TABLE 1.

The effects of advanced glycation end products (AGEs) on various layers of the skin and their molecular mechanisms.

Substance	Mechanism	Symptoms	References
Sebaceous membrane	(i) Decreased expression of ceramide synthase CERS3 reduces the content of ceramide (CER) and cholesterol (CHOL) in the epidermis (ii) Reduced epidermal lipid synthesis (iii) The function of structural proteins (filaggrin, transglutaminase-1) is affected	(i) The skin barrier is destroyed (ii) Decrease lamina, delaying the self-repair of the skin barrier (iii) The function of related proteins to establish the skin barrier is destroyed	(70–72)
Keratinocytes	(i) The stratification of keratinocytes in the epidermis is disordered and the cytoplasm is vacuolated (ii) With the reduction of epidermal lipid synthesis, the integrity of the stratum corneum decreases	(i) Loose skin structure (ii) Thinning of the epidermis	(71, 73–75)
Melanocytes	(i) AGEs bind to RAGEs, activate ERK and CREB signalling pathways, and increase MITF expression and tyrosinase activity	(i) The production of melanin in melanocytes is promoted and the skin is prone to photoaging	(76)
Epidermal ECM	(i) The RAGE-MAPK-ERK1/2 or p38 pathway upregulates the expression of MMP-9 in cells	(i) The overexpression of MMP-9 affects skin wound healing	(77)
Fibroblasts	(i) In the cell: expression of the CatD enzyme is reduced, ROS activation, expression of p38/JNK is induced, and the FOXO1 transcription factor is activated (ii) Cell membrane: The fluidity of the cell membrane and liposome membrane increases; mast cells release histamine and the production of hyaluronidase increases, and sodium hyaluronate HA reduces AGE-RAGE-MAPKs (p38, PI3K/Akt, ERK, JIKs), increases the production of ROS, activates the expression of the NF-kB transcription factor HMGB1, and after binding to RAGEs, induces the expression of the TRPV1 protein	(i) AGEs accelerate their deposition and accumulation in the skin, which further accelerates the senescence caused by photoaging; fibroblast apoptosis (ii) Inflammation (iii) Skin sensitivity to pain	(22, 78–84)
Dermis ECM	(i) The activities of the matrix metalloproteinases MMP-1, MMP-2, and MMP-9 all increase, which changes the expression of ECM-related genes in fibroblasts (ii) Cross-linking with collagen, vimentin, and elastin, and long-term protein accumulation	(i) Changes the balance between the synthesis and degradation of the extracellular matrix, which ultimately leads to impaired skin homeostasis (ii) Destruction of the protein structure and fibre deformation, making them unable to maintain their biomechanical properties and functions (iii) The browning of collagen causes skin yellowing, the loss of fibroblast contraction ability, and ultimately accelerates the ageing process (iv) Skin sensitivity to pain	(72, 74, 85–90)