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.