Enhancing S-adenosyl-methionine catabolism extends Drosophila lifespan.
Enhancing S-adenosyl-methionine catabolism extends Drosophila lifespan.
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DOI：
10.1038/ncomms9332
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发表时间：
2015-09-18
影响因子：
16.6
通讯作者：
Miura M
中科院分区：
文献类型：
--
作者：
Obata F;Miura M
甲硫氨酸限制延长了各种模式生物的寿命。限制S-腺苷甲硫氨酸（SAM）的合成，饮食蛋氨酸的第一个代谢反应，延长秀丽隐杆线虫的寿命，但加速哺乳动物的病理。在这里，我们表明，作为一种替代抑制SAM合成，增强SAM catalysts的甘氨酸N-甲基转移酶（Gnmt）延长果蝇的寿命。Gnmt通过在高蛋氨酸或低SAM条件下产生肌氨酸来强烈缓冲系统SAM水平。在衰老过程中，果蝇的系统SAM水平增加。Gnmt是转录诱导的dFoxO依赖的方式，但是，这是不足以完全抑制SAM海拔在老苍蝇。gnmt的过表达抑制了这种年龄依赖性SAM的增加并延长了寿命。促长寿方案，如饮食限制或减少胰岛素信号传导，减弱年龄依赖性SAM增加，并至少部分依赖于Gnmt功能发挥其延长果蝇寿命的作用。我们的研究表明，通过Gnmt调节SAM水平是延长寿命的关键组成部分。 抑制S-腺苷甲硫氨酸（SAM）的形成可以增加蠕虫的寿命，但不能增加苍蝇的寿命。在这里，作者表明，人类和苍蝇拥有SAM消耗酶Gnmt，其活性受到延长寿命干预措施的调节，并且Gnmt的敲除延长了苍蝇的寿命。
Methionine restriction extends the lifespan of various model organisms. Limiting S-adenosyl-methionine (SAM) synthesis, the first metabolic reaction of dietary methionine, extends longevity in Caenorhabditis elegans but accelerates pathology in mammals. Here, we show that, as an alternative to inhibiting SAM synthesis, enhancement of SAM catabolism by glycine N-methyltransferase (Gnmt) extends the lifespan in Drosophila. Gnmt strongly buffers systemic SAM levels by producing sarcosine in either high-methionine or low-sams conditions. During ageing, systemic SAM levels in flies are increased. Gnmt is transcriptionally induced in a dFoxO-dependent manner; however, this is insufficient to suppress SAM elevation completely in old flies. Overexpression of gnmt suppresses this age-dependent SAM increase and extends longevity. Pro-longevity regimens, such as dietary restriction or reduced insulin signalling, attenuate the age-dependent SAM increase, and rely at least partially on Gnmt function to exert their lifespan-extending effect in Drosophila. Our study suggests that regulation of SAM levels by Gnmt is a key component of lifespan extension. Inhibiting the formation of S-adenosyl-methionine (SAM) increases worm but not fly lifespan. Here the authors show that humans and flies possess the SAM-consuming enzyme Gnmt, the activity of which is regulated by lifespan-extending interventions, and that knockdown of Gnmt extends fly lifespan.