Differential methylation clock ages across buffy coat (BC), peripheral blood mononuclear cells (PBMC), and saliva in individuals approaching midlife

Epigenetic aging prior to midlife is gaining interest as an intervenable period to address health and cognitive aging. Epigenetic changes may index DNA methylation aging rates, but methylation profiles may not be substitutable across tissues. We compared DNA methylation clocks and age acceleration in saliva, buffy coat (BC), and peripheral blood mononuclear cells (PBMC) collected in 91 individuals (7 unpaired, 20 siblings, 64 twins; 18 monozygotic (MZ), 14 dizygotic (DZ) pairs) from the Colorado Adoption/Twin Study of Lifespan behavioral development and cognitive aging (CATSLife1; Mean age=30.90 years [range=28.07-41.13]; 50.5% female). Across 15 DNA methylation clocks, chronological age and DNA methylation ages were moderately associated (Mean Spearman correlations: r=0.36, Saliva; r=0.41, BC; r=0.36, PBMC). In mixed-effects models, saliva showed higher DNA methylation ages (B=3.83-16.46 years vs BC, p<0.001), whereas PBMC and BC were comparable (B=-0.06-0.39 years vs BC, p[&ge;]0.447). The exception was the next-generation clock DunedinPace showing comparability (p=0.486). Similar patterns were observed for age acceleration estimates. Altogether, MZ pairs (meta-analytic r=0.48, 95%CI=0.30,0.65) and DZ pairs (meta-analytic r=0.38, 95%CI=0.29,0.46) were moderately correlated (Spearman), but MZ pairs showed heterogeneity across tissues (p<0.020): saliva was lower (Mean r=0.31, SD=0.24) than BC (Mean r=0.63, SD=0.11) and PBMC (Mean r=0.47, SD=0.19). Next-generation PCGrimAge and DunedinPace clocks showed consistent cross-tissue correlations within zygosity, while multi-tissue clocks (e.g., ZhangQ) showed comparable MZ-DZ correlations. While saliva-based DNA methylation is not a direct substitute for blood-based DNA methylation, BC and PBMC show comparability; nevertheless, all tissue types may be appropriate for DNA methylation aging studies when compared within tissues. Key Policy HighlightsO_LISaliva-based methylation is not a direct substitute for blood-based methylation. C_LIO_LISaliva-based DNA methylation clocks demonstrated relatively older methylation ages and faster age accelerations relative to blood-based DNA methylation clocks. C_LIO_LIBlood-based DNA methylation clocks were comparable across buffy coat and peripheral blood mononuclear cell tissues. C_LIO_LITwin similarity, particularly among identical twins, was higher for blood-based DNA methylation clocks and newer generation DNA methylation clocks. C_LIO_LIThree clocks (one first-generation multi-tissue and two next-generation) showed consistency and/or comparability across tissues and showed moderate to strong correlations among identical and fraternal twins, supporting the importance of tool development. C_LI