Elevating acetyl-CoA levels reduces aspects of brain aging

  1. Antonio Currais  Is a corresponding author
  2. Ling Huang
  3. Joshua Goldberg
  4. Michael Petrascheck
  5. Gamze Ates
  6. António Pinto-Duarte
  7. Maxim N Shokhirev
  8. David Schubert
  9. Pamela Maher  Is a corresponding author
  1. The Salk Institute for Biological Studies, United States
  2. The Scripps Research Institute, United States

Abstract

Because old age is the greatest risk factor for dementia, a successful therapy will require an understanding of the physiological changes that occur in the brain with aging. Here, two structurally distinct Alzheimer's disease (AD) drug candidates, CMS121 and J147, were used to identify a unique molecular pathway that is shared between the aging brain and AD. CMS121 and J147 reduced cognitive decline as well as metabolic and transcriptional markers of aging in the brain when administered to rapidly aging SAMP8 mice. Both compounds preserved mitochondrial homeostasis by regulating acetyl-coenzyme A (acetyl-CoA) metabolism. CMS121 and J147 increased the levels of acetyl-CoA in cell culture and mice via the inhibition of acetyl-CoA carboxylase 1 (ACC1), resulting in neuroprotection and increased acetylation of histone H3K9 in SAMP8 mice, a site linked to memory enhancement. These data show that targeting specific metabolic aspects of the aging brain could result in treatments for dementia.

Data availability

Whole transcriptomic data have been deposited in NCBI's Gene Expression Omnibus and are accessible through GEO Series accession number GSE101112.

The following data sets were generated

Article and author information

Author details

  1. Antonio Currais

    Cellular Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, United States
    For correspondence
    acurrais@salk.edu
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4142-7054
  2. Ling Huang

    The Razavi Newman Integrative Genomics and Bioinformatics Core, The Salk Institute for Biological Studies, La Jolla, United States
    Competing interests
    No competing interests declared.
  3. Joshua Goldberg

    Cellular Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, United States
    Competing interests
    No competing interests declared.
  4. Michael Petrascheck

    Department of Molecular Medicine, The Scripps Research Institute, La Jolla, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1010-145X
  5. Gamze Ates

    Cellular Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, United States
    Competing interests
    No competing interests declared.
  6. António Pinto-Duarte

    Computational Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2215-7653
  7. Maxim N Shokhirev

    The Razavi Newman Integrative Genomics and Bioinformatics Core Facility, The Salk Institute for Biological Studies, La Jolla, United States
    Competing interests
    No competing interests declared.
  8. David Schubert

    Cellular Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, United States
    Competing interests
    David Schubert, is an unpaid advisor for Abrexa Pharmaceuticals, a company working on the development of J147 for AD therapy. The Salk Institute holds the patents for CMS121 and J147.
  9. Pamela Maher

    Cellular Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, United States
    For correspondence
    pmaher@salk.edu
    Competing interests
    No competing interests declared.

Funding

National Institutes of Health (R01 AG046153)

  • David Schubert
  • Pamela Maher

National Institutes of Health (RF1 AG054714)

  • David Schubert
  • Pamela Maher

Glenn Foundation for Medical Research

  • Joshua Goldberg

National Institutes of Health (R41 AI104034)

  • Pamela Maher

Edward N. and Della L. Thome Memorial Foundation

  • Pamela Maher

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Agnieszka Chacinska, University of Warsaw, Poland

Ethics

Animal experimentation: All experiments were performed in accordance with the US Public Health Service Guide for Care and Use of Laboratory Animals and protocol 12-00001 approved by the IACUC at Salk Institute.

Version history

  1. Received: April 23, 2019
  2. Accepted: November 18, 2019
  3. Accepted Manuscript published: November 19, 2019 (version 1)
  4. Version of Record published: November 28, 2019 (version 2)

Copyright

© 2019, Currais et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Antonio Currais
  2. Ling Huang
  3. Joshua Goldberg
  4. Michael Petrascheck
  5. Gamze Ates
  6. António Pinto-Duarte
  7. Maxim N Shokhirev
  8. David Schubert
  9. Pamela Maher
(2019)
Elevating acetyl-CoA levels reduces aspects of brain aging
eLife 8:e47866.
https://doi.org/10.7554/eLife.47866

Share this article

https://doi.org/10.7554/eLife.47866

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