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Although the role of mTORC1 in retinal pigmented epithelium (RPE) homeostasis and age\u2013related macular degeneration (AMD) pathogenesis is established, the function of mTORC2 remains unclear. We investigated both complexes in RPE health and disease. Therefore, in this study, we have attempted to demonstrate that the specific overexpression of mammalian lethal with Sec13 protein 8 (mLST8) in the mouse RPE activates both mTORC1 and mTORC2, inducing epithelial\u2013mesenchymal transition (EMT)\u2010like changes and subretinal\/RPE deposits resembling early AMD\u2010like pathogenesis. Aging in these mice leads to RPE degeneration, causing retinal damage, impaired debris clearance, and metabolic and mitochondrial dysfunction. Inhibition of mTOR with TORIN1 in\u00a0vitro or \u03b2A3\/A1\u2010crystallin in\u00a0vivo normalized mTORC1\/2 activity and restored function, revealing a novel role for the mTOR complexes in regulating RPE function, impacting retinal health and disease.<\/jats:p>","DOI":"10.1111\/acel.70018","type":"journal-article","created":{"date-parts":[[2025,2,17]],"date-time":"2025-02-17T03:35:36Z","timestamp":1739763336000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Activated\n                    <scp>mTOR<\/scp>\n                    Signaling in the\n                    <scp>RPE<\/scp>\n                    Drives\n                    <scp>EMT<\/scp>\n                    , Autophagy, and Metabolic Disruption, Resulting in\n                    <scp>AMD<\/scp>\n                    \u2010Like Pathology in 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