Cholesterol's hidden impact: the nonlinear link between remnant cholesterol (RC) and phenotypic age acceleration (PhenoAgeAccel)

Abstract

Cholesterol metabolism disorders have been shown to correlate with multiple physiopathologic aspects of cellular aging. However, whether indicators reflecting cholesterol metabolism [e.g., remnant cholesterol (RC)] can serve as biomarkers for biological aging remains unclear. To address this gap, this study aimed to explore the relationship between RC and phenotypic age acceleration (PhenoAgeAccel) using data from the National Health and Nutrition Examination Survey (NHANES) database. First, participants with complete information on RC, PhenoAgeAccel, and other essential covariates were included and analyzed. Subsequently, multivariable generalized linear regression models, subgroup analyses, interaction tests, and restricted cubic spline (RCS) analyses were utilized to explore the association. Results showed that a total of 4,471 participants were included for analysis. After adjusting for all potential covariates, a one-unit increase in RC was associated with a 0.724-year increase in PhenoAgeAccel (β = 0.724, 95% CI: 0.106-1.341). Notably, subgroup analyses and interaction tests further revealed a more pronounced RC-PhenoAgeAccel association in individuals with diabetes (β = 4.331, 95% CI: 1.607-7.055) and hypertension (β = 2.069, 95% CI: 0.887-3.251). In addition, RCS analysis identified a positive and nonlinear association between RC and PhenoAgeAccel (P for nonlinearity < 0.001), and threshold effect analysis determined an inflection point of 0.564 mmol/L for RC. Specifically, a positive and segmented RC-PhenoAgeAccel association was observed within the 0.564-mmol/L threshold (β = 9.653, 95% CI: 7.452-11.853), and such association remained significant beyond this point (β = 1.121, 95% CI: 0.193-2.049). In conclusion, RC was positively and nonlinearly associated with accelerated aging. Thus, controlling RC below 0.564 mmol/L might contribute to anti-aging effects and thereby help prevent aging-related diseases.

Keywords: Accelerated aging; Cholesterol metabolism; NHANES; PhenoAgeAccel; Remnant cholesterol.