Elevating acetyl-CoA levels reduces aspects of brain aging
- The Salk Institute for Biological Studies, United States
- 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.
Article and author information
Author details
Michael Petrascheck
António Pinto-Duarte
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
- 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
- Received: April 23, 2019
- Accepted: November 18, 2019
- Accepted Manuscript published: November 19, 2019 (version 1)
- 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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Elevating acetyl-CoA levels reduces aspects of brain aging
eLife 8:e47866.
https://doi.org/10.7554/eLife.47866
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