title: Metabolic drift in the aging brain.
abstract: Brain function is highly dependent upon controlled energy metabolism whose loss heralds cognitive impairments. This is particularly notable in the aged individuals and in age-related neurodegenerative diseases. However, how metabolic homeostasis is disrupted in the aging brain is still poorly understood. Here we performed global, metabolomic and proteomic analyses across different anatomical regions of mouse brain at different stages of its adult lifespan. Interestingly, while severe proteomic imbalance was absent, global-untargeted metabolomics revealed an energymetabolic drift or significant imbalance in core metabolite levels in aged mouse brains. Metabolic imbalance was characterized by compromised cellular energy status (NAD decline, increased AMP/ATP, purine/pyrimidine accumulation) and significantly altered oxidative phosphorylation and nucleotide biosynthesis and degradation. The central energy metabolic drift suggests a failure of the cellular machinery to restore metabostasis (metabolite homeostasis) in the aged brain and therefore an inability to respond properly to external stimuli, likely driving the alterations in signaling activity and thus in neuronal function and communication.
authors.affiliation: Metabolomics Research Platform, University of Lausanne, 1005 Lausanne, Switzerland.
authors.forename: Julijana
authors.initials: J
authors.lastname: Ivanisevic
authors.affiliation: Departments of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198-5800, USA.
authors.forename: Kelly L
authors.initials: KL
authors.lastname: Stauch
authors.affiliation: Departments of Chemical Physiology, Molecular and Cellular Neuroscience, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Petrascheck
authors.affiliation: Scripps Center for Metabolomics and Mass Spectrometry, Departments of Chemistry, Molecular and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: H Paul
authors.initials: HP
authors.lastname: Benton
authors.affiliation: Departments of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198-5800, USA.|Department of Radiology, University of Nebraska Medical Center, Omaha, NE 68198-1045, USA.
authors.forename: Adrian A
authors.initials: AA
authors.lastname: Epstein
authors.affiliation: Scripps Center for Metabolomics and Mass Spectrometry, Departments of Chemistry, Molecular and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.|School of Civil and Environmental Engineering, Nanyang Technological University, Singapore 639798, Singapore.
authors.forename: Mingliang
authors.initials: M
authors.lastname: Fang
authors.affiliation: Departments of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198-5800, USA.
authors.forename: Santhi
authors.initials: S
authors.lastname: Gorantla
authors.affiliation: Scripps Center for Metabolomics and Mass Spectrometry, Departments of Chemistry, Molecular and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Minerva
authors.initials: M
authors.lastname: Tran
authors.affiliation: Scripps Center for Metabolomics and Mass Spectrometry, Departments of Chemistry, Molecular and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Linh
authors.initials: L
authors.lastname: Hoang
authors.affiliation: Drug Metabolism and Pharmacokinetics, Innovative Medicine, AstraZeneca, Mölndal 431 83, Sweden.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Kurczy
authors.affiliation: Department of Radiology, University of Nebraska Medical Center, Omaha, NE 68198-1045, USA.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Boska
authors.affiliation: Departments of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198-5800, USA.
authors.forename: Howard E
authors.initials: HE
authors.lastname: Gendelman
authors.affiliation: Departments of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198-5800, USA.
authors.forename: Howard S
authors.initials: HS
authors.lastname: Fox
authors.affiliation: Scripps Center for Metabolomics and Mass Spectrometry, Departments of Chemistry, Molecular and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Gary
authors.initials: G
authors.lastname: Siuzdak
mesh_terms: D000375:Aging / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism*; D004734:Energy Metabolism / Q000502:physiology*; D055432:Metabolomics; D051379:Mice; D010085:Oxidative Phosphorylation; D040901:Proteomics
keywords: energy metabolism; healthy brain aging; metabolic drift; metabolomics; proteomics