Research Paper Advance Articles

Metabolic switch in the aging astrocyte supported via integrative approach comprising network and transcriptome analyses

Alejandro Acevedo1, , Felipe Torres2,3,4, , Miguel Kiwi2,3, , Felipe Baeza-Lehnert5, , L. Felipe Barros5,6, , Dasfne Lee-Liu7,8,9, , Christian González-Billault7,8,10, ,

  • 1 Instituto de Nutrición y Tecnología de Alimentos (INTA), Universidad de Chile, Santiago, Región Metropolitana 7800003, Chile
  • 2 Department of Physics, Universidad de Chile, Santiago, Región Metropolitana 7800003, Chile
  • 3 Center for the Development of Nanoscience and Nanotechnology, CEDENNA, Santiago, Región Metropolitana 7800003, Chile
  • 4 Department of Physics, Center for Advanced Nanoscience, University of California, San Diego, CA 92093, USA
  • 5 Centro de Estudios Científicos (CECs), Valdivia 5110466, Chile
  • 6 Facultad de Medicina y Ciencia, Universidad San Sebastián, Valdivia, Región de Los Ríos 5110773, Chile
  • 7 Department of Biology, Laboratory of Cellular and Neuronal Dynamics, Faculty of Sciences, Universidad de Chile, Santiago, Región Metropolitana 7800003, Chile
  • 8 Geroscience Center for Brain Health and Metabolism (GERO), Santiago, Región Metropolitana 7800003, Chile
  • 9 Facultad de Medicina y Ciencia, Universidad San Sebastián, Santiago, Región Metropolitana 7510157, Chile
  • 10 The Buck Institute for Research on Aging, Novato, CA 94945, USA

Received: December 22, 2022       Accepted: March 20, 2023       Published: April 18, 2023
How to Cite

Copyright: © 2023 Acevedo et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Dysregulated central-energy metabolism is a hallmark of brain aging. Supplying enough energy for neurotransmission relies on the neuron-astrocyte metabolic network. To identify genes contributing to age-associated brain functional decline, we formulated an approach to analyze the metabolic network by integrating flux, network structure and transcriptomic databases of neurotransmission and aging. Our findings support that during brain aging: (1) The astrocyte undergoes a metabolic switch from aerobic glycolysis to oxidative phosphorylation, decreasing lactate supply to the neuron, while the neuron suffers intrinsic energetic deficit by downregulation of Krebs cycle genes, including mdh1 and mdh2 (Malate-Aspartate Shuttle); (2) Branched-chain amino acid degradation genes were downregulated, identifying dld as a central regulator; (3) Ketone body synthesis increases in the neuron, while the astrocyte increases their utilization, in line with neuronal energy deficit in favor of astrocytes. We identified candidates for preclinical studies targeting energy metabolism to prevent age-associated cognitive decline.


α-KG: alpha-ketoglutarate; ACC: absolute centrality contribution; ANLS: astrocyte-neuron lactate shuttle; AO: absolute optimality; BCAA: branched-chain amino acid; DHG: differential hub genes; ETC: electron transport chain; FBA: flux balance analysis; FC: fold-change; FDR: false discovery rate; FRET: fluorescence resonance energy transfer; GGC: glutamate-glutamine cycle; GSH: glutathione; N-A: neuron-astrocyte; PDC: pyruvate dehydrogenase complex; PhPP: phenotypic phase planes; RNA-seq: RNA sequencing; SAM: S-adenosylmethionine; TCA: tricarboxylic acid; THF: tetrahydrofolate.