Abstract
Frailty is a common geriatric syndrome associated with increased mortality, yet its underlying biological mechanisms and potential value for early risk stratification remain inadequately understood. In this large prospective cohort of more than 260,000 UK Biobank participants with plasma metabolomic profiling, we identified and validated metabolomic signatures of physical frailty and a 49-item frailty index using 50-times repeated 10-fold cross-validated elastic-net regression. The signatures demonstrated strong internal stability and geographic reproducibility and reflected coordinated alterations across lipid, amino acid, energy, and inflammatory pathways. Higher signature levels were significantly associated with increased risks of all-cause and cause-specific mortality, including cancer, cardiovascular, respiratory, and digestive deaths. Individuals in the highest-risk tertile had more than 2.5-fold higher risks of cardiovascular, respiratory, and digestive mortality. At age 60, individuals above the median signature level were estimated to have 4.1 fewer years of life expectancy. Mediation analyses indicated that the metabolomic signatures statistically explained up to 35% of the observed frailty–mortality association. Associations were stronger among younger individuals and differed by sex and BMI. These findings suggest that frailty-related plasma metabolomic signatures capture systemic metabolic correlates of biological aging and may support early mortality risk prediction and personalized prevention strategies in aging populations.
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Data availability
The data that support the findings of this study are available from the UK Biobank (https://www.ukbiobank.ac.uk/), but restrictions apply to their availability. The data were used under licence for the current study and are therefore not publicly available. Access to the UK Biobank resource requires an approved application; researchers may apply for data access through the UK Biobank Access Management System.
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Acknowledgements
This study was conducted using data from the UK Biobank resource under application number 98679. We are grateful to all participants and professionals contributing to the UK Biobank. This work was supported by the National Natural Science Foundation of China to X.Z. (82304211), C.M. (82425052), C.D. (82271298), and X.F. (82201427), and by the Foundation of the National Health Commission Capacity Building and Continuing Education Center to C.D. (GWJJ2022100102). The funders had no role in the study design or conduct; data collection, management, analysis, or interpretation; manuscript preparation, review or approval; or the decision to submit the manuscript for publication.
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X.Z. and X.F. conceived and designed the study and contributed equally to this work. C.M. and C.D. supervised the study. X.Z., X.F., and Q.H. acquired, analyzed, and interpreted the data. X.Z., P.Z., and Z.L. provided statistical expertise. C.M., C.D., X.Z., X.F., W.L., and Q.H. contributed to the discussion and interpretation of the results. X.Z. and R.L. drafted the manuscript. All authors critically revised the manuscript for important intellectual content, approved the final version, and agreed to be accountable for all aspects of the work. C.M., C.D., X.Z., and X.F. secured funding. X.F. and Z.L. provided technical, material, or administrative support.
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Zhang, X., Feng, X., Liu, W. et al. Frailty-related plasma metabolomic signatures predict long-term mortality risk and implicate systemic aging pathways: evidence from a prospective cohort study. npj Aging (2026). https://doi.org/10.1038/s41514-025-00327-9
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DOI: https://doi.org/10.1038/s41514-025-00327-9
