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Impairments in autophagy processes are implicated in AMD progression, but the extent of autophagy's contribution and its therapeutic potential remain ambiguous. This study investigated age\u2010associated transcriptomic changes in autophagy pathways in the retinal pigment epithelium (RPE) and evaluated the protective effects of topical trehalose, an autophagy\u2010enhancing small molecule, against light\u2010induced outer retinal degeneration in mice. Transcriptomic analysis of human RPE\/choroid and mouse RPE revealed consistent downregulation of autophagy pathways with age, alongside variable changes as AMD severity progressed. Given the age\u2010 and AMD\u2010associated perturbation of autophagy pathways, we examined trehalose treatment in\u00a0vitro, which enhanced autophagic flux and restored mitochondrial respiratory function in primary murine RPE cells exposed to oxidative stress. In\u00a0vivo, topical trehalose improved autophagy\u2010lysosome activity in mouse RPE, as demonstrated by elevated LC3B turnover and SQSTM1\/p62 degradation. Furthermore, trehalose eyedrops protected mice from light\u2010induced damage to the RPE and photoreceptors, preserving outer nuclear layer thickness, RPE morphology, and junctional F\u2010actin organization. Taken together, the data support that age\u2010related decline and severe dysregulation in autophagy contributed to AMD progression. By restoring autophagic flux, topical trehalose demonstrates therapeutic potential to address early autophagy\u2010related pathological changes in AMD.<\/jats:p>","DOI":"10.1111\/acel.70081","type":"journal-article","created":{"date-parts":[[2025,4,28]],"date-time":"2025-04-28T10:29:16Z","timestamp":1745836156000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Age\u2010Associated Decline in Autophagy Pathways in the Retinal Pigment Epithelium and Protective Effects of Topical Trehalose in Light\u2010Induced Outer Retinal Degeneration in Mice"],"prefix":"10.1111","volume":"24","author":[{"given":"Katherine","family":"Cox","sequence":"first","affiliation":[{"name":"Academic Unit of Ophthalmology Translational Health Sciences, Bristol Medical School, University of Bristol  Bristol 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