The age-related decline in organismal fitness results in vulnerability to pathologies and eventual lethal decay. One way to counteract cellular aging and to delay and/or prevent the onset of age-related maladies is the reduction of calorie intake or the institution of fasting regimens. Caloric restriction mimetics (CRMs) have the ability to imitate the health-promoting and lifespan-extending effects of caloric restriction without the need for dietary restriction. CRMs induce an increase in autophagic flux in response to the deacetylation of cellular proteins in the absence of cytotoxicity. Here we report the development of a high-throughput discovery platform for novel CRMs that uses systems biology approaches, in vitro validation and functional tests employing in vivo disease models. This workflow led to the identification of 3,4-dimethoxychalcone (3,4-DC) as a novel CRM that stimulated TFEB (transcription factor EB)- and TFE3 (transcription factor E3)-dependent macroautophagy/autophagy. 3,4-DC showed cardioprotective effects and stimulated anticancer immunosurveillance in the context of immunogenic chemotherapy.

中文翻译：

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一个发现平台，可识别热量限制模拟物，具有广泛的健康改善作用。

与年龄有关的有机体适应能力下降会导致其容易患病，并最终导致致命的衰变。抵消细胞衰老和延迟和/或预防与年龄有关的疾病发作的一种方法是减少卡路里的摄入或禁食。热量限制模拟物（CRM）能够模仿热量限制对健康的促进和寿命延长的作用，而无需饮食限制。在没有细胞毒性的情况下，CRM响应细胞蛋白的脱乙酰作用诱导自噬通量的增加。在这里，我们报告了针对新型CRM的高通量发现平台的开发，该平台使用系统生物学方法，体外验证和采用体内疾病模型的功能测试。通过此工作流程，我们确定了3，4-二甲氧基查尔酮（3,4-DC）作为一种新型CRM，可刺激TFEB（转录因子EB）和TFE3（转录因子E3）依赖性的巨自噬/自噬。在免疫原性化学疗法的背景下，3，4-DC显示出心脏保护作用并刺激了抗癌免疫监视。