Plasma extracellular vesicle signatures of metabolic health and exercise response in a pilot study of older adults

Extracellular vesicles (EVs) are key mediators of intercellular communication and regulators of cellular function, yet their roles in metabolic health and exercise response are poorly understood. This pilot study analyzed plasma from older adults (<i>n</i> = 20) in subgroups of the well-characterized Studies Targeting Risk Reduction Interventions through Defined Exercise (STRRIDE) study to evaluate plasma EV biomarkers as minimally invasive biomarkers of metabolic health and exercise responsiveness. Plasma EVs comprised highly heterogeneous subpopulations defined by diverse surface markers reflecting complex cellular origins. At baseline, multiple EV biomarkers related to immune cells, skeletal muscle, and mesenchymal stem cells were associated with better indices of insulin action, including nine EV subpopulations with lower fasting insulin concentration and eight with lower Homeostatic Model Assessment for Insulin Resistance. Low-amount (∼1,300 kcal/wk), vigorous-intensity (65%-80% peak oxygen consumption) aerobic exercise increased the FABP4⁺ EV subpopulation in older adults (<i>n</i> = 12). High-amount (∼2,200 kcal/wk), vigorous-intensity exercise increased 15 EV subpopulations in older adults (<i>n</i> = 8). These subpopulations arise from a variety of cell sources, including immune cells (primarily lymphoid cells), skeletal and cardiac muscle, erythroid cells, mesenchymal and hematopoietic stem cells. Notably, eight out of 15 high-amount exercise-induced EV subpopulations were insulin action-related (CD29⁺, CD8⁺, CD56⁺, CD19⁺, MCAD⁺, CD73⁺, CD105⁺, and CD235a⁺). The EV-based profiling platform established here is ready for validation in larger human exercise cohorts, including the full STRRIDE cohort.<b>NEW & NOTEWORTHY</b> Specific plasma EV biomarkers related to immune subsets, skeletal muscle, and mesenchymal stem cells were associated with better indices of insulin action at baseline. High-volume, vigorous-intensity aerobic exercise increased many of these insulin action-related EV subpopulations. We developed a novel, minimally invasive platform that uses plasma EV surface markers to assess metabolic health and exercise responsiveness. This platform is ready for validation in larger human cohorts, including the full STRRIDE cohort.