In this work, we established a relationship between age, frequency or extent of age-related retinal lesions that precede AMD, and dietary GI in a murine model. The model faithfully recapitulates human epidemiologic data showing that aging is associated with more advanced lesions and that consuming low GI foods is associated with lower risk for onset and progress of early AMD. We also corroborated previous mechanistic findings by demonstrating tissue accumulation of AGEs in mice fed a higher GI diet and relating that to AGE accumulation in regions of age- and diet-associated retinal pathology.
The absence of a macula limits the capacity of the rodent retina to completely model human AMD; thus, researchers using mouse models72,75,104,108,109
rely on evaluations of retinal lesions that precede and accompany the human disease103,110–112
to determine associations between various treatments and risk for early stages of AMD. We found that on aging, mice fed either a high or a low GI diet showed increased retinal lesions such as accumulation of BLDs and cytoplasmic vacuoles, loss of basal infoldings, and loss of outer and inner nuclear layers, confirming previous reports of the age-associated nature of these lesions (, ).103,110–113
Importantly, we noted that in general, there were more robust age-related differences in lesion frequency and severity in high GI-fed mice than in low GI-fed mice, indicating that consumption of a low GI diet attenuates and may delay lesions.
The only difference in the diet between the high and low GI groups is the ratio of amylopectin/amylose. Only the lower GI diet contains amylose. The physiological changes associated with consumption of these carbohydrates may explain the differences in the frequency and severity of lesions between diet groups of age-matched mice.114–117
Amylopectin is digested at a faster rate than amylose, resulting in an increased flux of glucose and methylglyoxal into the retina.118
Glycative stress in the retina is demonstrated by increased levels of MG-H1 in the RPE and photoreceptors (). It has been shown that glycative stress from increased glucose catabolism increases the risk for diabetes and cardiovascular disease in humans.119,120
Our data suggest that this stress may impact the retina as well, creating an environment predisposed to the accumulation of lesions, as shown in , , , and . A plausible link between dietary GI, retinal stress, and retinal aging may be found in deposition of AGEs, the known cytotoxicity of AGEs, and the recently discovered impairment of protein editing caused by glycative stress in the retinas of mice consuming high GI diets.106
The retinal lesions that were accelerated in the high GI-fed mice have also been observed in diabetic rodents, suggesting that it may be possible to use these data to gain insight into nutritional amelioration of diabetic retinopathy, even though these mice are not diabetic. These lesions include vacuolization of the RPE, disorganization of photoreceptor outer segments, decreased thickness of the inner nuclear layer, and accumulation of AGEs in the inner retina.121–126
AGEs directly contribute to the vascular compromises of diabetic retinopathy by increasing levels of vascular endothelial growth factor (VEGF).127–134
Thus, it seems that consuming lower GI diets should reduce AGEs and the associated risk for the progression of diabetic retinopathy and of AMD.
Implementation of the high GI diet, with or without HQ, allowed us to evaluate the requirement for HQ to accelerate retinal aging and the etiology of age-related retinal lesions that precede AMD. Higher levels of lesions were not observed in animals that consumed a high GI diet with, rather than without, HQ, suggesting that HQ is not necessary to elicit these lesions in animals within the context of a high GI diet. A corollary is that consumption of a high GI diet alone (in the absence of HQ) can be used as a model for retinal aging.
This study shows that age is associated with increasing lesions in the murine retina and that a high GI diet augments this retinal pathology. Overall, the differences in AMD-like lesions appear to be greatest between low GI-fed younger animals and high GI-fed older animals. These data show that the model is responsive to environmental influences such as nutrition and will also be useful for studies of mechanisms of disease initiation. Additionally, the C57BL/6 mouse fed a high GI diet provides a new excellent platform on which to study the effects of modulators (drugs, nutraceuticals) on aging and risk for early AMD.