Abstract
Menopause-related metabolic remodeling may contribute to the excess cardiovascular disease (CVD) burden in aging women, yet the longitudinal metabolic correlates of time since menopause (TSM) and their prognostic value are unclear. In this prospective analysis of 67,582 postmenopausal women without baseline CVD from the UK Biobank, we profiled 251 plasma metabolites by nuclear magnetic resonance and followed participants for a median 13.7 years (8313 incident CVD events). Elastic net regression identified a 95‑metabolite TSM-associated metabolomic signature (Spearman r with TSM = 0.29). In multivariable Cox models, each 5-year increment in TSM (HR 1.14, 95% CI 1.11–1.16) and each 1–standard deviation increases in the metabolomic signature (HR 1.18, 95% CI 1.15–1.21) were independently associated with higher composite CVD risk, with consistent associations across myocardial infarction, ischemic heart disease, atrial fibrillation, heart failure and stroke. Mendelian randomization supported potential causal roles for 29 of the signature metabolites in CVD. Adding TSM or the metabolomic signature to SCORE2 improved 10‑year risk discrimination (area under the curve 0.584 to 0.657 and 0.660, respectively) and reclassification (net reclassification improvement +0.027 and +1.043). These findings implicate cumulative postmenopausal metabolic alterations in vascular risk and support metabolomic enhancement of risk stratification in postmenopausal women.
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The data described in the manuscript will be made available for researchers who apply to use the UK Biobank data set by registering and applying at http://www.ukbiobank.ac.uk/enable-your-research/register. Code availability: The underlying code for this study is not publicly available but may be made available to qualified researchers on reasonable request from the corresponding author.
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Acknowledgements
This research has been conducted using the UK Biobank resource (application number 227947). The authors are grateful to UK Biobank participants. We acknowledge the financial support from the National Natural Science Foundation of China (82273702). The funding sources had no role in the study design, data collection, data analysis, data interpretation, or writing of the report.
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All the authors contributed substantially to the completion of this study. DZ conceived of the presented idea. Q.W. and B.X. performed the data analyses, established the machine learning models, and drafted the manuscript. Q.W., B.X., C.F., M.L., and X.W. participated in data collection. N.S., S.S.V., and S.R.M. provided critical feedback. Q.W., B.X., and D.Z. had primary responsibility for study design and data interpretation. All authors have read and approved the final version of the manuscript.
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Wang, Q., Xie, B., Fu, C. et al. Integrating menopause duration and plasma metabolomics enhances cardiovascular risk stratification in aging women. npj Aging (2026). https://doi.org/10.1038/s41514-025-00323-z
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DOI: https://doi.org/10.1038/s41514-025-00323-z
