A low glycemic diet protects disease-prone Nrf2-deficient mice against age-related macular degeneration

Authors: ROWAN, SHELDON - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; JIANG, SHUHONG - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; CHANG, MIN-LEE - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; VOLKIN, JONATHAN - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; CASSALMAN, CHRISTA - Tufts University; SMITH, KELSEY - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; STREETER, MATTHEW - Yale University; SPIEGEL, DAVID - Yale University; MOREIRA-NETO, CARLOS - New England Eye Center; RABBANI, NAILA - University Of Warwick; THORNALLEY, PAUL - Qatar Biomedical Research Institute; SMITH, DONALD - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; WAHEED, NADIA - New England Eye Center; TAYLOR, ALLEN - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; JIANG, SHUHONG - Jean Mayer Human Nutrition Research Center On Aging At Tufts University

Submitted to: Free Radical Biology and Medicine
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 2/12/2020
Publication Date: 2/14/2020
Citation: Rowan, S., Jiang, S., Chang, M., Volkin, J., Cassalman, C., Smith, K.M., Streeter, M.D., Spiegel, D.A., Moreira-Neto, C., Rabbani, N., Thornalley, P.J., Smith, D.E., Waheed, N.K., Taylor, A., Jiang, S. 2020. A low glycemic diet protects disease-prone Nrf2-deficient mice against age-related macular degeneration. Free Radical Biology and Medicine. 150:75-86. https://doi.org/10.1016/j.freeradbiomed.2020.02.010.
DOI: https://doi.org/10.1016/j.freeradbiomed.2020.02.010

Interpretive Summary: Age-related Macular Degeneration (AMD) is the leading cause of blindness in the United States for older adults. AMD comes in two forms, wet and dry. The dry form of the disease is the most common in the United States. There is no treatment for vision loss once AMD becomes advanced. Exacerbating the situation, there are few good animal models of AMD. Both our genes and environment contribute to the risk for AMD, and dietary change may be the most promising route for prevention. A specific formulation of antioxidant vitamins and minerals appears to slow the rate of progression. Our past clinical and experimental studies have shown that the kind of carbohydrates eaten can also be an important factor for AMD risk. Carbohydrates that are rapidly broken down into sugar, termed high glycemic (HG), are associated with risk for AMD and, when fed to mice, lead to development of eye disease that resembles AMD. Mice fed low glycemic diets do not show these lesions. Similarly, clinical-epidemiologic data indicate that carbohydrates that are more slowly broken down into sugar, termed low glycemic (LG), reduce the risk for AMD in people. In this study we tested the impact of HG or LG diets in mice that were genetically modified to be at higher risk for AMD, through the deletion of an important antioxidant gene called Nrf2. When mice lacking Nrf2 were fed HG diets, they developed dry AMD at 18-months of age - an age when normal mice do not develop eye disease. If the mice were instead fed LG diets, they did not develop any apparent eye disease, indicating that consuming a low glycemic diet can completely prevent or delay development of eye disease in these mice. We explored the mechanisms by which diet could affect eye disease. HG diet led to obesity, high blood glucose, and formation of toxic glucose modifications to proteins in the eye. Mice fed the LG diet were lean, had normal blood glucose, and had much lower levels of the glucose-derived protein modifications. Within the eye, we also found higher levels of protective antioxidant enzymes in mice fed LG diets than in mice fed HG diets. These findings indicate that diet has the potential to prevent development of AMD, even in individuals that are genetically predisposed to develop disease. Our findings also detail a new mouse model for advanced dry AMD, something that has been particularly challenging to model, which might be useful for testing new drugs and treatments. Finally, our findings may help us understand the ways that diet can help or damage the eye and potentially lead to new avenues for treatment.

Technical Abstract: Age-related macular degeneration (AMD) is a major blinding disease, affecting over 14% of the elderly. Risk for AMD is related to age, diet, environment, and genetics. Dietary modulation of AMD risk is a promising treatment modality, but requires appropriate animal models to demonstrate advantages of diet. Mice lacking the antioxidant transcription factor Nrf2 (Nfe2l2) develop age-related retinopathy resembling human AMD. Here we evaluated the effect of consuming high glycemic (HG) or low glycemic (LG) diets until 18-months of age on development of AMD in Nrf2-null mice. Nrf2-null mice that consumed HG diets developed atrophic AMD, characterized by photoreceptor degeneration, retinal pigment epithelium (RPE) atrophy and pigmentary abnormalities, basal deposits, and loss of the choriocapillaris. In contrast, Nrf2-null-mice that consumed LG diets did not develop retinal disease phenotypes. Consumption of HG diets was associated with accumulation of advanced glycation end-products in the RPE and systemically, whereas consumption of the LG diet was associated with increased levels of anti-glycative and anti-oxidative detoxification machinery. Together our data indicate that the Nrf2-null HG mouse is a good model for atrophic AMD studies and that the LG diet can activate protective pathways to prevent AMD, even in a genetically predisposed animal.