Researchers here make some inroads into gathering and analyzing data relating to age-related alterations in the features and contents of extracellular vesicles taken from a blood sample. Much of the communication between cells involves secretion and uptake of vesicles, membrane-wrapped packages of diverse molecules. Taking a sample of extracellular vesicles from blood is thus a merged view into any number of complex interactions between systems and organs, a sizable blob of data that emerges from an intricate, evolving set of underlying processes. Generating meaningful insight into those processes from the data is not a straightforward exercise, but some progress is being made.
Extracellular vesicles (EVs) are key mediators of intercellular communication and may reflect physiological changes during aging. We analyzed plasma-derived EVs from a healthy aging cohort stratified by age, using size exclusion chromatography, surface profiling, nanoparticle tracking, and small RNA sequencing.
The age-dependent variation in EV surface markers - including decreased CD3, CD56, HLA-A, and CD45 and increased CD14 and CD69 - supports a shift in EV immunophenotype, consistent with immunosenescence and changes in circulating immune cell populations. These changes could reflect a reduced contribution of adaptive immune cells to the pool of circulating EVs and an increased release by activated monocytes. Interestingly, recent findings have shown that EV surface antigen profiling can be used as a biomarker of aging, reflecting features of inflammaging commonly observed in older people, as well as the cardiovascular risk of individuals. Furthermore, the alterations in the surface markers of EVs could not only indicate a differential cellular origin but could also affect the uptake of these EVs by different target cells. This could ultimately influence the intercellular communication mediated by EVs during aging.
The analysis of EV-associated small RNAs revealed distinct clustering by age group, with the young cohort showing a markedly different profile compared to middle-aged and older individuals. This early divergence in the EV miRNA signature suggests that some molecular hallmarks of aging are already encoded in EVs well before late-life decline becomes clinically evident. Older individuals showed shifts in EV immunophenotype consistent with immunosenescence and displayed distinct miRNA signatures enriched in muscle-specific and metabolism-related miRNAs, including miR-206, miR-143-3p, miR-122-5p, and miR-20b-3p - linked to muscle, metabolic, and vascular function. Notably, miR-6529-5p, associated with neuroprotection, was elevated in aging.
Target gene analysis revealed involvement in aging pathways such as Ras, VEGF, and MAPK signaling. EV miRNAs and particle counts correlated with biological aging markers, including GDF-15, visceral fat, and muscle quality. These findings highlight coordinated age-related changes in EVs reflecting musculoskeletal and metabolic aging and support their potential as minimally invasive biomarkers of biological aging and functional decline.
Link: https://doi.org/10.1038/s41514-025-00321-1
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