Aging is a risk factor for cardiovascular disease, the leading cause of death worldwide. Cardiac fibrosis is a harmful result of repeated myocardial infarction that increases risk of morbidity and future injury. Interestingly, both rates and outcomes of cardiac fibrosis differ between young and aged individuals, as well as men and women. Here, for the first time, we identify and isolate matrix-bound extracellular vesicles from the left ventricles (LVs) of young or aged males and females in both human and murine models. These LV vesicles (LVVs) show differences in morphology and content between these four cohorts in both humans and mice. LVV effects on fibrosis were also investigated in vitro, and aged male LVVs were pro-fibrotic while other LVVs were anti-fibrotic. From these LVVs, we could identify therapeutic miRNAs to promote anti-fibrotic effects. Four miRNAs were identified and together, but not individually, demonstrated significant cardioprotective effects when transfected. This suggests that miRNA synergy can regulate cell response, not just individual miRNAs, and also indicates that biological agent-associated therapeutic effects may be recapitulated using non-immunologically active agents. Furthermore, that chronic changes in LVV miRNA content may be a major factor in sex- and age-dependent differences in clinical outcomes of cardiac fibrosis.