Epigenetic Age Acceleration and Frailty Among People with HIV

DNA methylation is a hallmark of aging; yet, our understanding of epigenetic age acceleration (EAA) in relationship to frailty in people with HIV (PWH) is poor. We conducted an observational study among PWH from the Veterans Aging Cohort Study (VACS) to test the hypothesis that EAA markers were associated with frailty. Epigenome-wide DNA methylation data from blood samples were used to derive EAA markers based on four established epigenetic clocks: Horvath, Hannum, PhenoAge, and GrimAge. Frailty was defined using a previously studied VACS frailty-related phenotype based on ≥1 survey item characterizing frailty factors: exhaustion, slowness, low physical activity, or weight loss. Logistic regression tested the association of participant characteristics and EAA markers with frailty. Adjusted models included each EAA marker as the independent variable, with significant participant characteristics as covariates. Among 1,076 PWH, frailty was evident in 397 (36.9%) individuals. The characteristics associated with frailty included chronological age, CD4⁺ T-cell count, HIV-1 RNA viral load, smoking, and age-related comorbid conditions. GrimAge acceleration (GrimAA), PhenoAge acceleration (PhenoAA), and HannumAge acceleration (HannumAA) were associated with frailty, but HorvathAge acceleration (HorvathAA) was not. The strength of the association was attenuated with adjustment for characteristics but remained significant for the three markers. Age acceleration based on GrimAA (values >0) was independently associated with a 45% increased odds of frailty (OR_adj: 1.45, 95% CI, 1.10, 1.93). In <i>post hoc</i> analyses, only GrimAA was associated with exercise frequency. In conclusion, select EAA markers were associated with frailty, independently of the traditional predictors of frailty. GrimAA, in particular, may be useful in future research to develop treatment strategies for frailty tailored to PWH.