4,4'Dimethoxychalcone: a natural flavonoid that promotes health through autophagy-dependent and -independent effects

Andreas Zimmermann; Katharina Kainz; Sebastian J Hofer; Maria A Bauer; Sabrina Schroeder; Jörn Dengjel; Federico Pietrocola; Oliver Kepp; Christoph Ruckenstuhl; Tobias Eisenberg; Stephan J Sigrist; Frank Madeo; Didac Carmona-Gutierrez; Guido Kroemer

doi:10.1080/15548627.2019.1632623

4,4'Dimethoxychalcone: a natural flavonoid that promotes health through autophagy-dependent and -independent effects

Autophagy. 2019 Sep;15(9):1662-1664. doi: 10.1080/15548627.2019.1632623. Epub 2019 Jun 28.

Authors

Andreas Zimmermann^{1

2}, Katharina Kainz^{1

2}, Sebastian J Hofer^{1

3}, Maria A Bauer¹, Sabrina Schroeder¹, Jörn Dengjel⁴, Federico Pietrocola⁵, Oliver Kepp^{6

7

8

9}, Christoph Ruckenstuhl¹, Tobias Eisenberg^{1

3

10

11}, Stephan J Sigrist¹², Frank Madeo^{1

2

3

11}, Didac Carmona-Gutierrez¹, Guido Kroemer^{6

7

8

13

14

15

9}

Affiliations

¹ a Institute of Molecular Biosciences, NAWI Graz, University of Graz , Graz , Austria.
² b Division of Endocrinology and Diabetology, Department of Internal Medicine, Medical University of Graz , Graz , Austria.
³ c BioTechMed Graz , Graz , Austria.
⁴ d Department of Biology, Université de Fribourg , Fribourg , Switzerland.
⁵ e Institute for Research in Biomedicine; Barcelona , Spain.
⁶ f Equipe 11 labellisée Ligue contre le Cancer, Centre de Recherche des Cordeliers , INSERM U 1138, Paris , France.
⁷ g Metabolomics and Cell Biology Platforms, Gustave Roussy Comprehensive Cancer Center , Villejuif , France.
⁸ h Université Paris Descartes, Sorbonne Paris Cité , Paris , France.
⁹ n Université Pierre et Marie Curie , Paris , France.
¹⁰ i Central Lab Gracia, NAWI Graz, University of Graz , Graz , Austria.
¹¹ o BioHealth Graz , Graz , Austria.
¹² j Institute for Biology/Genetics, Freie Universität Berlin , Berlin , Germany.
¹³ k Pôle de Biologie, Hôpital Européen Georges Pompidou , Paris , France.
¹⁴ l Karolinska Institute, Department of Women's and Children's Health, Karolinska University Hospital , Stockholm , Sweden.
¹⁵ m Suzhou Institute for Systems Biology, Chinese Academy of Sciences , Suzhou , China.

Abstract

The age-induced deterioration of the organism results in detrimental and ultimately lethal pathologies. The process of aging itself involves a plethora of different mechanisms that should be subverted concurrently to delay and/or prevent age-related maladies. We have identified a natural compound, 4,4'-dimethoxychalcone (DMC), which promotes longevity in yeast, worms and flies, and protects mice from heart injury and liver toxicity. Interestingly, both the DMC-mediated lifespan extension and the cardioprotection depend on macroautophagy/autophagy whereas hepatoprotection does not. DMC induces autophagy by inhibiting specific GATA transcription factors (TFs), independently of the TORC1 kinase pathway. The autophagy-independent beneficial effects of DMC might involve its antioxidative properties. DMC treatment results in a phylogenetically conserved, systemic impact on the metabolome, which is most prominently characterized by changes in cellular amino acid composition. Altogether, DMC exerts multiple, geroprotective effects by igniting distinct pathways, and thus represents a potential pharmacological agent that delays aging through multipronged effects.

Keywords: Cardioprotection; GATA; flavonoid; liver protection; longevity.

Publication types

Research Support, Non-U.S. Gov't
Comment

MeSH terms

Aging
Animals
Autophagy*
Flavonoids
Longevity
Mechanistic Target of Rapamycin Complex 1
Mice

Substances

Flavonoids
Mechanistic Target of Rapamycin Complex 1

Grants and funding

F.M. and D.C-G. are grateful to the Austrian Science Fund FWF (SFB-LIPOTOX F3007&F3012, W1226, P29203, P29262), in particular for the project P27893 (“Pro-autophagic polyphenols and polyamines for longevity”) and the Austrian Federal Ministry of Education, Science and Research and the University of Graz for grants “Unkonventionelle Forschung” and “flysleep” (BMWFW-80.109/0001-WF/V/3b/2015). K.K. is a fellow of the Doctoral College “Metabolic and Cardiovascular Disease” (FWF W1226) and was funded by the University of Graz. We acknowledge support from NAWI Graz and the BioTechMed-Graz flagship project “EPIAge”. G.K. is supported by the Ligue contre le Cancer (équipe labelisée); Agence National de la Recherche (ANR) – Projets blancs; ANR under the frame of E-Rare-2, the ERA-Net for Research on Rare Diseases; Association pour la recherche sur le cancer (ARC); Cancéropôle Ile-de-France; Institut National du Cancer (INCa); Inserm (HTE); Institut Universitaire de France; Fondation pour la Recherche Médicale (FRM); the European Commission (ArtForce); the European Research Council (ERC); Fondation Carrefour; the LeDucq Foundation; the LabEx Immuno-Oncology; the RHU Torino Lumière, the Seerave Foundation, the SIRIC Stratified Oncology Cell DNA Repair and Tumour Immune Elimination (SOCRATE); the SIRIC Cancer Research and Personalised Medicine (CARPEM); and the Paris Alliance of Cancer Research Institutes (PACRI). N.V. would like to thank the Deutsche Forschungsgemeinschaft (DFG) and the Bundesministerium für Bildung und Forschung (BMBF) for funding.