PROJECT SUMMARY: Aging induces changes in the visual system, including decreased visual acuity, contrast and wavelength sensitivity, and processing of visual information. These changes are reflected in retinal pigment epithelium (RPE), retina and the visual cortex. RPE plays important roles in maintenance of the light-sensitive photoreceptors. Age-related macular degeneration (AMD), which is the major cause of blindness in the elderly, initially affects the RPE and gradually leads to secondary loss of photoreceptors. One of the two forms of AMD is the “dry” form, for which currently there is no effective treatment. Consequently, there is an unmet medical need for understanding the disease mechanisms during aging and developing new therapies for AMD. There is a higher prevalence for AMD in women compared to age-matched men, and there are sex-related differences in the pathophysiology of AMD. Specifically, sex hormone deficiency and its duration are associated with the development and progression of soft drusen in women but not in men. Gonadal hormones have been related to retinal disorders, and macular hole is reported to be more common among women than men, particularly in postmenopausal women. Despite these reports, the Royal College of Ophthalmologists guidelines indicate that the higher prevalence of AMD in female sex is due to their longer life expectancy and that female sex is not a risk factor for AMD. Thus, whether gonadal hormones or sex chromosomes are risk factors in age-related retinal degeneration remain elusive. To determine the role that sex plays in age-related visual decline, we propose to use the four-core genotype (FCG) mice, which will allow us to test the roles of sex chromosome complement (XX vs. XY), female and male hormone secretions, and the combined or interactive effects of these factors on RPE and visual cortex aging. The results of the proposed studies will further our understanding of how aging, sex chromosomes, and gonadal sex contribute to the visual system function during aging.