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

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.

Study Overview

• Status: Completed
• Conditions: Aging
• Intervention / Treatment: Behavioral: Exercise Intervention

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.

• Study Type: Interventional
• Enrollment (Actual): 46
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Flagstaff, Arizona, United States, 86011
      • Northern Arizona University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cell signaling	Nuclear Nrf2 protein content in peripheral mononuclear cells (PBMCs) in response to acute exercise	8 weeks
Resistance to oxidative stress	F2-isoprostane response to forearm ischemia-reperfusion	8 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cell signaling	GCLC protein abundance in PBMCs in response to acute exercise	8 weeks

Collaborators and Investigators

• Sponsor: Northern Arizona University
• Investigators: Principal Investigator: Tinna Traustadóttir, PhD, Northern Arizona University

Publications and helpful links

General Publications

• Ostrom EL, Traustadottir T. Aerobic exercise training partially reverses the impairment of Nrf2 activation in older humans. Free Radic Biol Med. 2020 Nov 20;160:418-432. doi: 10.1016/j.freeradbiomed.2020.08.016. Epub 2020 Aug 28.

Study record dates

Study Major Dates

• Study Start (Actual): June 1, 2017
• Primary Completion (Actual): May 30, 2020
• Study Completion (Actual): June 30, 2020

Study Registration Dates

• First Submitted: January 11, 2018
• First Submitted That Met QC Criteria: January 26, 2018
• First Posted (Actual): February 5, 2018

Study Record Updates

• Last Update Posted (Actual): August 26, 2020
• Last Update Submitted That Met QC Criteria: August 21, 2020
• Last Verified: August 1, 2020

More Information

Terms related to this study

• Keywords: Nrf2
• Other Study ID Numbers: R15AG055077 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No