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.

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