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ARS Home » Northeast Area » Boston, Massachusetts » Jean Mayer Human Nutrition Research Center On Aging » Research » Research Project #426629

Research Project: Vision, Aging, and Nutrition

Location: Jean Mayer Human Nutrition Research Center On Aging

2017 Annual Report


Objectives
LAB NAME: Nutrition and Vision Research 1. Determine how the interactions of specific foods/food components/dietary patterns with individual or population genetics are related to eye health during aging, and to aging per se. 1.1a - Laboratory animal experiments to determine nutrient-gene interactions 1.1b – Exploiting lower dietary GI to delay AMD 1.2 - Determine how intake of groups of foods affect risk for AMD and cataract and how these relationships are altered by genetics. 2. Identify nutritional etiologic factors that are causally related to onset, prevalence and progress of age-related macular degeneration and cataract. Identify mechanisms by which retina and lens functions are maintained throughout life. 2.1 –To determine if lutein/zeaxanthin and DHA supplementation can delay AMD-like features in UPS-compromised mice. 2.2- To investigate the ability of CHIP over-expression to enhance cellular capacity to degrade and/or refold damaged proteins we will use cataract-causing mutant proteins (R49C aA -, R120G aB - and T5P 'C-crystallins) as substrates in cultured lens epithelial cells or lens fibers in vivo. 2.3-UbcH7 works with a subset of its cognate ubiquitin ligase partners to affect cell migration. 3. Find new biomarkers of tissue function using readily available samples, i.e., blood, tears, cornea, skin, for in vivo assessment. 4. Determine how diet is related to the microbiome and eye health during aging.


Approach
LAB NAME: Nutrition and Vision Research Use of clinical epidemiologic studies to survey large human cohorts. Laboratory systems are exploited to model the diseases and elucidate mechanisms of action of potentially salutary modalities. At present, we are analyzing nutritional, ophthalmologic and genetic data from about 20,000 people. Studies in the laboratory are oriented to determine the pathobiologic mechanisms that underlie the epidemiologic observations. Thus, we are trying to understand how consuming a diet that provides high levels of readily digested carbohydrate (high dietary glycemic index) is related to increased risk for macular degeneration and cataract. The studies are complemented by investigations into the metabolome and microbiome, in order to gain a wholistic understanding of mechanisms by which nutrition affects function. We are also trying to understand why and how antioxidants confer visual benefit. A complementary aspect of this work involves elucidation how the cellular protein quality control machinery (lysosomal and cytoplasmic proteolytic capacities) are related to maintaining proper protein quality within lens and retina cells. Another aspect of this work involves trying to understand how this proteolytic machinery controls tissue formation and integrity and how its function is related to nutrition and varies over time or stress.


Progress Report
Loss of sight is among the greatest fears of the elderly and is associated with lower quality of life, loss of productivity, and high personal and public health costs. Almost all elderly will confront cataract, and about 15% will be stricken with age related macular degeneration (AMD). There are no means to delay the progress of these debilities. However, epidemiology and a few intervention trials suggest that nutrition can be beneficial. We focus on ways to preserve vision. The overall objectives of the Laboratory for Nutrition and Vision Research are to find nutritional means to diminish the prevalence or delay the onset or progress of major blinding diseases in the elderly. These are age-related cataract and age-related macular degeneration. We continue to exploit multiple human cohorts to determine relationships between nutrient intake and risk for onset or progress of these diseases. In order to elucidate mechanisms of disease or aging and how the nutrients are delivering salutary effects we model the nutrition-disease relationships in laboratory animals. We also are utilizing new technologies to design assays that will alert the subject to onset or early progress of disease far earlier, at times when intervention or change of dietary behavior will be effective in diminishing the rates of progress or even reverse disease processes. We have performed experiments to determine if moving from chronically high glycemia diets to lower glycemia diets provides salutary advantage. Using tissues from animals and new mass spectrometric capacities, we are establishing new bioassays for advanced glycation end products and many additional metabolites in urine or serum. In order to appreciate the contribution of the gut microbiota to metabolism in the mice fed higher or lower glycemia diets, we are analyzing the microbiome. We also committed a significant effort to developing model systems that will allow us to identify the proteolytic and signaling pathways that are involved in intracellular and intercellular responses to dietary glycemia. Additional research continues to define molecular mechanisms of lens formation that can be harnessed to retain lens clarity or even rebuild the natural lens. Our first objective for this fiscal year was to determine how relations between risk for AMD or cataract and one food group are affected by intake of other food groups or specific nutrients. Trying to identify individual nutrient risk factors for age-related eye disease continues to be of interest because people want to know what nutrients they might optimize in order to preserve vision. Accordingly, in all of our analyses, we try to separate out effects due to the nutrients that are known to be associated with retinal or lens health. These are vitamins E, C, and lutein. However, people do not eat single nutrients. Rather, they eat foods that are made of many ingredients or groups of foods and nutrients. Thus, we advanced to ask if groups or combinations of nutrients are related to eye health. We continue to find that consuming higher glycemia diets is associated with higher risk for AMD. More recently, we found that consuming diets that are more similar to canonical “Oriental/prudent” or “Mediterranean” diets is associated with preserved retinal integrity. Importantly, we find a quantitative relationship that indicates the more one adheres to a prudent diet the better the protection against age-related eye disease. Reciprocally, the more one adheres to the typical American diet, the greater their risk for AMD. Prudent diets are richer in fruits, vegetables, and fish and are lower in sweets and fats. Conversely, the America diet is richer in fatty and sweet foods, processed meats and sodas. Recently we showed a benefit of peanut-containing products with regard to risks for AMD as part of an analysis of patterns of food intakes. Our second objective was to determine the etiologic connection between consuming lower glycemia diets and protection against age-related eye disease. We completed the animal rearing of mice fed higher or lower glycemia diets. We also included a group that we switched from a high glycemia diet to a low glycemia diet in order to determine if we can arrest and possibly reverse damage that is caused by the higher glycemia diet. Analyses of the eyes and various other tissues are advancing. We also took samples of blood so we can determine systemic effects of the diets. For example, we are using these blood samples to design new assays for advanced glycation end products. These are harbingers of glycemia-related tissue damage. Additionally, we sampled the feces in order to determine if there is a change in the bacteria that reside in the stomach or gastrointestinal tract of these mice. This work was elicited by recent reports that our guts actually contain more cells than are in our body and that they produce chemicals that can enter the blood stream and alter metabolism or function. When the analyses are complete, these will be the most comprehensively analyzed animals that were reared on higher or lower glycemia diets. They will allow us to have a much more sophisticated and thorough appreciation of the effects of the diets than was previously possible. Preliminary analyses indicate that there is a dynamic relationship between the glycemia level of the diet, eye health, the microbiome and the metabolome. Another component of the analyses mentioned above was to elucidate the pathways that are involved in removal of proteins that are damaged by excess sugars in the diets. We found that the retinal cells have at least two different pathways via which they can remove damaged proteins. These are called the ubiquitin protein degradation pathway and the lysosomal protein degradation pathway. The latter also involves autophagy. We found that these two pathways work in concert to remove the damaged proteins. We also found that there is a vicious cycle in which the sugars or their derivatives can also compromise the functions of the pathways. Thus, when the mice are under glycemia stress, there is a race against time during which the sugars damage the very capacities that should be removing the glycated proteins. Finally, glycative damage not only produces damaged proteins but also limits the cells’ ability to remove them. We are trying to determine if this is when disease ensues. The Human Nutrition Research Center on Aging Laboratory for Nutrition and Vision Research also continues to elucidate critical processes in lens development and control of the proteolytic pathways that must rid cells of toxic proteins. A surprising result is that another proteolytic capacity, called the calcium activated protease, is upregulated when the ubiquitin pathway is perturbed. This wreaks havoc in the lens, virtually destroying it. Conversely, we found that expressing molecular chaperones or upregulating the ubiquitin capacities and perhaps the lysosomal proteases can protect lens constituents.


Accomplishments
1. Diets rich in complex carbohydrates are good for aging eyes. Research results show that consuming low glycemic diets (high in whole grains and low in sugar) can prevent and reverse age-related macular degeneration (AMD), the leading cause of vision loss in older adults. ARS-funded researchers in Boston, Massachusetts, have gained a greater understanding of the molecular mechanisms that cause AMD and found new evidence of a dynamic relationship between the glycemic level of a person’s diet, gut microbiota and eye health. In the lab, mice fed diets high in simple carbohydrates such as sugary beverages and white bread, also associated with cardiovascular disease and diabetes, developed AMD which was reversed when the diet was switched to one high in whole grains and low in sugar. These findings will lead to new ways to arrest or treat eye disease and improve heart health and risk of diabetes.


Review Publications
Rowan, S., Taylor, A. 2015. Gene-diet interactions in age-related macular degeneration. In: Bowes Rickman, C., editor. Advances in Experimental Medicine and Biology: Reginal Degenerative Diseases. Switzerland: Springer International. p.95-101. doi: 10.1007/978-3-319-17121-0_14
Chiu, C., Chang, M., Li, T., Gensler, G., Taylor, A. 2017. Visualization of dietary patterns and their associations with age-related macular degeneration. Investigative Ophthalmology and Visual Science. doi: 10.1167/iovs.16-20454.
Lei, L., Whitcomb, E., Jiang, S., Chang, M., Gu, Y., Duncan, M.K., Cvekl, A., Want, W., Limi, S., Reneker, L.W., Shang, F., Du, L., Taylor, A. 2016. Unfolded-protein response-associated stabilization of p27(Cdkn1b) interferes with lens fiber cell denucleation, leading to cataract. Journal of Federation of American Societies for Experimental Biology. 30(3):1087-1095. doi: 10.1096/fj.15-278036.
Rowan, S., Chang, M., Reznikov, N., Taylor, A. 2016. Disassembly of the lens fiber cell nucleus to create a clear lens: the p27 descent. Experimental Eye Research. 156:72-78. doi: 10.1016/j.exer.2016.02.011.