Cardiovascular diseases are the leading cause of death in older adults worldwide, with heart failure (HF) representing one of their most serious end stages. Aging is a non-modifiable risk factor that drives a series of structural and functional changes in the heart, both at the macro and subcellular levels. This review article analyzes how intracellular organelle dysfunction and the loss of coordination between them, a process termed “interorganelle miscommunication,” contribute to the progression of HF in the context of aging. We review experimental and clinical studies on the function of mitochondria, sarcoplasmic reticulum, lysosomes, lipid droplets, and the nucleus in aging cardiomyocytes. Particular emphasis is placed on how altered interactions between these organelles affect key processes such as ATP production, calcium handling, autophagy, epigenetic regulation, and oxidative stress control. We also discuss the impact of chronic low-grade inflammation (“inflammaging”) and cellular senescence as aggravating factors in cardiac functional decline. Collectively, the evidence indicates that dysregulation of interorganelle communication not only accelerates cardiac aging but also represents a central pathogenetic mechanism in HF. In this context, the concept of a “dysfunctional interorganellar network” may serve as a new hallmark of subcellular aging and an emerging therapeutic target for preventing or delaying age-related HF.

Myocardial infarction (MI) and age-related cardiac remodeling remain major causes of morbidity and mortality worldwide. Because the adult heart has only limited regenerative capacity, extracellular vesicles (EVs) have emerged as promising acellular mediators of tissue repair, with the potential to mitigate both ischemic injury and age-associated decline. Preclinical studies demonstrate that EVs derived from stem and progenitor cells exert anti-apoptotic, anti-fibrotic, anti-inflammatory, and pro-angiogenic effects. In aged hearts, EVs can help restore metabolic homeostasis, attenuate pro-senescent signaling, and improve functional resilience. Early-phase clinical trials suggest that EV-based or EV-enriched products are feasible and safe, although evidence of efficacy remains limited. This review synthesizes current mechanistic insights into EV-mediated regulation of inflammation, fibrosis, angiogenesis, oxidative and ferroptotic stress, and cellular senescence, underscoring the therapeutic potential of EVs in cardiac regeneration - particularly in older patients with impaired endogenous repair. Importantly, it uniquely integrates the dual roles of EVs in both myocardial infarction repair and cardiac aging, thereby addressing a critical gap in the literature. By linking mechanisms of post-infarction regeneration with age-related cardiac decline, we outline the translational challenges and opportunities of EV-based therapies. Further advances in EV engineering, targeting, dosing, potency assays, and standardization will be essential for successful clinical translation.

Nitric oxide (NO) is essential for maintaining normal cardiovascular function, and accumulating evidence suggests that its diminished bioavailability contributes to endothelial dysfunction, vascular stiffening, and impaired cardiac performance - hallmarks of cardiovascular aging. This review posits that reduced NO bioavailability with age stems from impaired endothelial and neuronal NO synthase activity, increased oxidative stress, and metabolic shifts that drive cardiovascular decline. We further discuss emerging research which highlights potential interventions, including dietary nitrate supplementation, caloric restriction, and exercise, that may restore NO signaling and counteract age-related cardiovascular dysfunction. These findings underscore the growing recognition of NO as a key regulator of cardiovascular aging and a promising therapeutic target. Addressing NO-related deficits could open new avenues for preventing and treating age-associated cardiovascular diseases, reshaping strategies for promoting healthy aging and longevity.