• Open Access

Lipoic acid restores age-associated impairment of brain energy metabolism through the modulation of Akt/JNK signaling and PGC1α transcriptional pathway

Authors

  • Tianyi Jiang,

    1. Pharmacology & Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, USA
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  • Fei Yin,

    1. Pharmacology & Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, USA
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  • Jia Yao,

    1. Pharmacology & Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, USA
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  • Roberta D. Brinton,

    1. Pharmacology & Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, USA
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  • Enrique Cadenas

    Corresponding author
    1. Pharmacology & Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, USA
    • Correspondence

      Enrique Cadenas, Pharmacology & Pharmaceutical Sciences, School of Pharmacy, University of Southern California, 1985 Zonal Avenue, Los Angeles, CA 90089, USA. Tel.: +1-323-442-1418; fax: +1-323-224-7473; e-mail: cadenas@usc.edu

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Summary

This study examines the progress of a hypometabolic state inherent in brain aging with an animal model consisting of Fischer 344 rats of young, middle, and old ages. Dynamic microPET scanning demonstrated a significant decline in brain glucose uptake at old ages, which was associated with a decrease in the expression of insulin-sensitive neuronal glucose transporters GLUT3/4 and of microvascular endothelium GLUT1. Brain aging was associated with an imbalance between the PI3K/Akt pathway of insulin signaling and c-Jun N-terminal kinase (JNK) signaling and a downregulation of the PGC1α-mediated transcriptional pathway of mitochondrial biogenesis that impinged on multiple aspects of energy homeostasis. R-(+)-lipoic acid treatment increased glucose uptake, restored the balance of Akt/JNK signaling, and enhanced mitochondrial bioenergetics and the PGC1α-driven mitochondrial biogenesis. It may be surmised that impairment of a mitochondria–cytosol–nucleus communication is underlying the progression of the age-related hypometabolic state in brain; the effects of lipoic acid are not organelle-limited, but reside on the functional and effective coordination of this communication that results in improved energy metabolism.

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