Modulation of soluble receptor for advanced glycation end-products (RAGE) isoforms and their ligands in healthy aging

The receptor for advanced glycation end-products (RAGE) recognizes several ligands involved in inflammatory diseases. Two circulating soluble isoforms exist: esRAGE derived from alternative splicing and cRAGE generated by the membrane-bound RAGE (FL-RAGE) proteolysis. Together, esRAGE and cRAGE constitute sRAGE and function as decoy receptors preventing FL-RAGE/ligands binding. We determined serum concentration of both, esRAGE and cRAGE, and their ligands AGEs, HMGB1 and S100A8/A9 in a healthy population of 169 subjects aged 20-90 years. cRAGE showed a negative (r=-0.375, P<0.0001) while AGEs (r=0.160, P=0.0384) and S100A8/A9 (r=0.207, P=0.0091) a positive correlation with age. esRAGE did not change during aging and inversely correlated with Hemoglobin, ALT, insulin, HOMA index, Waist-Hip ratio (W/H), Waist Circumference (WC) and positively with AGEs. cRAGE exhibited also an inverse correlation with WC, W/H, PAI-1, HMGB1, AGEs and S100A8/A9. Age, W/H, HMGB1, S100A8/A9 and AGEs are independent predictors of cRAGE, whereas W/H and AGEs associate with esRAGE. Treatment of cells with glycated albumin reduced cRAGE production and upregulated FL-RAGE. These results indicate that in a healthy population cRAGE is a biomarker of aging while esRAGE represents a more reliable marker of obesity and insulin resistance. Hence, sRAGE isoforms levels could be differentially associated with age-related diseases risk factors.