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Caloric restriction mimetics: towards a molecular definition

Abstract

Caloric restriction, be it constant or intermittent, is reputed to have health-promoting and lifespan-extending effects. Caloric restriction mimetics (CRMs) are compounds that mimic the biochemical and functional effects of caloric restriction. In this Opinion article, we propose a unifying definition of CRMs as compounds that stimulate autophagy by favouring the deacetylation of cellular proteins. This deacetylation process can be achieved by three classes of compounds that deplete acetyl coenzyme A (AcCoA; the sole donor of acetyl groups), that inhibit acetyl transferases (a group of enzymes that acetylate lysine residues in an array of proteins) or that stimulate the activity of deacetylases and hence reverse the action of acetyl transferases. A unifying definition of CRMs will be important for the continued development of this class of therapeutic agents.

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Figure 1: General properties of CRMs.
Figure 2: Links between protein acetylation and autophagy.
Figure 3: AcCoA metabolism and its modulation by pharmacological agents.

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Acknowledgements

The authors are supported by the Ligue contre le Cancer (équipe labellisée), Agence National de la Recherche, Association pour la Recherche sur le Cancer, Cancéropôle Ile-de-France, Institut National du Cancer (INCa), Fondation Bettencourt-Schueller, Fondation de France, Fondation pour la Recherche Médicale, the European Commission (ArtForce), the European Research Council, the LabEx Immuno-Oncology, the SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (Socrate), Cancer Research and Personalized Medicine (Carpem) and the Paris Alliance of Cancer Research Institutes. T.E. is a recipient of an APART (Austrian Programme for Advanced Research and Technology) fellowship of the Austrian Academy of Sciences at the Institute of Molecular Biosciences, University of Graz, Austria. F.M. is supported by the Austrian Science Fund FWF (grants LIPOTOX, I1000, P23490-B12 and P24381-B20).

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Glossary

Autophagy

A neologism (from the Greek 'auto' (self) and 'phagein' (to eat)) that describes the capacity of cells to sequester portions of their cytoplasm and to subject them to lysosomal degradation.

Caloric restriction

A dietary regimen that is based on low calorie intake without malnutrition.

Caloric restriction mimetics

Pharmaceutical agents that induce the same biochemical alterations as does caloric restriction.

Healthspan

The length of time that an individual is in optimal health.

Hyperinsulinaemic–euglycaemic clamp studies

A physiological test used on whole animals to measure insulin-stimulated glucose uptake by all tissues of the body, hence measuring insulin sensitivity or resistance.

Mitophagy

Specific autophagic removal of mitochondria, which are usually dysfunctional.

Rapamycin

A macrolide antibiotic produced by the bacteria Streptomyces hygroscopicus that inhibits a negative regulator of autophagy, namely the mechanistic target of mammalian target of rapamycin complex 1 (mTORC1).

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Madeo, F., Pietrocola, F., Eisenberg, T. et al. Caloric restriction mimetics: towards a molecular definition. Nat Rev Drug Discov 13, 727–740 (2014). https://doi.org/10.1038/nrd4391

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