title: Meta-analysis of global metabolomic data identifies metabolites associated with life-span extension.
abstract: The manipulation of distinct signaling pathways and transcription factors has been shown to influence life span in a cell-non-autonomous manner in multicellular model organisms such asCaenorhabditis elegans. These data suggest that coordination of whole-organism aging involves endocrine signaling, however, the molecular identities of such signals have not yet been determined and their potential relevance in humans is unknown. Here we describe a novel metabolomic approach to identify molecules directly associated with extended life span inC. elegansthat represent candidate compounds for age-related endocrine signals. To identify metabolic perturbations directly linked to longevity, we developed metabolomic software for meta-analysis that enabled intelligent comparisons of multiple different mutants. Simple pairwise comparisons of long-livedglp-1, daf-2, andisp-1mutants to their respective controls resulted in more than 11,000 dysregulated metabolite features of statistical significance. By using meta-analysis, we were able to reduce this number to six compounds most likely to be associated with life-span extension. Mass spectrometry-based imaging studies suggested that these metabolites might be localized toC. elegansmuscle. We extended the metabolomic analysis to humans by comparing quadricep muscle tissue from young and old individuals and found that two of the same compounds associated with longevity in worms were also altered in human muscle with age. These findings provide candidate compounds that may serve as age-related endocrine signals and implicate muscle as a potential tissue regulating their levels in humans.
authors.affiliation: Departments of Chemistry, Genetics, and Medicine, Washington University School of Medicine, 660 S Euclid Ave, Campus Box 8232, St. Louis, MO 63110, USA.
authors.forename: Gary J
authors.initials: GJ
authors.lastname: Patti
authors.affiliation: Departments of Chemistry and Molecular Biology, The Center for Mass Spectrometry and Metabolomics, The Scripps Research Institute, 10550 N Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Ralf
authors.initials: R
authors.lastname: Tautenhahn
authors.affiliation: Human Physiology, The Pennington Biomedical Research Center, Baton Rouge, LA, USA.
authors.forename: Darcy
authors.initials: D
authors.lastname: Johannsen
authors.affiliation: Departments of Chemistry and Molecular Biology, The Center for Mass Spectrometry and Metabolomics, The Scripps Research Institute, 10550 N Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Ewa
authors.initials: E
authors.lastname: Kalisiak
authors.affiliation: Human Physiology, The Pennington Biomedical Research Center, Baton Rouge, LA, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Ravussin
authors.affiliation: Department of Mouse Genetics and Metabolism, Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD), Institute for Genetics and Center for Molecular Medicine, University of Cologne (CMMC), Zülpicher Str. 47, 50674 Cologne, Germany.
authors.forename: Jens C
authors.initials: JC
authors.lastname: Brüning
authors.affiliation: Howard Hughes Medical Institute, Glenn Center for Aging Research, The Salk Institute for Biological Studies, La Jolla, CA, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Dillin
authors.affiliation: Departments of Chemistry and Molecular Biology, The Center for Mass Spectrometry and Metabolomics, The Scripps Research Institute, 10550 N Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Gary
authors.initials: G
authors.lastname: Siuzdak
keywords: Aging; C. elegans; Meta-analysis; Metabolism; Metabolomics; Sarcopenia