论文标题：The flavonoid 4,4′-dimethoxychalcone promotes autophagy-dependent longevity across species

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作者：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, Frank Madeo

发表时间：2019/02/19

数字识别码： 10.1038/s41467-019-08555-w

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根据本周《自然-通讯》在线发表的一篇论文The flavonoid 4,4′-dimethoxychalcone promotes autophagy-dependent longevity across species，一种天然化合物经鉴定对酵母、蠕虫和人类培养细胞等物种具有保护细胞和延缓衰老的作用。

图1 4,4-二甲氧基查耳酮延长酵母、线虫、果蝇和人体细胞的寿命。图源：Carmona-Gutierrez等

衰老会让细胞产生特定变化，大部分已知能延长寿命的方法都会激活细胞自噬。细胞自噬是一种循环利用机制，可以清除和降解细胞中受损的蛋白质和细胞器等成分，生成原料合成新分子。自噬功能障碍会让毒性分子或受损分子在细胞中积聚，从而导致年龄相关性病变，如神经退行性疾病。

图2：4,4-二甲氧基查耳酮诱导自噬。图源：Carmona-Gutierrez等

奥地利格拉茨大学的Frank Madeo和同事对酵母细胞中具有抗衰老功效的黄酮类化合物进行了筛选——黄酮类化合物是一类已知能促进细胞健康的植物源性分子。作者发现，明日叶（Angelica keiskei koidzumi）叶片中天然存在的4,4'-二甲氧基查耳酮（DMC）不仅能延长酵母、蠕虫和果蝇的寿命，还能减少人类培养细胞的年龄相关性细胞衰退。DMC能在长期心肌缺血（心脏血流减少）的情况下保护小鼠心脏细胞，减少组织死亡面积。作者发现，DMC发挥保护功效需要激活自噬反应，引发代谢的系统性改变——这些代谢过程在所有物种中都是保守性的。

图3： 4,4-二甲氧基查耳酮保护小鼠心脏细胞 图源：Carmona-Gutierrez等

观察结果证实了自噬对于细胞保护和寿命延长具有保守作用，是抗衰老药物疗法开发的一次进步。不过，该疗法是否能在人体内预防年龄相关性的衰退仍需进一步研究。

摘要：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.

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