Background: Shift work has been associated with increased risk of age-related morbidity and mortality. Biological age, estimated using DNA methylation (DNAm), may quantify the biological consequences of shift work on the risk of age-related disease. We examined whether prior employment in shift-working occupations was associated with epigenetic age acceleration. Methods: In a sample of non-Hispanic White women aged 35-74 (n = 2574), we measured DNAm using the Illumina Infinium Human450 BeadChip and calculated DNAm age using three established epigenetic clocks. Age-acceleration metrics were derived by regressing DNAm age on chronological age and predicting the residuals. Using linear regression, we estimated associations between shift work history and age acceleration. We also conducted an epigenome-wide association study using robust linear-regression models corrected with false discovery rate (FDR) q-values. Results: Approximately 7% of women reported any shift work. Higher age acceleration was observed for a 1-year increase in overall [beta = 0.11, 95% confidence interval (CI): 0.02-0.21] and night-specific shift work (beta = 0.12, 95% CI: 0.03-0.21). The association was strongest for >= 10 years of night shift work (beta = 3.16, 95% CI: 1.17-5.15). From the epigenome-wide association study, years of overall and night shift work were associated with DNAm at 66 and 85 CpG sites (FDR < 0.05), respectively. Years of night shift work was associated with lower methylation of a CpG in the gene body of ZFHX3 (cg04994202, q = 0.04), a gene related to circadian rhythm. Conclusions: Shift work was associated with differential CpG site methylation and with differential DNAm patterns, measured by epigenetic age acceleration, consistent with long-term negative health effects.
