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 for the elderly, leading to compromised life quality, loss of productivity, and high costs. We continue to focus on ways to preserve visual function because means to remediate lost vision are still not available, treatments that can delay loss of vision that is already in progress are of limited value, and it is always better to preserve vision rather than try to recapture it. Our approaches involve elucidating biochemical mechanisms to support findings from epidemiologic studies that show that consuming lower glycemic index diets is related to prolonged retina and lens function, and that the effects of dietary glycemia are complementary to effects on vision of other dietary components. This mechanistic approach is critical since there will probably never be an intervention trial regarding glycemic index and risk for onset or progress of age-related eye disease due to the time that such a study might require, and the fact that it might be unethical to do so since it is already established that consuming higher glycemic index diets is associated with elevated risk for heart disease and type 2 diabetes. We also expand our epidemiologic efforts to include additional data bases from new cohorts and compare our data with data from other cohorts. Small scale animal studies to test the hypothesis that consuming lower glycemic index diets is associated with diminished risk for indicators of early age-related macular degeneration are progressing well and the large volume of novel data we obtained compels us to scale these experiments up and also to try new, additional animal models with this dietary regime. Scaling up will allow us to investigate additional biochemical phenomena and new animal models are useful because they are affected by an alteration in the gene that was recently identified as causally related to risk for macular degeneration. Thus they model as closely as possible the human condition. It is well established that many age related syndromes are associated with the accumulation of damaged proteins. Because of this we are continuing to elucidate functions for the ubiquitin and lysosomal proteolytic pathways in the lens and retina. An unexpected fining is that the ubiquitin pathway also directs the proper differentiation and development in the lens. Specifically we solved an age-old enigma of how lens cells removes their cell nuclei. This is required for proper passage of light through the lens and failure to do so is associated with cataract. The data suggest that eventually, control of ubiquitin pathway genes may be used to remediate the lens or even rebuild a damaged lens. Additional work focuses again on lutein and its utility in the lens and retina. For publications relating to this project, see parent project #1950-51000-075-00D.
1. Eating a low glycemic index diet protects against progression of age-related macular degeneration. Age related macular degeneration (AMD) is the major cause of blindness among the elderly in the developed world. There is no widely applicable non-invasive pharmacologic means to treat AMD. Therefore, we seek nutritional means to delay the onset or progress of AMD. We related risk for onset and progress of AMD to the type and quantity of carbohydrate in the diet in a study of about 6000 subjects from around the USA. ARS-funded researchers from Tufts University in Boston, MA showed that subjects who consume a lower glycemic index diet are protected from onset and progress of AMD. The work inicates that we can eliminate about 100,000-200,000 cases of blinding AMD if we adhere to lower glycemic index diets. Moreover, this benefit can be gained by exchanging the equivalent of 5 pieces of white bread for 5 pieces of whole grain bread per day and requires no new technology. Thus we can gain crucial salutary benefit with only modest dietary modification. Since coronary heart disease and type 2 diabetes also respond to this dietary management, the data imply that common diet-related mechanisms pertain to these phenotypically diverse diseases and organ systems. The data were corroborated in several additional large cohorts, suggesting that the findings are consistent in different parts of the world, regardless of specific diets consumed. Thus consuming diets which provide lower glycemic index offers continued retina function.
2. Risk for age-related cataract may be diminished by consuming diets with lower carbohydrate Age-related cataract is the major cause of blindness world wide. Fortunately, in the USA, there are sufficient numbers of ophthalmologists to perform cataract extractions and to restore vision to those whose vision is compromised by cataract. But, in the USA the largest line item in the Medicare budget is for cataract extraction. In the lesser developed world, there are insufficient numbers of ophthalmologists. Consequently cataract victims remain blind. Thus, any means to diminish risk for cataract has tremendous benefit in terms of personal life quality, productivity and public health costs. ARS-funded researchers from Tufts University in Boston, MA found in the Vision Impairment Project cohort in Melbourne Australia that higher glycemic index diets or carbohydrate intake is related to increased risk for the two most prevalent types of cataract: nuclear and cortical cataract, respectively. Importantly, the difference in these relationships is informing about how metabolism in the different areas of the lens affects carbohydrate use. The data allow us to design dietary means to prolong vision by limiting carbohydrate intake. They are also directing us toward design of pharmaceuticals or neutraceuticals to achieve this objective.
3. Consuming lower glycemic index diets delay early AMD-like lesions. To confirm the results of epidemiologic studies that relate risk for AMD to glycemic index in order to devise nutritional or pharmacologic means to delay AMD it is crucial to: 1) demonstrate in animals or human intervention trial studies that risk for diseases is diminished in subjects or animals that consumed the diet and, and 2) understand the biochemical mechanism of these relationships. Human intervention trials are prohibitively costly, and perhaps, unethical since we would not want to put people on higher glycemic index diets. Thus, animal models are essential. But there are no good animal models of AMD. ARS-funded researchers from Tufts University in Boston, MA successfully created a model of early AMD and showed that animals that consumed lower glycemic index diets have lower levels of advanced glycation end products in multiple tissues which show age-related declines in humans. These include the retina, brain, and lens. Importantly, we demonstrated that consuming the lower glycemic index diets delays several manifestations of early AMD. We also gathered mechanistic information indicating that the lesions are related to decreased capacity to clear the proteins altered by glycation. Together these studies develop a new model to study effects of protein glycation in an in vivo setting with a relevant disease model. They will be an invaluable addition to the tools which are needed to design new diets and therapies for AMD.