Impaired insulin/IGF1 signaling extends life span by promoting mitochondrial L-proline catabolism to induce a transient ROS signal.
Impaired insulin/IGF1 signaling extends life span by promoting mitochondrial L-proline catabolism to induce a transient ROS signal.
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DOI：
10.1016/j.cmet.2012.02.013
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发表时间：
2012-04-04
期刊：
影响因子：
29
通讯作者：
Ristow M
中科院分区：
文献类型：
--
作者：
Zarse K;Schmeisser S;Groth M;Priebe S;Beuster G;Kuhlow D;Guthke R;Platzer M;Kahn CR;Ristow M
线虫daf-2突变体中受损的胰岛素和胰岛素样生长因子-1信号(IIIS)可使寿命延长两倍以上。从结构上讲，IIIS增加了线粒体的活性，降低了活性氧(ROS)的水平。相比之下，线虫体内daf-2的急性损伤减少了葡萄糖的摄取，并短暂地增加了ROS。与有丝分裂兴奋的概念一致，这种ROS信号通过诱导ROS防御酶(SOD、过氧化氢酶)导致适应性反应，最终导致ROS水平降低，尽管线粒体活性增加。抗氧化剂抑制这一ROS信号会使IIIS介导的寿命减少高达60%。ROS信号的诱导需要AAK-2(AMPK)，而逆行反应则需要PMK-1(P38)和SKN-1(NRF-2)。线粒体内L-脯氨酸的分解代谢上调，后者的破坏削弱了线虫的寿命延长能力，而补充L-脯氨酸则延长线虫的寿命。综上所述，IIIS促进L-脯氨酸代谢，产生ROS信号，适应性诱导内源性应激防御，延长寿命。
Impaired Insulin and IGF-1 Signaling (iIIS) in C. elegans daf-2 mutants extends lifespan more than two-fold. Constitutively iIIS increases mitochondrial activity and reduces reactive oxygen species (ROS) levels. By contrast, acute impairment of daf-2 in adult C. elegans reduces glucose uptake and transiently increases ROS. Consistent with the concept of mitohormesis, this ROS signal causes an adaptive response by inducing ROS-defense enzymes (SOD, catalase) culminating in ultimately reduced ROS levels despite increased mitochondrial activity. Inhibition of this ROS signal by antioxidants reduces iIIS-mediated longevity by up to 60%. Induction of the ROS signal requires AAK-2 (AMPK), while PMK-1 (p38) and SKN-1 (NRF-2) are needed for the retrograde response. IIIS upregulates mitochondrial L-proline catabolism, and impairment of the latter impairs the lifespan-extending capacity of iIIS while L-proline supplementation extends C. elegans lifespan. Taken together, iIIS promotes L-proline metabolism to generate a ROS signal for the adaptive induction of endogenous stress defense to extend lifespan.