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Advanced glycation end-products in skin ageing and photoageing: what are the implications for epidermal function? Mark D. Farrar Centre for Dermatology, Institute of Inflammation and Repair, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK Correspondence: Mark Farrar, Photobiology Unit, Dermatology Centre, University of Manchester, Salford Royal NHS Foundation Trust, Manchester, M6 8HD, UK. Tel.: +44 161 2060214, e-mail: [email protected] Word count: 898 Abbreviations: AGE, advanced glycation end-product; CML, carboxymethyl-lysine; GLO, glyoxalase; RAGE, receptor for AGE; UVR, ultraviolet radiation. Keywords: advanced glycation end-product; glyoxalase; human skin; ultraviolet radiation Ageing is characterized by a gradual decline in the physiological function of cells and tissues of the body, with associated accumulation of damage. In human skin, the effects of chronological (intrinsic) ageing manifest as fine wrinkles, loss of elasticity and changes in pigmentation in later life. Compounding this is the impact of external factors, predominantly exposure to ultraviolet radiation (UVR) in sunlight, termed photoageing (1). A prominent feature of ageing at the molecular level is the gradual accumulation of proteins that have undergone non-enzymatic modification, one of the commonest of which is glycation. Reducing sugars react with free amino groups on proteins (and other molecules) leading to the reversible production of reactive intermediates and ultimately to irreversible advanced glycation end-products (AGEs). Such modification can lead to reduced function (2). Longlived proteins such as those of the dermal matrix are particularly vulnerable to modification, the result of which is tissue stiffening, reduced elasticity, and potentially increased production of UVR-induced reactive oxygen species (3). AGE accumulation is countered by enzymes of the glyoxalase system, GLO-1 and GLO-2, which work in tandem to detoxify the reactive precursors of AGEs. There are yet few studies of AGEs and/or GLO enzymes in healthy human skin in vivo. A previous assessment of AGE abundance in human dermis showed the level of protein glycation to increase with age, with higher amounts in skin taken from photoexposed areas (4). Radjei et al. (5) now provide further insight into AGEs in human skin with an investigation into the epidermal abundance and distribution of AGEs and GLO enzymes. They explored how these differ in young and aged skin, and the impact of chronic photoexposure. Localisation of the most prevalent AGE modification, carboxymethyl-lysine (CML), and of GLO-1 and -2 was investigated in skin from 10 young (25-30 years) and 10 aged (61-65 years) volunteers. Photoprotected (upper inner arm) skin was examined to assess how GLO production changes with chronological ageing. The two GLO enzymes showed different localization within the epidermis, with GLO-1 primarily associated with the proliferative basal layer and GLO-2 more prominent in the differentiated upper layers. This pattern was similar in young and aged skin but both GLO-1 and -2 were more abundant in aged skin. Interestingly, staining of CML-modified AGEs revealed lower amounts in the basal epidermal layer in older skin compared with younger skin. This led the authors to conclude that accumulation of AGEs through chronological ageing is associated with higher production of glyoxalase enzymes and hence, lower amounts of AGEs. The authors went on to examine the impact of UVR exposure, finding that in young photoexposed (forearm) skin there was no difference in the amounts of GLO-1 or CML-modified protein from those detected in photoprotected skin. In older skin, there was a much greater accumulation of CML-modified protein in photoexposed skin but again, no difference in amount of GLO-1 compared to photoprotected skin. In both young and old skin, photoexposure was associated with lower production of GLO-2. The above in vivo immunohistochemical work was complemented in this study (5) by a series of in vitro experiments in human keratinocytes to further examine the expression and production of GLO-1, and also its potential regulation by the transcription factor Nrf2, which upregulates expression of genes encoding antioxidant proteins and has been shown to regulate GLO-1 expression in mammalian cells including human fibroblasts in vitro (6). Although preliminary in nature, these data indicated that the GLO-1 enzyme is present and active in primary keratinocytes from young and aged donors, and that activation of Nrf2 gene expression in HaCaT keratinocytes was associated with increased expression of GLO-1. It is evident from this study and the few previous reports, that chronic exposure to UVR in sunlight can promote AGE formation. However, the functional implications of AGE accumulation, particularly in the epidermis, are still unclear. The dermis contains long-lived proteins that are thus more susceptible to modification, but protein turnover in the epidermis is much more rapid and suprabasal layers undergo continual renewal such that modified proteins will eventually be lost as cells are replaced. Identifying which epidermal protein(s) most commonly undergo glycation and how long they persist may indicate potential impacts on function for further investigation. Further work is also required to elucidate the differential regulation of GLO-1 and -2. The presence of the receptor for AGE (RAGE) on keratinocytes indicates that AGEmediated activation may be possible with potentially negative consequences even over a short time period. A conveniently-timed Letter in Experimental Dermatology by Iwamura et al. (7) describes the distribution of RAGE protein in normal human skin with localization to keratinocytes and fibroblasts. Real-time PCR showed strong correlations of AGER (encoding RAGE) expression with that of genes encoding several pro-inflammatory cytokines and proapoptotic factors. These authors propose that membrane-bound RAGE expressed by keratinocytes responds to acute changes to maintain skin homeostasis but they do not speculate on longer term effects. The work presented by Radjei et al. is a ‘snapshot’ of AGE and GLO abundance and distribution and provides no information on shorter-term changes or the effects of acute UVR exposure. Further investigation of AGEs, RAGE and GLOs in human skin is required to elucidate their interaction, the potential negative functional outcomes of AGE accumulation, and whether AGE formation could be a target for therapeutic intervention. Acknowledgements The author thanks Professor Lesley Rhodes for helpful comments on the manuscript. Conflict of Interest The author declares no conflicting interests. References 1. Watson REB, Gibbs NK, Griffiths CEM, et al. Antioxid Redox Signal. 2014;21:1063– 1077. 2. Radjei S, Friguet B, Nizard C, et al. Biochem Soc Trans. 2014;42:518–522. 3. Bucala R, Cerami A. Adv Pharmacol. 1992;23:1–4. 4. Jeanmarie C, Danoux L, Pauly G. Br J Dermatol. 2001;145:10–18. 5. Radjei S, Gareil M, Moreau M, et al. Exp Dermatol. 2016;25:492-494. 6. Xue M, Rabbani N, Momiji H, et al. Biochem J. 2012;443:213–222. 7. Iwamura M, Yamamoto Y, Kitayama Y, et al. Exp Dermatol. 2016;25:235–237.