by aging, will address this critical knowledge gap. In this project, I will learn and establish the technologies in my laboratory needed to discover the neural correlates to our R01-funded investigations on the role of the HCN ion channel in adrenergic detrusor relaxation and the impact of aging on this process. Since we have hypothesized HCN as a mediator of neuroendocrine (sympathetic) and paracrine (mucosal) influences over detrusor activity, we will also determine the impact of aging on mucosal and HCN contributions to the age-increased heterogeneity of detrusor responsiveness observed in our in-vivo and in-vitro studies. Alongside this laboratory work, I will provide clinical and laboratory expertise with bladder control physiology to our recently formed multidisciplinary group of expert aging researchers. In addition to a more granular understanding of the neuroendocrine influence over bladder volume sensing, the laboratory tools developed under this Award will contribute to new projects focusing on the paracrine/mucosal determinants of detrusor activity, and spinal/brainstem processes, as these mechanisms of volume sensing control provide resilience to acute (bladder filling) and chronic (aging) challenges to control physiology. These same tools will also facilitate our investigations of the role of a bladder phenotype in urinary dysfunctions common in age- associated disease such as Alzheimer’s disease and other neurodegenerative conditions. The translational research tools developed in our collaborative group will support new projects aimed at greater understanding of the impact of aging and loss of cognitive reserve as allostatic loads compromising asymptomatic, socially appropriate bladder control despite the acute and chronic challenges associated with aging. Training in laboratory techniques and aging research are incorporated into the project plan. This training in combination with the research goals will allow me to achieve specific milestones, moving me towards my goal of career dedication to aging bladder research.