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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

2016 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, associated with lower quality of life, loss of productivity, and high 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 of 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 those 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 that are 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 pathways and the 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. Moreover, we also have advanced to ask if groups or combinations of nutrients are related to eye health. The latter is of importance because people generally do not consume individual nutrients. Rather, they consume foods that contain many nutrients. 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 “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. 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 reverse any 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. 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. 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 are damaging 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 Laboratory for Nutrition and Vision Research also continues to elucidate critical process 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 find that expressing molecular chaperones or upregulating the ubiquitin capacities and perhaps the lysosomal proteases, can protect lens constituents.


Accomplishments
1. Exploiting proteolytic pathways to maintain a clear eye lens. Solubility of the major lens proteins is required in order to establish and maintain a clear eye lens. A major challenge for the eye lens is to selectively eliminate proteins that are damaged and become insoluble upon aging and stresses. Tufts University researchers at USDA in Boston, Massachusetts, discovered pathways by which lens proteins are kept soluble and/or are recognized for degradation and elimination. The findings are essential in order to enhance our understanding of natural systems we can enhance with optimal nutrition in order to preserve vision and diminish the burden due to cataract, which afflicts 18,000,000 people in the world.

2. Optimization of dietary glycemia to prolong retina function. Robust epidemiologic data indicates that consuming lower glycemia diets protects the retina against damage that is associated with age related macular degeneration (AMD). At present we do not understand why that is the case. New insight into this protective mechanism would inform about nutritional strategies to protect against AMD. In order to gain such understanding we need animal models of AMD. Tufts University researchers at USDA in Boston, Massachusetts, used laboratory mice that were fed high and low glycemia diets to create such a model. With this new model of AMD we gained new molecular understanding of the pathobiologic mechanisms that are etiologic for AMD. Importantly, they also found, for the first time, that AMD-related damage can be arrested or reverse using lower glycemia diets.

3. Lutein is protective against light damage to retina cells. Retinal pigmented epithelial cells are the primary site where damaged retinal photoreceptors are degraded. This capacity is crucial in order to maintain a functional retina. Retinal pigment epithelium (RPE) cells are thought to be damaged by blue light. Using a model system in which Tufts University researchers at USDA in Boston, Massachusetts, irradiated RPE cells with blue light and found that the addition of lutein or zeaxanthin protects against blue light damage. This was indicated by diminished indicators of oxidative and inflammatory stresses. This is an important discovery in the effort to prevent age-related eye disease.


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