U-shaped association between HDL-C and epigenetic age acceleration: A cross-sectional analysis from NHANES 1999-2002

Notwithstanding extensive cardiovascular lipid investigations, the potential correlations between high-density lipoprotein cholesterol (HDL-C) and biological aging processes remain largely uncharted and inconclusive. HDL-C, with its established anti-inflammatory and antioxidant properties, may play important roles in aging-related mechanisms. Our investigative cross-sectional analysis explores the correlations between HDL-C levels and epigenetic age progression, utilizing the innovative GrimAge2 biomarker to unravel complex aging dynamics. We analyzed 2529 adults from the 1999 to 2002 National Health and Nutrition Examination Survey to examine associations between HDL-C levels and epigenetic age acceleration. We used multivariate linear regression with 3 progressive adjustment models to assess linear associations, and applied restricted cubic splines and threshold regression to evaluate nonlinear relationships. Comprehensive adjustment for demographic, metabolic, inflammatory, and lifestyle factors ensured the statistical rigor and interpretative precision of our findings. Multivariate regression analysis showed associations between HDL-C levels and epigenetic age acceleration. In the fully adjusted model, participants in the high HDL-C group demonstrated statistically significant aging deceleration relative to the reference group (β = -0.75, 95% confidence interval [CI]: -1.38 to -0.13; trend test P = .0205). Nonlinear threshold modeling revealed a U-shaped association with a critical transition point at 78 mg/dL. Below the threshold, incremental HDL-C elevations correlated with aging deceleration (β = -0.03, 95% CI: -0.04 to -0.01), while beyond this point, further increases were associated with aging acceleration (β = 0.07, 95% CI: 0.03-0.12). The nonlinear model provided significantly better fit than the linear model (P < .001). Our study reveals a nuanced biphasic association between HDL-C concentrations and epigenetic aging dynamics. Evidence indicates that HDL-C levels at both extremes might potentially modulate biological aging processes. These critical observations underscore the importance of precise HDL-C metabolic regulation and necessitate comprehensive longitudinal and mechanistic investigations to elucidate the intricate interactions between lipid metabolism and aging processes.