Circulating extracellular vesicles as systemic mediators of cardiac aging: Mechanisms, biomarkers, and therapeutic perspectives

Cardiac aging is a fundamental contributor to heart failure, arrhythmias, impaired stress tolerance, and reduced cardiovascular resilience in the elderly. While intrinsic myocardial aging has been widely examined, the systemic mechanisms driving age-related cardiac decline are not fully understood. Circulating extracellular vesicles (EVs) have emerged as key mediators of intercellular and inter-organ communication, transferring proteins, lipids, and nucleic acids that modify the phenotypes of recipient cells. Growing evidence indicates that EVs originating from cardiovascular cells as well as distant organs, including the liver, kidney, adipose tissue, lung, and intestine, participate in cardiac aging by influencing senescence-associated signaling, chronic inflammation, mitochondrial and metabolic dysfunction, fibrosis, microvascular remodeling, and contractile function. In this review, we outline the biological basis of circulating EVs in cardiac aging, describe their cellular and inter-organ sources, and examine how they promote progressive myocardial remodeling. We also consider their potential as biomarkers for cardiac aging and age-related heart disease, along with emerging therapeutic strategies such as blocking pathogenic EV signals, using reparative or engineered EVs, and implementing systemic interventions that modulate EV-mediated communication. Key translational challenges are highlighted, including EV heterogeneity, low tissue specificity, methodological inconsistencies, and the need to distinguish physiological cardiac aging from accelerated aging and age-related cardiovascular disease, as EV profiles may reflect systemic comorbidities rather than intrinsic cardiac aging. A deeper understanding of systemic EV crosstalk may offer new insights into the aging heart and support more precise methods for risk stratification, monitoring, and intervention.