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

Kim, G., Son, C., Lee, H. K., Choi, J., Lee, S., Oh, S., Chae, J.-B., Park, C.-W., Kim, C., Ryu, J.-H., Lee, S., Jang, J., Chung, H.

Pohang University of Science and Technology (POSTECH) · biorxiv

Paper

Abstract

Cellular senescence of retinal pigment epithelium (RPE) cells drives age-related visual decline, particularly in the pathology of age-related macular degeneration (AMD). While genome-wide association studies (GWAS) have identified genetic risk factors underlying AMD, the molecular mechanisms governing RPE senescence remain unclear. Here, single-cell RNA sequencing of young and old mouse RPE revealed dysregulated cell-matrix adhesion as a key feature of senescence, consistent with transcriptional changes in AMD patients. Hydrogel-based experiments confirmed that impaired integrin-mediated adhesion induces RPE senescence. Yes-associated protein 1 (YAP), a crucial mechanotransducer, mediated the protective effects of cell-matrix adhesion, and its activation alone reversed aging phenotypes in senescent RPE cells. Notably, treatment with TRULI, a small-molecule YAP activator, significantly improved visual function in AMD and naturally aged mice. These findings highlight the integrin-YAP mechanotransduction pathway as a fundamental regulator of RPE senescence and a potential therapeutic target for AMD.

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Research summary

Activation of YAP reverses aging-related visual dysfunction in retinal pigment epithelium cells. The study addresses the underlying mechanisms of cellular senescence in RPE cells, which is a root cause of age-related visual decline, thereby contributing to the understanding of aging and potential therapeutic interventions.

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