Sex differences in epigenetic ageing for older people living with HIV.

Abstract

Background: HIV-1 infection impacts biological ageing, and epigenetic clocks highlight epigenetic age acceleration in people with HIV. Despite evidence indicating sex differences in clinical, immunological, and virological measures, females have been underrepresented in most HIV epigenetic studies. Hence, we generated a more representative epigenetic dataset to examine sex differences in epigenetic ageing and relationships to clinical phenotypes and proteomics.

Methods: We calculated first, second, and third-generation epigenetic ages using DNA methylation data in an observational cohort of 52 females and 106 males with HIV age 50 and over. We profiled plasma biomarkers with Olink high-throughput proteomics to test associations with epigenetic age acceleration. Survival was ascertained over 5 years.

Findings: Epigenetic age acceleration measured by three principal-component based chronological epigenetic age clocks (p = 0.0029, 0.021, 0.010) and one epigenetic mortality risk clock was significantly lower in females living with HIV compared to males (p = 0.0011). Additionally, sex was significantly associated with epigenetic biomarker scores for proportion of naïve CD4+ T cells (p = 0.0006), physical fitness including DNAmGait (p = 0.0010), DNAmGrip (p < 0.0001), and DNAmV02 max (p < 0.0001). We found epigenetic age acceleration associated with plasma proteomic markers involved in inflammation, senescence, immune regulation, kidney function, and tissue homoeostasis (p < 0.0001). Higher epigenetic frailty risk scores were associated with lower CD4 T cell counts (p = 0.0072) and lower CD4/CD8 ratio (p = 0.0017). Slower gait (p = 0.0017), greater frailty (p = 0.0074), and history of smoking (p = 0.042) were associated with increased DNAmFitAge. Risk of death was increased in females with PCPhenoAge acceleration over a 5-year timespan compared to men with PCPhenoAge acceleration (p = 0.03).

Interpretation: These results highlight the importance of studying sex-specific differences in epigenetic ageing biomarkers for HIV-related geroscience research.

Funding: National Institute on Aging (K23AG072960), National Center for Advancing Translational Sciences (UL1TR000457), National Institute of Mental Health (R21 MH115821).