Epigenetic clocks, which utilize DNA methylation patterns to estimate biological age, have emerged as valuable tools in understanding aging processes, particularly in populations with unique health challenges. This review focuses on individuals living with HIV, a group that experiences accelerated biological aging compared to HIV-negative counterparts.
Background
Combination antiretroviral therapy has significantly improved survival rates among people living with HIV. However, these individuals often face a higher incidence of age-related diseases such as cardiovascular, metabolic, neurocognitive, and musculoskeletal conditions. Research indicates that DNA methylation-based epigenetic clocks can provide insights into this phenomenon by estimating biological age, which may differ from chronological age.
Main Findings
First-generation epigenetic clocks, such as the Horvath and Hannum clocks, suggest that people living with HIV can appear biologically 5 to 7 years older than their HIV-negative peers of the same chronological age. This discrepancy may be influenced by changes in immune-cell composition related to HIV.
Newer epigenetic measures, including PhenoAge, GrimAge, DunedinPACE, Retro-Age, and immune-composition-resistant clocks, assess various dimensions of biological aging, including physiological decline and mortality risk. The mechanisms underlying HIV-associated epigenetic aging are complex and include:
- Persistent viral activity
- Chronic immune activation
- Inflammation and immunosenescence
- Mitochondrial dysfunction and oxidative stress
- Altered one-carbon metabolism
- Glutathione deficiency and cellular senescence
- Treatment-related metabolic or mitochondrial effects
While antiretroviral therapy may mitigate some aspects of epigenetic age acceleration, it does not consistently restore biological age to that of HIV-negative individuals. Factors such as sex, menopause, metabolic dysfunction, and body composition also play a role in the relationship between epigenetic aging, frailty, and mortality.
Clinical Implications
Epigenetic clocks hold potential for enhancing the assessment of biological aging in individuals living with HIV. They could aid in risk stratification, early identification of frailty, and evaluation of therapeutic interventions. However, the authors emphasize the need for longitudinal validation, standardized methodologies, and adjustments for immune-cell composition. Additionally, there is a call for evidence linking changes in epigenetic clocks to meaningful clinical outcomes before these biomarkers can be routinely integrated into HIV care.
What this study does not show
This review does not provide direct evidence of clinical outcomes resulting from the use of epigenetic clocks in HIV care, nor does it establish a causal relationship between epigenetic age acceleration and specific health conditions.
Evidence scorecard
- Analytic validity: Established
- Clinical validity: Partial
- Clinical utility: Not established
The evidence is based on a review of existing literature.