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

Didac Carmona-Gutierrez, Andreas Zimmermann, Katharina Kainz, Federico Pietrocola, Guo Chen, Silvia Maglioni, Alfonso Schiavi, Jihoon Nah, Sara Mertel, Christine B. Beuschel, Francesca Castoldi, Valentina Sica, Gert Trausinger, Reingard Raml, Cornelia Sommer, Sabrina Schroeder, Sebastian J. Hofer, Maria A. Bauer, Tobias Pendl, Jelena Tadic, Christopher Dammbrueck, Zehan Hu, Christoph Ruckenstuhl, Tobias Eisenberg, Sylvere Durand, Noélie Bossut, Fanny Aprahamian, Mahmoud Abdellatif, Simon Sedej, David P. Enot, Heimo Wolinski, Jörn Dengjel, Oliver Kepp, Christoph Magnes, Frank Sinner, Thomas R. Pieber, Junichi Sadoshima, Natascia Ventura, Stephan J. Sigrist, Guido Kroemer () and Frank Madeo ()
Additional contact information
Didac Carmona-Gutierrez: University of Graz
Andreas Zimmermann: University of Graz
Katharina Kainz: University of Graz
Federico Pietrocola: Centre de Recherche des Cordeliers, INSERM U 1138
Guo Chen: Centre de Recherche des Cordeliers, INSERM U 1138
Silvia Maglioni: IUF - Leibniz Research Institute for Environmental Medicine
Alfonso Schiavi: IUF - Leibniz Research Institute for Environmental Medicine
Jihoon Nah: Rutgers New Jersey Medical School
Sara Mertel: Freie Universität Berlin
Christine B. Beuschel: Freie Universität Berlin
Francesca Castoldi: Centre de Recherche des Cordeliers, INSERM U 1138
Valentina Sica: Centre de Recherche des Cordeliers, INSERM U 1138
Gert Trausinger: Institute for Biomedicine and Health Sciences
Reingard Raml: Institute for Biomedicine and Health Sciences
Cornelia Sommer: University of Graz
Sabrina Schroeder: University of Graz
Sebastian J. Hofer: University of Graz
Maria A. Bauer: University of Graz
Tobias Pendl: University of Graz
Jelena Tadic: University of Graz
Christopher Dammbrueck: University of Graz
Zehan Hu: Medical University of Graz
Christoph Ruckenstuhl: University of Graz
Tobias Eisenberg: University of Graz
Sylvere Durand: Centre de Recherche des Cordeliers, INSERM U 1138
Noélie Bossut: Centre de Recherche des Cordeliers, INSERM U 1138
Fanny Aprahamian: Centre de Recherche des Cordeliers, INSERM U 1138
Mahmoud Abdellatif: Medical University of Graz
Simon Sedej: Medical University of Graz
David P. Enot: Centre de Recherche des Cordeliers, INSERM U 1138
Heimo Wolinski: University of Graz
Jörn Dengjel: Université de Fribourg
Oliver Kepp: Centre de Recherche des Cordeliers, INSERM U 1138
Christoph Magnes: Institute for Biomedicine and Health Sciences
Frank Sinner: Medical University of Graz
Thomas R. Pieber: Medical University of Graz
Junichi Sadoshima: Rutgers New Jersey Medical School
Natascia Ventura: IUF - Leibniz Research Institute for Environmental Medicine
Stephan J. Sigrist: Freie Universität Berlin
Guido Kroemer: Centre de Recherche des Cordeliers, INSERM U 1138
Frank Madeo: University of Graz

Nature Communications, 2019, vol. 10, issue 1, 1-17

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-08555-w

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