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Research Paper|Volume 8, Issue 5|pp 1000—1020

Metabolic drift in the aging brain

Julijana Ivanisevic1, Kelly L Stauch2, Michael Petrascheck3, H Paul Benton4, Adrian A Epstein2, Mingliang Fang4, Santhi Gorantla2, Minerva Tran4, Linh Hoang4, Michael E Kurczy7, Michael D Boska6, Howard E Gendelman2, Howard S Fox2, Gary Siuzdak4
  • 1Metabolomics Research Platform, University of Lausanne, 1005 Lausanne, Switzerland
  • 2Departments of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198-5800, USA
  • 3Departments of Chemical Physiology, Molecular and Cellular Neuroscience, The Scripps Research Institute, La Jolla, CA 92037, USA
  • 4Scripps Center for Metabolomics and Mass Spectrometry, Departments of Chemistry, Molecular and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA
  • 5Department of Radiology, University of Nebraska Medical Center, Omaha, NE 68198-1045, USA
  • 6School of Civil and Environmental Engineering, Nanyang Technological University, Singapore 639798, Singapore
  • 7Drug Metabolism and Pharmacokinetics, Innovative Medicine, AstraZeneca, Mölndal 431 83, Sweden
Received: February 26, 2016Accepted: April 28, 2016Published: May 5, 2016

Copyright: © 2016 Ivanisevic et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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.