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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

2022 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
We have used multiple models of age-related macular degeneration in mice and we showed similar responses to dietary manipulation across these multiple models. The laboratory experiments enable us to learn more about the mechanism of why consuming lower glycemic index diets is protective and then turn that information into clinical practice. However, the vision research scientific community is moving towards use of genetically modified mouse models to better mimic the human condition and more specifically focus on etiologic studies that will inform about the value of enhanced diets or drugs. Nrf2 is an antioxidant gene/transcription regulator. To that end, we have now introduced the Nrf2 knock out mouse to augment our animal models. We expected that if Nrf2 was knocked down the animals would be under such severe oxidative stress that diet would not be effective in altering the trajectory of AMD-related lesions. While we observed that the animals are under severe oxidative stress, even when Nrf2 is ablated mice consuming higher glycemic index diets develop AMD-related lesions more rapidly, but consuming lower glycemic index diets that limit oxidative stress, limits the appearance of these lesions. Also, Nrf2-/- develop senile cataracts. The findings indicate that lower glycemic index diets are powerful modulators of the most prevalent age-related eye diseases. In addition to demonstrating the power of the diets, these mice facilitate testing of diets, environment and new pharmaceutical or genetic approaches to limit the ravages of AMD. Eye lens cataracts remain the major cause of blindness in the non-industrialized world. Using the NRf2-/- mouse, we also showed in two cohorts, raised at different facilities, that the mice develop a senile cataract. This makes them among the best models of age-related cataract and will make them essential in the search for anti-cataract drugs. At present there are no treatments for cataract other than surgery to remove them. We finished a project that clearly defines major regulatory processes of lens development. Specifically, we showed that the essential process of lens fiber cell removal is controlled by Cdk1. Cdk1 is in turn regulated by Cdc25 and Wee1, and these are regulated by PP2A. We also explored how diet is related to gut microbiota. The population of gut microbiota to high or low glycemia diets is different in terms of the diversity of microbiota as well as in the relative amounts of each species. We found that transplanting microbiota from healthier low-glycemic index fed mice into mice that had been fed higher glycemic index diets extend health benefits. Mice aged 12-months received treatment for the subsequent 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, were used to remove “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. 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. Mice fed a low glycemic diet had significantly improved glucose tolerance and retinal health. Liver damage was indicated in mice fed high glycemia diets. Transplants increased the abundance of gut bacteria, Akkermansia muciniphila, which correlated with increased HDL cholesterol and improved fundus score. With the new bodies of epidemiologic and laboratory animal data indicating that consuming lower glycemic index diets is salutary with regard to age related eye disease, we think it is appropriate to demonstrate this in an intervention trial. To that end we are organizing and completing the design of Mediterranian Glucose Lowering and Vision Extension (M-GLOVE). This will test a lower glycemic index Mediterranean diet. This will be a randomized dietary intervention trial in which we will determine if consuming a lower glycemic index diet for up to 5 years will delay progression from early or intermediate AMD to more advanced grades.


Review Publications
Macy, C., Smith, K.M., Nixon, J.C., Hernandez, C.J., Rowan, S. 2021. Alterations to the gut microbiome impair bone tissue strength in aged mice. Bone Reports. 14:101065.