Treatment strategy to enhance Nrf2 signaling in older adults: combining acute exercise with the phytochemical sulforaphane

增强老年人 Nrf2 信号传导的治疗策略：急性运动与植物化学物质萝卜硫素相结合

• 批准号: 10444770
• 负责人: TINNA TRAUSTADOTTIR
• 金额: $ 44.88万
• 依托单位: NORTHERN ARIZONA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10444770
• 关键词: Acute; Age; Aging; Agreement; American; Animals; Antioxidants; Attenuated; Binding; Biological Assay; Biological Availability; Broccoli - dietary; Cardiovascular Diseases; Categories; Cell Culture Techniques; Cells; Chronic; Clinical Research; Combined Modality Therapy; Crossover Design; Cytoprotection; Dementia; Detection; Disease; Drug Metabolic Detoxication; Elderly; Environment; Enzymes; Equilibrium; Etiology; Exercise; Exhibits; GCLC gene; Gene Expression; Genes; Genetic Enhancer Element; Genetic Transcription; Health; Human; Impairment; Individual; Inflammation; Intermittent fasting; Intervention; Malignant Neoplasms; Measures; Mission; Modeling; Molecular; Mus; NF-E2-related factor 2; NQO1 gene; National Institute on Aging; Non-Insulin-Dependent Diabetes Mellitus; Nuclear; Oral; Organism; Oxidation-Reduction; Oxidative Stress; Oxides; Pathway interactions; Peripheral Blood Mononuclear Cell; Personal Satisfaction; Phase; Phytochemical; Placebo Control; Placebos; Play; Preventive Medicine; Problem Solving; Promoter Regions; Public Health; Randomized; Randomized Controlled Trials; Reporting; Resistance; Risk Factors; Sex Differences; Signal Transduction; Stimulus; Stress; Sulforaphane; Supplementation; Testing; Time; Translating; Up-Regulation; age related; animal data; clinical translation; cohort; cruciferous vegetable; desensitization; disorder prevention; disorder risk; exercise training; experimental study; functional decline; healthy lifestyle; improved; in vivo; insight; nuclear factor-erythroid 2; older men; older women; oral supplementation; polyphenol; response; stress resilience; transcription factor; treatment strategy; weapons

PROJECT SUMMARY: Redox balance plays a key role in the age-associated increased risk for diseases. One reason for the lower resistance to oxidative stress with age is a gradual shift in the redox state toward a more oxidized cellular environment resulting in disruption of cell signaling. Nuclear erythroid factor 2-related factor 2 (Nrf2) is the master regulator of antioxidant defenses. Nrf2 drives expression of a host of genes involved in cytoprotection and antioxidant defenses. Our lab was the first to demonstrate Nrf2 activation in response to acute exercise in humans, and in agreement with animal data, we found an age-related impairment in exercise-induced Nrf2 signaling. This underscores an important problem related to aging, namely that older individuals are less sensitive to an exercise stimulus compared to younger cohorts. The focus of the proposed study is to try to solve this problem by amplifying the signal and mitigating the “exercise desensitization” exhibited by older individuals to restore redox balance. This study will test the hypothesis that combining acute exercise with sulforaphane will improve Nrf2 activation and downstream signaling in older adults compared to either alone. Sulforaphane is a phytonutrient found in high concentrations in cruciferous vegetables and a potent Nrf2 activator. The hypothesis will be tested using two different approaches; the first experiment will use an in vivo–ex vivo approach, where peripheral blood mononuclear cells (PBMCs) collected from older men and women (≥60y, n=30) pre- and post-acute exercise (in vivo) will be cultured and stimulated with SFN (ex vivo). This allows for a greater experimental control of the SFN stimulus. The second experiment will test the clinical translation applying the sulforaphane stimulus in vivo through an oral supplementation of sulforaphane in the form of whole broccoli sprout material, prior to acute exercise, in the same individuals. This second experiment will be a randomized placebo-controlled cross-over design. For all trials Nrf2 signaling will be measured by Nrf2 activation through an ARE binding assay, nuclear to whole cell ratio of Nrf2 protein, and Nrf2-dependent gene expression (HO-1, GCLC, NQO1, GR). Potential sex differences will be investigated. The insights gained from this study are whether combining simple interventions in the category of healthy lifestyle and preventive medicine can improve the adaptive response to exercise in older individuals. This could have an enormous impact by improving the health and well-being of older Americans, an important mission of the National Institutes of Aging.

项目概要： 氧化还原平衡在与年龄相关的疾病风险增加中起着关键作用。降低的一个原因是 随着年龄的增长，对氧化应激的抵抗是氧化还原状态向更氧化的细胞的逐渐转变， 环境导致细胞信号传导中断。核红细胞因子2相关因子2（Nrf 2）是 抗氧化防御的调节剂。Nrf 2驱动参与细胞保护的许多基因的表达， 抗氧化防御我们的实验室是第一个证明Nrf 2在急性运动中激活的实验室。 与动物数据一致，我们发现运动诱导的Nrf 2 发信号。这突出了一个与老龄化有关的重要问题，即老年人 对运动刺激的敏感性。本研究的重点是试图解决 通过放大信号和减轻老年人表现出的“运动脱敏”来解决这个问题 来恢复氧化还原平衡本研究将检验急性运动与萝卜硫素相结合的假设 与单独使用相比，将改善老年人的Nrf 2激活和下游信号传导。萝卜硫素是 在十字花科蔬菜中发现的高浓度植物营养素和有效的Nrf 2激活剂。的 将使用两种不同的方法来检验假设;第一个实验将使用体内-离体方法， 其中外周血单核细胞（PBMC）采集自老年男性和女性（≥ 60岁，n=30）术前和术后， 急性运动后（体内）将用SFN（离体）培养和刺激。这使得更大的 SFN刺激的实验控制。第二个实验将测试临床翻译应用 通过口服补充完整西兰花形式的莱菔硫烷体内刺激 发芽材料，急性运动之前，在同一个人。第二个实验将是一个随机的 安慰剂对照交叉设计。对于所有试验，Nrf 2信号传导将通过Nrf 2活化通过免疫组织化学来测量。 ARE结合测定、Nrf 2蛋白的核与全细胞比率和Nrf 2依赖性基因表达（HO-1， GCLC、NQO1、GR）。将研究潜在的性别差异。从这项研究中获得的见解是 结合健康生活方式和预防医学的简单干预措施是否可以改善 老年人对运动的适应性反应。这可能会产生巨大影响， 美国老年人的健康和福祉，这是美国国立老龄研究院的一项重要使命。