PROJECT SUMMARY This proposal will train the candidate to become a leading expert on the role of biological aging in cognitive impairment that can affect persons with HIV (PWH). A detailed training plan has been developed, including advanced coursework and instruction in the biology of aging and the epigenome, machine learning and bioinformatics methods, and career-enhancing training through mentorship, leadership, and grant-writing courses. This plan will both promote the success of the proposed Research Aims and set the candidate on a trajectory toward an independent and productive career. Regular engagement with an experienced, multi- disciplinary mentorship team will ensure the candidate’s success during the award period. The proposed research study will investigate the relationship between HIV-related cognitive impairment and biological aging, including aging of the central nervous system. While combination antiretroviral therapy has improved life expectancy for PWH, cognitive symptoms persist in 20–50% of this population. Growing evidence indicates that elevated biological aging is associated with adverse health outcomes for PWH. However, it remains unclear whether accelerated aging still occurs in PWH with undetectable viral load, especially in diverse populations at greater risk for comorbidities and adverse social determinants of health. It is also unclear how biological aging relates to cognitive function in such populations. These questions are of crucial importance for the health and quality of life of the aging population of PWH in the US. The proposed study will address the central hypothesis that accelerated biological aging in PWH contributes to cognitive impairment, in combination with comorbidities and social risk factors. The study will represent a seminal effort to combine measures of biological aging from DNA methylation and brain magnetic resonance imaging (MRI) with machine learning methods to build and test robust models of cognitive impairment in PWH. This approach will be centered on two relatively novel but well-validated aging biomarkers. Epigenetic age acceleration (EAA) will be measured using DNA methylation clocks, such as GrimAge, which the candidate will derive from DNA methylation microarrays applied to blood samples from a diverse group of PWH and control persons without HIV (PWoH). Analogously, deep neural network models will be used to quantify brain-age acceleration (BAA) using volumetric brain MRI data from the same participants. The ultimate goal is to leverage epigenomics and brain morphology data to produce a predictive computational model of cognitive impairment. The role of non-AIDS HIV-associated comorbidities such as cardiovascular disease and social determinants of health including neighborhood deprivation will be considered in parallel with biological measures. This study will provide insights into the origins of HIV-associated cognitive impairment, a major clinical problem that reduces quality o...