New Insights Into Advanced Glycation End Products Induced Melanogenesis and Intervention Strategies.

BACKGROUND: Skin hyperpigmentation refers to areas of skin that become darker than the surrounding skin due to an increase in melanin production, which greatly impacts skin esthetics. UV exposure, intrinsic hormonal changes, or injury are the general causes of hyperpigmentation. Recently, studies indicated that advanced glycation end products (AGEs) contribute to hyperpigmentation. However, detailed mechanisms involved in this process as well as therapeutic solutions are yet to be explored. AIMS: This study aimed to investigate the underlying mechanisms as well as intervention strategies targeting AGEs-induced melanogenesis. METHODS: The study exposed skin cells and 3D epidermal models to AGEs and measured melanin production and tyrosinase activity. Dimethoxytolyl propylresorcinol (DP), niacinamide, and green tea extract were tested for their ability to inhibit AGEs-induced melanogenesis or related cytokines. The AGEs breaking efficacy of DP was assessed on glycated lysozyme by mass spectrometry, as well as on glycated skin cells and 3D full-thickness skin models. RESULTS AND CONCLUSIONS: Exposure to AGEs stimulates tyrosinase activity and melanin production in melanocytes and 3D melanocyte-containing epidermal skin models. AGEs upregulate IL-33 expression in fibroblasts via NLRP1/Caspase1 activation. DP was discovered to be an effective AGEs crosslink breaker and also capable of inhibiting AGEs induced melanin production in skin models. Moreover, niacinamide and green tea extract effectively inhibit IL-18/IL-33 secretion stimulated by AGEs. Those 3 components work collectively to target different stages of AGEs induced melanogenesis in skin and appear to be a potent intervention strategy to treat skin hyperpigmentation and sallowness issues during the aging process.