Landscape of the aortic valve interstitial cell senescence atlas

Background Lifelong management of aortic valve disease is critical, yet the molecular drivers of pre-pathological degeneration remain elusive. As the predominant cell population maintaining tissue integrity, valvular interstitial cell (VIC) senescence is a pivotal driver of disease. Currently, a high-resolution atlas detailing human VIC senescent evolution across the lifespan is lacking. Objective To construct the first comprehensive human VIC senescence atlas to resolve age-related heterogeneous evolution and molecular transitions. Methods We performed scRNA-seq on 224,412 VICs from 21 non-diseased human valves (6–63 years). Using manifold learning and clustering, we identified age-related subgroups and quantified functional states via senescence, fibrosis, and osteogenesis scoring. Evolutionary trajectories were reconstructed using Slingshot pseudotime, with mechanisms explored through TF networks, CellChat interactomes, and GSEA, followed by multi-level validation. Results Analysis partitioned VICs into 10 heterogeneous subgroups. Correlation with chronological age identified VIC 6 as the primary age-associated cluster undergoing significant expansion, while VIC 0 represented a homeostatic juvenile state. VIC 6 exhibited the most prominent senescent phenotype; conversely, VIC 3 and VIC 2 showed specialized fibrotic and dual fibrotic-osteogenic signatures, respectively. Pseudotime analysis positioned VIC 6 at the trajectory’s terminus, showing high concordance with biological age. Conclusion We established a high-resolution human VIC senescence atlas, identifying VIC 6 as the core driver of valvular aging. This subgroup's transition from homeostasis toward pro-inflammatory and senescent phenotypes provides a cellular foundation and specific molecular targets for the prevention of degenerative aortic valve disease.