NRF2 interactions with SIRT1 and its role on caloric restriction

NRF2 与 SIRT1 的相互作用及其在热量限制中的作用

• 批准号: 8335832
• 负责人: Rafael de Cabo
• 金额: $ 43.05万
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8335832
• 关键词: Adherence; Age; Aging; Animals; Antioxidants; Attenuated; Binding; Bioenergetics; Biologic Characteristic; Biological; Caenorhabditis elegans; Caloric Restriction; Carcinogens; Cell Nucleus; Cell membrane; Chemicals; Coupled; Curcumin; Cytoplasm; Development; Diet; Dietary Intervention; Disease; Drug Formulations; Drug Metabolic Detoxication; Electron Transport; Energy Intake; Enzymes; Equilibrium; Exposure to; Fasting; Gene Targeting; Genes; Genetic Transcription; Glutathione S-Transferase; Goals; Health; Human; Insulin; Insulin-Like Growth Factor I; Investments; Laboratories; Laboratory Rat; Longevity; Malignant Neoplasms; Mammals; Metabolism; Mitochondria; Molecular; Mus; NAD(P)H dehydrogenase (quinone) 1, human; NF-E2-related factor 2; NQO1 gene; Neurons; Nuclear; Oxidation-Reduction; Oxidative Stress; Pathway interactions; Physiological; Phytochemical; Prevention strategy; Production; Publishing; Quercetin; Regulation; Response Elements; Resveratrol; Role; Signal Transduction; Sirtuins; Stress; System; Tissues; Transplantation; Work; age related; attenuation; biological adaptation to stress; carcinogenesis; environmental agent; functional decline; heme oxygenase-1; insulin sensitivity; mimetics; mutant; nutrition; response; transcription factor; tumor

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.

大约一个世纪前，Moreschi 和 Rous 分别发表了关于热量限制 (CR) 对移植和诱导肿瘤影响的观察结果。几年后，麦凯和同事首次观察到维持 CR 饮食的实验室老鼠的寿命延长。从那时起，CR 得到了深入的研究，一致的结果表明它对各种物种和饮食配方的长寿、与年龄相关的疾病、减轻功能衰退和致癌作用具有有益作用。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发和自发癌变的保护、减少胰岛素/IGF-1 信号传导以及延长中位和最大寿命。 即使 CR 被证明有益于人类健康、提供癌症保护并延长寿命，但要坚持如此严格的饮食（可能需要减少 20-40% 的热量摄入）也是极其困难的。为此，大量投资集中在剖析调节 CR 益处的途径，这可能会刺激可能充当 CR 模拟物的药物制剂的开发。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），它们至少部分通过激活 NF-E2 相关因子 2 (Nrf2) 途径发挥作用。 Nrf2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。压力可能由多种原因引起，包括禁食、过度喂养、内源性化合物、接触化学品或环境因素，但通常会导致活性氧的产生。由于 ROS 暴露，Nrf2（通常在细胞质中与 Keap1 结合，经历蛋白水解降解和快速周转）被磷酸化并易位到细胞核，在细胞核中与 ARE 序列结合，诱导包括 NAD 在内的多种细胞保护酶的表达(P)H-醌氧化还原酶 1 (NQO1)、谷胱甘肽 S-转移酶 (GST) 和血红素加氧酶-1。哺乳动物 cap 'n' 项圈转录因子，例如 Nrf2，被认为与秀丽隐杆线虫基因 skn-1 关系最为密切。 SKN-1在功能上与Nrf2相似，它对氧化应激作出反应并上调解毒酶，并且与WT蠕虫相比，skn-1突变体的存活时间更短，应激反应减少。仅两个神经元中存在 skn-1 对于 CR 延长线虫的中值和最大寿命是必要的。由于秀丽隐杆线虫的寿命调节似乎依赖于 Nrf2 同源途径，因此 CR 在哺乳动物中的生存效应也可以通过 Nrf2 转录因子网络进行调节。 我们现在已经证明，Nrf2 负责保护 CR 免受诱导癌变。然而，缺乏 Nrf2 并不会减弱 Nrf2 KO 小鼠的寿命延长或改变胰岛素敏感性 CR 的改善。但是，现在看来，在哺乳动物中，除了 Nrf2 参与 CR 的抗癌保护之外，其他因素（可能是 SIRT1）也参与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，并且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，这种相互作用本身是一个有前途的目标，可以评估针对年龄相关疾病和环境诱发的癌症的预防策略。