Submitted to: Aging Cell
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/16/2011
Publication Date: 2/1/2012
Citation: Uchiki, T., Weikel, K.A., Jiao, W., Shang, F., Caceres, A., Pawlak, D., Handa, J.T., Brownlee, M., Nagaraj, R., Taylor, A. 2012. Glycation-altered proteolysis as a pathobiologic mechanism that links dietary glycemic index, aging, and age-related disease in non diabetics. Aging Cell. 11(1):1-13. Interpretive Summary: The glycemic index indicates how fast sugar is released into the blood after a person eats a fixed amount of a carbohydrate containing food. Earlier, we found that people who consume lower glycemic index foods are protected against age related macular degeneration and cataract. Together cataract and macular degeneration account for almost all of the blindness in the world and in the USA. Importantly, blindness is the second greatest fear among our elderly and medical care due to vision problems is among the most common requirements for services. Although the data that supports salutary effects of lower glycemic index diets is robust, there is no biochemical mechanism that explains why consuming lower glycemic index foods provides health benefit. Such data is crucial in order to determine how to replicate this effect using other foods or drugs and to design such foods and drugs. In this novel work, we 1) established mammalian models of dietary glycemic index, 2) we showed that consuming lower glycemic index diets is associated with delayed formation of age-related compromises to the retina, 3) we show that consuming higher glycemic index foods causes accumulation of proteins that are modified by sugars and that are toxic to cells, 4) we show that this accumulation of cytotoxic proteins occurs in many tissues, 5) this explains why consuming higher glycemic index diets compromises many tissues and organs, 6) we also show that the usual machinery that is responsible for removing damaged proteins is also rendered less functional by higher glycemic index diets. Thus there is a vicious cycle set up by the diet. This vicious cycle includes sugar induced stress, damage to cellular proteins, damage to the cellular machinery that usually removes damaged proteins, further accumulation and toxicity of damaged proteins and finally organ failure. Together these data lay the ground work for additional exploitation of lower glycemic index diets for prolonging health.
Technical Abstract: Epidemiologic studies indicate that the risks for major age-related debilities including coronary heart disease, diabetes, and age-related macular degeneration (AMD) are diminished in people who consume lower glycemic index (GI) diets, but lack of a unifying physiobiochemical mechanism that explains the salutary effect is a barrier to implementing dietary practices that capture the benefits of consuming lower GI diets. We established a simple murine model of age-related retinal lesions that precede AMD (hereafter called AMD-like lesions). We found that consuming a higher GI diet promotes these AMD-like lesions. However, mice that consumed the lower vs. higher GI diet had significantly reduced frequency (P < 0.02) and severity (P < 0.05) of hallmark age-related retinal lesions such as basal deposits. Consuming higher GI diets was associated with > 3 fold higher accumulation of advanced glycation end products (AGEs) in retina, lens, liver, and brain in the age-matched mice, suggesting that higher GI diets induce systemic glycative stress that is etiologic for lesions. Data from live cell and cell-free systems show that the ubiquitin-proteasome system (UPS) and lysosome/autophagy pathway [lysosomal proteolytic system (LPS)] are involved in the degradation of AGEs. Glycatively modified substrates were degraded significantly slower than unmodified substrates by the UPS. Compounding the detriments of glycative stress, AGE modification of ubiquitin and ubiquitin-conjugating enzymes impaired UPS activities. Furthermore, ubiquitin conjugates and AGEs accumulate and are found in lysosomes when cells are glycatively stressed or the UPS or LPS/autophagy are inhibited, indicating that the UPS and LPS interact with one another to degrade AGEs. Together, these data explain why AGEs accumulate as glycative stress increases.