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: 9147281
• 负责人: Rafael de Cabo
• 金额: $ 43.78万
• 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/9147281
• 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; Gerontology; Glutathione S-Transferase; Goals; Health; Human; Insulin; Insulin-Like Growth Factor I; Investments; Laboratories; Laboratory Rat; Longevity; Malignant Neoplasms; Mammals; 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; 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，莫雷斯基（Moreschi）和鲁斯（Rous）发表了关于热量限制（CR）对移植和诱导肿瘤的影响的单独观察。多年后，麦凯及其同事首先观察到在CR饮食中维持实验室大鼠的寿命延长。从那时起，对CR进行了深入的研究，结果表明其对寿命，与年龄相关的疾病，功能下降的衰减衰减以及各种物种和饮食配方中的致癌作用。但是，CR保护作用的基础机制仍然未知。但是，可以肯定地说，最广泛研究的CR的三个标志是对诱导和自发的癌变的保护，胰岛素/IGF-1信号的减少，中位和最大寿命增加。 即使证明CR有益于人类健康，赋予癌症保护并增加寿命，也很难遵守这种严格的饮食，这可能需要减少20-40％的热量摄入量。为此，大量的投资集中在剖析规范CR益处的途径上，这些途径可能刺激了可能充当CR Mimetics的药理学剂的发展。当前提出的几种CR Mimetics是植物化学物质（白藜芦醇，槲皮素和姜黄素），它们至少通过激活NF-E2相关因子2（NRF2）途径而起作用。 NRF2是与靶基因的抗氧化反应元件（IS）结合的转录因子，作为对氧化应激的适应性反应，并增加了多种抗氧化和致癌酶的转录。压力可能是由于禁食，过度喂养，内源性化合物，暴露于化学物质或环境剂的各种原因而造成的，但通常会导致ROS的产生。由于ROS暴露，NRF2通常与细胞质中的Keap1结合，在该NRF2中，它经历了蛋白水解降解和快速的转换，被磷酸化，并易位到核与核与核的结合，以诱导包括多个细胞保护酶的表达的序列， （P）H-夸酮氧化还原酶1（NQO1），谷胱甘肽S-转移酶（GSTS）和血红素加氧酶-1。哺乳动物帽'n'项圈转录因子（例如NRF2）被认为与秀丽隐杆线虫基因SKN-1最密切相关。 SKN-1在功能上与NRF2相似，因为它响应氧化应激并上调排毒酶，并且与WT蠕虫相比，SKN-1突变体的存活率较短，应力反应降低。 CR仅在两个神经元中仅存在SKN-1才能增加秀丽隐杆线虫中的中值和最大寿命。由于寿命的调节似乎取决于秀丽隐杆线虫中的NRF2同理途径，因此CR在哺乳动物中的存活效应也可以通过NRF2转录因子网络来调节。 我们现在已经表明，NRF2负责保护CR免受诱导的致癌作用。但是，缺乏NRF2并未减弱寿命延伸或改变NRF2 KO小鼠胰岛素敏感性的CR改善。但是，现在出现在哺乳动物中，除了NRF2参与CR的抗癌保护外，其他因素（也许是SIRT1）都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，并且正在努力剖析这种相互作用的生理和生物学含义。最后，最重要的是，这种相互作用将自己作为评估针对年龄相关疾病和环保癌症的预防策略的有希望的目标。