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

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< <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:msubsup><mml:mrow><mml:mi>h</mml:mi></mml:mrow> <mml:mrow><mml:mi>S</mml:mi> <mml:mi>N</mml:mi> <mml:mi>P</mml:mi></mml:mrow> <mml:mrow><mml:mn>2</mml:mn></mml:mrow> </mml:msubsup> </mml:math> < 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/ .