ABSTRACT The geroscience hypothesis (i.e., that multiple age-related conditions result from a finite set of evolutionarily conserved molecular processes) implies a dynamic balance between gerodrivers and geroprotectors over the life course. In the context of HIV, older persons living with HIV (PWH) are disproportionately burdened with age-related conditions and multimorbidity, including significant declines in functional capacity underscoring the need for geroprotectors. NAD+ is a key cofactor, both in cellular energy metabolism and in modulation of inflammatory signaling. In multiple species, NAD decline with age has been linked to deficits in mitochondrial function and metabolic capacity, and decline in the activity of sirtuins, a class of NAD+-dependent enzymes that control inflammation, mitochondrial metabolism and aging. Thus, repletion of NAD is an attractive therapeutic modality for potentially reducing age-related inflammation (i.e., inflammaging) and improving physical function. Our preliminary studies indicate that circulating concentrations of NAD, NMN and the NAD metabolome can be measured in blood using liquid chromatography tandem mass spectrometry and that MIB-626 1000-mg once daily or twice daily regimens were safe and associated with substantial dose-related increases in blood NAD levels and its metabolome (Fig 1) [1]. We also show that NAD levels were lower in monocytes (Fig 2) and skeletal muscle (Fig 3) in persons with chronic HIV infection from our MATCH cohort [2]. We also show that NAD levels in skeletal muscle were negatively correlated with inflammation (Fig 4) [2]. We also observed loss in endurance in MATCH participants based on a constant work rate treadmill fatigability test (Fig 5). Our prior studies have shown that older persons with HIV display bioenergetic deficits [3-5], including decline in physical activity (PA) based on objective assessment of free-living activity using wearable technology [3, 6], and we also recently observed declines in cognitive performance in PWH compared to uninfected [7]. The hypothesis tested in this proposal is that NAD levels in older persons with chronic HIV infection will be lower when compared to uninfected age-matched persons and will be associated with epigenetic changes in genes involved in the regulation of metabolic, inflammatory, and mitochondrial bioenergetic pathways, and with impairment of insulin sensitivity and whole person functional outcomes; including lab based measures of endurance and muscle fatigability and objective measures of PA using wearable technology.