title: Age-associated metabolic dysregulation in bone marrow-derived macrophages stimulated with lipopolysaccharide.
abstract: Macrophages are major contributors to age-associated inflammation. Metabolic processes such as oxidative phosphorylation, glycolysis and the urea cycle regulate inflammatory responses by macrophages. Metabolic profiles changes with age; therefore, we hypothesized that dysregulation of metabolic processes could contribute to macrophage hyporesponsiveness to LPS. We examined the intracellular metabolome of bone marrow-derived macrophages from young (6-8 wk) and old (18-22 mo) mice following lipopolysaccharide (LPS) stimulation and tolerance. We discovered known and novel metabolites that were associated with the LPS response of macrophages from young mice, which were not inducible in macrophages from old mice. Macrophages from old mice were largely non-responsive towards LPS stimulation, and we did not observe a shift from oxidative phosphorylation to glycolysis. The critical regulatory metabolites succinate, γ-aminobutyric acid, arginine, ornithine and adenosine were increased in LPS-stimulated macrophages from young mice, but not macrophages from old mice. A shift between glycolysis and oxidative phosphorylation was not observed during LPS tolerance in macrophages from either young or old mice. Metabolic bottlenecks may be one of the mechanisms that contribute to the dysregulation of LPS responses with age.
authors.affiliation: Department of Chemistry and Chemical Biology, McMaster University, Hamilton L8S4M1, Canada.|Department of Pathology and Molecular Medicine, Michael G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton L8N3Z5, Canada.
authors.forename: Fan
authors.initials: F
authors.lastname: Fei
authors.affiliation: Department of Pathology and Molecular Medicine, Michael G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton L8N3Z5, Canada.
authors.forename: Keith M
authors.initials: KM
authors.lastname: Lee
authors.affiliation: Department of Chemistry and Chemical Biology, McMaster University, Hamilton L8S4M1, Canada.
authors.forename: Brian E
authors.initials: BE
authors.lastname: McCarry
authors.affiliation: Department of Pathology and Molecular Medicine, Michael G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton L8N3Z5, Canada.
authors.forename: Dawn M E
authors.initials: DM
authors.lastname: Bowdish
mesh_terms: D000375:Aging / Q000276:immunology / Q000378:metabolism*; D000818:Animals; D001120:Arginine / Q000378:metabolism; D002478:Cells, Cultured; D006019:Glycolysis; D007249:Inflammation / Q000276:immunology / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000276:immunology; D008262:Macrophage Activation; D008264:Macrophages / Q000276:immunology*; D008659:Metabolic Diseases / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D010085:Oxidative Phosphorylation; D019802:Succinic Acid / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D008070:Lipopolysaccharides; D005680:gamma-Aminobutyric Acid; D001120:Arginine; D019802:Succinic Acid