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United States Department of Agriculture

Agricultural Research Service

Research Project: USING NUTRITION AND PROTEOLYSIS TO DELAY AGE RELATED MACULAR DEGENERATION AND CATARACTS

Location: Human Nutrition Research Center on Aging

2012 Annual Report


1a.Objectives (from AD-416):
1. Determine how specific foods, specific components of foods of particular patterns or dietary intake are related to eye health.

2. Identify nutritional etiologic factors that are causally related to onset, prevalence and progress of age-related macular degeneration and cataract. Design diets, dietary supplements or natural reagents to delay these diseases.

3. Identify mechanisms by which retina and lens function are maintained throughout life.


1b.Approach (from AD-416):
The 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 age related eye diseases such as cataract and age-related macular degeneration. These are the major blinding diseases. We approach these objectives using epidemiologic and laboratory techniques. At present we are analyzing nutritional, ophthalmologic and genetic data from about 15,000 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 (dietary glycemic index) is related to increased risk for macular degeneration and cataract. We are also trying to understand why antioxidants confer visual benefit. A complementary aspect of this work involves elucidation how the proteolytic machinery specifically, and the protein quality control machinery in general, is 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.


3.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) but there are no means to delay the progress of these debilities. However, epidemiology suggests that nutrition can be beneficial. We focus on ways to preserve vision. Our approaches involve epidemiologic surveys, animal models, or cell free systems to explain the biochemical mechanisms that support epidemiologic findings.

Much of our work focuses on why lower glycemic index (GI) diets are related to prolonged retina and lens function. The relationship between disease risk and dietary GI is important, because it is relatively simple to lower ones dietary GI and obtain the health benefit. We published results showing that 9000 subjects in the Age Related Eye Diseases Study (AREDS) and Vision Impairment Project cohorts who consume lower GI diets have diminished risk for onset and progress of AMD. Cataract risk is also diminished in people who consume low carbohydrate diets. Additional analyses regarding complete dietary patterns are in progress.

Consuming a low GI diet diminishes risk for diabetes, heart disease, AMD, and cataracts. We are trying to understand the etiological similarities of the various debilities that are all related to consuming higher GI diets but don’t appear to be related to each other. This mechanistic approach is critical in order to elucidate why and corroborate that GI has diverse salutary effects. This is important because there will probably never be an intervention trial regarding GI and risk for onset of age-related eye disease.

In efforts to begin to understand the mechanism of why lower GI diets promote health, we replicated feeding studies with the objective to find additional ways to prolong eye health. We added a new animal model which allows us to separate effects of inflammation/immune function genes from diet with regard to eye health. This is important because recent data indicate that inflammation is related to risk for AMD. An observation is that the high GI diet-related accumulation of sugar-modified proteins occurs in many tissues in addition to the eye. The findings inform us why low GI diets are beneficial for the many tissues that get age related diseases but do not seem to be metabolically related. Also, establishing these models created cell free and in-vivo platforms for testing new foods, ingredients, or derivatives to delay eyes diseases.

Encouraged by the findings, we are expanding epidemiologic efforts to include additional data bases. We related data regarding diets to genetics and measures of eye health. We found that mutation in IGF like receptor genes enhance risk for AMD in the AREDS cohort but not in the Rotterdam cohort. These findings in the AREDS cohort are consistent with findings that abnormal glucose metabolism is a risk factor for AMD. This paves the way for individualized medicine/nutrition approaches for preserving eye health.

Data regarding disease prevention or progress are most useful if one has a way to quantifiably predict who will get the disease. From our large data base of human ophthalmologic data, we were able to devise an algorithm for predicting whether an early AMD patient will progress to advanced AMD. This is useful for determining which patients would benefit from dietary and other types of interventions and which to monitor.

It is established that many age related syndromes are associated with the accumulation of damaged proteins. Cataract and macular degeneration are recent additions. We continue to find functions for the ubiquitin and lysosomal proteolytic pathways that remove damaged and toxic proteins in the cell in the lens and retina. We found evidence that the ubiquitin pathway directs lens formation and maintenance. These experiments not only solved an age-old enigma of how lens cells remove their nuclei but also inform us of biochemical and cell biologic programs that allow formation and maintenance of lens clarity. The data suggest that control of the ubiquitin pathway genes may be used to remediate or rebuild the lens. We are testing such molecules in efforts to delay damage to retinal cells.

It was thought that the ubiquitin pathway is unidirectional- once a protein gets ubiquitinated it eventually gets degraded. We showed that this process is dynamic and ubiquitin conjugates can go between soluble and insoluble forms. Thus we can avoid protein precipitation diseases, such as cataract, by reversing this flow. An associated finding is that an enzyme that was thought to put ubiquitin on proteins actually blocks ubiquitination of a major protein that controls cell proliferation. The ramifications are far ranging, including possible new ways to control or treat cancers.

There is contemporary interest in the salutatory effects of lutein. Additional work focuses on lutein and its utility in the lens and retina.


4.Accomplishments
1. Dietary intake is related to risk for age related macular degeneration. Age related macular degeneration (AMD) is the leading cause of blindness in America and there are no known means to delay the onset and progress of this disease. ARS-funded researchers at JMUSDA-HNRCA at Tufts University, Boston, Massachusetts, obtained epidemiologic information that indicates that consuming diets that release glucose into the bloodstream more slowly, called lower glycemic index diets, have lower risk for the onset and progress of AMD. We predict that with slight dietary modification to lower the dietary GI, over 100,000 people can be spared from AMD. In order to maximize the health advantages of the diet, animal models were required, but none existed. We developed the first animal model that shows AMD-like lesions are affected by the glycemic index of the diets the animals consumed. Importantly, animals that consumed the lower glycemic index diet developed lesions at far slower rates. This corroborates the human epidemiologic findings and gives us a biologic platform with which to improve the diets and determine mechanisms of action.

2. Elucidating mechanisms that relate dietary glycemia to retinal health. Mechanistic information regarding how dietary GI is related to risk for age related diseases such as AMD, diabetes and cardiovascular disease is critically needed in order to optimize diets and develop diet- or nutraceutical (nutrient derived pharmaceuticals)- based treatments for these diseases. We found that upon aging, proteins in animals that consumed the higher glycemic index diets were more modified by sugars (called glycation) than proteins from lower glycemic index-fed animals. These toxic “glycated” proteins accumulated in all tissues examined. These proteins are thought to be deleterious for the cells and result in limited tissue function, which might explain why several seemingly unrelated diseases show similar relations to dietary glycemic index. The results of cell culture models developed by us showed that after glycation the damaged proteins are not properly recognized by the cellular machinery that usually targets and destroys such damaged proteins. The glycation also compromises the damaged-protein recognition machinery. As a result of this research ARS-funded researchers at JMUSDA-HNRCA at Tufts University, Boston, Massachusetts, have identified a vicious cycle that starts with the consumption of a higher glycemic index diet. This causes protein damage, inability to recognize the damaged material, compromised ability to degrade the damaged proteins. It results in accelerated accumulation of glycated proteins, advancing cell toxicity and compromised organ function.

3. Protein degradation is related to lens formation and maintenance. Whereas AMD is the leading cause of blindness in the USA; cataract is the leading cause of blindness globally. As with AMD, there is no means to delay the onset or progress of cataract, perhaps, other than optimizing nutrition. We have spent the last two decades identifying nutrients that might prolong lens function. Because in the lens, proteins must function for a lifetime (they are the longest lived proteins in the body) it is crucial to understand when and how the proteins are formed and it is important to understand relationships between the processes that are involved in lens formation and those that are available to remove damaged proteins. During this year ARS-funded researchers at JMUSDA-HNRCA at Tufts University, Boston, Massachusetts, published the first documentation of how the protein degrading system controls lens formation. We elucidated for the first time how lens cells become the clear fiber optics that result in our ability to see, specifically how they remove their nuclei. With this information we can begin to seek new data to determine how nutrients affect these processes and to search for nutrients that can extend lens function.


Last Modified: 9/10/2014
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