Extracellular vesicles in longEVity medicines

As the global ageing population expands, there is an increasing demand for interventions that extend healthspan and lifespan. Extracellular vesicles (EVs), the mediators of intercellular communication, are promising therapeutic candidates for their systemic rejuvenating effects. The diverse molecular payloads and multiple signalling modes enable the modulation of several ageing pathways across different cell types. In this perspective, we critically evaluate the rejuvenating potential of young plasma-derived small EVs (sEVs) prompted by the landmark study by Chen et al. within the framework of the twelve hallmarks of ageing. Evidence indicated that young sEVs improve mitochondrial function, reduce cellular senescence, elevate stem cell activity, and restore physiological performance. These improvements occurred across multiple organ systems, including brain, muscle, heart, bone, and reproductive tissues, extending median lifespan by ~ 12% in aged mice. Mechanistically, these effects are linked to the enrichment of miRNAs that converge on the PGC-1α–mitochondrial axis. While this research provides bidirectional proof-of-concept for reversing decline, we critically assess current limitations, including unexamined hallmarks of ageing, such as genomic instability, epigenetic alterations, and chronic inflammation. Furthermore, significant gaps remain regarding durability after treatment cessation, alongside challenges related to manufacturing, standardisation, and regulatory translation. This work supports EVs as a distinct class of multi-specific biological therapeutics with the potential to reshape longevity medicine. It pinpoints key gaps that must be addressed to enable safe and effective clinical translation.