A new gene signature for endothelial senescence identifies self‐ RNA sensing by retinoic acid‐inducible gene I as a molecular facilitator of vascular aging

The number of senescent vascular endothelial cells increases during aging and their dysfunctional phenotype contributes to age‐related cardiovascular disease. Identification of senescent cells is challenging as molecular changes are often tissue specific and occur amongst clusters of normal cells. Here, we established, benchmarked, and validated a new gene signature called EndoSEN that pinpoints senescent endothelial cells. The EndoSEN signature was enriched for interferon‐stimulated genes (ISG) and correlated with the senescence‐associated secretory phenotype (SASP). SASP establishment is classically attributed to DNA damage and cyclic GMP–AMP synthase activation, but our results revealed a pivotal role for RNA accumulation and sensing in senescent endothelial cells. Mechanistically, we showed that endothelial cell senescence hallmarks include self‐RNA accumulation, RNA sensor RIG‐I upregulation, and an ISG signature. Moreover, a virtual model of RIG‐I knockout in endothelial cells underscored senescence as a key pathway regulated by this sensor. We tested and confirmed that RIG‐I knockdown was sufficient to extend the lifespan and decrease the SASP in endothelial cells. Taken together, our evidence suggests that targeting RNA sensing is a potential strategy to delay vascular aging.