Advanced Glycation End Products in the Skin: Molecular Mechanisms, Methods of Measurement, and Inhibitory Pathways

Abstract

Advanced glycation end products (AGEs) are a series of stable compounds produced under non-enzymatic conditions by the amino groups of biomacromolecules and the free carbonyl groups of glucose or other reducing sugars commonly produced by thermally processed foods. AGEs can cause various diseases, such as diabetes, atherosclerosis, neurodegeneration, and chronic kidney disease, by triggering the receptors of AGE (RAGEs) in the human body. There is evidence that AGEs can also affect the different structures and physiological functions of the skin. However, the mechanism is complicated and cumbersome and causes various harms to the skin. This article aims to identify and summarise the formation and characteristics of AGEs, focussing on the molecular mechanisms by which AGEs affect the composition and structure of normal skin substances at different skin layers and induce skin issues. We also discuss prevention and inhibition pathways, provide a systematic and comprehensive method for measuring the content of AGEs in human skin, and summarise and analyse their advantages and disadvantages. This work can help researchers acquire a deeper understanding of the relationship between AGEs and the skin and provides a basis for the development of effective ingredients that inhibit glycation.

Keywords: advanced glycation end products; fibroblasts; keratinocytes; matrix metalloproteinase; measurement methods; protein cross-linking; skin barrier.

FIGURE 1

The main pathway for the formation of AGEs. The condensation of the carbonyl group of the reducing sugar with the amino acid carbonyl amine forms a Schiff base, which is rearranged by an Amadori reaction to form a stable Amadori product. Some Amadori products are converted to AGEs by the Hodge pathway, and others are oxidized and cleaved to active dicarbonyl compounds. Active dicarbonyl compounds are further cross-linked with proteins to generate AGEs. These carbonyl intermediates are also generated by the Wolff pathway, Namiki pathway, and Polyol pathway.

FIGURE 2

Classification of advanced glycation end products. AGEs are classified according to their crosslinking structure and fluorescence characteristics into three categories. (A) Fluorescent, cross-linked. (B) Non-fluorescent, cross-linked. (C) Non-fluorescent, non-cross-linked.

FIGURE 3

The effect of AGEs on the epidermis of the skin. (A) AGEs obstruct skin wound healing. (B) AGEs reduce the contents of ceramide (CER) and cholesterol (CHOL) in the epidermis, eventually leading to a reduction in skin lipid content. (C) AGEs destroy the keratinocyte cell structure in the epidermis. (D) AGEs promote the production of melanin in melanocytes.

FIGURE 4

The effect of AGEs on the dermis of the skin. AGEs and collagen are cross-linked, causing the protein to brown and the fibers to deform. Elastin fiber becomes thinner, less rigid, and loses its biological properties. Glycosylated vimentin leads to the loss of fibroblasts’ contraction ability and the inability to maintain the basic cell shape. AGEs bind to RAGE receptors to regulate gene expression and mediate a series of signal pathways.

FIGURE 5

The mechanisms of AGEs inhibition. (A) Maintain and stabilize the protein structure. (B) Chelation of transition metals. (C) Capture and block dicarbonyl compounds. (D) Neutralize, inhibit, and scavenge oxidative free radicals. (E) Activation of the glyoxalase detoxification system. (F) Inhibition of aldose reductase. (G) Activation of the proteolytic system. (H) Regulation of AGE-RAGE signal transduction. (I) Disruption of protein cross-linking.