DNA Methylation "GrimAge" Acceleration Mediates Sex/Gender Differences in Verbal Memory and Processing Speed: Findings From the Health and Retirement Study

Abstract

Whether sex/gender differences in rates of biological aging mediate sex/gender differences in cognition in older adults has not been fully examined. The aim of the current study was to investigate this association. Data from up to 1 928 participants (mean age = 75, standard deviation = 7.04, female = 57%) who took part in the 2016 Harmonized Cognitive Assessment Protocol and Venous Blood Study; substudies of the Health and Retirement Study were included in the current study. The residuals from 4 age-adjusted epigenetic clocks (Horvath, Hannum, PhenoAge, and GrimAge) were used to measure biological age acceleration. Sex/gender differences in cognition were tested using a series of analyses of covariance. Mediation analyses tested whether the measures of age acceleration accounted for these sex/gender differences, controlling for age, education, smoking status, and white blood cell count. Women outperformed men on measures of verbal learning, verbal memory, visual scanning, and processing speed. No other significant sex/gender differences were identified. Results from mediation analyses revealed that women's slower rates of GrimAge fully accounted for their faster processing speeds and partially accounted for their better performances on verbal learning, verbal memory, and visual scanning measures. None of the other measures of age acceleration were significant mediators. Accounting for sex/gender differences in biological aging may differentiate between cognitive sex/gender differences that are driven by universal (ie, age-related) versus sex-specific mechanisms. More broadly, these findings support the growing evidence that the GrimAge clock outperforms other clocks in predicting cognitive outcomes.

Keywords: Biological age; Cognition; DNA methylation; Sex/gender differences.