Caloric restriction mimetics (CRMs) are natural or synthetic compounds that mimic the health-promoting and longevity-extending effects of caloric restriction. CRMs provoke the deacetylation of cellular proteins coupled to an increase in autophagic flux in the absence of toxicity. Here, we report the identification of a novel candidate CRM, namely 3,4-dimethoxychalcone (3,4-DC), among a library of polyphenols. When added to several different human cell lines, 3,4-DC induced the deacetylation of cytoplasmic proteins and stimulated autophagic flux. At difference with other well-characterized CRMs, 3,4-DC, however, required transcription factor EB (TFEB)- and E3 (TFE3)-dependent gene transcription and mRNA translation to trigger autophagy. 3,4-DC stimulated the translocation of TFEB and TFE3 into nuclei both in vitro and in vivo, in hepatocytes and cardiomyocytes. 3,4-DC induced autophagy in vitro and in mouse organs, mediated autophagy-dependent cardioprotective effects, and improved the efficacy of anticancer chemotherapy in vivo. Altogether, our results suggest that 3,4-DC is a novel CRM with a previously unrecognized mode of action.

中文翻译：

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3,4-Dimethoxychalcone 通过激活转录因子 TFE3 和 TFEB 诱导自噬。

热量限制模拟物 (CRM) 是天然或合成的化合物，可模拟热量限制的促进健康和延长寿命的效果。在没有毒性的情况下，CRM 会引起细胞蛋白的脱乙酰化，从而增加自噬通量。在这里，我们报告了在多酚库中鉴定出一种新型候选 CRM，即 3,4-二甲氧基查耳酮 (3,4-DC)。当添加到几种不同的人类细胞系中时，3,4-DC 会诱导细胞质蛋白的去乙酰化并刺激自噬通量。然而，与其他充分表征的 CRM 不同，3,4-DC 需要转录因子 EB (TFEB) 和 E3 (TFE3) 依赖的基因转录和 mRNA 翻译来触发自噬。3,4-DC 在体外和体内均刺激 TFEB 和 TFE3 易位进入细胞核，在肝细胞和心肌细胞中。3,4-DC 在体外和小鼠器官中诱导自噬，介导自噬依赖性心脏保护作用，并提高体内抗癌化疗的疗效。总之，我们的结果表明 3,4-DC 是一种新型 CRM，具有以前未被识别的作用模式。