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Research Project: Exploiting Nutrition and Protein Quality Controls to Delay Age-related Macular Degeneration and Cataracts

Location: Jean Mayer Human Nutrition Research Center On Aging

2021 Annual Report

Objective 1: Determine how diet, the interactions of diet and specific foods/food components with individual/population genetics and/or the microbiome, as well as how etiologic factors including nutrients, metabolites, and enzymes, are related to eye health and the onset, prevalence, and progress of age-related macular degeneration (AMD) and cataract during aging. Sub-objective 1A: Accumulation of AMDf and advanced glycation end products (AGEs) in high-glycemic (HG) fed mice can be arrested or reversed using GLO1 overexpression(GLO1-OE) or low-glycemic (LG) diet, but deletion of Nrf2 will compromise the eyes in the animals. Objective 2: Identify mechanisms by which retina and lens function are maintained throughout life. Sub-objective 2A: To test the hypothesis that specific gut microbiota are related to risk for AMDf and cataract, using microbe transfer and gnotobiotic mice. Subobjective 2B: To test the hypothesis that enhancing autophagic lysosomal proteolytic system (ALPS) will improve protein quality control. Subobjective 2C: To test the novel hypothesis that in order to accomplish the unidirectional process of lens fiber cell denucleation (LFCD), the lens has adopted many of the regulators, including the activation of cyclin dependent kinase (Cdk1) and the Cdk1 autoregulatory loop. Objective 3: Find new biomarkers of eye tissue function using readily available samples, i.e., blood, urine, tears, cornea, skin, for in vivo assessment. Sub-objective 3A: In order to gain more insight into the mechanisms behind the relationships between dietary glycemia, retina and lens phenotypes, AGEs, inflammatory markers, etc. we will identify and quantify the products produced and the changes to metabolism due to the diet in each genotype of animals from Objective 1. We use three platforms to accomplish these analyses. Together, they identify and quantify the broadest array of metabolites. These analyses will also identify many new potential biomarkers in urine and plasma from HG-, LG- mice. Sub-objective 3B: Identification of novel biomarkers of human AMD.

Vision is our most cherished sense. Eyesight, however, deteriorates with age, leading to lowered quality of life among aged populations and increased public health expenditures. While no known cures exist for cataract and dry age-related macular degeneration (AMD), the most prevalent age-related eye diseases, our lab is discovering nutritional interventions that appear to delay onset or progression of these diseases. Micronutrients, including vitamin E, vitamin C, vitamin A, lutein and zinc, have been established as vital to eye health. We have new evidence that limiting intake of certain types of macronutrients, specifically, highly refined grains and highly processed carbohydrates – now a big part of the Western diet – can prolong visual function. We are building on this discovery. Our research will further define relations between diet, genotypes, the microbiome and metabolic products produced in response to dietary carbohydrate. This research will use human data, laboratory models and cell free approaches to find ways to stave off age-related eye disease and prolong vision. This includes elucidating pathways via which development is regulated and damaged proteins are removed. As people continue to live longer in the United States, it becomes imperative to identify ways to prevent the onset of these debilitating diseases, especially as we know almost all older adults will be affected by cataracts and close to 30 percent of people over 75 years will be diagnosed with age-related macular degeneration.

Progress Report
Robust prior human epidemiologic and laboratory studies continue to indicate that consuming lower glycemic index diets is healthful with regard to delaying age-related macular degeneration and similar phenotypes in mice. The laboratory experiments enable us to learn more about why consuming lower glycemic index diets is protective and then turn that information into clinical practice. We corroborated prior findings that indicated that consuming lower glycemia diets is protective against age-related macular degeneration (AMD) using an animal (Nrf2-/-) that is more subject to oxidative stress. These animals show AMD phenotypes much earlier than wild-type mice. These mice will now make testing of diets, environment, and new pharmaceutical or genetic approaches much shorter and more effective. Experiments continued in which we tested the effect of transplanting microbiota from healthier low-glycemic-index fed mice into mice fed higher glycemic index diets. All mice were male C57Bl6/J mice aged 12-months then received treatment for 10 months. Mice fed isocaloric but high glycemic diet had significantly increased body weight and body fat compared with mice fed a low glycemic diet. Antibiotics ampicillin and neomycin removed “native, endogenous” microbiota before introducing microbiota from the test group. A high glycemic diet containing ampicillin and neomycin was lethal in high glycemic index-fed mice. The clear gastrointestinal disease was observed in these mice. This did not occur in the low glycemic diet containing antibiotics. Antibiotics attenuated the effect of diet on body weight. Antibiotics increased plasma alanine transaminase, indicating liver damage, but aspartate transaminase was not increased. Antibiotics increased colonic expression of tight junction proteins Occludin and Claudin-2 and decreased bone tissue quality. Importantly, weekly fecal microbiota transplants from mice fed a low glycemic diet to mice fed a high glycemic diet dramatically altered the host microbiome and significantly improved glucose tolerance and retinal health. Transplants increased the abundance of gut bacteria, Akkermansia muciniphila, which correlated with increased HDL cholesterol and improved fundus score. While epidemiology showed robust relations between people who consumed lower glycemia diets and diminished risk for AMD and even for progression of AMD, such studies cannot establish causality. Nor can they assure that if we can change people from consuming the typical high glycemia American diet to eating lower glycemia diets, we can assure lower risk for AMD or progress of AMD. The Glucose Lowering and Vision Extension (GLOVE) trials will do that. We progressed with designing the human randomized, blinded clinical feeding studies to determine if people who consume lower glycemia diets are protected against AMD. Eye lens cataracts remain the major cause of blindness in the non-industrialized world. We also complemented our solution of how a clear lens is formed by elucidating a pathway controlling a major lens development regulator. This work will inform ways to avoid congenital or inherited cataracts.

1. Diet and gut microbiota influence eye health in older adults. Age-related macular degeneration (AMD) involves loss of photoreceptor cells crucial for receiving light signals. Compromised vision or complete blindness due to AMD affects about 15% of older adults and rates increase exponentially as people age. With more people living to very old age, AMD is becoming epidemic. The condition known as dry AMD affects more than 10 million people in the United States. AMD patients lose vision in the central part of their visual field and presently there is no effective treatment. ARS-funded researchers in Boston, Massachusetts, have discovered that diet and our microbiota robustly influence risk for AMD and can slow the progression of AMD in both human and animal studies. By studying records of thousands of people, they found that consuming diets that slow the rate of sugar into the bloodstream diminish risk and delays progress for AMD. This means that diet can be used to delay progress of vision-stealing AMD. Using laboratory animals, researchers found that low glycemic index diets delay formation of damage associated with AMD. They also found gut microbiota are influenced by our diet, drugs, and may influence vision. These findings have enormous public health ramifications, especially since age-related macular degeneration is expected to double to nearly 22 million by 2050.

Review Publications
Francisco, S.G., Smith, K.M., Aragones, G., Whitcomb, E., Weinberg, J., Wang, X., Bejarano-Fernandez, E., Taylor, A., Rowan, S. 2020. Dietary patterns, carbohydrates, and age-related eye diseases. Nutrients.
Aragones, G., Dasuri, K., Olukorede, O., Francisco, S.G., Renneburg, C., Kumsta, C., Hansen, M., Kageyama, S., Komatsu, M., Rowan, S., Volkin, J., Workman, M., Yang, W., Daza, P., Ruano, D., Dominguez-Martin, H., Rodriguez-Navarro, J.A., Du, X., Brownlee, M.A., Bejarano, E., Taylor, A. 2020. Autophagic receptor p62 protects against glycation-derived toxicity and enhances viability. Aging Cell.
Streeter, M.D., Rowan, S., Ray, J., McDonald, D.M., Volkin, J., Clark, J., Taylor, A., Spiegel, D.A. 2020. Generation and characterization of anti-glucosepane antibodies enabling direct detection of glucosepane in retinal tissue. ACS Chemical Biology. 15(10):2655-2661.
Aragones, G., Rowan, S., Francisco, S.G., Yang, W., Weinberg, J., Taylor, A., Bejarano, E. 2020. Glyoxalase system as a therapeutic target against diabetic retinopathy. Antioxidants. 9(11):1062.