Nrf2, a Guardian of Healthspan and Gatekeeper of Species Longevity
Nrf2, a Guardian of Healthspan and Gatekeeper of Species Longevity
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DOI：
10.1093/icb/icq034
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发表时间：
2010-11-01
影响因子：
2.6
通讯作者：
Buffenstein, Rochelle
中科院分区：
文献类型：
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作者：
Lewis, Kaitlyn N.;Mele, James;Buffenstein, Rochelle
虽然衰老是一个普遍存在于所有生物体中的过程，但控制功能下降速率和发病年龄的机制仍然难以捉摸。在自然长寿物种和延长寿命的实验模型中通常观察到深刻的组成性上调细胞保护反应（例如，遗传改变的和/或实验操作的生物体），如对应激的抗性增强和细胞保护性核因子红细胞2相关因子2（Nrf 2）信号传导途径的下游组分上调所示。转录因子Nrf 2在所有组织中组成型表达，尽管器官之间的水平可能不同，关键解毒器官（肾脏和肝脏）表现出最高水平。Nrf 2还可被细胞应激源诱导，包括内源性活性氧或外源性亲电体。Nrf 2信号通路通过激活200多个基因的转录介导多种细胞保护途径，这些基因在药物和毒素的代谢中至关重要，保护免受氧化应激和炎症，以及在蛋白质的稳定性和通过蛋白酶体降解或自噬去除受损蛋白质中发挥不可或缺的作用。Nrf 2与其他重要的细胞调节因子相互作用，如肿瘤抑制蛋白53（p53）和核因子-κ β（NF-κ B B），并通过它们的组合相互作用是健康的守护者，防止许多与年龄有关的疾病，包括癌症和神经退行性疾病。我们推测，这一信号通路在决定物种寿命方面起着关键作用，并且这一通路可能确实是衰老过程的主要调节器。
Although aging is a ubiquitous process that prevails in all organisms, the mechanisms governing both the rate of decline in functionality and the age of onset remain elusive. A profound constitutively upregulated cytoprotective response is commonly observed in naturally long-lived species and experimental models of extensions to lifespan (e.g., genetically-altered and/or experimentally manipulated organisms), as indicated by enhanced resistance to stress and upregulated downstream components of the cytoprotective nuclear factor erythroid 2-related factor 2 (Nrf2)-signaling pathway. The transcription factor Nrf2 is constitutively expressed in all tissues, although levels may vary among organs, with the key detoxification organs (kidney and liver) exhibiting highest levels. Nrf2 may be further induced by cellular stressors including endogenous reactive-oxygen species or exogenous electrophiles. The Nrf2-signaling pathway mediates multiple avenues of cytoprotection by activating the transcription of more than 200 genes that are crucial in the metabolism of drugs and toxins, protection against oxidative stress and inflammation, as well as playing an integral role in stability of proteins and in the removal of damaged proteins via proteasomal degradation or autophagy. Nrf2 interacts with other important cell regulators such as tumor suppressor protein 53 (p53) and nuclear factor-kappa beta (NF-kappa B) and through their combined interactions is the guardian of healthspan, protecting against many age-related diseases including cancer and neurodegeneration. We hypothesize that this signaling pathway plays a critical role in the determination of species longevity and that this pathway may indeed be the master regulator of the aging process.