Investigating Senolytic Properties in Pulmonary Rehabilitation and Metformin in COPD Exacerbations (INSPIRE-COPD-E).

Duke University, Durham NC

Investigators

Linked publications, trials & patents

Abstract

PROJECT ABSTRACT In older adults (age ≥ 65), chronic obstructive pulmonary disease (COPD) exacerbations are a major health problem, leading to recurrent hospitalizations and early death. Available treatments are often ineffective, as 50% of patients on maximal therapy continue to have exacerbations. To develop better therapies, we must first identify the biological mechanisms underlying COPD exacerbations. One such possibility is systemic immune system dysfunction, resulting in impaired host immunity leading to greater susceptibility to respiratory viral infection, the most common cause of COPD exacerbations. Older adults with COPD demonstrate accelerated age-related decline in immune system function (e.g., accelerated immunosenescence) characterized by greater levels of senescent T-cells, which are functionally inactive but secrete pro-inflammatory cytokines termed senescence associated secretory phenotype (SASP). Thus, to decrease the likelihood of COPD exacerbations, we need to identify therapies that target cellular senescence — senotherapeutics — under the assumption that senotherapeutics improve immune response, which in turn increases protection against respiratory infections and lowers COPD exacerbation risk. This project has been designed to evaluate two senotherapeutic approaches: pulmonary rehabilitation (PR) and Metformin. First, PR is a non-pharmacological, supervised, structured exercise intervention, which is a safe and effective treatment to prevent COPD exacerbations in older adults. In healthy older adults, exercise interventions reduce senescent T-cells, leading to proliferation of naïve T-cells resulting in an improved immune response. I hypothesize that PR is effective in preventing COPD exacerbations, because it leads to removal of senescent T-cells, which leads to reduction in SASP levels, proliferation of naïve T-cells, and, by extension, improvement in immune response. I will use PR as a model-system to determine whether changing the ratio of senescent to naïve T cells in favor of naïve T cells and reducing SASP levels can serve as a viable senotherapeutic approach for COPD exacerbation prevention. Second, even though PR is an effective approach to prevent COPD exacerbations, participation in PR among older adults with COPD is low due to numerous barriers. Therefore, in this project I will evaluate whether Metformin, a treatment for diabetes, which is considered a promising gerotherapeutic medication due to its’ low cost and impact on numerous hallmarks of aging, is safe and feasible among older adults with COPD without diabetes. If I confirm safety and feasibility of Metformin, I will be well positioned to test the effectiveness and safety of Metformin to prevent COPD exacerbations in a future R01 proposed phase II clinical trial. Together, this project has great potential to advance the fields of COPD and geroscience. This project will also allow me to complete a structured, personalized career development plan and transition into academic independence as a leader in geriatric pulmonology.