Dietary CML-enriched protein induces functional arterial aging in a RAGE-dependent manner in mice

Mol Nutr Food Res. 2015 May;59(5):927-38. doi: 10.1002/mnfr.201400643. Epub 2015 Mar 20.


Scope: Advanced glycation end-products (AGEs) are endogenously produced and are present in food. N(ε)-carboxymethyllysine (CML) is an endothelial activator via the receptor for AGEs (RAGEs) and is a major dietary AGE. This work investigated the effects of a CML-enriched diet and RAGE involvement in aortic aging in mice.

Methods and results: After 9 months of a control diet or CML-enriched diets (50, 100, or 200 μg(CML)/g of food), endothelium-dependent relaxation, RAGE, vascular cell adhesion molecule-1, and sirtuin-1 expression, pulse wave velocity and elastin disruption were measured in aortas of wild-type or RAGE(-/-) male C57BL/6 mice. Compared to the control diet, endothelium-dependent relaxation was reduced in the wild-type mice fed the CML-enriched diet (200 μg(CML)/g) (66.8 ± 12.26 vs. 94.3 ± 2.6%, p < 0.01). RAGE and vascular cell adhesion molecule-1 (p < 0.05) expression were increased in the aortic wall. RAGE(-/-) mice were protected against CML-enriched diet-induced endothelial dysfunction. Compared to control diet, the CML-enriched diet (200 μg(CML)/g) increased the aortic pulse wave velocity (86.6 ± 41.1 vs. 251.4 ± 41.1 cm/s, p < 0.05) in wild-type animals. Elastin disruption was found to a greater extent in the CML-fed mice (p < 0.05). RAGE(-/-) mice fed the CML-enriched diet were protected from aortic stiffening.

Conclusion: Chronic CML ingestion induced endothelial dysfunction, arterial stiffness and aging in a RAGE-dependent manner.

Keywords: Aging; Aorta; Endothelium; Glycation; Nutrition.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging
  • Animals
  • Arteries / physiology*
  • Dietary Proteins / administration & dosage*
  • Endothelium, Vascular / physiology
  • Lysine / administration & dosage
  • Lysine / analogs & derivatives*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Pulse Wave Analysis
  • Receptor for Advanced Glycation End Products / physiology*
  • Sirtuin 1 / analysis
  • Vascular Cell Adhesion Molecule-1 / analysis
  • Vascular Stiffness


  • Dietary Proteins
  • Receptor for Advanced Glycation End Products
  • Vascular Cell Adhesion Molecule-1
  • N(6)-carboxymethyllysine
  • Sirt1 protein, mouse
  • Sirtuin 1
  • Lysine