Reproductive factors and biological aging: the association with all-cause and cause-specific premature mortality

STUDY QUESTION: Are reproductive factors associated with biological aging, and does biological aging mediate the associations of reproductive factors with premature mortality? SUMMARY ANSWER: Multiple reproductive factors are related to phenotypic age acceleration (PhenoAge-Accel), while adherence to a healthy lifestyle mitigates these harmful effects; PhenoAge-Accel mediated the associations between reproductive factors and premature mortality. WHAT IS KNOWN ALREADY: Accelerated aging is a key contributor to mortality, but knowledge about the effect of reproductive factors on aging is limited. STUDY DESIGN, SIZE, DURATION: This prospective cohort study included 223 729 women aged 40-69 years from the UK biobank in 2006-2010 and followed up until 12 November 2021. PARTICIPANTS/MATERIALS, SETTING, METHODS: Reproductive factors were collected through a touchscreen questionnaire. Biological aging was assessed through PhenoAge-Accel. Multiple linear regression models were used to examine the relationships of reproductive factors with PhenoAge-Accel and estimate the modified effect of a healthy lifestyle. Furthermore, we applied mediation analysis to explore the mediating role of PhenoAge-Accel in the associations between reproductive factors and premature mortality. MAIN RESULTS AND THE ROLE OF CHANCE: Early menarche (<12 years vs 13 years, β: 0.37, 95% CI: 0.30, 0.44), late menarche (≥15 years vs 13 years, β: 0.18, 95% CI: 0.11, 0.25), early menopause (<45 years vs 50-51 years, β: 0.62, 95% CI: 0.51, 0.72), short reproductive lifespan (<30 years vs 35-39 years, β: 0.81, 95% CI: 0.70, 0.92), nulliparity (vs two live births, β: 0.36, 95% CI: 0.30, 0.43), high parity (≥4 vs 2 live births, β: 0.49, 95% CI: 0.40, 0.59), early age at first live birth (<20 years vs 25-29 years, β: 0.66, 95% CI: 0.56, 0.75), and stillbirth (β: 0.51, 95% CI: 0.36, 0.65) were associated with increased PhenoAge-Accel. Furthermore, PhenoAge-Accel mediated 6.0%-29.7% of the associations between reproductive factors and premature mortality. Women with an unfavorable lifestyle and reproductive risk factors had the highest PhenoAge-Accel compared to those with a favorable lifestyle and without reproductive risk factors. LIMITATIONS, REASONS FOR CAUTION: The participants in the UK Biobank were predominantly of White ethnicity; thus, caution is warranted when generalizing these findings to other ethnic groups. WIDER IMPLICATIONS OF THE FINDINGS: Our findings reveal the harmful effects of multiple reproductive factors on biological aging and the mediating role of biological aging in the associations between reproductive factors and premature mortality. They highlight the significance of adhering to a healthy lifestyle to slow biological aging as a potential way to reduce premature mortality among women with reproductive risk factors. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by the National Natural Science Foundation of China (82003479, 82073660, 72204215), Hubei Provincial Natural Science Foundation of China (2023AFB663), Zhejiang Province Public Welfare Technology Application Research Project (GF22H269155), and China Postdoctoral Science Foundation (2019M662646, 2020T130220). The authors have no competing interests to disclose. TRIAL REGISTRATION NUMBER: N/A.