Abstract This Mentored Patient-Oriented Research Career Development Award (K23) seeks to equip Dr. Grace Lee with the skill requisites needed to develop into a leading translational geroscientist focused on evaluating pharmacological interventions to improve immunological health. The career development program outlines supervised research and educational activities to achieve the following training objectives: (1) gain skills in integrating clinical and molecular approaches in prospective clinical trials of aging; (2) interpret and apply immunogenetic data to characterize immune resilience in aging; and (3) gain skills needed to transition to independent funding. Deterioration of immune function is a hallmark of most age-associated diseases. Thus, identifying therapeutically modifiable pathways that underpin the aging-associated immune decline are needed to improve health span/lifespan. The overall objective of this study is to test a widely used diabetes drug, metformin, to improve immunological integrity as a marker of resilience. This K23 application builds on preliminary data acquired while as a RL5 Pepper Center Scholar, which (i) identified that metformin was associated with improved pneumococcal conjugate vaccine (PCV13) responses in mice, and (ii) established feasibility of a clinical trial using metformin to improve immunological resilience in older adults. Additionally, through evaluation of a ~70,000 person cohort, working with my mentor, we have identified genomic and immunologic correlates of an immunosenescence-mediating program that contributes to age-associated decline in immunological integrity, including vaccine responses and mortality. For this K23, we propose to conduct a pilot double-blind randomized placebo-controlled clinical trial of adults 50 to 65 years of age. Eligible subjects will be randomized in a 1:1 ratio to metformin (titrated to 2,000 mg/day) or placebo for a total duration of 5 months. After completing a 16 week course of study drug, subjects will be administered the PCV13, then followed for an additional 4 weeks on treatment. We will compare PCV13 vaccine responsiveness and improvements in novel genomic signatures associated immunological integrity in adults treated with metformin compared to placebo. The findings from this study will provide the necessary pilot data for future, more definitive studies that will advance our understanding of metformin’s role on the aging immune system. This proposal is supported by a mentorship team of renowned scientists in immunology/genomics (Dr. Ahuja), aging research (Drs. Musi and Espinoza), and pneumococcal diseases (Dr. Restrepo), and an advisor in biostatistics (Dr. Gelfond). This team, along with resources available through the San Antonio Pepper Center and Barshop Institute for Longevity and Aging Studies, comprise an ideal environment for Dr. Lee to successfully reach her goal to promote healthy aging.

PROJECT NARRATIVE Deterioration of immune function is a hallmark of most age-associated diseases. This proposed study will provide a better understanding of how a widely used diabetes medication, metformin, can improve immunological health and vaccine responsiveness. Given the wide ranging health consequences of impaired immune health, the identification of therapeutically modifiable pathways that underpin aging-associated immune decline has a considerable public health relevance and the potential to improve health span/lifespan.