YAP activation reverses aging-related visual dysfunction caused by impaired cell-matrix adhesion

Cellular senescence of retinal pigment epithelium (RPE) cells is a major contributor to age-related visual decline, particularly in the pathology of age-related macular degeneration (AMD). While genome-wide association studies (GWAS) have advanced our understanding of the genetic factors underlying AMD, the molecular mechanisms driving RPE senescence remain poorly understood. In this study, we performed single-cell RNA sequencing (scRNA-seq) on RPE cells from young and old mice, uncovering a close relationship between dysregulated genes involved in cell-matrix adhesion and RPE senescence. Using hydrogel systems to manipulate integrin-mediated cell-matrix adhesion, we demonstrated that impaired adhesion can induce cellular senescence in RPE cells. Mechanistically, we identified the mechanotransducer Yes-associated protein (YAP) as a key protector against RPE senescence. Notably, YAP activation alone was sufficient to trigger stem cell transcriptional programs and reverse aging phenotypes in senescent RPE cells. Furthermore, treatment with TRULI, a small-molecule YAP activator, significantly restored visual function in both an AMD mouse model and naturally aged mice. Our findings highlight the integrin-YAP mechanotransduction pathway as a fundamental mechanism preventing RPE senescence, positioning YAP activation as a promising strategy to reverse RPE aging and restore visual function.