A decade of epigenetic change in aging twins: Genetic and environmental contributions to longitudinal DNA methylation

BACKGROUND: Epigenetic changes may result from the interplay of environmental exposures and genetic influences and contribute to differences in age-related disease, disability, and mortality risk. However, the etiologies contributing to stability and change in DNA methylation have rarely been examined longitudinally. METHODS: We considered DNA methylation in whole blood leukocyte DNA across a 10-year span in two samples of same-sex aging twins: (a) Swedish Adoption Twin Study of Aging (SATSA; N = 53 pairs, 53% female; 62.9 and 72.5 years, SD = 7.2 years); (b) Longitudinal Study of Aging Danish Twins (LSADT; N = 43 pairs, 72% female, 76.2 and 86.1 years, SD=1.8 years). Joint biometrical analyses were conducted on 358,836 methylation probes in common. Bivariate twin models were fitted, adjusting for age, sex, and country. RESULTS: Overall, results suggest genetic contributions to DNA methylation across 358,836 sites tended to be small and lessen across 10 years (broad heritability M = 23.8% and 18.0%) but contributed to stability across time while person-specific factors explained emergent influences across the decade. Aging-specific sites identified from prior EWAS and methylation age clocks were more heritable than background sites. The 5037 sites that showed the greatest heritable/familial-environmental influences (p < 1E-07) were enriched for immune and inflammation pathways while 2020 low stability sites showed enrichment in stress-related pathways. CONCLUSIONS: Across time, stability in methylation is primarily due to genetic contributions, while novel experiences and exposures contribute to methylation differences. Elevated genetic contributions at age-related methylation sites suggest that adaptions to aging and senescence(definition) may be differentially impacted by genetic background.