Abstract Body: Introduction. All-cause and cause-specific mortality remain major measures of public health burden, despite the rising number of individuals achieving longevity (≥85 years). Although many mortality-related metabolites have been identified, metabolite predictors of long-term mortality and longevity across diverse populations remain understudied. We aim to identify novel metabolites associated with mortality and longevity.

Methods. Circulating metabolite profiling was performed across seven cohorts in the Trans-Omics for Precision Medicine project. Cox models were used to examine the associations of 1,121 metabolites with all-cause, cardiovascular (CV), cancer, and respiratory mortality. Logistic regression was used to assess longevity, defined as living past 85 years at the end of follow-up, adjusting for clinical risk factors (CRF). Random-effects meta-analysis was used to estimate joint effects, and subgroup analyses were conducted by sex and race. Replication was performed using independent samples.

Results. During an average follow-up of ten years among 26,091 participants (57% women, 41% Whites), there were 6,315 deaths, including 1,649 (26%), 1,387 (22%), and 314 (5%) from CV, cancer, and respiratory diseases, and 4,216 participants achieved longevity. A total of 183, 101, 12, and 23 metabolites were discovered and replicated (FDR < 0.05) for all-cause, CV, cancer, and respiratory mortality, with a range of 20% to 98% risk difference per SD increase of the metabolite. Nearly half of the metabolites were novel, and carnitines, glycerophospholipids, ceramides, and sphingolipids were leading pathways. A metabolite risk score derived from all-cause mortality-related metabolites improved the prediction of all-cause mortality by an average of 3.3%, using Harrell’s C, beyond CRF across participating cohorts. In the longevity analyses, 38 metabolites were discovered and replicated, and 31 were shared with all-cause mortality (correlation r = -0.97). Among the seven metabolites uniquely linked to longevity, taurocholate, glycocholate, and glycoursodeoxycholate suggested distinct bile acid metabolism, possibly driven by enterohepatic or microbiome-related processes. Subgroup analyses of all-cause mortality and longevity by sex and race revealed no significant heterogeneity across strata.

Conclusions. We identified circulating metabolites associated with mortality and longevity, providing insight into slowing aging and the identification of at-risk populations.