Research Paper Volume 8, Issue 5 pp 1000—1020
Metabolic drift in the aging brain
- 1 Metabolomics Research Platform, University of Lausanne, 1005 Lausanne, Switzerland
- 2 Departments of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198-5800, USA
- 3 Departments of Chemical Physiology, Molecular and Cellular Neuroscience, The Scripps Research Institute, La Jolla, CA 92037, USA
- 4 Scripps Center for Metabolomics and Mass Spectrometry, Departments of Chemistry, Molecular and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA
- 5 Department of Radiology, University of Nebraska Medical Center, Omaha, NE 68198-1045, USA
- 6 School of Civil and Environmental Engineering, Nanyang Technological University, Singapore 639798, Singapore
- 7 Drug Metabolism and Pharmacokinetics, Innovative Medicine, AstraZeneca, Mölndal 431 83, Sweden
Received: February 26, 2016 Accepted: April 28, 2016 Published: May 5, 2016
https://doi.org/10.18632/aging.100961How to Cite
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.