Collagen glycation triggers the formation of aged skin in vitro

Glycation products accumulate during the aging of many slowly renewing tissues, including skin. We have developed an in vitro model of chronologic aging of skin based on reconstructed skin modified by artificially glycating the collagen used to prepare the dermal compartment. The morphology of the modified skin is close to the morphology usually observed except that the dermis is altered in its fibrillar structure. Moreover, the analysis of skin markers revealed several unexpected biological and morphological modifications, which reflect in vivo aging and could be related to glycation per se. These include the activation of fibroblasts, increase of matrix molecules (collagen type III and collagen type IV) and metalloproteinase production (MMP1, MMP2 and MMP9), thickening of the basement membrane zone, and more strikingly, the modification of alpha6 and beta1 integrin patterns especially in epidermis, in a way closely resembling aged skin in vivo. We also found that these effects could be related to the production of putative diffusible factors by the dermal fibroblasts activated by glycation. Finally, we show that all these effects are likely to be glycation specific since they could be inhibited by aminoguanidine, a well-known glycation inhibitor. We conclude that the reconstructed skin model modified by glycation of the collagen closely mimics chronologic aging of skin in vivo. Taken together, these results strengthen the importance of glycation reactions in skin aging.