Background: 1H-NMR metabolomics and DNA methylation in blood are widely known biomarkers predicting age-related physiological decline and mortality yet exert mutually independent mortality and frailty signals.
Methods: Leveraging multi-omics data in four Dutch population studies (N = 5238, ∼40% of which male) we investigated whether the mortality signal captured by 1H-NMR metabolomics could guide the construction of DNA methylation-based mortality predictors.
Findings: We trained DNA methylation-based surrogates for 64 metabolomic analytes and found that analytes marking inflammation, fluid balance, or HDL/VLDL metabolism could be accurately reconstructed using DNA-methylation assays. Interestingly, a previously reported multi-analyte score indicating mortality risk (MetaboHealth) could also be accurately reconstructed. Sixteen of our derived surrogates, including the MetaboHealth surrogate, showed significant associations with mortality, independent of relevant covariates.
Interpretation: The addition of our metabolic analyte-derived surrogates to the well-established epigenetic clock GrimAge demonstrates that our surrogates potentially represent valuable mortality signal.
Funding: BBMRI-NL, X-omics, VOILA, Medical Delta, NWO, ERC.
Keywords: Ageing biomarkers; DNA methylation predictors; Epidemiology; Epigenetic clock; Metabolic risk score; NMR metabolomics.
Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.