Epigenetic aging in people with HIV across the life course: a systematic review and meta-analysis

Abstract Epigenetic aging algorithms are emerging tools for understanding the biological effects of human immunodeficiency virus (HIV). A growing body of literature has applied DNA methylation-based epigenetic clocks in people living with HIV (PWH) across the life course, examining epigenetic age acceleration (EAA) in relation to HIV infection, antiretroviral therapy (ART), comorbidities, and clinical biomarkers (e.g., viral load, CD4 T-cell counts). This systematic review (Prospero: CRD420251126874) summarizes and synthesizes the current evidence on epigenetic aging in PWH across the life course and identifies critical knowledge gaps for future research. We searched PubMed, Scopus, and Medline through June 26, 2026. The review followed PRISMA guidelines and assessed studies for risk of bias using the Newcastle-Ottawa Scale. We created a narrative synthesis of results and performed a random-effects meta-analysis of HorvathAge EAA. Fifty-five studies met the inclusion criteria. More than half (n = 33) examined EAA in PWH compared to an uninfected control population. We identified heterogeneity in study populations and design, biospecimens profiled, platforms used for DNA methylation analysis, and epigenetic clocks employed. Only 6 studies included participants younger than 18 years and no studies focused exclusively on individuals over 65 years. Only 10 studies examined longitudinal changes in EAA. Thirty-seven papers evaluated associations between EAA and comorbidities. A meta-analysis of HorvathAge EAA across 14 studies found a mean difference of 3.41 years (95%CI 2.22, 4.60) in PWH relative to controls. Current evidence supports accelerated EAA among PWH but highlights substantial methodological heterogeneity and important knowledge gaps. Longitudinal studies of EAA in PWH are needed in populations under 18 and over 65, to clarify the effects of ART, clinical biomarkers, and age-related comorbidities, and determine the clinical utility of epigenetic aging biomarkers.