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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.
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3. Bucala R, Cerami A. Adv Pharmacol. 1992;23:1–4.
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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.