Hwang Ara B, Ryu Eun-A, Artan Murat, Chang Hsin-Wen, Kabir Mohammad Humayun, Nam Hyun-Jun, Lee Dongyeop, Yang Jae-Seong, Kim Sanguk, Mair William B, Lee Cheolju, Lee Siu Sylvia, Lee Seung-Jae
Department of Life Sciences, Division of Information Technology Convergence Engineering, School of Interdisciplinary Bioscience and Bioengineering, Pohang University of Science and Technology, Pohang 790-784, South Korea;
Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14853;
Proc Natl Acad Sci U S A. 2014 Oct 21;111(42):E4458-67. doi: 10.1073/pnas.1411199111. Epub 2014 Oct 6.
Mild inhibition of mitochondrial respiration extends the lifespan of many species. In Caenorhabditis elegans, reactive oxygen species (ROS) promote longevity by activating hypoxia-inducible factor 1 (HIF-1) in response to reduced mitochondrial respiration. However, the physiological role and mechanism of ROS-induced longevity are poorly understood. Here, we show that a modest increase in ROS increases the immunity and lifespan of C. elegans through feedback regulation by HIF-1 and AMP-activated protein kinase (AMPK). We found that activation of AMPK as well as HIF-1 mediates the longevity response to ROS. We further showed that AMPK reduces internal levels of ROS, whereas HIF-1 amplifies the levels of internal ROS under conditions that increase ROS. Moreover, mitochondrial ROS increase resistance to various pathogenic bacteria, suggesting a possible association between immunity and long lifespan. Thus, AMPK and HIF-1 may control immunity and longevity tightly by acting as feedback regulators of ROS.
对线粒体呼吸的轻度抑制可延长许多物种的寿命。在秀丽隐杆线虫中，活性氧（ROS）通过响应线粒体呼吸减少激活缺氧诱导因子1（HIF-1）来促进长寿。然而，ROS诱导长寿的生理作用和机制尚不清楚。在这里，我们表明ROS的适度增加通过HIF-1和AMP激活的蛋白激酶（AMPK）的反馈调节增加了秀丽隐杆线虫的免疫力和寿命。我们发现AMPK以及HIF-1的激活介导了对ROS的长寿反应。我们进一步表明，AMPK降低了ROS的内部水平，而HIF-1在增加ROS的条件下放大了内部ROS的水平。此外，线粒体ROS增加了对各种病原菌的抵抗力，表明免疫力和长寿之间可能存在关联。因此，AMPK和HIF-1可能通过作为ROS的反馈调节因子来紧密控制免疫力和寿命。
