Treatment Strategy to Enhance Nrf2 Signaling in Older Adults

Study Overview
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Brief Summary
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Exercise is the cornerstone of disease prevention and often an important component of treatment. However, the efficacy of an exercise stimulus is reduced with aging. This study will investigate whether adding a treatment with phytonutrients found in cruciferous vegetables can improve the exercise response in older individuals.

Detailed Description
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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. The Traustadottir lab was the first to demonstrate Nrf2 activation in response to acute exercise in humans, and in agreement with animal data, 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 (SFN) 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.

Official Title
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Treatment Strategy to Enhance Nrf2 Signaling in Older Adults: Combining Acute Exercise With the Phytochemical Sulforaphane

Conditions
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Aging Problems

Intervention / Treatment
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* Dietary Supplement: Sulforaphane
* Dietary Supplement: Placebo capsules


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men and women, 60 years and older Competent to independently give informed consent Successful completion of screening Maximal oxygen consumption below the 60th percentile based on gender: Women: ≤ 21.2 mL/kg/min Men: ≤ 30.5 mL/kg/min Exclusion Criteria: Estrogen supplementation (in any form) within the previous 6 months Any medication that could affect outcome measures such as statins, blood pressure medications, or anti-depressives Use of anti-oxidant supplements, in excess of standard multi-vitamins (1 tablet/day) and/or any supplements known to target Nrf2 including resveratrol, Protandim, and sulforaphane Current smoker Body Mass Index (BMI) greater than 33 kg/m2 (Class I Obesity) Any chronic illness that could affect outcome measures, including diabetes, liver or renal disease, or cancer (other than skin cancer) History of a myocardial infarction within the last 6 months, clinically significant aortic stenosis, use of cardiac defibrillator, or uncontrolled angina Clinically significant arrhythmia on a resting EKG or significant EKG changes during the baseline VO2 max test Any other condition that would contraindicate maximal exercise testing, including elevated blood pressure at rest (systolic BP >150 or diastolic BP >90 mm Hg on at least 2 measurements, at least 10 minutes apart) or musculoskeletal problems

Ages Eligible for Study
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Minimum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Supportive Care
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Humans
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SFN supplement<br>The oral sulforaphane supplement is a myrosinase-active whole broccoli sprout material (EnduraCell Bioactive, Cell-Logic, Queensland, AU) containing 14 mg SFN per capsule. Three capsules will be consumed 90 min prior to the start of the acute exercise trial. The dose of 3 capsules is equivalent to approximately 220 µmol of SFN, which is comparable to that of other studies using broccoli sprout extracts and the recommended single dose. | Dietary Supplement: Sulforaphane<br>* Myrosinase-active whole broccoli sprout material<br>* Other names: EnduraCell Bioactive;Dietary Supplement: Placebo capsules<br>* Placebo capsules<br>|
| Placebo Comparator: Placebo<br>Placebo capsules provided by Cell-Logic. | Dietary Supplement: Sulforaphane<br>* Myrosinase-active whole broccoli sprout material<br>* Other names: EnduraCell Bioactive;Dietary Supplement: Placebo capsules<br>* Placebo capsules<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Nrf2 activation in response to acute exercise | Nrf2/ARE Binding Assay | Comparing trials separated by one week (supplement vs. placebo) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| NQO1 gene expression in response to acute exercise | NQO1 mRNA measured with RT-qPCR | Comparing trials separated by one week (supplement vs. placebo) | 
| HO-1 gene expression in response to acute exercise | HO-1 mRNA measured with RT-qPCR | Comparing trials separated by one week (supplement vs. placebo) | 
| Glutathione reductase (GR) gene expression in response to acute exercise | GR mRNA measured with RT-qPCR | Comparing trials separated by one week (supplement vs. placebo) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Redox, Sulforaphane, Nrf2, Exercise