ABSTRACT Modern antiretroviral therapy (ART) has extended the survival of HIV infected (HIV+) adults into their later years, raising the possibility that age-related organ changes, including neurodegeneration and cerebrovascular disease, might amplify the effects of HIV on the brain. Thus far, data on premature or accelerated central nervous system (CNS) decline have been mostly limited to cross-sectional studies of persons younger than 60 years of age. No longer-term longitudinal studies of HIV+ individuals entering their 7th decade and beyond have been reported. We propose to take advantage of the detailed neuromedical and neurobehavioral information available on 400 HIV+ adults who were initially evaluated as part of the CNS HIV Anti-Retroviral Therapy Effects Research (CHARTER) study between 2003 and 2007. Follow-up of this cohort, 200 of whom will be 60 or older, will provide unique 12-year longitudinal data on the combined effects of HIV and ART on CNS decline and resultant functional disability. The major aim will be to build on prior cross-sectional findings comparing HIV+ and HIV- adults to determine if older HIV+ adults (≥ 60 years) have greater CNS decline over 12 years than younger HIV+ adults (< 60 years), while controlling for effects of “normal aging” on neurocognitive function. Adding to the timeliness and relevance of this study: We propose to determine a) how the viral, immune, metabolic/vascular, and pharmacologic correlates of CNS decline differ with age and b) the extent to which indicators of biological aging account for the observed correlations. The project will incorporate multiple state- of-the-art assessments including HIV DNA measurements (an indicator of HIV integration), telomere length and mitochondrial DNA (as indicators of biological aging), and population pharmacokinetic modeling of ART drug concentrations in CSF. CHARTER consists of 6 U.S. academic sites (Johns Hopkins, Baltimore; Icahn School of Medicine at Mt. Sinai, NYC; UC San Diego; UTMB Galveston; Univ. of Washington, Seattle; Washington Univ., St. Louis) that are united by a Coordinating Unit based at UC San Diego. The proposed project will provide the first large scale outcome data on neuroAIDS and aging, and link these to possible mechanisms. In addition, this study will make data and samples available to the scientific community, continuing our strong record of jumpstarting new research and further leveraging the value of the investment in this study.