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, Sara Mertel, Christine Beuschel, Francesca Castoldi, Valentina Sica, Jihoon Nah, Gert Trausinger, Reingard Raml, Cornelia Sommer, Sabrina Schroeder, Sebastian Hofer, Maria Bauer, Tobias Pendl, Jelena Tadic, Christopher Dammbrueck, Zehan Hu, Christoph Ruckenstuhl, Tobias Eisenberg, Sylvere Durand, Noélie Bossut, Fanny Aprahamian, Mahmoud Abdellatif, Simon Sedej, David Enot, Heimo Wolinski, Jörn Dengjel, Christoph Magnes, Frank Sinner, Thomas Pieber, Junichi Sadoshima, Natascia Ventura, Stephan Sigrist, Guido Kroemer, Frank Madeo
Nature Communications , 2/2019
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.
Keywords: Open Access