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AMD is caused by degeneration in the macula of the retina. The retina is the highest oxygen consuming tissue in our body and is prone to oxidative damage. DNA damage is one hallmark of aging implicated in loss of organ function. Genome instability has been associated with several disorders that result in premature vision loss. We hypothesized that endogenous DNA damage plays a causal role in age\u2010related retinal changes. To address this, we used a genetic model of systemic depletion of expression of the DNA repair enzyme ERCC1\u2010XPF. The neural retina and retinal pigment epithelium (RPE) from <jats:italic>Ercc1<\/jats:italic><jats:sup><jats:italic>\u2212\/\u0394<\/jats:italic><\/jats:sup> mice, which models a human progeroid syndrome, were compared to age\u2010matched wild\u2010type (WT) and old WT mice. By 3\u2010months\u2010of age, <jats:italic>Ercc1<\/jats:italic><jats:sup><jats:italic>\u2212\/\u0394<\/jats:italic><\/jats:sup> mice presented abnormal optokinetic and electroretinogram responses consistent with photoreceptor dysfunction and visual impairment. <jats:italic>Ercc1<\/jats:italic><jats:sup><jats:italic>\u2212\/\u0394<\/jats:italic><\/jats:sup> mice shared many ocular characteristics with old WT mice including morphological changes, elevated DNA damage markers (\u03b3\u2010H2AX and 53BP1), and increased cellular senescence in the neural retinal and RPE, as well as pathological angiogenesis. The RPE is essential for the metabolic health of photoreceptors. The RPE from <jats:italic>Ercc1<\/jats:italic><jats:sup><jats:italic>\u2212\/\u0394<\/jats:italic><\/jats:sup> mice displayed mitochondrial dysfunction causing a compensatory glycolytic shift, a characteristic feature of aging RPE. Hence, our study suggests spontaneous endogenous DNA damage promotes the hallmarks of age\u2010related retinal degeneration.<\/jats:p>","DOI":"10.1111\/acel.14419","type":"journal-article","created":{"date-parts":[[2024,11,28]],"date-time":"2024-11-28T05:20:22Z","timestamp":1732771222000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["The <i>Ercc1<\/i><sup>\u2212\/\u0394<\/sup> mouse model of <scp>XFE<\/scp> progeroid syndrome undergoes accelerated retinal degeneration"],"prefix":"10.1111","volume":"24","author":[{"given":"Akilavalli","family":"Narasimhan","sequence":"first","affiliation":[{"name":"Institute on the Biology of Aging and Metabolism University of Minnesota Medical School  Minneapolis Minnesota USA"},{"name":"Department of Biochemistry, Molecular Biology and Biophysics University of Minnesota  Minneapolis Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seok 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