Associations of breast DNA methylation–based measures of biological ageing with obesity-related breast cancer risk markers

Advancing age and deregulated obesity are well-established risk factors for breast cancer risk. While epigenetic ageing, a measure of biological ageing, has been linked to breast cancer risk, prior studies have mainly focused on blood-based measures. We aimed to study well-established epigenetic age estimates in normal breast tissue in relation to obesity-related metabolic markers. We analysed breast tissue from 91 cancer-free women, using DNA methylation age (mAge) clocks, including first-generation clocks (Hannum, Horvath), mortality-related clocks (Grim, Pheno), and methylation-based telomere length (DNAmTL). Pearson correlations assessed relationships among the clocks. Linear regression was used to associate mAge clocks with obesity-related blood markers (leptin, adiponectin, IGF-1, IGFBP-3), adjusting for chronological age, race, body mass index (BMI), and smoking, applying a false discovery rate threshold of 0.1. We explored effect modification by menopausal status using interaction terms. In the normal breast tissue, the strongest correlation of mAge estimates was observed between Horvath-mAge and Grim-mAge (r = 0.85). BMI was positively associated with all mAge estimates except Pheno-mAge. Older Grim-mAge and longer DNAmTL were associated with higher levels of adiponectin, IGF-1, and IGFBP-3, while older Horvath-mAge was associated only with IGF-1. Associations of DNAmTL with IGF-1 and adiponectin differed statistically by menopausal status. Epigenetic age in breast tissue, particularly Grim and DNAmTL, is associated with obesity-related metabolic markers, independent of chronological age, BMI, and smoking. Although limited by a moderate sample size, our findings indicate a potential biological pathway linking mAge-related metabolic dysregulation that may provide insight into breast cancer risk.