Circulating Metabolomic Analysis following Cecal Ligation and Puncture in Young and Aged Mice Reveals Age-Associated Temporal Shifts in Nicotinamide and Histidine/Histamine Metabolic Pathways

Abstract

Introduction. Aged individuals are at higher risk for morbidity and mortality following acute stressors than similarly stressed young people. Evaluation of age-associated metabolic changes could lead to the identification of specific therapeutic targets to improve outcomes from acute stressors, such as infections, in the elderly. We thus compared the plasma metabolomes of both young and old mice following cecal ligation and puncture (CLP), an accepted model of acute infection and stress. Methods. Young (9-17 wks) and aged (78-96 wks) male C57bl/6 mice were subjected to a retro-orbital bleed and two-week recovery prior to sham surgery (laparotomy alone) or CLP. Animals were sacrificed at 4 h, 8 h, or 12 h following intervention, and plasma was isolated from blood for subsequent analysis. Metabolomic analysis of samples were performed (Metabolon; Durham, NC). Results. Aged animals demonstrated greater intraprocedural mortality than young (30.2% vs. 17.4%, ${\chi }^2$ $p=0.0004$ ), confirming enhanced frailty. Principal component analysis and partial-least squares discriminant analysis of 566 metabolites demonstrated distinct metabolomic shifts following sham surgery or CLP in both young and aged animals. Identification of metabolites of interest using a consensus statistical approach revealed that both the histidine/histamine pathway and the nicotinamide pathway have significant age-associated alterations following CLP. Conclusions. The application of untargeted plasma metabolomics identified key pathways underpinning metabolomic responses to CLP in both young and aged animals. Ultimately, these data provide a robust foundation for future mechanistic studies that may assist in improving outcomes in frail patients in response to acute stressors such as infection, trauma, or surgery.