Location: Jean Mayer Human Nutrition Research Center On Aging
2020 Annual Report
Objectives
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.
Approach
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
In big picture terms, our objectives for this year were to move prior etiologic studies regarding relations between consuming higher glycemic diets and risk for age-related eye disease toward trying to delay such disease. This required setting up new animal models. After encountering several problems with animals that did not perform according to published data, we obtained, bred and started a mice colony that will allow us to determine if expressing enzymes that destroy dangerous sugar metabolites or limiting the impact of dietary carbohydrates can be harnessed to delay age-related eye disease in vivo. An impediment to research on age-related eye diseases is the lack of suitable animal models. By rearing Nrf2-/- mice, we established a robust model of age-related cataracts. We also honed the high glycemic diet-fed mouse to create many phenotypes of age-related macular degeneration (AMD). These models are being used to test drugs that are approved by FDA for other purposes for efficacy against the two major age related eye diseases: macular degeneration and cataracts. These studies are being complemented by interrogation of large human medical databases. We are also preparing to launch human feeding trials to determine if: 1) we can encourage eating according to specific dietary patters for prolonged periods of time, and eventually 2) if we can move AMD patients from high to lower glycemic diets to delay the progress of AMD.
Related to carbohydrate effects on the body, we are the first to show high amounts of the sugar metabolite glucosepane in the retina and the vessels that feed it. We also found that glucosepane levels increase with aging. We also observed that glucosepane and carboxymethyl lysine are new useful indicators of aberrant glucose metabolism and diabetes. In our analysis of Nrf2 -/- mice, we found that glucosepane levels were higher in mice fed high glycemic diets and that developed AMD-like pathology than mice fed low glycemic diets that appeared healthy.
We also adapted methods and technologies to create microbe-limited mice and determined the effect of feeding them diets with more or less digestible carbohydrates with regard to various health, function, and vision parameters. In order to gain more insight into the etiology of congenital cataracts we continue using the ubiquitin mutant mouse to compare it with other models.
Accomplishments
Review Publications
Rowan, S., Bejarano-Fernandez, E., Taylor, A. 2018. Mechanistic targeting of advanced glycation end-products in age-related diseases. Biochimica et Biophysica Acta. 1864(12):3631-3643. https://doi.org/10.1016/j.bbadis.2018.08.036.
Rowan, S., Jiang, S., Chang, M., Volkin, J., Cassalman, C., Smith, K.M., Streeter, M.D., Spiegel, D.A., Moreira-Neto, C., Rabbani, N., Thornalley, P.J., Smith, D.E., Waheed, N.K., Taylor, A., Jiang, S. 2020. A low glycemic diet protects disease-prone Nrf2-deficient mice against age-related macular degeneration. Free Radical Biology and Medicine. 150:75-86. https://doi.org/10.1016/j.freeradbiomed.2020.02.010.
