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.

项目摘要： 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。较低的原因之一 抗氧化应激随着年龄的抗性是氧化还原态向更氧化细胞的坡度变化 环境导致细胞信号破坏。核红细胞因子2相关因子2（NRF2）是主 抗氧化剂防御的调节剂。 NRF2驱动了参与细胞保护和的许多基因的表达和 抗氧化剂防御。我们的实验室是第一个证明响应急性运动的NRF2激活的实验室 人类，并且与动物数据一致，我们发现运动引起的NRF2中与年龄相关的损害 信号。这强调了与衰老有关的重要问题，即老年人较少 与年轻的队列相比，对运动刺激敏感。拟议的研究的重点是尝试解决 通过扩增信号并减轻老年人暴露的“运动脱敏”来通过 恢复氧化还原平衡。这项研究将检验以下假设，即将急性运动与硫烷相结合 与单独的任何一个相比，老年人的NRF2激活和下游信号传导将改善NRF2的激活和下游信号传导。磺胺是 在十字花科蔬菜和潜在的NRF2激活剂中发现的植物营养素。这 假设将使用两种不同的方法进行检验。第一个实验将使用体内体内方法， 其中从老年男性和女性（≥60Y，n = 30）收集的外周血单核细胞（PBMC）前和 急性后运动（体内）将通过SFN培养并刺激（Ex vivo）。这使得更大 SFN刺激的实验控制。第二个实验将测试应用的临床翻译 通过整个西兰花的形式，通过口服补充硫烷在体内刺激性刺激 在急性运动之前，在同一个人中发芽材料。第二个实验将是一个随机的 安慰剂控制的跨界设计。对于所有试验，NRF2信号将通过NRF2激活来测量 是结合测定，NRF2蛋白的核与全细胞比，而NRF2依赖性基因表达（HO-1， GCLC，NQO1，GR）。潜在的性别差异将被研究。从这项研究中获得的见解是 将简单的干预措施结合在健康生活方式和预防医学类别中是否可以改善 老年人对运动的适应性反应。通过改善 美国衰老研究所的重要使命是美国老年人的健康和福祉。