Accumulation of advanced glycation end products (AGEs) on nucleotides, lipids, and peptides/proteins are an inevitable component of the aging process in all eukaryotic organisms, including humans. To date, a substantial body of evidence shows that AGEs and their functionally compromised adducts are linked to and perhaps responsible for changes seen during aging and for the development of many age-related morbidities. However, much remains to be learned about the biology of AGE formation, causal nature of these associations, and whether new interventions might be developed that will prevent or reduce the negative impact of AGEs-related damage. To facilitate achieving these latter ends, we show how invertebrate models, notably Drosophila melanogaster and Caenorhabditis elegans, can be used to explore AGE-related pathways in depth and to identify and assess drugs that will mitigate against the detrimental effects of AGE-adduct development.
Over the past 2 decades there has been increasing evidence supporting an important contribution from food-derived advanced glycation end products (AGEs) to the body pool of AGEs and therefore increased oxidative stress and inflammation, processes that play a major role in the causation of chronic diseases. A 3-d symposium (1st Latin American Symposium of AGEs) to discuss this subject took place in Guanajuato, Mexico, on 1-3 October 2014 with the participation of researchers from several countries. This review is a summary of the different presentations and subjects discussed, and it is divided into 4 sections. The first section deals with current general knowledge about AGEs. The second section dwells on mechanisms of action of AGEs, with special emphasis on the receptor for advanced glycation end products and the potential role of AGEs in neurodegenerative diseases. The third section discusses different approaches to decrease the AGE burden. The last section discusses current methodologic problems with measurement of AGEs in different samples. The subject under discussion is complex and extensive and cannot be completely covered in a short review. Therefore, some areas of interest have been left out because of space. However, we hope this review illustrates currently known facts about dietary AGEs as well as pointing out areas that require further research.
Background & Aims Consumption of sugar is associated with obesity, type 2 diabetes mellitus, non-alcoholic fatty liver disease, and cardiovascular disease. The conversion of fructose to fat in liver (de novo lipogenesis, DNL) may be a modifiable pathogenetic pathway. We determined the effect of 9 days of isocaloric fructose restriction on DNL, liver fat, visceral fat (VAT), subcutaneous fat, and insulin kinetics in obese Latino and African American children with habitual high sugar consumption (fructose intake more than 50 g/day). Methods Children (9–18 years old; n = 41) had all meals provided for 9 days with the same energy and macronutrient composition as their standard diet, but with starch substituted for sugar, yielding a final fructose content of 4% of total kcal. Metabolic assessments were performed before and after fructose restriction. Liver fat, VAT, and subcutaneous fat were determined by magnetic resonance spectroscopy and imaging. The fractional DNL area under the curve value was measured using stable isotope tracers and gas chromatography/mass spectrometry. Insulin kinetics were calculated from oral glucose tolerance tests. Paired analyses compared change from day 0 to day 10 within each child. Results Compared with baseline, on day 10, liver fat decreased from a median of 7.2% (inter-quartile range, 2.5%–14.8%) to 3.8% (inter-quartile range, 1.7%–15.5%)(P<.001) and VAT decreased from 123 cm3 (inter-quartile range, 85–145 cm3) to 110 cm3 (inter-quartile range, 84–134 cm3) (P<.001). The DNL area under the curve decreased from 68% (inter-quartile range, 46%–83%) to 26% (inter-quartile range, 16%–37%) (P<0.001). Insulin kinetics improved (P<.001). These changes occurred irrespective of baseline liver fat. Conclusions Short-term (9 day) isocaloric fructose restriction decreased liver fat, VAT, and DNL, and improved insulin kinetics in children with obesity. These findings support efforts to reduce sugar consumption. ClinicalTrials.gov no: NCT01200043
The presence of excessive amounts of advanced glycation end products (AGE) in tissues or in the circulation may critically affect the progression of diabetic nephropathy. Circulating AGE levels, mainly in the form of small peptides, increase in diabetic patients or in patients with end-stage renal disease. This rise correlates with the severity of the nephropathy. However, so far little is known about the fate of AGE-proteins and AGE-peptides in renal tissue, and in order to elucidate this issue we undertook the present study. AGE-bovine serum albumin (AGE-BSA) and AGE-peptides were prepared, characterized by spectrophotometry, spectrofluorometry, chromatography and SDS-PAGE. AGE-peptides reacted in vitro with LDL producing biochemical and ultrastructural modifications. Using colloidal gold post-embedding immunoelectron microscopy with an anti-AGE antibody generated in our laboratory, we followed, in a short-term kinetic study, the cellular and sub-cellular localisation of circulating AGE-products throughout the nephron. AGE-peptides or AGE-BSA were injected into otherwise normal rats and detected by protein A-gold immuno-cytochemistry after 15, 30 or 45 min of circulation. Most of the AGE-BSA was found in the lumen of capillary vessels and distributed along the endothelial side of the glomerular basement membrane. Presence on mesangial matrix was also apparent. AGE-peptides were easily filtered and actively reabsorbed by the proximal convoluted tubule. At 15 min, little labelling was found in the glomerular wall. Instead, the labelling was present in the urinary space and microvilli of epithelial cells. Early endosomes displayed intense labelling as well. At 45 min, late endosomes and lysosomes added to the pattern of labelling. The distal tubule epithelial cells were devoid of labelling for any of the intervals studied. AGE-peptides but not AGE-BSA could be detected in the urine of injected rats. These observations point to participation of the endo-lysosomal apparatus of the proximal convoluted tubule to the disposal of AGE-peptides, while giving an ultrastructural support for a key role of the kidney in AGE catabolism.
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