Nucleocytosolic depletion of the energy metabolite acetyl-coenzyme a stimulates autophagy and prolongs lifespan
Open accessAbstract
Healthy aging depends on removal of damaged cellular material that is in part mediated by autophagy. The nutritional status of cells affects both aging and autophagy through as-yet-elusive metabolic circuitries. Here, we show that nucleocytosolic acetyl-coenzyme A (AcCoA) production is a metabolic repressor of autophagy during aging in yeast. Blocking the mitochondrial route to AcCoA by deletion of the CoA-transferase ACH1 caused cytosolic accumulation of the AcCoA precursor acetate. This led to hyperactivation of nucleocytosolic AcCoA-synthetase Acs2p, triggering histone acetylation, repression of autophagy genes, and an age-dependent defect in autophagic flux, culminating in a reduced lifespan. Inhibition of nutrient signaling failed to restore, while simultaneous knockdown of ACS2 reinstated, autophagy and survival of ach1 mutant. Brain-specific knockdown of Drosophila AcCoA synthetase was sufficient to enhance autophagic protein clearance and prolong lifespan. Since AcCoA integrates various nutrition pathways, our findings may explain diet-dependent lifespan and autophagy regulation.
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Acetyl-CoA controls longevity and autophagy in a panel of model systems.
“In fact, acetyl-CoA controls longevity and autophagy in a panel of model systems (Eisenberg et al., 2014; Mariño et al., 2014): This energy metabolite integrates various nutrition pathways and is the only known donor in acetylation reactions.”
From The Search for Antiaging Interventions: From Elixirs to Fasting Regimens (2014) · cites this paper as Eisenberg et al., 2014
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References 52 · Cited by 256
- Authors
- Eisenberg, T., Schroeder, S., Andryushkova, A., Pendl, T., Küttner, V., Bhukel, A., Mariño, G., Pietrocola, F., Harger, A., Zimmermann, A., Moustafa, T., Sprenger, A., Jany, E., Büttner, S., Carmona-Gutierrez, D., Ruckenstuhl, C., Ring, J., Reichelt, W., Schimmel, K., Leeb, T., Moser, C., Schatz, S., Kamolz, L.-P., Magnes, C., Sinner, F., Sedej, S., Fröhlich, K.-U., Juhasz, G., Pieber, T. R., Dengjel, J., Sigrist, S. J., Kroemer, G., & Madeo, F.
- Affiliations
- University of Graz (AT)
- University of Freiburg (DE)
- NeuroCure Cluster of Excellence (DE)
- Université Paris-Sud (FR)
- Medical University of Graz (AT)
- Joanneum Research (AT)
- Corresponding author
- Kroemer, Guido
- Madeo, Frank
- ORCID
- Eisenberg, Tobias
- Pendl, Tobias
- Bhukel, Anuradha
- Mariño, Guillermo
- Pietrocola, Federico
- Zimmermann, Andreas
- Moustafa, Tarek
- Büttner, Sabrina
- Ruckenstuhl, Christoph
- Ring, Julia
- Schimmel, Katharina
- Schatz, Stefanie
- Kamolz, Lars-Peter
- Magnes, Christoph
- Sinner, Frank
- Sedej, Simon
- Pieber, Thomas R.
- Dengjel, Jörn
- Sigrist, Stephan J.
- Kroemer, Guido
- Madeo, Frank
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2014-03
- Volume
- 19
- Issue
- 3
- Pages
- 431-444
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC3988959
- OpenAlex
- W2050532980
- Cited by
- 256
- References
- 52
- Citations by year
- 2026: 12 · 2025: 7 · 2024: 9 · 2023: 14 · 2022: 14 · 2021: 25 · 2020: 16 · 2019: 27 · 2018: 28 · 2017: 20 · 2016: 31 · 2015: 28 · 2014: 25
- FWCI
- 26.05
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Cell Metabolism (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Repository of the Academy's Library (Library of the Hungarian Academy of Sciences) (acceptedVersion)
- HAL (submittedVersion, cc-by-nc-nd)
- Consultation of the Doctoral Thesis Database (TESEO) (Ministerio de Educación, Cultura y Deporte) (submittedVersion)
- Consultation of the Doctoral Thesis Database (TESEO) (Ministerio de Educación, Cultura y Deporte) (submittedVersion, cc-by-nc-nd)
- Funders
- Österreichischen Akademie der Wissenschaften
- Austrian Science Fund
- Ligue Contre le Cancer
- Topics
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- acetyl-CoA, autophagy, lifespan extension, aging, histone acetylation, acetate, mitochondrial metabolism, nutrient signaling, Drosophila, yeast, protein clearance
- MeSH terms
- Autophagy-Related Protein 7, Acetyl Coenzyme A, Acetylation, Aging, Animals, Autophagy, Coenzyme A Ligases, Drosophila, Energy Metabolism, Histones, Longevity, Membrane Proteins, Mitochondria, Saccharomyces cerevisiae, Up-Regulation, Phosphotransferases (Alcohol Group Acceptor), Saccharomyces cerevisiae Proteins, Drosophila Proteins
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