Significance: Food is medicine, and diet impacts the risk for and progression of age-related macular degeneration AMD, but we have few clues as to why. We found that wild-type mice fed a high-glycemic-index diet similar in composition to the Western diet developed a disease state that resembles dry AMD. To gain insight into the mechanism, we used LC-MS– and NMR-based metabolomics to discover diet-, metabolic-, and AMD-associated phenotypes. These studies revealed changes in the gut microbiota that altered the production of metabolites that protected against AMD, including serotonin. Changing the diet to a low-glycemic-index diet, even late in life, arrested the development of AMD, offering dietary interventions for AMD.

Summary: Epidemiologic studies indicate that the risks for major age‐related debilities including coronary heart disease, diabetes, and age‐related macular degeneration (AMD) are diminished in people who consume lower glycemic index (GI) diets, but lack of a unifying physiobiochemical mechanism that explains the salutary effect is a barrier to implementing dietary practices that capture the benefits of consuming lower GI diets. We established a simple murine model of age‐related retinal lesions that precede AMD (hereafter called AMD‐like lesions). We found that consuming a higher GI diet promotes these AMD‐like lesions. However, mice that consumed the lower vs. higher GI diet had significantly reduced frequency (P < 0.02) and severity (P < 0.05) of hallmark age‐related retinal lesions such as basal deposits. Consuming higher GI diets was associated with > 3 fold higher accumulation of advanced glycation end products (AGEs) in retina, lens, liver, and brain in the age‐matched mice, suggesting that higher GI diets induce systemic glycative stress that is etiologic for lesions. Data from live cell and cell‐free systems show that the ubiquitin–proteasome system (UPS) and lysosome/autophagy pathway [lysosomal proteolytic system (LPS)] are involved in the degradation of AGEs. Glycatively modified substrates were degraded significantly slower than unmodified substrates by the UPS. Compounding the detriments of glycative stress, AGE modification of ubiquitin and ubiquitin‐conjugating enzymes impaired UPS activities. Furthermore, ubiquitin conjugates and AGEs accumulate and are found in lysosomes when cells are glycatively stressed or the UPS or LPS/autophagy are inhibited, indicating that the UPS and LPS interact with one another to degrade AGEs. Together, these data explain why AGEs accumulate as glycative stress increases.

Lens opacification or cataract reduces vision in over 80 million people worldwide and blinds 18 million. These numbers will increase dramatically as b

Lens epithelial cells and early lens fiber cells contain the typical complement of intracellular organelles. However, as lens fiber cells mature they must destroy their organelles, including nuclei, in a process that has remained enigmatic for over a century, but which is crucial for the formation of the organelle-free zone in the center of the lens that assures clarity and function to transmit light. Nuclear degradation in lens fiber cells requires the nuclease DNase IIβ (DLAD) but the mechanism by which DLAD gains access to nuclear DNA remains unknown. In eukaryotic cells, cyclin-dependent kinase 1 (CDK1), in combination with either activator cyclins A or B, stimulates mitotic entry, in part, by phosphorylating the nuclear lamin proteins leading to the disassembly of the nuclear lamina and subsequent nuclear envelope breakdown. Although most post-mitotic cells lack CDK1 and cyclins, lens fiber cells maintain these proteins. Here, we show that loss of CDK1 from the lens inhibited the phosphorylation of nuclear lamins A and C, prevented the entry of DLAD into the nucleus, and resulted in abnormal retention of nuclei. In the presence of CDK1, a single focus of the phosphonuclear mitotic apparatus is observed, but it is not focused in CDK1-deficient lenses. CDK1 deficiency inhibited mitosis, but did not prevent DNA replication, resulting in an overall reduction of lens epithelial cells, with the remaining cells possessing an abnormally large nucleus. These observations suggest that CDK1-dependent phosphorylations required for the initiation of nuclear membrane disassembly during mitosis are adapted for removal of nuclei during fiber cell differentiation.

Background:Age-related macular degeneration (AMD) is the major cause of irreversible blindness. AMD appears to share several carbohydrate-related mechanisms and risk factors with diabetes-related diseases, including retinopathy and cardiovascular disease (CVD); however, to date, only one small study has addressed this issue. Objective:The objective was to test the hypothesis that dietary glycemic index (dGI), which has been related to the risk of diabetes and CVD, is associated with the risk and severity of AMD in nondiabetic elderly populations. Design:Dietary information was obtained from 4099 participants aged 55–80 y (56% women) in the Age-Related Eye Disease Study (AREDS). A total of 8125 eligible eyes at baseline were classified into 1 of 5 AMD groups according to the size and extent of drusen, the presence of geographic atrophy, and neovascular changes. We used a generalized estimating approach to evaluate the relations between dGI and risk and severity of AMD with eyes as the unit of analysis. Results:Compared with eyes in the first quintile of dGI, eyes in the fourth and fifth quintiles had a significantly or suggestively higher risk of large drusen, geographic atrophy, and neovascularization. The multivariate-adjusted odds ratios (95% CIs) for the highest quintile were 1.42 (1.09, 1.84), 1.78 (0.81, 3.90), and 1.41 (0.95, 2.08), respectively, of which only the odds ratio for large drusen was significant. A significant positive relation between dGI and severity of AMD was also noted (P for trend < 0.001). There was a 49% increase in the risk of advanced AMD (geographic atrophy plus neovascularization) for persons with a dGI higher than the sex median (women: ≥77.9; men: ≥79.3). This result indicated that 20% of prevalent cases of AMD would have been eliminated if the AREDS participants consumed diets with a dGI below the median. Conclusion:The association between dGI and AMD from the AREDS cross-sectional analysis at baseline suggests that a reduction in the dGI, a modifiable risk factor, may provide a means of diminishing the risk of AMD.