Senolysis by glutaminolysis inhibition ameliorates various age-associated disorders
Senolysis by glutaminolysis inhibition ameliorates various age-associated disorders
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DOI：
10.1126/science.abb5916
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发表时间：
2021-01-15
期刊：
影响因子：
56.9
通讯作者：
Nakanishi, Makoto
中科院分区：
文献类型：
--
作者：
Johmura, Yoshikazu;Yamanaka, Takehiro;Nakanishi, Makoto
去除衰老细胞（衰老作用）已被认为有利于改善与年龄相关的病理，但这种衰老作用的分子途径尚未出现。在这里，我们确定谷氨酰胺酶 1 (GLS1) 是人类衰老细胞生存的必需基因。溶酶体膜损伤导致衰老细胞的细胞内 pH 值降低，从而降低 pH 值诱导的肾型谷氨酰胺酶 (KGA) 表达。由此产生的增强的谷氨酰胺分解诱导氨产生，从而中和较低的pH值并提高衰老细胞的存活率。抑制老年小鼠中 KGA 依赖性谷氨酰胺分解可特异性消除衰老细胞，并改善与年龄相关的器官功能障碍。我们的结果表明衰老细胞依赖于谷氨酰胺分解，其抑制为诱导体内衰老提供了一种有前景的策略。
Removal of senescent cells (senolysis) has been proposed to be beneficial for improving age-associated pathologies, but the molecular pathways for such senolytic activity have not yet emerged. Here, we identified glutaminase 1 (GLS1) as an essential gene for the survival of human senescent cells. The intracellular pH in senescent cells was lowered by lysosomal membrane damage, and this lowered pH induced kidney-type glutaminase (KGA) expression. The resulting enhanced glutaminolysis induced ammonia production, which neutralized the lower pH and improved survival of the senescent cells. Inhibition of KGA-dependent glutaminolysis in aged mice eliminated senescent cells specifically and ameliorated age-associated organ dysfunction. Our results suggest that senescent cells rely on glutaminolysis, and its inhibition offers a promising strategy for inducing senolysis in vivo.