Salicylate, the active derivative of aspirin (acetylsalicylate), recapitulates the mode of action of caloric restriction inasmuch as it stimulates autophagy through the inhibition of the acetyltransferase activity of EP300. Here, we directly compared the metabolic effects of aspirin medication with those elicited by 48 h fasting in mice, revealing convergent alterations in the plasma and the heart metabolome. Aspirin caused a transient reduction of general protein acetylation in blood leukocytes, accompanied by the induction of autophagy. However, these effects on global protein acetylation could not be attributed to the mere inhibition of EP300, as determined by epistatic experiments and exploration of the acetyl-proteome from salicylate-treated EP300-deficient cells. Aspirin reduced high-fat diet-induced obesity, diabetes, and hepatosteatosis. These aspirin effects were observed in autophagy-competent mice but not in two different models of genetic (Atg4b^−/− or Bcln1^+/−) autophagy-deficiency. Aspirin also improved tumor control by immunogenic chemotherapeutics, and this effect was lost in T cell-deficient mice, as well as upon knockdown of an essential autophagy gene (Atg5) in cancer cells. Hence, the health-improving effects of aspirin depend on autophagy.

水杨酸，阿司匹林（乙酰水杨酸）的活性衍生物，概括了热量限制的作用方式，因为它通过抑制EP300的乙酰转移酶活性来刺激自噬。在这里，我们直接比较了阿司匹林药物与小鼠禁食48小时所产生的代谢作用，揭示了血浆和心脏代谢组的趋同变化。阿司匹林引起血液白细胞中一般蛋白质乙酰化的短暂降低，并伴随自噬的诱导。然而，对这些蛋白质的总体乙酰化的影响不能仅仅归因于对EP300的抑制，这是通过上位性实验和对水杨酸盐处理过的EP300缺陷细胞的乙酰蛋白质组的探索所确定的。阿司匹林减少了高脂饮食引起的肥胖，糖尿病和肝脂肪变性。Atg4b ^-/-或Bcln1 ^+/-）自噬缺陷。阿司匹林还可以通过免疫原性化学疗法改善肿瘤控制，这种作用在T细胞缺陷型小鼠中以及在敲除癌细胞中的必需自噬基因（Atg5）时就消失了。因此，阿司匹林对健康的改善作用取决于自噬。