The flavonoid 4,4'-dimethoxychalcone promotes autophagy-dependent longevity across species PMID: 30783116

ADC Targets in Oncology

2026-04-10

The flavonoid 4,4'-dimethoxychalcone promotes autophagy-dependent longevity across species

Nat Commun. 2019 Feb 19;10(1):651. doi: 10.1038/s41467-019-08555-w.

Didac Carmona-Gutierrez ^# ¹ , Andreas Zimmermann ^# ¹ ² , Katharina Kainz ¹ , Federico Pietrocola ³ ⁴ ⁵ ⁶ , Guo Chen ³ ⁴ ⁵ ⁶ , Silvia Maglioni ⁷ , Alfonso Schiavi ⁷ , Jihoon Nah ⁸ , Sara Mertel ⁹ , Christine B Beuschel ⁹ , Francesca Castoldi ³ ⁴ ⁵ ⁶ ¹⁰ , Valentina Sica ³ ⁴ ⁵ ⁶ , Gert Trausinger ¹¹ , Reingard Raml ¹¹ , Cornelia Sommer ¹ , Sabrina Schroeder ¹ , Sebastian J Hofer ¹ , Maria A Bauer ¹ , Tobias Pendl ¹ , Jelena Tadic ¹ , Christopher Dammbrueck ¹ , Zehan Hu ¹² , Christoph Ruckenstuhl ¹ , Tobias Eisenberg ¹ , Sylvere Durand ³ ⁴ , Noélie Bossut ³ ⁴ , Fanny Aprahamian ³ ⁴ , Mahmoud Abdellatif ¹² , Simon Sedej ¹² ¹³ , David P Enot ³ ⁴ , Heimo Wolinski ¹ , Jörn Dengjel ¹⁴ , Oliver Kepp ³ ⁴ ⁵ ⁶ , Christoph Magnes ¹¹ , Frank Sinner ² ¹¹ , Thomas R Pieber ² ¹¹ , Junichi Sadoshima ⁸ , Natascia Ventura ⁷ ¹⁵ , Stephan J Sigrist ⁹ ¹⁶ , Guido Kroemer ¹⁷ ¹⁸ ¹⁹ ²⁰ ²¹ ²² , Frank Madeo ²³ ²⁴

Affiliations

1. Institute of Molecular Biosciences, NAWI Graz, University of Graz, Graz, 8010, Austria.
2. Division of Endocrinology and Diabetology, Department of Internal Medicine, Medical University of Graz, Graz, 8036, Austria.
3. Equipe 11 labellisée Ligue contre le Cancer, Centre de Recherche des Cordeliers, INSERM U 1138, Paris, France.
4. Metabolomics and Cell Biology Platforms, Gustave Roussy Comprehensive Cancer Center, Villejuif, France.
5. Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
6. Université Pierre et Marie Curie, Paris, France.
7. IUF - Leibniz Research Institute for Environmental Medicine, Düsseldorf, 40225, Germany.
8. Department of Cell Biology and Molecular Medicine, Rutgers New Jersey Medical School, Newark, NJ, USA.
9. Institute for Biology/Genetics, Freie Universität Berlin, Berlin, 14195, Germany.
10. Sotio a.c, 17000, Prague, Czech Republic.
11. Joanneum Research Forschungsgesellschaft m.b.H., HEALTH, Institute for Biomedicine and Health Sciences, Graz, 8010, Austria.
12. Department of Cardiology, Medical University of Graz, Graz, 8036, Austria.
13. BioTechMed Graz, Graz, 8010, Austria.
14. Department of Biology, Université de Fribourg, Chemin du Musée 10, 1700, Fribourg, Switzerland.
15. Institute for Clinical Chemistry and Laboratory Diagnostic, Medical Faculty of the Heinrich Heine University, Moorenstrasse 5, 40225, Düsseldorf, Germany.
16. NeuroCure, Charité, Berlin, 10117, Germany.
17. Equipe 11 labellisée Ligue contre le Cancer, Centre de Recherche des Cordeliers, INSERM U 1138, Paris, France. [email protected].
18. Metabolomics and Cell Biology Platforms, Gustave Roussy Comprehensive Cancer Center, Villejuif, France. [email protected].
19. Université Paris Descartes, Sorbonne Paris Cité, Paris, France. [email protected].
20. Université Pierre et Marie Curie, Paris, France. [email protected].
21. Pôle de Biologie, Hôpital Européen Georges Pompidou, Paris, France. [email protected].
22. Karolinska Institute, Department of Women's and Children's Health, Karolinska University Hospital, Stockholm, Sweden. [email protected].
23. Institute of Molecular Biosciences, NAWI Graz, University of Graz, Graz, 8010, Austria. [email protected].
24. BioTechMed Graz, Graz, 8010, Austria. [email protected].
# Contributed equally.

Abstract

Ageing constitutes the most important risk factor for all major chronic ailments, including malignant, cardiovascular and neurodegenerative diseases. However, behavioural and pharmacological interventions with feasible potential to promote health upon ageing remain rare. Here we report the identification of the flavonoid 4,4'-dimethoxychalcone (DMC) as a natural compound with anti-ageing properties. External DMC administration extends the lifespan of yeast, worms and flies, decelerates senescence of human cell cultures, and protects mice from prolonged myocardial ischaemia. Concomitantly, DMC induces Autophagy, which is essential for its cytoprotective effects from yeast to mice. This pro-autophagic response induces a conserved systemic change in metabolism, operates independently of TORC1 signalling and depends on specific GATA transcription factors. Notably, we identify DMC in the plant Angelica keiskei koidzumi, to which longevity- and health-promoting effects are ascribed in Asian traditional medicine. In summary, we have identified and mechanistically characterised the conserved longevity-promoting effects of a natural anti-ageing drug.