Hydralazine induces stress resistance and extends C. elegans lifespan by activating the NRF2/SKN-1 signalling pathway.
Hydralazine induces stress resistance and extends C. elegans lifespan by activating the NRF2/SKN-1 signalling pathway.
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DOI：
10.1038/s41467-017-02394-3
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发表时间：
2017-12-20
影响因子：
16.6
通讯作者：
Mirzaei H
中科院分区：
文献类型：
--
作者：
Dehghan E;Zhang Y;Saremi B;Yadavali S;Hakimi A;Dehghani M;Goodarzi M;Tu X;Robertson S;Lin R;Chudhuri A;Mirzaei H
核因子（红细胞衍生2）样2及其秀丽隐杆线虫直系同源物SKN-1是在氧化应激反应、细胞稳态和生物体寿命中具有关键作用的转录因子。与其他防御系统类似，NRF 2介导的应激反应在衰老和神经退行性疾病中受到损害。在这里，我们报告FDA批准的药物肼苯哒嗪是NRF 2/SKN-1信号通路的真正激活剂。我们证明肼苯哒嗪延长了野生型和tau蛋白病模型C的健康寿命（约25%）。elegans至少与其他抗衰老化合物如姜黄素和二甲双胍一样有效。我们发现肼苯哒嗪介导的寿命延长是SKN-1依赖性的，其机制最有可能模仿热量限制。使用体外和体内模型，我们继续证明肼苯哒嗪对内源性和外源性应激源具有神经保护作用。我们的数据表明，肼苯哒嗪可能是一个可行的候选人，用于治疗与年龄有关的疾病。肼苯哒嗪是FDA批准的用于治疗高血压的药物。Dehghan等人报道肼苯哒嗪通过激活NRF 2/SKN-1信号传导触发细胞氧化应激反应，并延长C. elegans的健康寿命，这表明肼苯哒嗪可能有潜力更广泛地治疗与年龄相关的疾病。
Nuclear factor (erythroid-derived 2)-like 2 and its Caenorhabditis elegans ortholog, SKN-1, are transcription factors that have a pivotal role in the oxidative stress response, cellular homeostasis, and organismal lifespan. Similar to other defense systems, the NRF2-mediated stress response is compromised in aging and neurodegenerative diseases. Here, we report that the FDA approved drug hydralazine is a bona fide activator of the NRF2/SKN-1 signaling pathway. We demonstrate that hydralazine extends healthy lifespan (~25%) in wild type and tauopathy model C. elegans at least as effectively as other anti-aging compounds, such as curcumin and metformin. We show that hydralazine-mediated lifespan extension is SKN-1 dependent, with a mechanism most likely mimicking calorie restriction. Using both in vitro and in vivo models, we go on to demonstrate that hydralazine has neuroprotective properties against endogenous and exogenous stressors. Our data suggest that hydralazine may be a viable candidate for the treatment of age-related disorders. Hydralazine is an FDA approved drug for the treatment of hypertension. Here, Dehghan et al. report that hydralazine triggers the cellular oxidative stress response by activating NRF2/SKN-1 signaling and extends C. elegans healthy lifespan, suggesting hydralazine may have potential to treat age-associated diseases more broadly.
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影响因子：
3.7
作者：
Cook AL;Vitale AM;Ravishankar S;Matigian N;Sutherland GT;Shan J;Sutharsan R;Perry C;Silburn PA;Mellick GD;Whitelaw ML;Wells CA;Mackay-Sim A;Wood SA
通讯作者：
Wood SA
影响因子：
5.3
作者：
Liao, Vivian Hsiu-Chuan;Yu, Chan-Wei;Wang, Teng-Ting
通讯作者：
Wang, Teng-Ting
影响因子：
3.5
作者：
Fatouros, Chronis;Pir, Ghulam Jeelani;Baumeister, Ralf
通讯作者：
Baumeister, Ralf
DOI：
10.1523/jneurosci.0490-10.2010
发表时间：
2010-05-26
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Clinton LK;Blurton-Jones M;Myczek K;Trojanowski JQ;LaFerla FM
通讯作者：
LaFerla FM
DOI：
10.18632/aging.100683
发表时间：
2014-08
期刊：
Aging
影响因子：
--
作者：
Edwards C;Canfield J;Copes N;Rehan M;Lipps D;Bradshaw PC
通讯作者：
Bradshaw PC