Research Paper|Volume 11, Issue 6|pp 1648—1663

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

Francesco Scavello¹, Filippo Zeni¹, Calogero C. Tedesco², Emanuela Mensà³, Fabrizio Veglia², Antonio Domenico Procopio^3,⁴, Anna Rita Bonfigli⁵, Fabiola Olivieri^3,⁴, Angela Raucci¹

¹Unit of Experimental Cardio-Oncology and Cardiovascular Aging, Centro Cardiologico Monzino-IRCCS, Milan, Italy
²Unit of Biostatistics, Centro Cardiologico Monzino-IRCCS, Milan, Italy
³Department of Clinical and Molecular Sciences, DISCLIMO, Università Politecnica delle Marche, Ancona, Italy
⁴Center of Clinical Pathology and Innovative Therapy, IRCCS INRCA, Ancona, Italy
⁵Scientific Direction, IRCCS INRCA, Ancona, Italy

* * Equal contribution

Received: November 23, 2018Accepted: March 6, 2019Published: March 23, 2019

https://doi.org/10.18632/aging.101860

Copyright: © 2019 Scavello et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

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.