Epigenetic changes are widely considered to play an important role in aging, but experimental evidence to support this hypothesis has been scarce. We have used array-based analysis to determine genome-scale DNA methylation patterns from human skin samples and to investigate the effects of aging, chronic sun exposure, and tissue variation. Our results reveal a high degree of tissue specificity in the methylation patterns and also showed very little interindividual variation within tissues. Data stratification by age revealed that DNA from older individuals was characterized by a specific hypermethylation pattern affecting less than 1% of the markers analyzed. Interestingly, stratification by sun exposure produced a fundamentally different pattern with a significant trend towards hypomethylation. Our results thus identify defined age-related DNA methylation changes and suggest that these alterations might contribute to the phenotypic changes associated with skin aging.
Tyrosinase is the rate-limiting enzyme of melanin production and, accordingly, is the most prominent target for inhibiting hyperpigmentation. Numerous tyrosinase inhibitors have been identified, but most of those lack clinical efficacy because they were identified using mushroom tyrosinase as the target. Therefore, we used recombinant human tyrosinase to screen a library of 50,000 compounds and compared the active screening hits with well-known whitening ingredients. Hydroquinone and its derivative arbutin only weakly inhibited human tyrosinase with a half-maximal inhibitory concentration (IC) in the millimolar range, and kojic acid showed a weak efficacy (IC > 500 μmol/L). The most potent inhibitors of human tyrosinase identified in this screen were resorcinyl-thiazole derivatives, especially the newly identified Thiamidol (Beiersdorf AG, Hamburg, Germany) (isobutylamido thiazolyl resorcinol), which had an IC of 1.1 μmol/L. In contrast, Thiamidol only weakly inhibited mushroom tyrosinase (IC = 108 μmol/L). In melanocyte cultures, Thiamidol strongly but reversibly inhibited melanin production (IC = 0.9 μmol/L), whereas hydroquinone irreversibly inhibited melanogenesis (IC = 16.3 μmol/L). Clinically, Thiamidol visibly reduced the appearance of age spots within 4 weeks, and after 12 weeks some age spots were indistinguishable from the normal adjacent skin. The full potential of Thiamidol to reduce hyperpigmentation of human skin needs to be explored in future studies.
Background Hyperpigmentary disorders like melasma, actinic and senile lentigines are a major cosmetic concern.
The processes of aging and photoaging are associated with an increase in cellular oxidation. This may be in part due to a decline in the levels of the endogenous cellular antioxidant coenzyme Q10 (ubiquinone, CoQ10). Therefore, we have investigated whether topical application of CoQ10 has the beneficial effect of preventing photoaging. We were able to demonstrate that CoQ10 penetrated into the viable layers of the epidermis and reduce the level of oxidation measured by weak photon emission. Furthermore, a reduction in wrinkle depth following CoQ10 application was also shown. CoQ10 was determined to be effective against UVA mediated oxidative stress in human keratinocytes in terms of thiol depletion, activation of specific phosphotyrosine kinases and prevention of oxidative DNA damage. CoQ10 was also able to significantly suppress the expression of collagenase in human dermal fibroblasts following UVA irradiation. These results indicate that CoQ10 has the efficacy to prevent many of the detrimental effects of photoaging.
Atopic eczema is a chronic inflammatory skin disease characterized by cutaneous nerve fiber sprouting and epidermal hyperplasia, pointing to an involvement of the peripheral nervous system in cutaneous homeostasis. However, the interaction of sensory neurons and skin cells is poorly understood. Using an innervated skin model, we investigated the influence of sensory neurons on epidermal morphogenesis. Neurons induced the proliferation of keratinocytes, resulting in an increase in the epidermal thickness. Inhibition of calcitonin gene-related peptide (CGRP), but not substance P (SP) signaling, reversed this effect. Human CGRP enhanced keratinocyte proliferation and epidermal thickness in skin models, demonstrating a key role of CGRP in modulating epidermal morphogenesis, whereas SP had only a moderate effect. Innervated skin models composed of atopic skin cells showed increased neurite outgrowth, accompanied by elevated CGRP release. As atopic keratinocytes were sensitized to CGRP owing to higher expression levels of the CGRP receptor components, receptor activity-modifying protein 1 (RAMP1) and receptor component protein (RCP), atopic innervated skin models displayed a thicker epidermis than did healthy controls. We conclude that neural CGRP controls local keratinocyte growth. Our results show that the crosstalk of the cutaneous peripheral nervous system and skin cells significantly influences epidermal morphogenesis and homeostasis in healthy and atopic skin.
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