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DNA methylation age (DNAmAge), or ‘epigenetic clocks’, surpass chronological age in their ability to predict age-related morbidities and mortality. This study utilized data from 287 middle-aged twins in the Lousiville Twin Study, including 60 monozygotic and 41 dizygotic complete twin pairs (mean age 51.9 years ± 7.03). We investigated the effect of DNAmAge acceleration on change in cognition between childhood and midlife, while testing early-life socioeconomic status (SES) as a moderator of the relationship. DNAmAge was estimated with five commonly used epigenetic clock algorithms. A factor analysis of the five clocks produced a two-factor structure which we identified as first generation and second generation clocks. Genetically informed, quasi-causal regression models were fitted in which adult IQ was predicted from childhood IQ, DNAmAge, and the interaction between DNAmAge and SES. Accelerated second generation DNAmAge predicted more negative change in IQ from childhood to midlife (b = −0.18, SE=0.07, p <.05), after accounting for genetic and environmental confounds shared by identical twins. There was an interaction such that the effect of second generation DNAmAge on IQ change was greater in twins raised in low SES households (b = 0.07, SE=0.03, p <.05). Second generation DNAmAge measures trained to estimate phenotypic biological age show promise in their predictive value for cognitive decline in midlife. Moreover, the longitudinal twin design of the LTS serves as a quasi-experimental framework to investigate hypothesized causal effects of DNAmAge on cognitive aging. Finally, these results suggest that the epigenome is a potential pathway through which early-life stressors become biologically embedded, impacting midlife aging outcomes.
