Experimental Gerontology Review Examines Epigenetic Age Acceleration in People Living with HIV

A systematic review in Experimental Gerontology indicates that first-generation epigenetic clocks estimate a five-to-seven-year biological age acceleration in people living with HIV, highlighting both the opportunity for advanced clocks to act as clinical biomarkers and the need for longitudinal validation.

A short review published in Experimental Gerontology examined the application of DNA methylation-based epigenetic clocks to evaluate biological age in people living with HIV.

The author reported that first-generation epigenetic clocks, such as the Horvath and Hannum clocks, generally indicate that people living with HIV are biologically older by approximately five to seven years compared to chronologically age-matched HIV-negative individuals.

The review highlighted that newer clocks—including PhenoAge, GrimAge, DunedinPACE, and Retro-Age—assess different facets of biological decline and physiological risk, and some are designed to resist biases introduced by HIV-related immune-cell composition shifts.

The review documented that HIV-associated accelerated aging is driven by complex mechanisms including persistent viral activity, chronic immune activation, immunosenescence, mitochondrial dysfunction, altered one-carbon metabolism, cellular senescence, and antiretroviral-related toxicities.

Although combination antiretroviral therapy reduces epigenetic age acceleration, evidence shows it does not fully restore biological age to levels typical of HIV-negative cohorts.

The author concluded that while epigenetic clocks could eventually guide risk stratification and clinical trial evaluations in HIV management, they require further longitudinal validation and methodological standardization before routine clinical adoption.

The review underscores the industrial demand for robust, immune-composition-resistant biological age metrics (such as DunedinPACE or Retro-Age) that can reliably function as clinical endpoints.

Establishing validated epigenetic biomarkers in clinical cohorts characterized by accelerated aging could pave the way for regulatory frameworks that accept surrogate aging biomarkers in wider clinical trials.

The identification of clear biological drivers of accelerated aging in this population, such as cellular senescence and mitochondrial dysfunction, suggests that these cohorts could serve as valuable trial populations for developers of targeted longevity therapeutics.

Longitudinal clinical validation trials that correlate changes in advanced epigenetic clock metrics with concrete clinical outcomes and physical frailty in accelerated aging cohorts.