People living with HIV infection (PLWH) are living longer but with advancing age experience accelerated functional decline (decreased strength, slowed gait, reduced exercise tolerance) and increased frailty, as compared to non-infected individuals. The syndromes of functional decline and frailty are associated with impaired quality of life, increased vulnerability to superimposed stresses, and the likelihood of premature morbidity and mortality. The mechanisms underlying this accelerated dysfunction and disability, however, are poorly understood. The proposed project examines the contribution of altered skeletal muscle (SM) mitochondrial function and high energy phosphate metabolism to the related, but distinct syndromes of fatigue, exercise intolerance, and frailty often present in older PLWH. Considerable pre-clinical data and our pilot clinical studies using a 31P magnetic resonance spectroscopy (MRS) fatigability test during and following lower- extremity exercise suggest an ?energetic myopathy? as a possible basis for the fatigue and decreased performance in older PLWH individuals. However the extent, underlying responsible factors, and functional significance of altered SM mitochondrial bioenergetics in this population have not been characterized. In addition, two potential mechanisms responsible for altered SM high energy phosphate metabolism in other populations, increased inflammation and SM lipid accumulation, have not been examined and related to muscle energetics in PLWH and so these too will be examined. The central hypothesis is that impaired SM mitochondrial energy metabolism, initiated by aging and accelerated in the setting of contemporary HIV, is a central contributor to the geriatric syndromes of fatigue, exercise intolerance, and frailty in older PLWH. We propose to use state-of-the art 31P MRS exercise testing, detailed muscle and whole body composition measures, functional assessments during observed and free-living conditions, and biomarkers of inflammation and immune activation in 200 older (age>=60) women and men derived from four local NIH-sponsored cohorts to address these questions. The specific aims are 1) to define the scope of SM metabolic changes in older women and men living with HIV, 2) to probe whether inflammation, skeletal fat and other underlying factors are related to the energetic abnormalities in older PLWH and 3) to determine the functional significance of SM energetic changes in older PLWH by examining the relationships between the energetic changes and exercise tolerance and other functional assessments as well as the frailty phenotype. Fatigue, exercise intolerance, and frailty are common in older PLWH and the underlying mechanisms remain poorly understood These novel, timely studies will provide new insights and guide future intervention strategies designed to attenuate or reverse mitochondrial and bioenergetic decline and thereby reduce the personal and societal toll of these geriatric conditions in older women and men living with HIV.