Premature aging in vitamin D receptor mutant mice.
Hypervitaminosis vitamin D(3) has been recently implicated in premature aging through the regulation of 1alpha hydroxylase expression by klotho and fibroblast growth factor-23 (Fgf-23). Here we examined whether the lack of hormonal function of vitamin D(3) in mice is linked to aging phenomena. For this, we used vitamin D(3) receptor (VDR) "Tokyo" knockout (KO) mice (fed with a special rescue diet) and analyzed their growth, skin and cerebellar morphology, as well as overall motor performance. We also studied the expression of aging-related genes, such as Fgf-23, nuclear factor kappaB (NF-kappaB), p53, insulin like growth factor 1 (IGF1) and IGF1 receptor (IGF1R), in liver, as well as klotho in liver, kidney and prostate tissues. Overall, VDR KO mice showed several aging related phenotypes, including poorer survival, early alopecia, thickened skin, enlarged sebaceous glands and development of epidermal cysts. There was no difference either in the structure of cerebellum or in the number of Purkinje cells. Unlike the wildtype controls, VDR KO mice lose their ability to swim after 6 months of age. Expression of all the genes was lower in old VDR KO mice, but only NF-kappaB, Fgf-23, p53 and IGF1R were significantly lower. Since the phenotype of aged VDR knockout mice is similar to mouse models with hypervitaminosis D(3), our study suggests that VDR genetic ablation promotes premature aging in mice, and that vitamin D(3) homeostasis regulates physiological aging.
Keisala
Tiina
T
Department of Anatomy, Medical School, University of Tampere, Tampere 33014, Finland. tiina.keisala@uta.fi
Minasyan
Anna
A
Lou
Yan-Ru
YR
Zou
Jing
J
Kalueff
Allan V
AV
Pyykkö
Ilmari
I
Tuohimaa
Pentti
P
D019588:Aging, Premature / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001835:Body Weight; D002531:Cerebellum / Q000166:cytology; D002762:Cholecalciferol / Q000378:metabolism; D005260:Female; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism; D005966:Glucuronidase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism; D000090265:Klotho Proteins; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000378:metabolism; D018167:Receptors, Calcitriol / Q000235:genetics / Q000378:metabolism; D012867:Skin / Q000033:anatomy & histology / Q000378:metabolism / Q000473:pathology; D015996:Survival Rate; D013550:Swimming; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
C000717427:FGF23 protein, human; C000717428:Fgf23 protein, mouse; D016328:NF-kappa B; D018167:Receptors, Calcitriol; D016159:Tumor Suppressor Protein p53; D002762:Cholecalciferol; D005346:Fibroblast Growth Factors; D007334:Insulin-Like Growth Factor I; D000089703:Fibroblast Growth Factor-23; D017526:Receptor, IGF Type 1; D005966:Glucuronidase; D000090265:Klotho Proteins