Selective destruction of senescent cells Senescent cells are associated with a variety of age-related medical conditions and thus have been proposed as potential targets for therapy, but we do not yet have a full understanding of the underlying mechanisms. Johmura et al. used RNA interference to screen for enzymes essential to the survival of senescent cells (see the Perspective by Pan and Locasale). The authors identified a key role for glutamine metabolism, particularly the enzyme glutaminase 1, and demonstrated that inhibition of this pathway induced the death of senescent cells. Glutaminase targeting also ameliorated aging-related organ dysfunction and obesity-related disorders in mouse models, suggesting the potential therapeutic value of this approach. Science, this issue p. 265; see also p. 234 Senescent cells rely on glutaminolysis, the inhibition of which ameliorates age- and senescence-associated disorders in mice. 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.

中文翻译：

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抑制谷氨酰胺分解的衰老可改善各种与年龄相关的疾病

选择性破坏衰老细胞 衰老细胞与多种与年龄相关的医学状况有关，因此已被提议作为潜在的治疗靶点，但我们尚未完全了解其潜在机制。乔穆拉等人。使用 RNA 干扰来筛选对衰老细胞存活至关重要的酶（参见 Pan 和 Locasale 的观点）。作者确定了谷氨酰胺代谢的关键作用，尤其是谷氨酰胺酶 1，并证明抑制该途径会诱导衰老细胞的死亡。谷氨酰胺酶靶向还改善了小鼠模型中与衰老相关的器官功能障碍和肥胖相关的疾病，表明这种方法的潜在治疗价值。科学，这个问题 p。265; 另见第 234 衰老细胞依赖谷氨酰胺分解，其抑制可改善小鼠的年龄和衰老相关疾病。已经提出去除衰老细胞（senolysis）有利于改善与年龄相关的病理，但尚未出现这种衰老活性的分子途径。在这里，我们将谷氨酰胺酶 1 (GLS1) 鉴定为人类衰老细胞存活的必需基因。溶酶体膜损伤降低了衰老细胞的细胞内 pH 值，这种降低的 pH 值会诱导肾型谷氨酰胺酶 (KGA) 表达。由此产生的增强的谷氨酰胺分解诱导了氨的产生，从而中和了较低的 pH 值并提高了衰老细胞的存活率。在老年小鼠中抑制 KGA 依赖性谷氨酰胺分解可特异性地消除衰老细胞并改善与年龄相关的器官功能障碍。