Unravelling of hidden secrets: The role of vitamin D in skin aging

The skin is the only tissue in the human body that represents both a target tissue for biologically active vitamin D compounds including 1,25-dihydroxyvitamin D [1,25(OH)(2)D] and has the capacity for the synthesis of 1,25(OH)(2)D from 7-dehydrocholesterol (7-DHC). Recent findings indicate that the vitamin D endocrine system (VDES), besides multiple other important functions, regulates aging in many tissues, including skin. This concept is strongly supported by several independent studies in genetically modified mice (including FGF23(−/−) and Klotho(−/−) mice) that are characterized by altered mineral homeostasis caused by a high vitamin D activity. These mice typically have phenotypic features of premature aging that include, besides short lifespan, retarded growth, ectopic calcification, immunological deficiency, osteoporosis, atherosclerosis, hypogonadism, skin and general organ atrophy. Notably, it has been demonstrated that these phenotypic features can be reversed by normalizing mineral homeostasis and/or vitamin D status. Interestingly, the aging phenotypes of mice suffering from hypovitaminosis D (VDR(−/−) and CYP27B1(−/−) mice) are quite similar to those suffering from hypervitaminosis D (including FGF-23(−/−) and Klotho(−/−) mice). Consequently, it has been hypothesized that thus, both hypo- and hypervitaminosis D may enhance aging. Aging seems to show a U-shaped response curve to vitamin D status, and, therefore normovitaminosis D seems to be important for preventing premature aging. Additionally, laboratory investigations have now convincingly shown that vitamin D compounds protect the skin against the hazardous effects of various skin aging-inducing agents, including ultraviolet (UV) radiation. In conclusion, these findings support the concept that UV-radiation exerts both skin aging -promoting and -inhibiting effects, the latter via induction of cutaneous vitamin D synthesis. Future studies will clarify the effect of vitamin D compounds on expression and function of potential key regulators of skin aging, such as TAp63 or the IGF-1 signaling pathway. Furthermore, the efficacy of topically applied vitamin D compounds in the prevention of skin aging has to be evaluated in future clinical trials.