Tuohimaa Pentti
Medical School, 33014 University of Tampere, Finland.
J Steroid Biochem Mol Biol. 2009 Mar;114(1-2):78-84. doi: 10.1016/j.jsbmb.2008.12.020.
Recent studies using genetically modified mice, such as FGF23-/- and Klotho-/- mice that exhibit altered mineral homeostasis due to a high vitamin D activity showed features of premature aging that include retarded growth, osteoporosis, atherosclerosis, ectopic calcification, immunological deficiency, skin and general organ atrophy, hypogonadism and short lifespan. The phenotype reversed by normalizing vitamin D and/or mineral homeostasis. Thus, hypervitaminosis D due to an increased 1alpha-hydroxylase activity seems to be a cause of the premature aging. In several studies, we have described that a complete or partial lack of vitamin D action (VDR-/- mice and CYP27B1-/-) show almost similar phenotype as FGF23-/- or Klotho-/- mice. VDR mutant mice have growth retardation, osteoporosis, kyphosis, skin thickening and wrinkling, alopecia, ectopic calcification, progressive loss of hearing and balance as well as short lifespan. CYP27B1-/- mice do not show alopecia nor balance deficit, which might be apoVDR-dependent or calcidiol-dependent. The features are typical to premature aging. The phenotype is resistant to a normalization of the mineral homeostasis by a rescue diet containing high calcium and phosphate. Taken together, aging shows a U-shaped dependency on hormonal forms of vitamin D suggesting that there is an optimal concentration of vitamin D in delaying aging phenomena. Our recent study shows that calcidiol is an active hormone. Since serum calcidiol but not calcitriol is fluctuating in physiological situations, calcidiol might determine the biological output of vitamin D action. Due to its high serum concentration and better uptake of calcidiol-DBP by the target cells through the cubilin-megalin system, calcidiol seems to be an important circulating hormone. Therefore, serum calcidiol might be associated with an increased risk of aging-related chronic diseases more directly than calcitriol. Aging and cancer seem to be tightly associated phenomena. Accumulation of damage on DNA and telomeres cause both aging and cancer, moreover the signalling pathways seem to converge on tumour suppressor protein, p53, which seems to be regulated by vitamin D. Also, the insulin-like growth factor signalling pathway (IGF-1, IGFBPs, IGFR) and fibroblast growth factor-23 (FGF-23) regulate growth, aging and cancer. Vitamin D can regulate these signalling pathways, too. Also NF-kappaB and telomerase reverse transcriptase (TERT) might be molecular mechanisms mediating vitamin D action in aging and cancer. Calcidiol serum concentrations show a U-shaped risk of prostate cancer suggesting an optimal serum concentration of 40-60 nmol/L for the lowest cancer risk. Therefore, it is necessary to study several common aging-associated diseases such as osteoporosis, hypertension and diabetes known to be vitamin D-dependent before any recommendations of an optimal serum concentration of calcidiol are given.
最近使用基因改造小鼠的研究，如FGF23基因敲除和Klotho基因敲除小鼠，由于维生素D活性高而表现出矿物质稳态改变，呈现出早衰特征，包括生长迟缓、骨质疏松、动脉粥样硬化、异位钙化、免疫缺陷、皮肤和全身器官萎缩、性腺功能减退和寿命缩短。通过使维生素D和/或矿物质稳态正常化，该表型得以逆转。因此，由于1α-羟化酶活性增加导致的维生素D过多似乎是早衰的一个原因。在多项研究中，我们描述了维生素D作用完全或部分缺乏（VDR基因敲除小鼠和CYP27B1基因敲除小鼠）表现出与FGF23基因敲除或Klotho基因敲除小鼠几乎相似的表型。VDR突变小鼠有生长迟缓、骨质疏松、脊柱后凸、皮肤增厚和皱纹、脱发、异位钙化、听力和平衡逐渐丧失以及寿命缩短等症状。CYP27B1基因敲除小鼠没有脱发和平衡缺陷，这可能依赖于载脂蛋白VDR或骨化二醇。这些特征是早衰的典型表现。该表型对含高钙和高磷救援饮食使矿物质稳态正常化具有抗性。综上所述，衰老显示出对维生素D激素形式呈U形依赖性，表明在延缓衰老现象方面存在最佳维生素D浓度。我们最近的研究表明骨化二醇是一种活性激素。由于血清骨化二醇而非骨化三醇在生理情况下会波动变化，骨化二醇可能决定维生素D作用的生物学效应。由于其血清浓度高且通过cubilin - megalin系统被靶细胞更好地摄取，骨化二醇似乎是一种重要的循环激素。因此，血清骨化二醇可能比骨化三醇更直接地与衰老相关慢性疾病风险增加有关。衰老和癌症似乎是紧密相关的现象。DNA和端粒上的损伤积累会导致衰老和癌症，此外信号通路似乎汇聚于肿瘤抑制蛋白p53，而p53似乎受维生素D调节。同样地，胰岛素样生长因子信号通路（IGF - 1、IGFBPs、IGFR）和成纤维细胞生长因子 - 23（FGF - 23）调节生长、衰老和癌症。维生素D也可以调节这些信号通路。此外，核因子κB和端粒酶逆转录酶（TERT）可能是介导维生素D在衰老和癌症中作用的分子机制。血清骨化二醇浓度显示出前列腺癌呈U形风险，表明血清浓度为40 - 60 nmol/L时癌症风险最低。因此，在给出骨化二醇最佳血清浓度的任何建议之前，有必要研究几种常见的与衰老相关的疾病，如已知依赖维生素D的骨质疏松、高血压和糖尿病。
