Age Acceleration is Associated with Reduced Cognitive Function in Older Men: Results from the Normative Aging Study

BACKGROUND AND AIM: DNA methylation (DNAm) has been used to quantify the biological effects of external factors on aging processes. This study examined the association between age acceleration and cognitive function in older men using DNAm-based clocks. METHODS: We evaluated the associations of age acceleration on cognitive function among participants in the Normative Aging Study (NAS). We tested GrimAgeAccel (a biomarker linked with mortality), PhenoAgeAccel (capturing risks for diverse outcomes), Intrinsic (IEAA), and Extrinsic (EEAA) Age Acceleration, and the DNAm-related mortality risk score (DNAmRS). DNAm was determined using Illumina 450K arrays. We modeled six cognitive tests (Mini-Mental State Examination [global function], Word List Memory Task [recent memory], Digit Span Backwards [executive function], Verbal Fluency Test [language], Sum of Drawings [visuospatial ability], and Pattern Comparison Task [visuospatial function]) in linear mixed models adjusted for chronological age, alcohol, smoking status, fish consumption, physical activity, hypertension, diabetes mellitus, English as the first language, computer experience, education, body mass index, and methylation technical covariates. RESULTS: We evaluated 549 men (mean age: 74.3 years, standard deviation: 6.5 years), mostly white (91.23%). GrimAgeAccel showed significant negative associations with global cognition (β = -0.029, 95% Confidence Interval [95%CI] -0.043, -0.015, p-value < 0.001) and visospatial ability (β = -0.018, 95% CI -0.033, -0.003, p-value = 0.019). PhenoAgeAccel was negatively associated with executive function (β = -0.009, 95% CI -0.017, -0.001, p-value = 0.041) and visuospatial ability (β = -0.019, 95% CI -0.029, -0.008, p-value < 0.001). DNAmRS was negatively associated with recent memory and executive function. IEAA and EEAA did not show consistent results. CONCLUSIONS: Selected age acceleration biomarkers were associated with accelerated cognitive decline in older men. DNAm-based biological clocks may help identify individuals at higher risk for age-related cognitive decline. KEYWORDS: Aging, age acceleration, cognitive function, age-related, DNA methylation.