GLP-1RA and the possible skin aging

Abstract

"Ozempic face" and facial aging have been observed as side effects in many patients after glucagon like peptide 1 receptor agonists (GLP-1RA) therapy for type 2 diabetes mellitus (T2DM) and obesity. However, those medications can reduce systemic inflammation and possibly promote skin health. The rapid weight loss observed with GLP-1RA has been implicated in facial aging. However, recent evidence suggests further pathophysiological mechanisms for this side effect. The aim of this article is to review the literature and present available data on the possible mechanisms of GLP-1RA on skin aging. Indeed, GLP-1RA may affect other types of skin cells, which may accelerate the process of skin aging itself. More specifically, GLP-1RA can act on adipose-derived stem cells (ADSC) and fibroblasts, that present GLP-1R on their surface. Stimulation of the receptor reduces the ability of ADSC to produce protective cytokines. The absence of those cytokines promotes the production of reactive oxygen species (ROS) and causes oxidative damage on fibroblasts. GLP-1RA also reduce the glucose intake of the ADSC, leading to reduced production of ATP and apoptosis. Finally, the stimulation of GLP-1R on ADSCs reduces indirectly the production of estrogens from dermal white adipose tissues (DWAT), which reduces stimulation of fibroblasts to produce collagen. GLP-1RA can also affect the process of skin aging through interaction with advanced glycation end products (AGEs) and RAGE (receptors of AGEs) activation. In conclusion, many patients receiving GLP-1RA suffer from "Ozempic face" and facial aging. It seems that this complication is not exclusively related to decreased facial fat, but there are more aging mechanisms that have to be elucidated.

Keywords: AGEs; Aging; GLP-1RA; Obesity; Skin; Type 2 diabetes.

Fig. 1

Suggested mechanisms of GLP-1RA on skin aging. GLP-1RA can act on ADSCs and fibroblasts through GLP-1R on their surface. Stimulation of the receptor reduces the ability of the ADSC to produce protective cytokines. The absence of those cytokines promotes the production of ROS and causes oxidative damage on fibroblasts. GLP-1RA also reduces the glucose intake of the ADSC, leading to reduced production of ATP and apoptosis. Finally, the stimulation of GLP-1R on ADSCs, indirectly reduces the production of estrogen from DWAT. The decreased amount of estrogen cannot stimulate fibroblasts to produce collagen. GLP-1RA can also affect the process of skin aging through AGEs. GLP-1RA can reduce the production of AGEs and thus, the cross-link with collagen. Moreover, GLP-1RA can interfere with the stimulating pathway after RAGE activation, by inhibiting NF-kB. That leads to decreased production of inflammatory cytokines, inhibition of NADPH oxidase and ROS production, inhibition of fibroblast apoptosis, production of collagen and decreased activity of MMPs. This figure suggests that there are two conflicted mechanisms in which GLP-1RA can affect skin aging. The effect of GLP-1RA on ADSCs, indicates the deterioration of skin health and the acceleration of skin aging. On the other hand, GLP-1RA, by reducing AGEs production and by inhibiting RAGEs activation, benefits skin health and delays skin aging