PROJECT SUMMARY/ABSTRACT The candidate’s career goal is to become an independent physician-scientist studying HIV and aging, and the increased burden of medical co-morbidities and geriatric syndromes in older adults with HIV (OAH). The candidate has laid the foundation for achieving this goal by gaining clinical expertise in caring for OAH, conducting research, and obtaining a Master’s Degree in Clinical and Translational Investigation. To achieve her career goal, the candidate will need to expand upon her geroscience and translational research skills, including additional biostatistics and research methods training which are described in this resubmission. A key component of the candidate’s training will be conducting the proposed research project. Despite effective antiretroviral medications, OAH bear a greater burden of medical co-morbidities and geriatric syndromes than their HIV-negative peers. Translational research investigating biomarkers inflammation offers as opportunity for insight to the process of accelerated/accentuated aging that is observed in OAH. Cell-free mitochondrial DNA (cfmtDNA) is released from cells undergoing stress and necroptosis-mediated cell death and has the potential to serve as a mediator and marker of chronic immune activation and dysregulation. We hypothesize that cfmtDNA will be associated with lower cognitive performance and greater frailty in a longitudinal study of OAH. Previously, we have studied a cohort of OAH (age 55 and over) at our institution, and those with cognitive impairment had higher average levels of cfmtDNA in plasma than participants without cognitive impairment. We propose to leverage this existing study to investigate the following specific aims: 1) Determine the association between cfmtDNA and cognition in OAH; 2) Determine the association between cfmtDNA and longitudinal physical function in OAH; and 3) Evaluate the immunostimulatory potential of cfmtDNA from OAH with and without cognitive decline. Participants from our existing cohort will be invited back for two study visits separated by 18-24 months, each visit will include detailed neurocognitive assessment, physical function measures, falls and instrumental and activities of daily living, and blood and urine specimen collection for analysis and creation of a biorepository. Together, these investigations will shed light on the relationship between cfmtDNA, immune activation and geriatric-related syndromes in OAH. This project proposes a five-year, multifaceted training program under the mentorship of Dr. Marshall Glesby as the primary mentor, as well as Drs. Mary Choi, Lishomwa Ndhlovu, and Eugenia Siegler as co-mentors. Together with a Scientific Advisory Committee, they will provide the expertise in research design, biomarkers, immunology and geroscience that will allow support the success of this project. The completion of the proposed project will lead to an enhanced understanding of cfmtDNA as a biomarker of geriatric syndromes i...