TITLE: Pulmonary Rehabilitation as a Senolytic Intervention to Reduce Exacerbations in COPD (PERSPIRE-COPD) PROJECT ABSTRACT Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) are responsible for over 250,000 hospitalizations per year in older American adults (age ≥ 65). Current therapies are ineffective at preventing AECOPD resulting in an urgent and unmet need to develop more effective treatments. A major barrier to progress is identification of a modifiable biologic target. Among currently available treatments, pulmonary rehabilitation (PR) is safe and effective at preventing AECOPD in older adults. However, the biological mechanisms responsible for AECOPD prevention are not well understood. To address this gap in knowledge, we will leverage PR as a model to identify modifiable biologic targets to prevent AECOPD. Our findings will allow further PR optimization and provide biologic targets for future therapeutic drug development. Host immunity likely plays an important role in AECOPD prevention as a majority of events are caused by respiratory viral infections. Considering this, I propose that age-related decline in immune system function (i.e. immunosenescence) predisposes patients to higher AECOPD risk. Greater immunosenescence leads to more AECOPD events. Immunosenescence is characterized by high levels of senescent T-cells and senescence associated secretory phenotype (SASP). Therapies that eliminate senescent cells (i.e. senolytics) could potentially lower AECOPD risk. Exercise interventions have been shown to remove senescent T-cells and increase naïve T-cell proliferation. Considering PR is an exercise training intervention. I hypothesize that PR reduces the relative frequency of senescent T-cells to naïve T-cells and SASP levels. These changes will increase resilience to respiratory infections, lower AECOPD risk, and accelerate recovery from AECOPD. In preparation for future investigations into AECOPD risk, we will test the hypothesis that PR is associated with a decrease in relative frequency of senescent to naïve T-cells and SASP levels and determine the correlation of these changes with an improvement in physical performance and HRQoL. To begin to address this line of investigation, I’ve developed a PR biorepository that contains biospecimens collected at standardized intervals and pre/post-PR measurements of physical performance and HRQoL. Completion of these aims will support my professional development towards a career as a translational scientist with a focus in aging biology and clinical trials in older adults with COPD. The GEMSSTAR will deepen my knowledge of SASP biomarkers, T-cell immunology, immunosenescence, and within-subjects methodology and foster collaborations within the geriatrics research community. The project will result in 3 published manuscripts, 2 presentations at national conferences, and preliminary data towards a subsequent K76 Paul B. Beeson Career Development Award. Altogether, the GEMSSTAR award will play a critical role towards my development as an independent physician scientist and future leader in geriatric pulmonology.
