MSC-Derived Exosomes in Preserving Autophagy through Key Signaling Pathways: A Preventive Strategy against Cardiovascular Aging.

Cardiac aging is a major risk factor for cardiovascular disease (CVD), primarily driven by a progressive decline in autophagy. Autophagy is a key factor in the aging process of the heart. In recent years, stem cells have emerged as a promising option for tissue regeneration and anti-aging treatment. However, some adverse effects like tumor formation and host rejection, have limited their clinical application. On the other hand, one of the secretory products of stem cells, exosomes (a subset of extracellular vesicles, with 30–150 nm in diameter), has shown a promising choice for cardiac aging prevention with low adverse effects. Evidence demonstrates that exosomes act as context-dependent regulators of autophagic flux: they restore impaired autophagy during ischemia/reperfusion injury via AMPK/mTOR and Akt/mTOR pathways, while suppressing excessive autophagy in conditions such as drug-induced cardiotoxicity. Exosomal cargo, including miRNAs (e.g., miR-455-3p, miR-125b5p, miR-93-5p), proteins (e.g., GDF-15, OPTN, NR4A2), and lncRNAs (e.g., LINC00174, KLF3-AS1), targets key signaling networks to balance autophagy and reduce apoptosis and preserve mitochondrial function. These findings highlight MSC-derived exosomes as potent autophagic rheostats that maintain cardiac homeostasis, prevent maladaptive remodeling, and offer a cell-free therapeutic strategy against cardiovascular aging. Nonetheless, translation into clinical practice requires standardized isolation, rigorous functional assays, optimized dosing, and long-term safety evaluation.