1H-NMR metabolomics-guided DNA methylation mortality predictors

1 H-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. Leveraging multi-omics data in four Dutch population studies (N=5238) we investigated whether the mortality signal captured by 1 H-NMR metabolomics could guide the construction of novel DNA methylation-based mortality predictors. Hence, 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 other relevant covariates. Finally, adding our novel surrogates to previously established DNA-methylation markers, such as GrimAge, showed significant improvement for predicting all-cause mortality, indicating that our metabolic analyte-derived surrogates potentially represent novel mortality signal.