Epigenetic clocks and accelerated biological aging in people living with HIV: Emerging mechanisms and clinical...

Combination antiretroviral therapy has significantly improved survival among people living with HIV. However, many people living with HIV develop cardiovascular, metabolic, neurocognitive, musculoskeletal, and frailty-related conditions earlier or more frequently than HIV-negative individuals of a similar chronological age. DNA methylation-based epigenetic clocks provide a method for estimating biological age and may help explain this increased burden of age-related disease. This short review aims to summarize current evidence on epigenetic age acceleration in people living with HIV, describe the biological mechanisms that may contribute to accelerated aging, examine the effects of antiretroviral therapy and sex-related factors, and discuss the possible clinical applications of epigenetic clocks.

First-generation epigenetic clocks, including the Horvath and Hannum clocks, generally indicate that people living with HIV are approximately 5 to 7 years biologically older than HIV-negative individuals of a similar chronological age. However, these clocks may be affected by HIV-related changes in immune-cell composition. Newer measures, including PhenoAge, GrimAge, DunedinPACE, Retro-Age, and immune-composition-resistant clocks, assess different aspects of biological aging, such as physiological decline, mortality risk, the pace of aging, and retroelement-associated methylation. HIV-associated epigenetic aging appears to involve persistent viral activity, chronic immune activation, inflammation, immunosenescence, mitochondrial dysfunction, oxidative stress, altered one‑carbon metabolism, glutathione deficiency, cellular senescence, and treatment-related metabolic or mitochondrial effects. Antiretroviral therapy may reduce epigenetic age acceleration, but it does not consistently restore biological age to the level observed in HIV-negative individuals. Sex, menopause, metabolic dysfunction, and body composition may also influence the relationship between epigenetic aging, frailty, and mortality.

Epigenetic clocks may improve the assessment of biological aging in people living with HIV and could support risk stratification, early identification of frailty, and evaluation of interventions. However, longitudinal validation, standardized methods, adjustment for immune-cell composition, and evidence linking clock changes with meaningful clinical outcomes are required before these biomarkers can be used routinely in HIV care.