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Cell Signaling and Resistance to Oxidative Stress: Effects of Aging and Exercise

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT03419988
Recruitment Status : Completed
First Posted : February 5, 2018
Last Update Posted : August 26, 2020
Information provided by (Responsible Party):
Tinna Traustadottir, Northern Arizona University

Brief Summary:
Advanced age is the main risk factor for chronic diseases such as cardiovascular disease, type 2 diabetes, Alzheimer's disease and cancer. One reason may be due to decreased resistance to oxidative stress as antioxidant defenses and cell protection is reduced with aging. This has been shown in animal studies and also that the impairment can be somewhat restored with exercise. This will be the first study to test this in humans by comparing young and older inactive adults before and after an exercise intervention, a practical and cost-effective intervention that can have tremendous public health impact by lowering risk for disease and medical-related costs.

Condition or disease Intervention/treatment Phase
Aging Behavioral: Exercise Intervention Not Applicable

Detailed Description:
Advanced age substantially increases the risk for a host of diseases including cardiovascular disease, type 2 diabetes, Alzheimer's disease, and cancer. A major factor that appears to underlie this increased risk with age is reduced capacity to resist oxidative injury or oxidative stress. Therefore, maintaining or increasing the capacity to resist oxidative stress appears critical to the prevention of age-related disease and promotion of successful aging. One potential reason for the lower resistance to oxidative stress with age is a gradual shift in the redox state toward a more oxidized cellular environment potentially disrupting cell-signaling. Nuclear erythroid-2-p45-related factor-2 (Nrf2) is the master regulator of antioxidant defenses. Nrf2 drives expression of a host of genes involved in cellular detoxification and antioxidant defenses. There is strong evidence from animal studies that Nrf2 signaling is reduced with aging and can be at least partially restored with moderate exercise training, however the gap in current knowledge is whether these data do in fact translate to humans. This study will test the following hypotheses in young and older men and women: i) aging is associated with impaired Nrf2 signaling in response to acute exercise and ii) moderate exercise training will improve Nrf2 signaling in older, inactive individuals, and this will increase their resistance to oxidative stress. These hypotheses will be tested by comparing 25 young (18-28y) and 25 older (≥60y) inactive individuals before and after an 8-week exercise intervention (n=15 per age group) and in comparison to non-exercising age-matched control groups (n=10 per age group). Nrf2 signaling will be measured in peripheral blood mononuclear cells (PBMCs) in response to acute exercise and will include gene expression (NRF2, NQO1, HO1, GCLC), protein abundance (NRF2, KEAP1, NQO1, HO1, GCLC) and Nrf2-ARE binding capacity. Resistance to oxidative stress will be measured by plasma F2-isoprostane response to forearm ischemia/reperfusion. The results will increase understanding of the mechanisms of diminished stress resilience with aging and the plasticity of these pathways. This will determine whether targeting Nrf2 signaling will be effective for prevention or treatment of these age-related changes which has an enormous public health impact due to the potential of lowering disease risk and medical costs. An additional significance of this project is creating opportunity for undergraduate and graduate students to become involved in research, an important purpose of the Academic Research Enhancement Award (AREA) program and a mission of Northern Arizona University.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 46 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Randomized control trial: exercise intervention versus non-exercise control
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Cell Signaling and Resistance to Oxidative Stress: Effects of Aging and Exercise
Actual Study Start Date : June 1, 2017
Actual Primary Completion Date : May 30, 2020
Actual Study Completion Date : June 30, 2020

Resource links provided by the National Library of Medicine

Arm Intervention/treatment
Experimental: Exercise Intervention
8-weeks exercise intervention: 3-days per week for 45-55 minutes per session
Behavioral: Exercise Intervention
24 sessions of aerobic exercise

No Intervention: Control
8-weeks control: asked not to change anything or start exercising.

Primary Outcome Measures :
  1. Cell signaling [ Time Frame: 8 weeks ]
    Nuclear Nrf2 protein content in peripheral mononuclear cells (PBMCs) in response to acute exercise

  2. Resistance to oxidative stress [ Time Frame: 8 weeks ]
    F2-isoprostane response to forearm ischemia-reperfusion

Secondary Outcome Measures :
  1. Cell signaling [ Time Frame: 8 weeks ]
    GCLC protein abundance in PBMCs in response to acute exercise

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes

Inclusion Criteria:

  • Men and women, 18-28 years or 60 years and older
  • Competent to independently give informed consent
  • Successful completion of screening
  • No regular exercise for the past 6-months (by self-report)
  • A score below 3.0 on the Historical Lifetime Physical Activity Questionnaire

Exclusion Criteria:

  • Estrogen supplementation within the previous 6 months
  • Use of anti-oxidant supplements, in excess of standard multi-vitamins (1 tablet/day)
  • Current smoker
  • Body Mass Index (BMI) ≤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 maximal oxygen consumption (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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT03419988

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United States, Arizona
Northern Arizona University
Flagstaff, Arizona, United States, 86011
Sponsors and Collaborators
Northern Arizona University
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Principal Investigator: Tinna Traustadóttir, PhD Northern Arizona University
Publications automatically indexed to this study by Identifier (NCT Number):
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Responsible Party: Tinna Traustadottir, Associate Professor, Biological Sciences, Northern Arizona University Identifier: NCT03419988    
Other Study ID Numbers: R15AG055077 ( U.S. NIH Grant/Contract )
First Posted: February 5, 2018    Key Record Dates
Last Update Posted: August 26, 2020
Last Verified: August 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Tinna Traustadottir, Northern Arizona University: