Abstract MP22: Plasma Metabolomic Profiles Associated With Mortality and Longevity in a Prospective Study of 13,401 Individuals

Background: Recent advances in metabolomic studies have shown promise in elucidating the biological pathways underpinning aging processes and mortality in animal models, but data in humans are lacking. We aimed to evaluate the associations between metabolite profiles, all-cause and cause-specific mortality, and longevity. Methods: Within three prospective cohorts (Nurses’ Health Study [NHS], NHSII, and Health Professional’s Follow-up Study), we measured plasma metabolites from 11,523 participants (mean age 54 years, 86% female) using high-throughput liquid chromatography-mass spectrometry. Participants were free of cardiovascular disease and cancer at blood collection. Metabolome-wide association analyses were conducted for all-cause, cardiovascular, and cancer mortality using Cox proportional hazards regression and longevity (attaining 85 years of age) using logistic regression. Both pre-defined and data-driven metabolite groups were also evaluated. We further developed a multi-metabolite profile score for all-cause mortality using an elastic-net regularized Cox model and assessed its associations with mortality and longevity. Results for all-cause mortality were replicated among 1878 participants (mean age 67 years, 58% female) from the PREDIMED trial. Results: We documented 4252 deaths (including 864 cardiovascular deaths and 1070 cancer deaths) and 3048 achieving longevity over a median follow-up of 22.6 years in the NHS/NHSII/HPFS, and 126 deaths during a follow-up of 4.7 years in the PREDIMED. Higher levels of three nucleosides (N2,N2-dimethylguanosine, pseudouridine, and N4-acetylcytidine), 4-acetamidobutanoic acid, triacylglycerols with ≤56 carbons and ≤3 double bonds, and several other lipids were associated with increased risk of all-cause mortality and corresponding decreased likelihood of longevity; whereas L-serine, L-glutamine, and TAGs with >56 carbons or >3 double bonds were associated with lower mortality risk and higher odds of achieving longevity. A multi-metabolite profile score comprising 73 metabolites was positively associated with all-cause (HR per 1-SD increment=1.25 [95% CI: 1.21, 1.30] in NHS/NHSII/HPFS and 1.47 [95% CI: 1.22, 1.78] in PREDIMED), cardiovascular (HR=1.34 [95% CI:1.24, 1.45]), and cancer mortality (HR=1.15 [95% CI:1.08, 1.24]) and inversely associated with longevity (OR=0.79 [95% CI: 0.74, 0.86]). Conclusions: We identified multiple metabolites associated with mortality and longevity. Our findings provide insights into the biological pathways that lead to death and open up new avenues to incorporate these metabolomic markers in clinical and research settings.