1404 Melatonin Improves Mitochondrial Function in Human Skin Ex Vivo and May Unfold Significant Anti-Aging Properties

Since skin is constantly exposed to multiple extrinsic and intrinsic aging-promoting stressors, and shows easily visible signs of aging, there is a need for the development of effective skin senolytics. The endogenous, well-tolerated indoleamine neurohormone, melatonin, which is also synthesized in skin itself, is a very attractive candidate senolytic since it displays numerous anti-aging properties, including free radical scavenging as well as oxidative, mitochondrial and DNA damage repair. Therefore, we have asked in this pilot study whether melatonin unfolds significant anti-aging activities also in human skin. For this, we have used serum-free skin organ culture, which we have shown to greatly accelerate skin aging ex vivo and examined how melatonin impacts on selected aging-related biomarkers. We used upper eyelid skin (given that it is sun-exposed and targeted by anti-aging cosmetics; 3-4 donors; 49-70 years old) and treated it “systemically” by adding melatonin to the culture medium for 6 days every other day. Quantitative immunohistomorphometry revealed that 100uM melatonin up-regulates mitochondrial activity, as shown by significantly increased epidermal expression of MTCO1 and TFAM protein. 100uM melatonin also tendentially increased SIRT1. Instead, epidermal pS6 protein expression was slightly decreased, suggesting downregulation of the aging-promoting mTOR pathway. Interestingly, melatonin did not alter epidermal expression of VEGF-A protein, which we had shown to be both sufficient and required for human skin rejuvenation in vivo and ex vivo. This suggests that the observed effects of melatonin are VEGF-A-independent. We are currently complementing the above read-outs with additional aging-related biomarkers. These preliminary skin organ culture data already support the concept that “systemically” applied melatonin (e.g., as nutraceutical) is an effective human skin senolytic.