PROJECT SUMMARY Aging is a major driver of neurodegenerative disorders such as Parkinson’s disease (PD) and skeletal diseases including osteoporosis, which inflict significant economic burdens and suffering on the healthcare system, patients, and their caregivers. Recent clinical and animal studies suggest that the two diseases share a common etiology, i.e., the accumulation of senescent cells. Thus, pharmaceutical clearance of senescent cells is being actively pursued in both fields using various senolytic compounds. However, despite the intrinsic links between the brain and bone, the evaluation of the treatment outcomes has been narrowly focused on either the neural or skeletal system alone. Emerging evidence demonstrates that senolytics elicit tissue- and cell-specific responses. There is an urgent need for a holistic evaluation of senolytic effects on both organ systems. Furthermore, clinical practice and preclinical investigation clearly show the benefits of moderate exercise in delaying age-associated diseases and improving brain and bone functions. Thus, exercise could be complementary to senolytics for PD and osteoporosis treatment. However, the synergy between exercise and senolytics has not been investigated. To fill this knowledge gap, we propose a team science project that will take a multi-disciplinary approach. Taking the advantage of the team’s complementary expertise in PD animal models and senolytics (Kim), bone mechanobiology and exercise (Wang), and mouse brain in vivo MRI (Chow), we will test the hypothesis that senolytic ABT-263 decreases the senescent cell burden in both brain and bone tissues of aged PD mice based on a critical time-window and cell-type specificity, and the treatment mitigates the secondary damages from senescent cells, leading to favorable local cellular and biochemical environments for brain and skeletal cells. We further hypothesize that subsequent exercise like treadmill running provides additional protection and acts in synergy with senolytics in protecting bone and brain from degeneration in aged PD mice. To test the hypotheses, our specific aim is to holistically evaluate the bone and brain responses to senolytic ABT-263 treatment alone or in combination with treadmill running at the cell, tissue, and brain circuit levels in a novel PD mouse model. Alignment with the Parent Project: The proposed work will test a novel dual-treatment in PD patients with the goal of improving the musculoskeletal function, a focus of the parent COBRE. Future plans: The completion of the supplement will strengthen the synergy among the three research groups and further propel the momentum of collaboration that has been built up during the preparation of the supplement. We will leverage the resources and expertise through the parent COBRE and existing INBRE at UD and DSU, a prominent HBCU in Delaware. The team sets their goal of developing a larger multi-PI R01 project to further optimize treatments for PD and osteoporoti...