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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

2018 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
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 – 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. This year we added the Physicians Health Study and the Health Professionals Follow Up study cohorts to the databases that we use to pursue our investigations. In order to elucidate mechanisms of disease or aging and how 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 reversing 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. This year we collected samples from animals that lack the transcription factor Nrf2. Nrf2-null mice cannot mount robust antioxidant-stress responses. Thus one might not expect them to show differences between consuming lower and higher glycemia diets. Surprisingly, the Nrf2-null mice show the same salutary responses to lower glycemia diets as observed in wild type mice. This attests to the power of lower glycemia diets for prolonging health. 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 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. Among the lens regulatory pathways we study is the ubiquitin pathway. This pathway is of interest because the ubiquitin pathway is involved in controlling most regulatory cellular machines, including lens epithelial cell proliferation and lens fiber cell denucleation. During these studies we found that one ubiquitin conjugating enzyme, UbcH7, stabilizes the key cell regulatory protein p27. This is of keen interest because there are no examples of this class of enzyme stabilizing a protein. Rather, all prior examples show that such enzymes catalyze protein degradation. The substrate, p27, is of major interest because it is one of the master regulators of cell proliferation. Thus, our work plowed completely novel terrain in suggesting that the ubiquitin pathways may reversibly regulate stability of proteins, including crucial regulators of lens fiber cell denucleation and cell proliferation. We then went on to decipher the molecular mechanism of action that allows UbcH7 to stabilize proteins. It does so by assembling polymers of ubiquitin that attach to substrates but prevent it from being recognized and subsequently degraded by the associated cellular proteolytic machine, the proteasome. Another objective for this fiscal year was to continue to decipher relations between risk for age-related macular degeneration (AMD) or cataract with various food groups and 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 can optimize in order to preserve their 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 age related macular degeneration. More recently, we found that consuming diets similar to the canonical “prudent/healthy” or “Mediterranean” diets is associated with preserved retinal integrity. Importantly, we find a quantitative relationship that indicates that 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 age-related macular degeneration. Prudent diets are richer in fruits, vegetables, and fish and are lower in sweets and fats. Conversely, the American diet is richer in fatty and sweet foods, as well as processed meats and sodas. Recently, we showed a benefit of peanut-containing products with regard to risks for age-related macular degeneration as part of an analysis of patterns of food intakes. We pursued this finding in two cohorts: the Nurse’s Health Study cohort and the Health Professionals Follow Study cohort. We found that even when female nurses were consuming less than optimal diets, those who consumed more peanuts had lower risk for AMD. This relationship is being pursued in males in the Health Professionals Follow Study cohort. Finally, we obtained samples from the Physicians Health Study to investigate relations between their metabolome and AMD status. Those data have been collected and analysis is beginning.


Accomplishments
1. Consuming diets low in sugar lower risk for age-related macular degeneration and cataract. Age-related macular degeneration (AMD) and cataracts are the leading causes of vision loss in adults over 50 and result in a lower quality of life for many millions. ARS-funded researchers in Boston, Massachusetts discovered that switching to a low-sugar diet, even late in life, delays age-related retinal damage and may prevent disease. The researchers found that lower sugar intake has a positive effect on gut bacteria which is beneficial to the health of many organs in the body, including eyes. The researchers also identified potential biomarkers for AMD which may lead to detection of disease. If people follow these findings it could result in hundreds of thousands of fewer cases of AMD and blindness in the United States.


Review Publications
Rowan, S., Jiang, S., Korem, T., Szymanski, J., Chang, M., Szelog, J., Cassalman, C., Dasuri, K., Mcguire, C., Nagai, R., Du, X., Brownlee, M., Rabbani, N., Thornalley, P.J., Baleja, J.D., Deik, A., Pierce, K.A., Scott, J.M., Clish, C.B., Smith, D.E., Weinberger, A., Avnit-Sagi, T., Lotan-Pompan, M., Segal, E., Taylor, A. 2017. Involvement of a gut-retina axis in protection against dietary glycemia induced age-related macular degeneration. Proceedings of the National Academy of Sciences. 114(22):E4472-E4481. https://doi.org/10.1073/pnas.1702302114.
Chiu, C., Rabbani, N., Rowan, S., Chang, M., Sawyer, S., Hu, F.B., Willett, W.C., Thornalley, P., Anwar, A., Bar, L., Kang, J.H., Taylor, A. 2018. Studies of advanced glycation end products and oxidation biomarkers for type 2 diabetes. Biofactors. https://doi.org/10.1002/biof.1423.
Rowan, S., Taylor, A. 2018. The role of microbiota in retinal disease. Advances in Experimental Medicine and Biology. p. 429-435. https://doi.org/10.1007/978-3-319-75402-4_53.
Kang, J.H., Wu, J., Cho, E., Ogata, S., Jacques, P.F., Taylor, A., Chiu, C., Wiggs, J.L., Seddon, J.M., Hankinson, S.E., Schaumberg, D.A., Pasquale, L.R. 2016. Contribution of the Nurses' Health Study to the epidemiology of cataract, age-related macular degeneration, and glaucoma. American Journal of Public Health. 106(9):1684-1689. https://doi.org/10.2105/AJPH.2016.303317.
Liu, K., Lyu, L., Chin, D., Gao, J., Sun, X., Shang, F., Caceres, A., Chang, M., Rowan, S., Peng, J., Mathias, R., Kasahara, H., Jiang, S., Taylor, A. 2015. Altered ubiquitin causes perturbed calcium homeostasis, hyperactivation of calpain, dysregulated differentiation, and cataract. Proceedings of the National Academy of Sciences. 112(4):1071-1076. https://doi.org/10.1073/pnas.1404059112.