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Cell Rep. 2018 Feb 27;22(9):2395-2407. doi: 10.1016/j.celrep.2018.02.024.

Aspirin Recapitulates Features of Caloric Restriction.

Author information

1
Gustave Roussy Cancer Campus, Villejuif, France; INSERM, U1138, Paris, France; Equipe 11 labellisée par la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France; Université Paris Descartes/Paris V, Sorbonne Paris Cité, Paris, France; Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, Villejuif, France; Université Pierre et Marie Curie, Paris, France.
2
Gustave Roussy Cancer Campus, Villejuif, France; INSERM, U1138, Paris, France; Equipe 11 labellisée par la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France; Université Paris Descartes/Paris V, Sorbonne Paris Cité, Paris, France; Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, Villejuif, France; Université Pierre et Marie Curie, Paris, France; Université Paris-Sud/Paris XI, Faculté de Médecine, Kremlin-Bicêtre, France, Paris, France; Sotio a.c., Prague, Czech Republic.
3
Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology-Hellas, Heraklion 70013, Crete, Greece.
4
Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, Villejuif, France.
5
Department of Cell Biology and Molecular Medicine, Rutgers-New Jersey Medical School, Newark, NJ, USA.
6
Gustave Roussy Cancer Campus, Villejuif, France; INSERM, U1138, Paris, France; Equipe 11 labellisée par la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France; Université Paris Descartes/Paris V, Sorbonne Paris Cité, Paris, France; Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, Villejuif, France; Université Pierre et Marie Curie, Paris, France; Department of Biochemistry, Sargodha Medical College, Sargodha, Pakistan.
7
Université Paris Descartes/Paris V, Sorbonne Paris Cité, Paris, France; Institut Necker-Enfants Malades (INEM), Paris, France; INSERM, U1151, Paris, France; CNRS, UMR8253, Paris, France.
8
Departamento de Biología Fundamental, Universidad de Oviedo, Fundación para la Investigación Sanitaria del Principado de Asturias (FINBA), Oviedo, Spain; Instituto de Investigación Sanitaria del Principado de Asturias (IISPA), Oviedo, Spain.
9
Scientific Computing, LGCR, Sanofi R&D, 94403 Vitry-sur-Seine, France.
10
Institute of Molecular Biosciences, NAWI Graz, University of Graz, Humboldtstraße 50, 8010 Graz, Austria; BioTechMed-Graz, Humboldtstraße 50, 8010 Graz, Austria.
11
Structure Design & Informatics, LGCR, Sanofi R&D, 94403 Vitry-sur-Seine, France.
12
Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology-Hellas, Heraklion 70013, Crete, Greece; Department of Basic Sciences, Faculty of Medicine, University of Crete, Heraklion 70013, Crete, Greece.
13
Gustave Roussy Cancer Campus, Villejuif, France; INSERM, U1138, Paris, France; Equipe 11 labellisée par la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France; Université Paris Descartes/Paris V, Sorbonne Paris Cité, Paris, France; Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, Villejuif, France; Université Pierre et Marie Curie, Paris, France; Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France; Karolinska Institute, Department of Women's and Children's Health, Karolinska University Hospital, Stockholm, Sweden. Electronic address: kroemer@orange.fr.

Abstract

The age-associated deterioration in cellular and organismal functions associates with dysregulation of nutrient-sensing pathways and disabled autophagy. The reactivation of autophagic flux may prevent or ameliorate age-related metabolic dysfunctions. Non-toxic compounds endowed with the capacity to reduce the overall levels of protein acetylation and to induce autophagy have been categorized as caloric restriction mimetics (CRMs). Here, we show that aspirin or its active metabolite salicylate induce autophagy by virtue of their capacity to inhibit the acetyltransferase activity of EP300. While salicylate readily stimulates autophagic flux in control cells, it fails to further increase autophagy levels in EP300-deficient cells, as well as in cells in which endogenous EP300 has been replaced by salicylate-resistant EP300 mutants. Accordingly, the pro-autophagic activity of aspirin and salicylate on the nematode Caenorhabditis elegans is lost when the expression of the EP300 ortholog cpb-1 is reduced. Altogether, these findings identify aspirin as an evolutionary conserved CRM.

KEYWORDS:

EP300; acetylation; aging; autophagy; longevity; metabolome; salicylate

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