Physical Activity Modifies Exercise Responsiveness

Significance to VA: Sedentary behavior has emerged as a major risk factor for chronic conditions that are highly prevalent among older Veterans, including obesity, diabetes, and cardiovascular disease Innovation and Impact: Exercise is the cornerstone of rehabilitation and is an essential part of treatment plans for these conditions; however, our understanding of why certain individuals respond positively to exercise while others do not remains unclear. Epidemiological findings indicate that adhering to established exercise guidelines does not lower multimorbidity rates or mortality risk in individuals who spend most of their non-exercising time sedentary. Indeed, the negative impact of sedentary behavior on health cannot be offset by exercise alone, highlighting the critical need to prioritize reducing sedentary time in the treatment of age-related diseases. Preliminary data support these epidemiological findings and provide novel evidence that physical inactivity minimizes the beneficial effects of exercise, limiting exercise adaptation and rehabilitation effectiveness. This is particularly concerning as physical inactivity and sedentary behavior continue to increase among older Veterans coinciding with alarming levels of multimorbidity (60-80% of older Veterans have multimorbidity). Although the factors linking physical inactivity and exercise response variability have yet to be identified, aging and multimorbidity are associated with disruptions in redox homeostasis and impaired Nrf2 (nuclear factor erythroid 2-related factor 2) signaling. Nrf2 is a crucial exercise-responsive transcription factor that regulates antioxidant defenses, mitochondrial health, autophagy, and cellular resilience - processes essential for maintaining cellular function during aging. Our central hypothesis is that improving redox homeostasis by decreasing sedentary time or through targeted Nrf2 activation will enhance exercise responsiveness and improve vascular and skeletal muscle function.

Specific Aim 1: Determine the impact of the Sit Less, Interact, Move More (SLIMM) intervention on exercise responsiveness, vascular function, and skeletal muscle function in older Veterans with multimorbidity. Hypothesis: The investigators hypothesize that reducing sedentary behavior and increasing physical activity through SLIMM will restore redox balance and, thereby, improve exercise responsiveness and enhance vascular and skeletal muscle function.

Specific Aim 2: Determine the impact of targeted Nrf2 activation with PB125 on exercise responsiveness, vascular function, and skeletal muscle function in older Veterans with multimorbidity. Hypothesis: The investigators hypothesize that targeted Nrf2 activation will serve as an effective redox-based therapy to enhance exercise responsiveness and promote vascular and skeletal muscle function. Methodology: The investigators will use a SMART (Sequential Multiple Assignment Randomized Trial) study design in which older Veterans with multimorbidity will first undergo our Sit Less, Interact, Move More (SLIMM) intervention to decrease sedentary behavior and increase physical activity. Veterans that are compliant with SLIMM will continue with SLIMM for a total of 24 weeks. Participants that are not compliant with SLIMM will transition to targeted Nrf2 therapy with PB125, a novel and naturally occurring Nrf2 activator, at week 12 and will continue PB125 for 12 weeks. Exercise responsiveness, vascular function, and skeletal muscle function will be examined before and after the SLIMM and PB125 interventions.

Path to Translation/Implementation: This project will provide evidence that redox homeostasis is critical for initiating and coordinating cellular and molecular processes underlying exercise adaptation and improvements in vascular and skeletal muscle health. The impact of this project is high and timely given the alarming rates of multimorbidity among older Veterans and the current gap in effective strategies to enhance physical function and health in this vulnerable population.

Inclusion criteria

• Physically inactive, ≤5,000 steps/day
• Multimorbidity Weighted Index between 6 to 11
• Ability to sign informed consent
• Montreal cognitive assessment (MOCA) exam score ≥26
• Free-living and ambulatory prior to admission

Exclusion criteria

• Multimorbidity Weighted Index < 6 or > 11
• Cancer or history of successfully treated cancer (less than 1 year) other than basal cell carcinoma
• Currently on a weight-loss diet or body mass index (BMI) > 35 kilograms per square meter (kg/m2) (a BMI of 35 kg/m2, which includes individuals that fall into to the Class I obesity category, has been selected to improve inclusion and generalizability to a greater percentage of the general population)
• Human immunodeficiency virus (HIV) or hepatitis B or C
• Recent anabolic or corticosteroids use (within 3 months)
• Subjects with hemoglobin or hematocrit lower than accepted lab values
• Alcohol abuse (> 2 drinks per day) or drug abuse (inappropriate use of prescription medications or use of any illicit/illegal drugs for recreational use)
• Unwilling to cease dietary supplements 4 weeks prior to initiation intervention