Journal Article

Multi-organ metabolome biological age implicates cardiometabolic conditions and mortality risk

Davatzikos, Christos, Ko, Sarah, Anagnostakis, Filippos, Wang, Jingyue, Saadatinia, Mehrshad, Wen, Junhao

2025

Overview

Multi-organ biological aging clocks across different organ systems have been shown to predict human disease and mortality. Here, we extend this multi-organ framework to plasma metabolomics, developing five organ-specific metabolome-based biological age gaps (MetBAGs) using 107 plasma non-derivatized metabolites from 274,247 UK Biobank participants. Our age prediction models achieve a mean absolute error of approximately 6 years (0.25< r  < 0.42). Crucially, including composite metabolites (e.g. sums or ratios of raw metabolites) results in poor generalizability to independent test data due to multicollinearity. Genome-wide associations identify 405 MetBAG-locus pairs (P < 5 × 10 −8 /5). Using SBayesS, we estimate the SNP-based heritability (0.09< h S N P 2  < 0.18), negative selection signatures (−0.93 <  S  < −0.76), and polygenicity (0.001< Pi  < 0.003) for the 5 MetBAGs. Genetic correlation and Mendelian randomization analyses reveal potential causal links between the 5 MetBAGs and cardiometabolic conditions (e.g., metabolic disorders and hypertension). Integrating multi-organ and multi-omics features improves disease category and mortality predictions. The 5 MetBAGs extend existing biological aging clocks to study human aging and disease across multiple biological scales. All results are publicly available at https://labs-laboratory.com/medicine/ . Aging affects multiple organs and tracking these changes could improve our understanding of disease risk. Here, the authors show that metabolomics-based organ-specific aging clocks can predict future risk of cardiometabolic disease and mortality.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 45 / 45/43 / 49 / 631/208/205/2138 / 692/53/2423 / 692/700/459 / Adult / Aged / Aged, 80 and over / Aging / Aging - genetics / Aging - metabolism / Biological effects / Cardiovascular Diseases - genetics / Cardiovascular Diseases - metabolism / Cardiovascular Diseases - mortality / Clocks / Female / Genome-Wide Association Study / Health risks / Heritability / Humanities and Social Sciences / Humans / Hypertension / Male / Mendelian Randomization Analysis / Metabolic Diseases - genetics / Metabolic Diseases - metabolism / Metabolic Diseases - mortality / Metabolic disorders / Metabolites / Metabolome - genetics / Metabolomics / Metabolomics - methods / Middle Aged / Mortality / Mortality risk / multidisciplinary / Polymorphism, Single Nucleotide / Prediction models / Risk / Science / Science (multidisciplinary) / Single-nucleotide polymorphism / United Kingdom