This administrative supplement to the the Johns Hopkins Older Americans Independence Center (OAIC) is designed to capitalize on the Center's expertise on intersecting biological pathways that drive early onset of physical frailty in a subset of individuals living with HIV through the study of mitochondrial decline as articulated in this proposal. Among people with HIV (PWH), frailty predicts mortality, comorbidities, and hospitalization, and is an important indicator of quality of life. The underlying mechanisms for frailty development are likely multifaceted, due in part to features of biological aging such as mitochondrial decline and chronic inflammation. A major driver of the aging process in PWH is mitochondrial damage, resulting from chronic HIV infection, chronic inflammation, and the effects of some antiretroviral therapies. However, the role of changes in mitochondrial function in the etiology of frailty among PWH remains unclear. Furthermore, each immune cell type may develop different metabolic adaptations in response to stress. The interplay between mitochondrial function and immune activation and senescence in the etiology of frailty development remains unclear. We propose to evaluate the association of immune cell type- specific mitochondrial function measurements, including mitochondrial content, membrane potential, and superoxide, with HIV infection and frailty by leveraging longitudinal data, specimens, and infrastructure from two established HIV cohorts: 1) the AIDS Linked to the IntraVenous Experience cohort; and 2) the Multicenter AIDS Cohort Study. These cohorts uniquely include PWH and comparable HIV uninfected adults. We propose the following aims to accomplish these goals: (1) to characterize immune cell activation and senescence and cell type- specific mitochondrial function, stratified by HIV infection status; and (2) to assess the association between cell type-specific mitochondrial function and frailty during longitudinal follow-up among people with and without HIV. We will apply a novel machine learning approach to characterize the complex and high-dimensional biomarker data in immune aging and mitochondrial function to achieve these aims. With expertise and resources from the OAIC, we will provide data on the longitudinal change of cell type-specific mitochondrial function profiles before and after frailty development, which will allow us to observe variations in mitochondrial function among people with and without HIV. These aims will provide new understanding of the interplay between HIV infection, immune aging, and mitochondrial function in the etiology of frailty.