Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, 15355 Lambda Drive, STCBM 2.2, San Antonio, TX 78245, USA.
Integr Comp Biol. 2010 Nov;50(5):829-43. doi: 10.1093/icb/icq034. Epub 2010 May 6.
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-κB) 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.
尽管衰老是一种普遍存在于所有生物体中的过程，但控制功能下降速度和发病年龄的机制仍然难以捉摸。在自然长寿物种和寿命延长的实验模型（例如，基因改变和/或实验操作的生物体）中，通常观察到一种深刻的组成性上调的细胞保护反应，表现为对压力的抵抗力增强和细胞保护核因子红细胞 2 相关因子 2（Nrf2）信号通路的下游成分上调。转录因子 Nrf2 在所有组织中持续表达，尽管水平可能因器官而异，关键解毒器官（肾脏和肝脏）表现出最高水平。Nrf2 可能进一步被细胞应激源诱导，包括内源性活性氧或外源性亲电子化合物。Nrf2 信号通路通过激活超过 200 个基因的转录来介导多种细胞保护途径，这些基因在药物和毒素代谢、氧化应激和炎症保护以及蛋白质稳定性以及通过蛋白酶体降解或自噬清除受损蛋白质中发挥重要作用。Nrf2 与其他重要的细胞调节剂相互作用，如肿瘤抑制蛋白 53（p53）和核因子-κB（NF-κB），并通过它们的共同相互作用，成为健康寿命的守护者，预防许多与年龄相关的疾病，包括癌症和神经退行性疾病。我们假设该信号通路在确定物种寿命方面起着关键作用，并且该通路可能确实是衰老过程的主要调节剂。
