Unveiling the lncRNA cargo of extracellular vesicles: A new language of aging communication

Aging is characterized by systemic dysregulation of intercellular communication, with extracellular vesicles (EVs) serving as key mediators that transport bioactive molecules, including long non-coding RNAs (lncRNAs), to modulate tissue homeostasis and aging processes. In this review, we summarize how EVs selectively package and deliver lncRNAs between cells, thereby transmitting senescence-related signals. These EV-associated lncRNAs regulate core aging-related signaling pathways such as p53, mammalian target of rapamycin (mTOR), and sirtuins, influencing cellular senescence, stress adaptation, and systemic aging. In age-related diseases, including neurodegenerative, cardiovascular, and metabolic disorders, as well as osteoarthritis, EV-lncRNAs play significant pathophysiological roles by mediating inflammation, metabolic dysregulation, and tissue repair. Owing to the protection provided by the vesicular membrane and the selectivity of their loading, EV-lncRNAs exhibit exceptional stability and cell-type specificity in biofluids, positioning them as candidate biomarkers for aging clocks and disease risk stratification. Furthermore, they also hold potential as vehicles for therapeutic delivery. However, progress in this field is constrained by methodological heterogeneity in EV isolation and characterization, a lack of causal in vivo validation, and an incomplete understanding of lncRNA sorting mechanisms. Emerging advances in experimental and analytical technologies are expected to overcome these bottlenecks and facilitate the translation of EV-lncRNA regulatory networks into precision diagnostics and aging-targeted therapeutic strategies.