Early vascular aging endothelial-derived EVs drove T-cell activation and exhaustion via RNA-dependent mechanisms, whereas late-aging individuals retained more functional CD4+ naïve T cells.
Cross-Sectional
Premature vascular aging is characterized by endothelial-derived extracellular vesicles that drive T-cell exhaustion and death, whereas healthy vascular aging preserves CD4+ naïve T-cell function.
Abstract Background Whereas chronological aging is a predefined and linear process, biological aging reflects functional cellular decline. Pulse wave velocity (PWV), the gold-standard measure of arterial stiffness, enables stratification of individuals of similar chronological age into early (high PWV, stiffer vessels), normal, or late (low PWV, elastic vessels) vascular aging groups, with increased stiffness indicating premature biological aging. Purpose The aim of our study was to investigate whether premature or biologically young vascular aging influences immune composition, function, and endothelial-immune communication in a healthy, age-matched cohort. Methods Mass cytometry (CyTOF) was used to profile immune subsets across PWV-defined groups followed by ex vivo functional assays and RNA-seq. Results Monocyte subsets were comparable across groups; however, both early and late vascular aging exhibited distinct lymphocyte remodeling. Both groups showed reduced CD8+ memory T cells and late NK cells, accompanied by an enrichment of CD4+CD57+ central-memory senescent T cells. Only late-aging individuals displayed increased CD4+ naïve-like effector T cells. Early vascular aging further showed higher reactive oxygen species levels in CD4+ T cells and elevated DNA damage across lymphocyte subsets. Functionally, CD4+ naïve T cells from late-aging individuals showed enhanced tumor-cell killing capacity and produced more IFN-γ and IL-6, whereas NK cells from both early and late groups displayed increased exhaustion and reduced cytotoxicity. Early aging was marked by higher KLRG1 expression in CD8+ memory and CD4+CD57+ T cells, and increased NK cells and CD8+ memory T cells proliferation in both early and late groups. Endothelial-derived EVs from early-aging donors expressed higher levels of the senescence marker CAP1 and triggered a distinctive activation/exhaustion program in CD4+ naïve T cells, increasing CD69, CD39, PD-1, and KLRG1 expression while reducing cell viability. RNase pretreatment fully abrogated these effects, indicating an RNA-dependent mechanism. Supporting this, RNA-seq of EV-stimulated CD4+ naïve T cells revealed extensive transcriptional remodeling in response to early-aging EVs, whereas late-aging EVs induced only modest shifts relative to normal controls. Conclusion Vascular biological aging involves coordinated remodeling of T and NK cells. Early-aging endothelial-derived EVs drive of T-cell activation, exhaustion, and cell death through RNA-dependent mechanisms, whereas late-aging individuals retain more functional CD4+ naïve T cells. These findings highlight coordinated immune-endothelial interactions and preserved CD4+ naïve T-cell function as complementary hallmarks distinguishing premature from healthy vascular aging.
Boccuni et al. (Fri,) conducted a cross-sectional in Vascular aging. Early and late vascular aging (PWV-defined) vs. Normal vascular aging was evaluated on Immune composition, function, and endothelial-immune communication. Early vascular aging endothelial-derived EVs drove T-cell activation and exhaustion via RNA-dependent mechanisms, whereas late-aging individuals retained more functional CD4+ naïve T cells.