Unraveling the aging-reversal potency of stem cell-derived extracellular vesicles in a rat model of premature cardiac senescence

Cardiosphere-derived cells (CDCs) and their extracellular vesicles (CDC-EVs) can rejuvenate and improve cardiac function, but their efficacy varies among donors. This study aimed to identify predictors of CDC-EV potency. CDCs from human donors were analyzed for phenotypical and biological properties. The anti-aging activity of CDC-EVs was tested using an <i>in vitro</i> matrix assay. Results showed that donor age did not determine potency, but CDC senescence correlated with most bioactive properties. However, senescence alone was insufficient to predict CDC-EV potency. CDC-EVs were classified as more potent (P-EVs) or less potent (NP-EVs) based on assay performance. In a rat model of premature cardiac aging, P-EVs reduced senescence-associated <i>GLB1</i> gene expression and protected against hypertrophy and fibrosis, while NP-EVs had negative effects. The study concludes that CDC-EV anti-aging potency cannot be predicted by donor age or CDC senescence, proposing an <i>in vitro</i> potency assay for evaluating CDC-EVs before clinical use.