Age-associated decline in autophagy pathways in the retinal pigment epithelium and protective effects of topical trehalose in light-induced outer retinal degeneration in mice
Cox, Katherine Shi, Gongyu Read, Neve Patel, Mohamed T Ou, Kepeng Liu, Zijia Wu, Jiahui Cendanawati, Suci Le Brun Powell, Jenna Oppenheimer, Pola Goldberg
Cox, Katherine
Shi, Gongyu
Read, Neve
Patel, Mohamed T
Ou, Kepeng
Liu, Zijia
Wu, Jiahui
Cendanawati, Suci
Le Brun Powell, Jenna
Oppenheimer, Pola Goldberg
Affiliation
University of Bristol; University of Aberdeen; University of Birmingham; University College London; Moorfields Eye Hospital
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Publication date
2025-04-28
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Abstract
Age is a primary risk factor for chronic conditions, including age-related macular degeneration (AMD). 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-associated transcriptomic changes in autophagy pathways in the retinal pigment epithelium (RPE) and evaluated the protective effects of topical trehalose, an autophagy-enhancing small molecule, against light-induced 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- and AMD-associated perturbation of autophagy pathways, we examined trehalose treatment in vitro, which enhanced autophagic flux and restored mitochondrial respiratory function in primary murine RPE cells exposed to oxidative stress. In vivo, topical trehalose improved autophagy-lysosome activity in mouse RPE, as demonstrated by elevated LC3B turnover and SQSTM1/p62 degradation. Furthermore, trehalose eyedrops protected mice from light-induced damage to the RPE and photoreceptors, preserving outer nuclear layer thickness, RPE morphology, and junctional F-actin organization. Taken together, the data support that age-related decline and severe dysregulation in autophagy contributed to AMD progression. By restoring autophagic flux, topical trehalose demonstrates therapeutic potential to address early autophagy-related pathological changes in AMD.
Citation
Cox K, Shi G, Read N, Patel MT, Ou K, Liu Z, Wu J, Cendanawati S, Le Brun Powell J, Oppenheimer PG, Hill LJ, Nicholson LB, Dick AD, Liu J. Age-Associated Decline in Autophagy Pathways in the Retinal Pigment Epithelium and Protective Effects of Topical Trehalose in Light-Induced Outer Retinal Degeneration in Mice. Aging Cell. 2025 Apr 28:e70081. doi: 10.1111/acel.70081. Epub ahead of print.
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Article