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

NCT ID: NCT03419988

Last Updated: 2020-08-26

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 46 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-06-01
• Study Completion Date: 2020-06-30

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.

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.

Conditions

Aging

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Exercise Intervention

8-weeks exercise intervention: 3-days per week for 45-55 minutes per session

Group Type: EXPERIMENTAL

Exercise Intervention

Intervention Type: BEHAVIORAL

24 sessions of aerobic exercise

Control

8-weeks control: asked not to change anything or start exercising.

Group Type: NO_INTERVENTION

No interventions assigned to this group

Interventions

Exercise Intervention

24 sessions of aerobic exercise

Intervention Type: BEHAVIORAL

Eligibility Criteria

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Northern Arizona University

OTHER

Sponsor Role: lead

Responsible Party

Tinna Traustadottir

Associate Professor, Biological Sciences

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Tinna Traustadóttir, PhD

Role: PRINCIPAL_INVESTIGATOR

Northern Arizona University

Locations

Northern Arizona University

Flagstaff, Arizona, United States

Countries

United States

References

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.

Reference Type: DERIVED

PMID: 32866619 (View on PubMed)

Other Identifiers

R15AG055077

Identifier Type: NIH

Identifier Source: org_study_id

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