Physical Activity Modifies Exercise Responsiveness

Significance to VA: Sedentary behavior has emerged as a major risk factor for chronicconditions that are highly prevalent among older Veterans, including obesity, diabetes,and cardiovascular disease Innovation and Impact: Exercise is the cornerstone ofrehabilitation and is an essential part of treatment plans for these conditions; however,our understanding of why certain individuals respond positively to exercise while othersdo not remains unclear. Epidemiological findings indicate that adhering to establishedexercise guidelines does not lower multimorbidity rates or mortality risk in individualswho spend most of their non‐exercising time sedentary. Indeed, the negative impact ofsedentary behavior on health cannot be offset by exercise alone, highlighting thecritical need to prioritize reducing sedentary time in the treatment of age‐relateddiseases. Preliminary data support these epidemiological findings and provide novelevidence that physical inactivity minimizes the beneficial effects of exercise, limitingexercise adaptation and rehabilitation effectiveness. This is particularly concerning asphysical inactivity and sedentary behavior continue to increase among older Veteranscoinciding with alarming levels of multimorbidity (60‐80% of older Veterans havemultimorbidity). Although the factors linking physical inactivity and exercise responsevariability have yet to be identified, aging and multimorbidity are associated withdisruptions in redox homeostasis and impaired Nrf2 (nuclear factor erythroid 2‐relatedfactor 2) signaling. Nrf2 is a crucial exercise‐responsive transcription factor thatregulates antioxidant defenses, mitochondrial health, autophagy, and cellular resilience‐ processes essential for maintaining cellular function during aging. Our centralhypothesis is that improving redox homeostasis by decreasing sedentary time or throughtargeted Nrf2 activation will enhance exercise responsiveness and improve vascular andskeletal 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 functionin older Veterans with multimorbidity. Hypothesis: The investigators hypothesize thatreducing sedentary behavior and increasing physical activity through SLIMM will restoreredox balance and, thereby, improve exercise responsiveness and enhance vascular andskeletal muscle function.Specific Aim 2: Determine the impact of targeted Nrf2 activation with PB125 on exerciseresponsiveness, vascular function, and skeletal muscle function in older Veterans withmultimorbidity. Hypothesis: The investigators hypothesize that targeted Nrf2 activationwill serve as an effective redox‐based therapy to enhance exercise responsiveness andpromote vascular and skeletal muscle function. Methodology: The investigators will use aSMART (Sequential Multiple Assignment Randomized Trial) study design in which olderVeterans with multimorbidity will first undergo our Sit Less, Interact, Move More (SLIMM)intervention to decrease sedentary behavior and increase physical activity. Veterans thatare compliant with SLIMM will continue with SLIMM for a total of 24 weeks. Participantsthat are not compliant with SLIMM will transition to targeted Nrf2 therapy with PB125, anovel and naturally occurring Nrf2 activator, at week 12 and will continue PB125 for 12weeks. Exercise responsiveness, vascular function, and skeletal muscle function will beexamined before and after the SLIMM and PB125 interventions.Path to Translation/Implementation: This project will provide evidence that redoxhomeostasis is critical for initiating and coordinating cellular and molecular processesunderlying exercise adaptation and improvements in vascular and skeletal muscle health.The impact of this project is high and timely given the alarming rates of multimorbidityamong older Veterans and the current gap in effective strategies to enhance physicalfunction and health in this vulnerable population.