NRF2 interactions with SIRT1 and its role on caloric restriction

大约世纪前，Moreschi和Rous发表了他们关于热量限制（CR）对移植和诱导肿瘤影响的单独观察结果。几年后，McCay和同事们首次观察到维持CR饮食的实验室大鼠的寿命延长。从那时起，CR已被深入研究，一致的结果显示其对长寿，年龄相关疾病，功能衰退的衰减以及各种物种和饮食配方的致癌作用的有益影响。然而，CR保护作用的潜在机制仍然未知。尽管如此，可以肯定地说，CR的三个最广泛研究的标志是增强对诱导和自发致癌作用的保护，减少胰岛素/IGF-1信号传导，以及增加中位和最长寿命。 即使CR被证明有益于人类健康，赋予癌症保护，并延长寿命，但要坚持如此严格的饮食，可能需要减少20-40%的热量摄入，这将是非常困难的。为此，大量的投资集中在解剖调节CR益处的途径上，这可能会刺激可能用作CR模拟物的药理学药物的开发。目前提出的几种CR模拟物是植物化学物质（白藜芦醇、槲皮素和姜黄素），其至少部分地通过激活NF-E2相关因子2（Nrf 2）途径起作用。Nrf 2是一种转录因子，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物解毒酶的转录。应激可由多种原因引起，包括禁食、过度喂养、内源性化合物、暴露于化学品或环境因子，但通常导致ROS的产生。ROS暴露的结果是，Nrf 2（通常与细胞质中的Keap 1结合，在细胞质中发生蛋白水解降解和快速周转）被磷酸化并易位至细胞核，在细胞核中与ARE序列结合，诱导多种细胞保护酶的表达，包括NAD（P）H-醌氧化还原酶1（NQO 1）、谷胱甘肽S-转移酶（GST）和血红素加氧酶-1。哺乳动物帽领转录因子，如Nrf 2，被认为是最密切相关的秀丽隐杆线虫基因skn-1。SKN-1在功能上与Nrf 2相似，因为它响应氧化应激并上调解毒酶，与WT蠕虫相比，skn-1突变体具有更短的存活时间和降低的应激反应。skn-1仅在两个神经元中的存在对于CR增加C中的中值和最大寿命是必需的。优雅因为在C.在哺乳动物中，CR的生存效应也可以通过Nrf 2转录因子网络进行调节。 我们现在已经表明，Nrf 2是负责保护CR对诱导的致癌作用。然而，缺乏Nrf 2并没有减弱寿命延长或改变Nrf 2 KO小鼠中胰岛素敏感性的CR改善。但是，现在在哺乳动物中，除了Nrf 2参与CR的抗癌保护外，其他因素，可能是SIRT 1，参与了哺乳动物寿命的调节。我们最近发现了这两种分子之间的相互作用，我们正在研究这种相互作用的生理和生物学意义。最后，也是最重要的是，这种相互作用本身是一个有前途的目标，以评估预防战略，对年龄相关的疾病和环境引起的癌症。

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.