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

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, 4,4ʹ-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
• flavonoid
• GATA
• liver protection
• longevity

Acknowledgments

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). J.T. is funded by the FWF (W 1226, DK Metabolic and Cardiovascular Disease) at the University of Graz. 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.

Disclosure statement

O. Kepp, G. Kroemer, D. Carmona-Gutierrez and F. Madeo are the scientific co-founders of Samsara Therapeutics.

Additional information

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.