Potential Role of Vitamin D and Fibroblast Growth Factor 23–Klotho System in Aging

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Although vitamin D is commonly perceived as a bone-forming vitamin, it in fact exerts numerous essential physiological functions ranging from the maintenance of mineral ion homeostasis to the regulation of the immune system [1-5]. The synthesis of vitamin D is a complex and multiorgan process that begins in the skin and continues further in the liver, and is then converted into biologically active 1,25 dihydroxyvitamin D3 [1,25(OH)2D3] in the kidney. Two sequential hydroxylations are involved in the production of the bioactive metabolite 1,25(OH)2D3; rst, by the enzyme 25 hydroxylase (CYP27A1) in the liver to 25 hydroxyvitamin D [25(OH)2D], and then by 1α hydroxylase [1α(OH)ase; CYP27B1] in the kidney to 1,25(OH)2D3. To keep the homeostatic balance of 1,25(OH)2D3, the enzyme 24-hydroxylase (CYP24) generates 24,25(OH)2Din the liver or kidney for eventual inactivation. The bioactive form, 1,25(OH)2D3, can interact with the high-afnity vitamin D receptor (VDR), which is a ligand-dependent transcription factor [6]. Besides classic genomic functions through VDR, 1,25(OH)2D3 could also exert its bioactivities through a VDR-independent rapid response system that is presumed to be mediated either by separate sets of cell membrane receptors or its caveolae components [6]. In addition to intestine, bone, kidney, and the parathyroid gland, the VDR receptors are also widely present in tissues and organs that are not considered to be involved in calcium metabolism, implicating a wide range of functions for vitamin D; indeed, such involvement is proposed in hypertension, immunoregulation, embryogenesis, and tumorigenesis [5]. Studies have shown a strong association between hypovitaminosis D and various aging-related conditions such as osteoporosis, cancer, diabetes, autoimmune disorders, hypertension, atherosclerosis, 14.1 Vitamin D Synthesis ............................................................................................................. 351 14.2 Hypovitaminosis D ............................................................................................................... 351 14.3 Fibroblast Growth Factor 23 ................................................................................................. 352 14.4 Klotho ................................................................................................................................... 353 14.5 Vitamin D and Vascular Changes ........................................................................................ 355 14.6 Vitamin D and FGF23-Klotho System in Tumors ............................................................... 355 14.7 Vitamin D and FGF23-Klotho System in Aging ................................................................. 356 14.8 Concluding Remarks ............................................................................................................ 357 References ...................................................................................................................................... 358

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