Biological age measured by DNA methylation clocks and reproductive history: Systematic review and meta-analysis

Reproductive history has implications for long-term health, with menopausal timing and parity associated with chronic disease risk. DNA methylation (DNAm) clocks are biomarkers of aging and estimate epigenetic age acceleration (EAA) in reproductive tissues and systemically. DNAm clocks provide mechanistic insight into how reproductive history relates to aging. This study aimed to identify associations between reproductive history and DNAm clocks. Twenty-nine studies comprising 550,550 participants (median mean age=35.4 (IQR: 30.3-62.7) years, 100% female) assessing associations between reproductive history and EAA were included. Across studies, preterm birth and earlier age at menopause was consistently associated with higher EAA, yet age at menarche, pregnancy complications, and adverse birth outcomes showed mixed findings. Meta-analysis of cross-sectional studies showed each one-year earlier age at menopause was significantly associated with higher EAA, strongest in GrimAge (n=5920, β=-0.08 years, 95% CI: -0.11, -0.05). No relationship was found between age at menarche and EAA in any DNAm clocks. Meta-analysis of parity showed associations with EAA using PhenoAge (n=4508, β=0.13 years per delivery, 95% CI: 0.04, 0.21). These findings highlight that aspects of reproductive history are cross-sectionally associated with higher EAA, particularly measured with 2^nd generation DNAm clocks (PhenoAge, GrimAge).