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在衰老的Klotho小鼠模型中，ASK1信号体响应内源性氧化应激水平调节p38丝裂原活化蛋白激酶活性。

The ASK1-Signalosome regulates p38 MAPK activity in response to levels of endogenous oxidative stress in the Klotho mouse models of aging.

作者信息

Hsieh C-C, Kuro-o Makoto, Rosenblatt Kevin P, Brobey Reynolds, Papaconstantinou John

机构信息

Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX 77555, USA.

出版信息

Aging (Albany NY). 2010 Sep;2(9):597-611. doi: 10.18632/aging.100194.

DOI:10.18632/aging.100194
PMID:20844314
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC2984608/
Abstract

Reactive oxygen species (ROS) and elevated levels of p38 MAPK activity accelerate physiological aging. This emphasizes the importance of understanding the molecular mechanism(s) that link ROS production to activation of the p38 mediated promotion of aging, longevity, and resistance to oxidative stress. We examined Klotho(-/-) (elevated ROS) and Klotho overexpressing mice (low ROS and resistance to ROS) to determine whether the ROS-sensitive apoptosis signal-regulating kinase (ASK1)-signalosome -> p38 MAPK pathway plays a role in the accelerated aging of Klotho(-/-), and resistance to oxidative stress and extended lifespan in the Klotho overexpressing models. Our results suggest that increased endogenous ROS generated by Klotho(-/-) and resistance to oxidative stress in Klotho overexpression are linked to the regulation of ASK1-signalosome -> p38 activity. We propose that (a) the ASK1-signalosome -> p38 MAPK pathway is activated by oxidative stress due to ablation of the Klotho gene; (b) increased longevity by Klotho overexpression is linked to suppression of the ASK1-signalosome-p38 MAPK activity; (c) the ROS-responsive ASK1-signalosome regulates physiological aging via its regulation of p38 MAPK, through a mechanism that balances the levels of inhibitory vs. activating ASK1-signalosomes. We conclude that the Klotho suppressor-of-aging activity is linked to the ASK1-signalsome, a physiological ROS-sensitive signaling center.

摘要

活性氧（ROS）和p38丝裂原活化蛋白激酶（MAPK）活性的升高会加速生理衰老。这凸显了理解将ROS产生与p38介导的衰老、长寿及抗氧化应激促进作用激活相联系的分子机制的重要性。我们检测了Klotho基因敲除小鼠（ROS水平升高）和Klotho过表达小鼠（ROS水平低且抗氧化应激），以确定ROS敏感的凋亡信号调节激酶（ASK1）-信号体 -> p38 MAPK通路是否在Klotho基因敲除小鼠的加速衰老、抗氧化应激能力及Klotho过表达模型的延长寿命中发挥作用。我们的结果表明，Klotho基因敲除产生的内源性ROS增加以及Klotho过表达时的抗氧化应激能力与ASK1-信号体 -> p38活性的调节有关。我们提出：（a）由于Klotho基因缺失导致的氧化应激激活了ASK1-信号体 -> p38 MAPK通路；（b）Klotho过表达导致的寿命延长与ASK1-信号体-p38 MAPK活性的抑制有关；（c）ROS反应性ASK1-信号体通过调节p38 MAPK来调节生理衰老，其机制是平衡抑制性与激活性ASK1-信号体的水平。我们得出结论，Klotho的抗衰老活性与ASK1信号体有关，ASK1信号体是一个对生理ROS敏感的信号中心。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/20da/2984608/9aea69744e3d/aging-02-597-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/20da/2984608/491356e89151/aging-02-597-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/20da/2984608/25f7127d7e60/aging-02-597-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/20da/2984608/57d7e0cc4453/aging-02-597-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/20da/2984608/10e946dab6e7/aging-02-597-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/20da/2984608/195a9f98cc50/aging-02-597-g004.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/20da/2984608/9aea69744e3d/aging-02-597-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/20da/2984608/491356e89151/aging-02-597-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/20da/2984608/25f7127d7e60/aging-02-597-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/20da/2984608/57d7e0cc4453/aging-02-597-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/20da/2984608/10e946dab6e7/aging-02-597-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/20da/2984608/195a9f98cc50/aging-02-597-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/20da/2984608/6afcd793174f/aging-02-597-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/20da/2984608/9aea69744e3d/aging-02-597-g006.jpg

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