Extracellular Vesicles as Dynamic Sensors of Redox-Inflammatory Balance: Potential Implications for Aging in Healthy...

Background/Objectives: Chronological age does not fully capture the heterogeneity of physiological aging among healthy individuals. Immune aging and redox imbalance are key hallmarks of biological aging, yet their interaction and relationship with circulating extracellular vesicles (EVs) remain incompletely understood. This study aimed to investigate whether endothelial- and platelet-derived EVs are associated with immune and oxidative aging processes in clinically healthy subjects. Methods: Circulating EVs were isolated and characterized by flow cytometry in a cohort of healthy volunteers spanning a wide age range. Endothelial-derived EVs (EeEVs) and platelet-derived EVs (PEVs) were quantified and analyzed in relation to chronological age, immune function parameters, redox biomarkers, ImmunolAge (an immune aging index), and OxyScore (a composite redox index). A normalized EV-Score was developed using an age- and sex-adjusted Z-score approach. Associations were assessed using correlation analyses, non-linear regression models, generalized additive models, and receiver operating characteristic (ROC) curves. Results: Both EeEVs and PEVs increased non-linearly with age, with a pronounced rise during midlife. EV concentrations were positively associated with molecular aging markers and inversely related to multiple immune function parameters. EVs were also linked to redox biomarkers, although oxidative status alone did not explain EV variability. EV-Score was strongly associated with immune aging and showed context-dependent relationships with oxidative status. Notably, high EV-Score values were observed primarily in individuals with accelerated immune aging, whereas subjects with high oxidative status but preserved immune aging exhibited low EV-Score values. ROC analyses demonstrated that the discriminative capacity of EV-Score for immune or oxidative aging depended on the combined immune-redox context. Conclusions: Circulating EVs may reflect the integrated state of immune and redox aging rather than chronological age alone. These findings suggest the potential utility of EVs as dynamic biomarkers of biological aging in healthy individuals and highlight the importance of considering immune and oxidative processes jointly to interpret EV-associated aging signatures.