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Metabolomic aging and mortality clocks based on ensemble learning identify systemic aging risk across the human lifespan in 18,476 individuals

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Sep 01, 2026 version files 13.29 MB

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Abstract

Aging is characterized by progressive functional decline, yet metabolomic signatures across the human lifespan remain incompletely defined. Here, we profiled plasma metabolomes from 18,476 participants aged 1-96 years across six centers in China using nano-assisted laser desorption/ionization mass spectrometry (LDI-MS) and identified 56 representative age-associated metabolites. In a healthy cohort, we developed a stacking ensemble model to estimate metabolomic age (mAge) and quantified metabolomic age acceleration (mAA) as the deviation of mAge from chronological age (cAge). Higher mAA was associated with health deterioration and unfavorable lifestyle factors. During 5.5 years of follow-up, individuals with accelerated mAA showed increased risk of incident chronic diseases, such as cancer, hypertension, and diabetes, as well as increased all-cause mortality. In a diseased cohort, we further developed a mortality-linked metabolomic measure (age deviation) that quantifies individualized departures from age-expected mortality risk inferred from plasma metabolites. Age deviation was associated with composite clinical health measures and increased with multi-system disease involvement and higher multimorbidity burden. Together, these findings establish a scalable, lifespan-wide metabolomics framework that yields clinically interpretable metabolomic aging metrics and captures disease-related departures from age-expected risk.