Perspective: Modulating the integrated stress response to slow aging and ameliorate age-related pathology.
Perspective: Modulating the integrated stress response to slow aging and ameliorate age-related pathology.
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DOI：
10.1038/s43587-021-00112-9
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发表时间：
2021-09
期刊：
影响因子：
--
通讯作者：
Denzel MS
中科院分区：
文献类型：
--
作者：
Derisbourg MJ;Hartman MD;Denzel MS
健康的衰老需要多种应激信号通路的协调，这些信号通路汇聚在蛋白质稳态网络上。综合应激反应（Integrated Stress Response， ISR）可被多种刺激激活，导致真核翻译起始因子elF2 α-亚基磷酸化。在饱和条件下，elF2协调5 '帽依赖性mRNA翻译，因此负责一般蛋白质合成。elF2α磷酸化是ISR的关键事件，它减少了mRNA的翻译，同时增强了一系列应激反应基因的表达。尽管蛋白质质量控制在健康衰老和许多长寿途径中起着关键作用，但ISR在长寿中的作用在很大程度上仍未被探索。ISR活动随着年龄的增长而增加，这表明它与衰老过程有潜在的联系。虽然在ISR激活过程中发生的蛋白质生物合成减少与寿命延长有关，但最近的数据表明，ISR的抑制延长了线虫的存活时间，并增强了老年小鼠的认知功能，因此寿命受到ISR的限制。在这里，我们探讨了衰老如何影响ISR， ISR在调节衰老中的作用，以及调节ISR的药物干预。最后，我们将探讨ISR作为衰老和年龄相关疾病临床干预的合理目标。
Healthy aging requires the coordination of numerous stress signaling pathways that converge on the protein homeostasis network. The Integrated Stress Response (ISR) is activated by diverse stimuli, leading to phosphorylation of the eukaryotic translation initiation factor elF2 in its α-subunit. Under replete conditions, elF2 orchestrates 5’ cap-dependent mRNA translation and is thus responsible for general protein synthesis. elF2α phosphorylation, the key event of the ISR, reduces global mRNA translation while enhancing the expression of a signature set of stress response genes. Despite the critical role of protein quality control in healthy aging and in numerous longevity pathways, the role of the ISR in longevity remains largely unexplored. ISR activity increases with age, suggesting a potential link with the aging process. Although decreased protein biosynthesis, which occurs during ISR activation, have been linked to lifespan extension, recent data show that lifespan is limited by the ISR as its inhibition extends survival in nematodes and enhances cognitive function in aged mice. Here we survey how aging affects the ISR, the role of the ISR in modulating aging, and pharmacological interventions to tune the ISR. Finally, we will explore the ISR as a plausible target for clinical interventions in aging and age-related disease.
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DOI：
10.1016/j.bbrc.2015.11.019
发表时间：
2015-12-25
影响因子：
3.1
作者：
Chalil, Sreeda;Pierre, Nicolas;Deldicque, Louise
通讯作者：
Deldicque, Louise
DOI：
10.1126/science.aaa4484
发表时间：
2015-04-10
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
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通讯作者：
Bertolotti A
DOI：
10.1093/brain/awab167
发表时间：
2021-10-22
期刊：
Brain : a journal of neurology
影响因子：
--
作者：
Dalla Bella E;Bersano E;Antonini G;Borghero G;Capasso M;Caponnetto C;Chiò A;Corbo M;Filosto M;Giannini F;Spataro R;Lunetta C;Mandrioli J;Messina S;Monsurrò MR;Mora G;Riva N;Rizzi R;Siciliano G;Silani V;Simone I;Sorarù G;Tugnoli V;Verriello L;Volanti P;Furlan R;Nolan JM;Abgueguen E;Tramacere I;Lauria G
通讯作者：
Lauria G
影响因子：
4.2
作者：
Brown MK;Chan MT;Zimmerman JE;Pack AI;Jackson NE;Naidoo N
通讯作者：
Naidoo N
影响因子：
16.8
作者：
Carrara M;Sigurdardottir A;Bertolotti A
通讯作者：
Bertolotti A