Reduced insulin/IGF signaling (IIS) extends lifespan in multiple organisms. Different processes in different tissues mediate this lifespan extension, with a set of interplays that remain unclear. We here show that, in Drosophila, reduced IIS activity modulates methionine metabolism, through tissue‐specific regulation of glycine N‐methyltransferase (Gnmt), and that this regulation is required for full IIS‐mediated longevity. Furthermore, fat body‐specific expression of Gnmt was sufficient to extend lifespan. Targeted metabolomics showed that reducing IIS activity led to a Gnmt‐dependent increase in spermidine levels. We also show that both spermidine treatment and reduced IIS activity are sufficient to extend the lifespan of Drosophila, but only in the presence of Gnmt. This extension of lifespan was associated with increased levels of autophagy. Finally, we found that increased expression of Gnmt occurs in the liver of liver‐specific IRS1 KO mice and is thus an evolutionarily conserved response to reduced IIS. The discovery of Gnmt and spermidine as tissue‐specific modulators of IIS‐mediated longevity may aid in developing future therapeutic treatments to ameliorate aging and prevent disease.

中文翻译：

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响应于降低的胰岛素信号传导的长寿需要甘氨酸N-甲基转移酶依赖性亚精胺的产生。

减少的胰岛素/ IGF信号传导（IIS）延长了多种生物的寿命。不同组织中的不同过程介导了这一寿命的延长，但一系列相互作用尚不清楚。我们在这里显示，在果蝇中， IIS的活性降低是通过组织对甘氨酸N甲基转移酶（Gnmt）的特异性调节来调节蛋氨酸的代谢，而这种调节对于完整的IIS介导的寿命是必需的。此外，Gnmt的脂肪特异性表达足以延长其寿命。靶向代谢组学研究表明，降低IIS活性导致亚精胺水平的Gnmt依赖性增加。我们还表明，亚精胺治疗和降低的IIS活性都足以延长果蝇的寿命，但仅在Gnmt存在的情况下。寿命的延长与自噬水平的提高有关。最后，我们发现Gnmt的表达增加在肝脏特异性IRS1 KO小鼠的肝脏中发生，因此是对IIS减少的进化保守反应。Gnmt和亚精胺作为IIS介导的寿命的组织特异性调节剂的发现，可能有助于开发未来的治疗方法，以改善衰老和预防疾病。