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Review
. 2018 Dec;1864(12):3631-3643.
doi: 10.1016/j.bbadis.2018.08.036. Epub 2018 Aug 29.

Mechanistic targeting of advanced glycation end-products in age-related diseases

Sheldon Rowan  1 , Eloy Bejarano  1 , Allen Taylor  2
Affiliations
Review

Mechanistic targeting of advanced glycation end-products in age-related diseases

Sheldon Rowan et al. Biochim Biophys Acta Mol Basis Dis. 2018 Dec.

Abstract

Glycative stress, caused by the accumulation of cytotoxic and irreversibly-formed sugar-derived advanced glycation end-products (AGEs), contributes to morbidity associated with aging, age-related diseases, and metabolic diseases. In this review, we summarize pathways leading to formation of AGEs, largely from sugars and glycolytic intermediates, and discuss detoxification of AGE precursors, including the glyoxalase system and DJ-1/Park7 deglycase. Disease pathogenesis downstream of AGE accumulation can be cell autonomous due to aggregation of glycated proteins and impaired protein function, which occurs in ocular cataracts. Extracellular AGEs also activate RAGE signaling, leading to oxidative stress, inflammation, and leukostasis in diabetic complications such as diabetic retinopathy. Pharmaceutical agents have been tested in animal models and clinically to diminish glycative burden. We summarize existing strategies and point out several new directions to diminish glycative stress including: plant-derived polyphenols as AGE inhibitors and glyoxalase inducers; improved dietary patterns, particularly Mediterranean and low glycemic diets; and enhancing proteolytic capacities of the ubiquitin-proteasome and autophagy pathways that are involved in cellular clearing of AGEs.

Keywords: Advanced glycation end-products; Age-related macular degeneration; Autophagy; Cataract; Diabetes; Diabetic retinopathy; Glyoxalase; RAGE; Ubiquitin-proteasome system.

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Figures

Fig. 1.
Fig. 1.
Formation and detoxification of advanced glycation end-products (AGEs) from dietary sugars. AGEs are derived by different pathways including Maillard reaction with the generation of Schiff bases and Amadori products and reactions that involve oxaldehydes (glyoxal, methylglyoxal, 3-deoxyglucosone) derived, in part, from glycolytic intermediates. Fructosyl-lysine, a fructosamine, is an Amadori product that can further go on to form CML. Detoxifying routes (highlighted in red) and AGEs (highlighted in purple) are shown. DHAP: dihydroxyacetone phosphate; GSH: reduced glutathione; CML: Nε-(carboxymethyl)-lysine; CMA: Nε-(carboxymethyl)-arginine; GOLD: glyoxal-derived lysyl dimer; 3-DG: 3-deoxyglucosone; GH-1,2,3: glyoxal-derived hydroimidazolone; MGH-1,2,3: methylglyoxal-derived hydroimidazolone; CEL: Nε-(carboxyethyl)-lysine; CEA: Nε-(carboxyethyl)-arginine; MOLD: methylglyoxal-derived lysine dimer; dG: deoxyguanosine residue on DNA; GdG: 3-(2′-deoxyribosyl)-6,7-dihydro-6,7-dihydroxyimidazo-[2,3-b]purin-9(8)one; CMdG: N2-carboxymethyl-deoxyguanosine; MGdG: 3-(2′-deoxyribosyl)-6,7-dihydro-6,7-dihydroxyimidazo-[2,3-b]purin-9(8)one; CEdG: N2-(1-carboxyethyl)-deoxyguanosine.
Fig. 2.
Fig. 2.
Dietary glycative-stress induced accumulation of AGEs. Under low glycemia diets (LG, left), intracellular proteolytic pathways are involved in the clearance of AGEs to preserve cellular function. During normal aging or under high glycemia diets (HG, right), proteolytic capacities are insufficient and AGEs accelerate the formation of aggregates/oligomers, leading to the onset of age-related diseases.
Fig. 3.
Fig. 3.
Glycation of crystallins in cataractogenesis. Direct glycation of α-crystallins and γ-crystallins induces a loss of chaperone activity and aggregation, as examples of intracellular and RAGE-independent glycative damage. DHAP: dihydroxyacetone phosphate.
Fig. 4.
Fig. 4.
RAGE signaling in glycative stress. Interactions of exogenous or endogenous AGEs in circulation with RAGE in plasma membrane trigger different signaling routes responsible for cytopathological responses, including apoptosis, inflammation, generation of reactive oxygen species (ROS), angiogenesis, and vasopermeability.
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