NRF2 interactions with SIRT1 and its role on caloric restriction

近一个世纪前，莫雷斯基和罗斯分别发表了他们关于卡路里限制(CR)对移植和诱导肿瘤的影响的观察。几年后，McCay和他的同事首次观察到服用CR饮食的实验室大鼠的寿命延长。从那时起，人们对CR进行了深入的研究，一致的结果表明，它对长寿、年龄相关疾病、缓解功能衰退以及各种种类和饮食配方的致癌作用都是有益的。然而，CR保护作用的潜在机制(S)仍不清楚。然而，可以肯定地说，CR的三个最广泛研究的特征是增强了对诱发和自发癌变的保护，减少了胰岛素/IGF-1信号，以及延长了中位和最长寿命。 即使CR被证明有益于人类健康，提供癌症保护，并延长寿命，要坚持如此严格的饮食，可能需要减少20-40%的卡路里摄入量，也是极其困难的。为此，大量的投资集中在解剖调节CR益处的途径上，这些途径可能刺激潜在地作为CR模拟物的药理学药物的发展。目前提出的CR模拟物中有几种是植物化学物质(白藜芦醇、栎素和姜黄素)，它们至少部分地通过激活核因子-E2相关因子2(NRF2)途径发挥作用。NRF2是一种转录因子，它与靶基因的抗氧化反应元件(ARE)结合，作为对氧化应激的适应性反应，并增加多种抗氧化和致癌解毒酶的转录。压力可以由多种原因引起，包括禁食、过量进食、内源性化合物、接触化学品或环境制剂，但通常会导致ROS的产生。作为ROS暴露的结果，NRF2通常与细胞质中的Keap1结合，在那里它经历蛋白质降解和快速周转，被磷酸化并转移到细胞核，在那里它与Are序列结合，诱导多种细胞保护酶的表达，包括NAD(P)H-QO1、谷胱甘肽S转移酶(GSTs)和血红素加氧酶-1。哺乳动物的衣冠转录因子，如Nrf2，被认为与秀丽隐杆线虫基因SKn-1关系最密切。SKN-1在功能上与Nrf2相似，因为它对氧化应激做出反应，并上调解毒酶，与WT蠕虫相比，SKN-1突变体的存活时间更短，应激反应更少。只有在两个神经元中存在SKN-1才是CR延长线虫中位和最长寿命所必需的。由于线虫寿命的调节似乎依赖于Nrf2同源途径，因此CR在哺乳动物中的生存效应也可能通过Nrf2转录因子网络来调节。 我们现在已经证明，Nrf2负责保护CR免受诱发癌变的影响。然而，缺乏Nrf2并没有减弱Nrf2KO小鼠的寿命延长或改变其对胰岛素敏感性的CR改善。但是，目前在哺乳动物中，似乎除了Nrf2参与CR的抗癌保护外，其他因素，可能是SIRT1，也参与了哺乳动物寿命的调节。我们最近发现了这两个分子之间的相互作用，我们正在努力剖析这种相互作用的生理和生物学意义。最后，也是最重要的是，这种相互作用本身就是一个有希望的目标，可以用来评估预防年龄相关疾病和环境诱发癌症的战略。

Almost a century ago Moreschi and Rous published their separate observations on the impact of caloric restriction (CR) on transplanted and induced tumors. Years later, McCay and colleagues first observed lifespan extension in laboratory rats maintained on a CR diet. Since then, CR has been studied intensively with consistent results showing its beneficial effects on longevity, age-associated diseases, attenuation of functional declines, and carcinogenesis across a variety of species and diet formulations. However, the mechanism(s) underlying the effects of CR protection still remain unknown. Nevertheless, it is safe to say that the three most extensively studied hallmarks of CR are enhanced protection against induced and spontaneous carcinogenesis, reduced insulin/IGF-1 signaling, and increased median and maximum lifespan. Even if CR was shown to benefit human health, confer cancer protection, and increase longevity, it would be extremely difficult to achieve adherence to such a stringent diet that might require a reduction of 20-40% in caloric intake. To this end, considerable investment has been focused on dissecting the pathways that regulate CR benefits that could spur development of pharmacological agents potentially acting as CR mimetics. Several of the currently proposed CR mimetics are phytochemicals (resveratrol, quercetin, and curcumin) that act, at least in part, through the activation of the NF-E2-related factor 2 (Nrf2) pathway. Nrf2 is a transcription factor that binds to the antioxidant response element (ARE) of target genes as an adaptive response to oxidative stress and increases the transcription of a variety of anti-oxidative and carcinogen detoxification enzymes. Stress can result from a variety of causes including fasting, overfeeding, endogenous compounds, exposure to chemicals or environmental agents but generally leads to the production of ROS. As a result of ROS exposure, Nrf2, which is typically bound to Keap1 in the cytoplasm, where it undergoes proteolytic degradation and rapid turnover, is phosphorylated and translocates to the nucleus where it binds to ARE sequences to induce expression of multiple cytoprotective enzymes including NAD(P)H-quinone oxidoreductase 1 (NQO1), glutathione S-transferases (GSTs), and heme oxygenase-1. Mammalian cap 'n' collar transcription factors, such as Nrf2, are thought to be most closely related to the Caenorhabditis elegans gene skn-1. SKN-1 is functionally similar to Nrf2 in that it responds to oxidative stress and up-regulates detoxifying enzymes, and skn-1 mutants have shorter survival and reduced stress response compared with WT worms. The presence of skn-1 in only two neurons is necessary for CR to increase median and maximum lifespan in C. elegans. Because the regulation of lifespan appears dependent on Nrf2-homologous pathways in C. elegans, the survival effects of CR in mammals could be also regulated through Nrf2 transcription factor networks. We have now shown that Nrf2 is responsible for the protection of CR against induced carcinogenesis. However, the lack of Nrf2 did not attenuate lifespan extension or alter the CR improvement on insulin sensitivity in the Nrf2 KO mice. But, it appears now in mammals that besides the involvement of Nrf2 on anti-carcinogenic protection by CR, other factors, perhaps SIRT1, are involved in the regulation of mammalian longevity. We have recently discovered the interaction between these two molecules and we are working on dissecting the physiological and biological meaning of this interaction. Finally and most importantly, this interaction presents itself as a promising target to evaluate preventive strategies against age related diseases and environmentally induced cancers.