Abstract
BACKGROUND/OBJECTIVES: Menopause and related metabolites are associated with mortality. However, the relationship between earlier menopause, premature mortality, and the role of metabolomic signatures remains underexplored. This study investigated the association between earlier menopause and premature mortality, and the mediating effect of metabolomic signatures. METHODS: This prospective cohort study used data from the UK Biobank, including 33,687 post-menopausal women aged 40-69 years. Age at menopause was obtained from a baseline self-reported questionnaire and analyzed both as a continuous variable and in categories (<40, 40-49, and ≥50 years). Premature mortality was defined as deaths before 75 years. Cox regression was used to estimate hazard ratios (HRs), and elastic net regression identified metabolomic signatures related to menopause age. Mediation analysis was conducted to assess the proportion of the association explained by the metabolomic signature. RESULTS: During a median follow-up of 13.7 years, 1612 cases of premature mortality occurred. Compared to menopause at ≥50 years, earlier menopause (HR 1.17, 95% CI 1.04-1.30) and premature menopause (HR 1.60, 95% CI 1.28-2.00) were associated with higher risks of premature mortality. A metabolomic signature inversely associated with premature mortality (HR per SD increment, 0.79; 95% CI, 0.75-0.83) mediated 13.6% (95% CI, 1.9%-28.3%) of the association between earlier menopause and premature mortality. CONCLUSIONS: Earlier menopause is associated with an increased risk of premature mortality, partially mediated by a metabolomic signature related to age at menopause. These findings highlight the importance of metabolomic profiling in understanding menopause and mortality risks.