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A chemical biology approach to identifying molecular pathways associated with aging

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Abstract

The understanding of how aging contributes to dementia remains obscure. To address this problem, a chemical biology approach was used employing CAD031, an Alzheimer’s disease (AD) drug candidate identified using a discovery platform based upon phenotypic screens that mimic toxicities associated with the aging brain. Since CAD031 has therapeutic efficacy when fed to old symptomatic transgenic AD mice, the chemical biology hypothesis is that it can be used to determine the molecular pathways associated with age-related disease by identifying those that are modified by the compound. Here we show that when CAD031 was fed to rapidly aging SAMP8 mice starting in the last quadrant of their lifespan, it reduced many of the changes in gene, protein, and small molecule expression associated with mitochondrial aging, maintaining mitochondria at the younger molecular phenotype. Network analysis integrating the metabolomics and transcription data followed by mechanistic validation showed that CAD031 targets acetyl-CoA and fatty acid metabolism via the AMPK/ACC1 pathway. Importantly, CAD031 extended the median lifespan of SAMP8 mice by about 30%. These data show that specific alterations in mitochondrial composition and metabolism highly correlate with aging, supporting the use AD drug candidates that limit physiological aging in the brain.

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Acknowledgments

We thank Joseph Chambers, Maria Encizo, and Karen Suter for help with breeding and husbandry of mice.

Funding

This work was supported by the Shiley-Marcos Alzheimer’s Disease Research Center at University of California San Diego (AC), and grants from the NIH (RF1 AG054714) and the California Institute of Regenerative Medicine to PM and DS. The Razavi Newman Integrative Genomics and Bioinformatics Core Facility of the Salk Institute is funded by NIH-NCI CCSG: P30 014195, and the Helmsley Trust.

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Authors and Affiliations

  1. Cellular Neurobiology Laboratory, The Salk Institute for Biological Studies, 10010 N. Torrey Pines Rd., La Jolla, CA, 92037, USA

    Antonio Currais, Pamela Maher & David Schubert

  2. The Razavi Newman Integrative Genomics and Bioinformatics Core, The Salk Institute for Biological Studies, 10010 N. Torrey Pines Rd., La Jolla, CA, 92037, USA

    Ling Huang

  3. Department of Molecular Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA, 92037, USA

    Michael Petrascheck

Authors
  1. Antonio Currais
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  2. Ling Huang
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  3. Michael Petrascheck
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  4. Pamela Maher
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  5. David Schubert
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Contributions

Antonio Currais, conceptualization, data curation, formal analysis, supervision, investigation, methodology, writing-original draft, project administration, writing-review and editing; Ling Huang, data curation, formal analysis, validation, investigation, methodology, writing-review and editing; Michael Petrascheck, data curation, formal analysis, methodology, writing-review and editing; Pamela Maher, conceptualization, formal analysis, validation, investigation, writing-review and editing; David Schubert, conceptualization, supervision, writing-review and editing.

Corresponding authors

Correspondence to Antonio Currais or David Schubert.

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Conflict of interest

The Salk Institute holds the patent for CAD031.

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Figure S1

Body weights. Body weights of (A) female SAMP8 mice (n = 12/group) and (B) male SAMP8 mice (n = 22/group) fed with control or CAD031 diets. (JPG 196 kb)

Figure S2

KEGG pathway analysis. Top KEGG pathways and respective enrichment scores associated with the (A) 485 genes with altered expression in 9 months vs 13 months SAMP8 mice and the (B) 479 genes with altered expression in 13 months vs 13 months old mice plus CAD031. (JPG 440 kb)

Figure S3

GAM network analysis. (A) Network analysis was carried out integrating both the transcriptomic and the metabolomic data obtained from the brains of 13 months vs 13 months+CAD031 SAMP8 mice. Nodes represent the metabolites; links represent the genes that encode the corresponding enzymes of the reactions (solid line) or trans-reaction (dashed line). Larger nodes represent lower p values. Red color indicates upregulation; green color indicates downregulation; blue color indicates missing data. Network analysis was also carried out with the whole transcriptomic data obtained from (B) HT22 nerve cells and (C) rat primary neurons treated with 1 μM of CAD031 for 24 h. Circles represent the metabolites and squares represent the genes that encode the corresponding enzymes of the reactions. Acetyl-CoA is identified in all graphs with a red circle. (JPG 765 kb)

Table S1

List of the DE genes found in 9 vs 13 months old SAMP8 mice and 13 months vs 13 months+CAD031 female SAMP8 mice. (XLSX 271 kb)

Table S2

List of all 496 metabolites quantified in the brain cortex of 9 months, 13 months and 13 months + CAD031 female SAMP8 mice. Fold changes and specific P values are indicated. One-way ANOVA (n = 6/group). (XLSX 66 kb)

Table S3

List of acylcarnitines and fatty acids in the brain and plasma of male SAMP8 and female C57Bl6 mice. (XLSX 38 kb)

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Currais, A., Huang, L., Petrascheck, M. et al. A chemical biology approach to identifying molecular pathways associated with aging. GeroScience 43, 353–365 (2021). https://doi.org/10.1007/s11357-020-00238-5

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  • DOI: https://doi.org/10.1007/s11357-020-00238-5

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