DNA Damage

Researchers have uncovered significant insights into retinal aging through inspecting the neural retina and retinal pigment epithelium (RPE) of Ercc1−/Δ mice, a mouse model which simulates the human XFE progeroid syndrome. The model also accumulates DNA damage more rapidly, as well as aging approximately six times more quickly when compared with wild-type (WT) mice.

Published in Aging Cell, the study demonstrates that spontaneous DNA damage and impaired repair mechanisms can drive age-related retinal degeneration and vision loss, highlighting the role of oxidative stress in retinal health.

The UC Irvine-led study found that these Ercc1−/Δ mice exhibited severe visual impairments, including abnormal optokinetic responses and reduced electroretinogram amplitudes, as early as three months of age. The mice also displayed retinal thinning, photoreceptor loss, and vascular abnormalities similar to those observed in age-related macular degeneration (AMD). Elevated markers of DNA damage and cellular senescence were observed across retinal layers, implicating these processes as primary drivers of retinal aging.

The RPE of Ercc1−/Δ mice was particularly affected, displaying mitochondrial dysfunction and a metabolic shift toward glycolysis, a hallmark of aging cells. This disruption in energy production likely exacerbates photoreceptor degeneration, underscoring the critical symbiosis between the RPE and the neural retina.

The research emphasizes the potential of targeting DNA repair pathways and cellular senescence in developing novel treatments for AMD and other retinal diseases. By establishing the Ercc1−/Δ mouse as a model for retinal aging, the study offers a platform from which to further evaluate age-related retinal degeneration, as well as testing potential therapeutic interventions. The authors note that their work also reinforces existing literature’s claims that medications targeting both oxidative DNA damage and senescent cells could potentially be used for future AMD treatments.