VDR
Vitamin D3 receptor (VDR) (1,25-dihydroxyvitamin D3 receptor) (Nuclear receptor subfamily 1 group I member 1) [NR1I1]
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To clarify the regulation of astragalus on the aging BMSCs model and the effect of astragalus on Vitamin D (VD)-FGF23-Klotho axis. siRNA was used to interfere the expression of VDR gene in aging BMSCs. Serum containing astragalus in different concentrations was added to the cultured cells. The expression of osteocalcin and alkaline phosphatase were detected by alizarin red staining and ELISA. Cell vitality was detected by flow cytometry, CCK-8 test, and [i]β[/i]-galactosidase staining. The expression of FGF23, Klotho, CYP27B1, and CYP24A1 was detected by qRT-PCR and western blot. The results showed that after reducing VDR gene expression, the aging BMSCs model showed decreased activity and osteogenic ability, increased expression of FGF23, Klotho and CYP24A1, and decreased expression of CYP27B1. After adding serum-containing astragalus, the activity of cells and the osteogenic ability was increased; the expression levels of FGF23, Klotho and CYP24A1 were decreased, the expression levels of CYP27B1 were increased, and the trend was more obvious with the increase of astragalus concentration. This study confirmed that astragalus could inhibit the aging of BMSCs and improve the osteogenesis ability by regulating the VD-FGF23-Klotho pathway. This study provided a certain research basis for the therapeutic of traditional Chinese medicine (TCM) on primary osteoporosis.
Keywords
- Astragalus
- BMSCs
- VD-FGF23-Klotho axis
- aging
- osteogenesis differentiation
Diabetes is a known age-related disease. Inflammaging has recently been shown to result in diabetic complications. Vitamin D is related to aging in the latest study but little is known about the underlying mechanism. Here, we investigated the effects of 25-Hydroxyvitamin D (25(OH)D ) on inflammaging in diabetic periodontitis, a common chronic inflammatory diabetic complication. A model of Porphyromonas gingivalis-infected db/db mice as experimental type 2 diabetic periodontitis was adopted in the whole study. A range of techniques, including microCT, western blotting, ELISA, histological and immunohistochemical analysis, were carried out in this study. The distinctive senescence-associated secretory phenotype (SASP) in serum was measured by Luminex technology. We found an archetypal inflammaging status occurred in db/db mice. An increased SASP, senescent enhancement, and periodontal destruction were observed in periodontitis-db/db mice. Upon administration with 25(OH)D , periodontitis-db/db mice presented increased levels of serum 25(OH)D , 1α,25-Dihydroxyvitamin D and calcium. Moreover, decreased p16/p21-positive cells, relieved periodontal conditions and ameliorated serum SASP secretion were found in the periodontitis-db/db mice after treatment. Gingival tissue exhibited increased level of VDR and decreased expression of SOCS3, p-STAT3/STAT3, p-STAT5/STAT5, NF-κB and IL-1β, which were consistent with the change of p16/p21 expression. Diabetic periodontitis appeared to develop an inflammaging status resulted in periodontal infection. 25(OH)D could inhibit SASP secretion through reducing SOCS3 expression in experimental diabetic periodontitis, dependently inactivating NF-κB pro-inflammatory signaling. The reversible effect further documented that the inflammaging might be a highly likely contributor in diabetic periodontitis.
Keywords
- 25-Hydroxyvitamin D(3)
- Diabetic periodontitis
- Inflammaging
- SOCS3
- Senescence
- Senescence-associated secretory phenotypes
To determine whether 1,25-dihydroxyvitamin D (1,25(OH) D) can exert an anti-osteoporosis role through anti-aging mechanisms, we analyzed the bone phenotype of mice with 1,25(OH) D deficiency due to deletion of the enzyme, 25-hydroxyvitamin D 1α-hydroxylase, while on a rescue diet. 1,25(OH) D deficiency accelerated age-related bone loss by activating the p16/p19 senescence signaling pathway, inhibiting osteoblastic bone formation, and stimulating osteoclastic bone resorption, osteocyte senescence, and senescence-associated secretory phenotype (SASP). Supplementation of exogenous 1,25(OH) D corrected the osteoporotic phenotype caused by 1,25(OH) D deficiency or natural aging by inhibiting the p16/p19 pathway. The proliferation, osteogenic differentiation, and ectopic bone formation of bone marrow mesenchymal stem cells derived from mice with genetically induced deficiency of the vitamin D receptor (VDR) were significantly reduced by mechanisms including increased oxidative stress, DNA damage, and cellular senescence. We also demonstrated that p16 deletion largely rescued the osteoporotic phenotype caused by 1,25(OH) D deficiency, whereas 1,25(OH) D could up-regulate the enzyme Ezh2 via VDR-mediated transcription thereby enriching H3K27me3 and repressing p16/p19 transcription. Finally, we demonstrated that treatment with 1,25(OH) D improved the osteogenic defects of human BM-MSCs caused by repeated passages by stimulating their proliferation and inhibiting their senescence via the VDR-Ezh2-p16 axis. The results of this study therefore indicate that 1,25(OH) D plays a role in preventing age-related osteoporosis by up-regulating Ezh2 via VDR-mediated transcription, increasing H3K27me3 and repressing p16 transcription, thus promoting the proliferation and osteogenesis of BM-MSCs and inhibiting their senescence, while also stimulating osteoblastic bone formation, and inhibiting osteocyte senescence, SASP, and osteoclastic bone resorption.
MeSH Terms
- 25-Hydroxyvitamin D3 1-alpha-Hydroxylase
- Aging
- Animals
- Bone and Bones
- Cells, Cultured
- Cyclin-Dependent Kinase Inhibitor p16
- Cyclin-Dependent Kinase Inhibitor p19
- DNA Damage
- Enhancer of Zeste Homolog 2 Protein
- Female
- Histones
- Male
- Mesenchymal Stem Cells
- Mice
- Mice, Knockout
- Osteocytes
- Osteogenesis
- Osteoporosis
- Oxidative Stress
- Receptors, Calcitriol
- Vitamin D
Keywords
- Ezh2
- Vitamin D
- cellular senescence
- osteogenesis
- osteoporosis
- p16
Non-alcoholic fatty liver disease (NAFLD) refers to an accumulation of excess fat in liver due to causes other than alcohol use. The relationship between vitamin D (VD) and NAFLD has been previously studied. Therefore, we aimed to explore the mechanism involved active VD regulating the progression of NAFLD by inhibiting cell senescence and to provide a potential approach for further nutritional treatment of NAFLD. Following the induction with high-fat diet and intraperitoneal injection of corn oil, the successfully established NAFLD rat models were treated with 1,25(OH) D at 1μg/kg, 5μg/kg or 10μg/kg. Meanwhile, the levels of factors related to oxidative stress, cell senescence, the p53-p21 signaling pathway and inflammation in liver were determined. Then, cell senescence was also measured by using senescence-associated β-galactosidase (SAβ-gal) staining. It was also found that active VD increased the concentration of VD in serum and VDR in liver of NAFLD rats, and alleviated hepatic fibrosis. Besides, treatment of 1,25(OH) D at 1μg/kg, 5μg/kg or 10μg/kg reduced oxidative stress and inflammation, inhibited the p53-p21 signaling pathway and consequent cell senescence. Furthermore, treatment of 1,25(OH) D at a dosage of 5μg/kg made the most impact on these factors. Collectively, the evidences from this study demonstrated that active VD could alleviate the development of NAFLD through blocking the p53-p21 signaling pathway, which provided a novel nutritional therapeutic insight for NAFLD.
Keywords
- Active vitamin D
- Cell senescence
- Non-alcoholic fatty liver disease
- Oxidative stress
- P53-p21 signaling pathway
- Vitamin D receptor
The age-associated imbalances between proliferation and apoptosis lead to impaired spermatogenesis and infertility. The age-associated decline in vitamin D3 levels has been reported and suggested the anti-aging potential of vitamin D3. However, the age-associated decline levels of vitamin D3 has not been studied in relation to the testicular activity. Thus, we investigated the effect of vitamin D3 on the expression of testicular proliferation markers, apoptotic markers, antioxidants system and oxidative stress in a D-gal-induced aged rat model. The present study investigated the levels of vitamin D3 and AGE in serum and testes along with the expression of the AGE-receptor (AGER) in the testis. Vitamin D3 treatment significantly increases cell proliferation and decreases apoptosis in a D-gal-induced aged rat testis. Furthermore, vitamin D3 significantly decreases oxidative stress in aged rat testis by improving the antioxidant defense systems. The expression of AGER was down-regulated by vitamin D3 treatment in aged testis. The circulating and intra-testicular AGE was higher in aged groups, however, only circulating vitamin D3 levels decreased in aged groups. The immunolocalization of VDR showed increased immunostaining in the testis by vitamin D3 treatment. Thus, it can be concluded that vitamin D3 delays testicular senescence by regulating proliferation and apoptosis.
MeSH Terms
- Aging
- Animals
- Antioxidants
- Apoptosis
- Cell Proliferation
- Cholecalciferol
- Down-Regulation
- Galactose
- Male
- Oxidative Stress
- Rats
- Spermatogenesis
- Testis
Accumulating evidence shows that genetic polymorphism of the vitamin D receptor (VDR) gene is associated with intervertebral disc degeneration (IDD), implying that VDR may be involved in the pathogenesis of IDD. However, the exact relationship between VDR and IDD remains unknown. The aim of this study was to investigate the age-dependent expression of VDR in rat intervertebral discs and to determine the effect of VDR on oxidative stress-induced cell apoptosis of the annulus fibrosus (AF) and the underlying mechanism. Sprague-Dawley rats were subjected to magnetic resonance imaging (MRI) and CT scans at young (2-3 months), adult (6-7 months), and old (14-15 months) ages. The images revealed age-related degeneration of the lumbar intervertebral discs and endplates. Immunohistochemistry demonstrated positive expression of VDR in the AF. The expression level of VDR in aged rats was significantly reduced compared with that in the young and adult animals and exhibited a negative correlation to IDD severity. Western blot analysis further demonstrated that the amount of VDR protein was significantly decreased in severe degenerative discs. AF cells were also isolated from young rat lumbar discs and subjected to different concentrations of hydrogen peroxide (H O ) for various amounts of time. The results revealed that H O inhibited the viability of AF cells and induced mitochondrial pathway apoptosis. However, pretreatment of AF cells with 10 and 10 M 1,25-dihydroxyvitamin D3 [1,25(OH) D ] effectively increased cell viability, increased mitochondrial membrane potential, decreased the level of reactive oxygen species, increased mitochondrial ATP content, reserved the activity of key enzymes in the oxidative respiratory chain, and thus protected the mitochondria from H O -induced damage. Whereas, siRNA knock-down of VDR abolished the protective effects of 1,25(OH) D . Moreover, 1,25(OH) D inhibited H O -induced autophagy of AF cells through inhibition of the mTOR/p70S6K signal pathway. Our study demonstrated that decreased expression of VDR may play a role in age-related intervertebral disc degeneration in rats and that activation of VDR ameliorates oxidative stress-induced apoptosis in AF cells by preserving mitochondrial functions.
MeSH Terms
- Aging
- Animals
- Apoptosis
- Cells, Cultured
- Hydrogen Peroxide
- Intervertebral Disc
- Intervertebral Disc Degeneration
- Male
- Oxidative Stress
- Rats
- Rats, Sprague-Dawley
- Receptors, Calcitriol
Keywords
- Annulus fibrosus
- Apoptosis
- Intervertebral disc degeneration
- Oxidative stress
- Vitamin D receptor
- mTOR/p70S6K signal pathway
In this study, we investigated the relationship between sarcopenia (evaluated in term of fibers atrophy), vitamin d receptor protein expression and [i]TaqI/Cdx2/FokI[/i] VDR genotypes in an Italian cohort of osteoporosis(n=44) and osteoarthritis (n=55) patients. Muscle biopsies were fixed and investigated by both immunohistochemistry (vitamin d receptor expression) and transmission electron microscopy (satellite stem cells niches). Vitamin d receptor polymorphisms were studied on DNA extracted from muscle paraffin sections. For the first time, we reported that aging differently affects the VDR activation in OA and OP patients. In particular, while in OP patients we observed a significant reduction of VDR positive myonuclei with age, no "age effect" was observed in OA patients. The frequent activation of VDR could explain the lower number of atrophic fiber that we observed in OA patients respect to OP. From genetic point of view, we showed a putative association among polymorphisms [i]FokI[/i] and [i]Cdx2[/i] of VDR gene, vitamin d receptor activation and the occurrence of sarcopenia. Altogether these data open new prospective for the prevention and cure of age-related muscle disorders.
Keywords
- Vitamin d receptor
- aging
- osteoarthritis
- osteoporosis
- polymorphisms
- sarcopenia
Protective roles have been proposed for vitamin D in prostate cancer, which has the advanced age as the major risk factor. However, little is known about the expression of the vitamin D receptor (VDR) in the aging prostate and its association with the development of epithelial lesions that affect tissue homeostasis and may precede prostate tumors. VDR expression in the prostatic complex of young adults to senile Wistar rats, a natural model to study age-related prostatic disorders, was evaluated by immunohistochemical, Western blotting, and image-assisted analyzes. Results were correlated with the plasma levels of vitamin D and testosterone, the occurrence of punctual histopathological changes in the aging prostate, and the expression of retinoid X receptors (RXR). VDR was widely distributed in the prostatic complex at all ages analyzed, with the highest immunoexpression found in basal epithelial cells. As the animals aged, VDR levels increased, except in punctual areas with intraepithelial proliferation, metaplasia, or proliferative inflammatory atrophy, which had reduced expression of this receptor concomitantly with increased cell proliferation. Interestingly, RXR expression in the aging prostate was similar to that found for its partner VDR, indicating that components of the VDR/RXR complex required for vitamin D signaling are affected in aging-related prostatic lesions. Moreover, plasma vitamin D levels declined at the same ages when prostatic alterations appeared. Although circulating levels of testosterone also decreased with aging, the changes observed in the components of the vitamin D system were not correlated with androgens. Our data indicate that the aging prostate suffers from an imbalance on the intricate mechanism of tissue regulation by the vitamin D responsive system. We argue that the status of VDR expression might be determinant for the development of histopathological alterations in the aging prostate, which include premalignant lesions.
MeSH Terms
- Age Factors
- Animals
- Male
- Prostatic Neoplasms
- Rats
- Rats, Wistar
- Receptors, Calcitriol
- Testosterone
- Vitamin D
Keywords
- aging
- prostate
- prostate lesions
- vitamin D receptor
- vitamin D signaling
Diabetic nephropathy (DN) is a major cause of end-stage renal disease and proteinuria is one of the most prominent clinical manifestations. The expression of Vitamin D receptor (VDR) in patients with chronic kidney diseases was decreased, while VDR agonists could partially alleviate the proteinuria of DN in animal models. The present study was designed to determine the expression of VDR in renal tissues and its relationship with proteinuria the diabetic model db/db mice. The regulation effects of VDR on the Wnt signaling pathway were analyzed using RNA interference and VDR agonist paricalcitol. With the increase in age of the db/db mice, the VDR protein and mRNA levels in renal tissues were decreased, proteinuria increased, and the protein and mRNA levels of GSK-3β of and β-catenin increased. Paricalcitol treatment resulted in the up-regulation of VDR and down-regulation of GSK-3β and β-catenin, indicating that VDR had a regulatory effect on the Wnt signaling pathway. VDR activation could reduce proteinuria of DN mice and alleviate high-glucose-induced injury of kidneys and podocytes by regulating the key molecules of Wnt signaling pathway.
MeSH Terms
- Aging
- Animals
- Cells, Cultured
- Diabetic Nephropathies
- Down-Regulation
- Ergocalciferols
- Glucose
- Glycogen Synthase Kinase 3 beta
- Kidney
- Male
- Mice
- Mice, Inbred C57BL
- Podocytes
- Proteinuria
- RNA Interference
- Receptors, Calcitriol
- Up-Regulation
- Wnt Signaling Pathway
- beta Catenin
Keywords
- Diabetic nephropathy
- Paricalcitol
- Podocytes
- Proteinuria
- Vitamin D receptor
- Wnt signaling pathway
1,25(OH) D (vitamin D) is well-recognized as a neurosteroid that modulates multiple brain functions. A growing body of evidence indicates that vitamin D plays a pivotal role in brain development, neurotransmission, neuroprotection and immunomodulation. However, the precise molecular mechanisms by which vitamin D exerts these functions in the brain are still unclear. Vitamin D signalling occurs via the vitamin D receptor (VDR), a zinc-finger protein in the nuclear receptor superfamily. Like other nuclear steroids, vitamin D has both genomic and non-genomic actions. The transcriptional activity of vitamin D occurs via the nuclear VDR. Its faster, non-genomic actions can occur when the VDR is distributed outside the nucleus. The VDR is present in the developing and adult brain where it mediates the effects of vitamin D on brain development and function. The purpose of this review is to summarise the in vitro and in vivo work that has been conducted to characterise the genomic and non-genomic actions of vitamin D in the brain. Additionally we link these processes to functional neurochemical and behavioural outcomes. Elucidation of the precise molecular mechanisms underpinning vitamin D signalling in the brain may prove useful in understanding the role this steroid plays in brain ontogeny and function.
MeSH Terms
- Aging
- Animals
- Brain
- Calcium
- Humans
- Neurogenesis
- Neuroprotection
- Receptors, Calcitriol
- Vitamin D
- Vitamin D Deficiency
Keywords
- Brain
- Genomic and non-genomic action
- VDR
- Vitamin D
This study aimed to discover genetic variants in the entire 101 kB vitamin D receptor (VDR) gene for vitamin D deficiency in a group of postmenopausal Filipino women using targeted next generation sequencing (TNGS) approach in a case-control study design. A total of 50 women with and without osteoporotic fracture seen at the Philippine Orthopedic Center were included. Blood samples were collected for determination of serum vitamin D, calcium, phosphorus, glucose, blood urea nitrogen, creatinine, aspartate aminotransferase, alanine aminotransferase and as primary source for targeted VDR gene sequencing using the Ion Torrent Personal Genome Machine. The variant calling was based on the GATK best practice workflow and annotated using Annovar tool. A total of 1496 unique variants in the whole 101-kb VDR gene were identified. Novel sequence variations not registered in the dbSNP database were found among cases and controls at a rate of 23.1% and 16.6% of total discovered variants, respectively. One disease-associated enhancer showed statistically significant association to low serum 25-hydroxy vitamin D levels (Pearson chi-square P-value=0.009). The transcription factor binding site prediction program PROMO predicted the disruption of three transcription factor binding sites in this enhancer region. These findings show the power of TNGS in identifying sequence variations in a very large gene and the surprising results obtained in this study greatly expand the catalog of known VDR sequence variants that may represent an important clue in the emergence of vitamin D deficiency. Such information will also provide the additional guidance necessary toward a personalized nutritional advice to reach sufficient vitamin D status.
MeSH Terms
- 25-Hydroxyvitamin D 2
- Aged
- Aging
- Calcifediol
- Case-Control Studies
- Computational Biology
- Female
- Genetic Association Studies
- Genetic Predisposition to Disease
- High-Throughput Nucleotide Sequencing
- Humans
- Incidence
- Middle Aged
- Osteoporosis, Postmenopausal
- Osteoporotic Fractures
- Philippines
- Pilot Projects
- Polymorphism, Single Nucleotide
- Receptors, Calcitriol
- Risk Factors
- Vitamin D Deficiency
- Vitamin D Response Element
Keywords
- Filipino women
- Fragility fracture
- Next generation sequencing
- Vitamin D
- Vitamin D receptor gene
Ventilation heterogeneity is impossible to detect with spirometry. Alternatively, pulmonary ventilation can be imaged three-dimensionally using inhaled Xe magnetic resonance imaging (MRI). To date, such images have been quantified primarily based on ventilation defects. Here, we introduce a robust means to transform Xe MRI scans such that the underlying ventilation distribution and its heterogeneity can be quantified. Quantitative Xe ventilation MRI was conducted in 12 younger (24.7 ± 5.2 years) and 10 older (62.2 ± 7.2 years) healthy individuals, as well as in 9 younger (25.9 ± 6.4 yrs) and 10 older (63.2 ± 6.1 years) asthmatics. The younger healthy population was used to establish a reference ventilation distribution and thresholds for six intensity bins. These bins were used to display and quantify the ventilation defect region (VDR), the low ventilation region (LVR), and the high ventilation region (HVR). The ventilation distribution in young subjects was roughly Gaussian with a mean and standard deviation of 0.52 ± 0.18, resulting in VDR = 2.1 ± 1.3%, LVR = 15.6 ± 5.4%, and HVR = 17.4 ± 3.1%. Older healthy volunteers exhibited a significantly right-skewed distribution (0.46 ± 0.20, P = 0.034), resulting in significantly increased VDR (7.0 ± 4.8%, P = 0.008) and LVR (24.5 ± 11.5%, P = 0.025). In the asthmatics, VDR and LVR increased in the older population, and HVR was significantly reduced (13.5 ± 4.6% vs 18.9 ± 4.5%, P = 0.009). Quantitative Xe MRI also revealed altered ventilation heterogeneity in response to albuterol in two asthmatics with normal spirometry. Quantitative Xe MRI provides a robust and objective means to display and quantify the pulmonary ventilation distribution, even in subjects who have airway function impairment not appreciated by spirometry.
MeSH Terms
- Adult
- Albuterol
- Asthma
- Bronchodilator Agents
- Female
- Healthy Volunteers
- Humans
- Lung
- Magnetic Resonance Imaging
- Male
- Middle Aged
- Pulmonary Ventilation
- Respiration
- Spirometry
- Xenon Isotopes
- Young Adult
Keywords
- Asthma
- aging
- albuterol
Cumulative exposure to lead is associated with cardiovascular outcomes. Polymorphisms in the δ-aminolevulinic acid dehydratase (ALAD), hemochromatosis (HFE), heme oxygenase-1 (HMOX1), vitamin D receptor (VDR), glutathione S-transferase (GST) supergene family (GSTP1, GSTT1, GSTM1), apolipoprotein E (APOE),angiotensin II receptor-1 (AGTR1) and angiotensinogen (AGT) genes, are believed to alter toxicokinetics and/or toxicodynamics of lead. We assessed possible effect modification by genetic polymorphisms in ALAD, HFE, HMOX1, VDR, GSTP1, GSTT1, GSTM1, APOE, AGTR1 and AGT individually and as the genetic risk score (GRS) on the association between cumulative lead exposure and incident coronary heart disease (CHD) events. We used K-shell-X-ray fluorescence to measure bone lead levels. GRS was calculated on the basis of 22 lead-related loci. We constructed Cox proportional hazard models to compute adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for incident CHD. We applied inverse probability weighting to account for potential selection bias due to recruitment into the bone lead sub-study. Significant effect modification was found by VDR, HMOX1, GSTP1, APOE, and AGT genetic polymorphisms when evaluated individually. Further, the bone lead-CHD associations became larger as GRS increases. After adjusting for potential confounders, a HR of CHD was 2.27 (95%CI: 1.50-3.42) with 2-fold increase in patella lead levels, among participants in the top tertile of GRS. We also detected an increasing trend in HRs across tertiles of GRS (p-trend = 0.0063). Our findings suggest that lead-related loci as a whole may play an important role in susceptibility to lead-related CHD risk. These findings need to be validated in a separate cohort containing bone lead, lead-related genetic loci and incident CHD data.
MeSH Terms
- Aged
- Aging
- Bone and Bones
- Coronary Disease
- Environmental Exposure
- Female
- Genetic Predisposition to Disease
- Humans
- Lead
- Male
- Middle Aged
- Polymorphism, Genetic
This study aimed to evaluate the relationship between the cardiometabolic profile, vitamin D status and BsmI polymorphism of the VDR gene in non-institutionalized elderly subjects. A cross-sectional study was conducted with a random and representative sample of 142 elderly subjects selected by cluster and recruited from a municipal assistance program. Clinical, nutritional, biochemical and inflammatory profiles, oxidative stress and genotyping for the BsmI polymorphism were evaluated. Participants had mean age of 69.9 (7.0) years, BMI of 28.3 (4.4) kg/m(2) and 80.3% were women. The prevalence of a 25-hydroxyvitamin D [25(OH)D] status <75nmol/L was 40.8%. A vitamin D level<75nmol/L was found to be associated with gender and fish consumption. The INSUF/DEF group [25(OH)D<75nmol/L] showed higher fasting blood glucose MDA values when compared to the SUF group [25(OH)D≥75nmol/L]; this relationship was maintained only for women in the analysis by sex. The BsmI polymorphism showed allelic frequencies in the SUF group of B 49% and b 51% and in the INSUF/DEF group B 38% and b 62%. The frequency of bb homozygosity was significantly associated with lower serum total cholesterol and LDL cholesterol concentrations compared to Bb, both in the general population and in the SUF group. Among individuals with bb, the INSUF/DEF group showed higher levels of triglycerides and VLDL cholesterol. Blood glucose levels and oxidative stress were increased in elderly subjects with 25(OH)D<75nmol/L. The presence of the bb genotype with adequate vitamin D status resulted in lower total and LDL cholesterol, but the benefit was lost when vitamin D insufficiency or deficiency was present.
MeSH Terms
- Aged
- Aging
- Blood Glucose
- Brazil
- Cholesterol, LDL
- Cross-Sectional Studies
- Female
- Gene Frequency
- Homozygote
- Humans
- Hyperglycemia
- Male
- Malondialdehyde
- Middle Aged
- Oxidative Stress
- Polymorphism, Genetic
- Receptors, Calcitriol
- Vitamin D
- Vitamin D Deficiency
Keywords
- Elderly
- Hyperglycemia
- Oxidative stress
- Polymorphism
- Vitamin D
Vitamin D is a seco-sterol produced endogenously in the skin or obtained from certain foods. It exerts its action through binding to intracellular vitamin D receptor (VDR). Lately, the role of vitamin D has been revised regarding its potential advantage on delaying the process of aging. The aim of this study was to assess the contribution of VDR gene polymorphisms in healthy aging and longevity. We evaluated the frequency of four polymorphisms of the VDR gene (FokI, BsmI, ApaI, and TaqI) in centenarians (102 subjects, mean age: 102.3 ± 0.3 years), compared to septuagenarians (163 subjects, mean age: 73.0 ± 0.6 years) and we analyzed a variety of pathophysiologically relevant functions in centenarians. BsmI and ApaI provided a significant association with longevity: there was a highly significant difference in the frequency of BsmI genotypes (p = 0.037), ApaI genotypes (p = 0.022), and ApaI alleles (p = 0.050) in centenarians versus septuagenarians. Furthermore, we found a significant correlation of all the VDR gene polymorphisms in centenarians with some measured variables such as hand grip strength, body mass index, blood pressure, HDL cholesterol, and mini-mental state examination. We also found a correlation with the prevalence of medical history of hypertension, acute myocardial infarction, angina, venous insufficiency, dementia, chronic obstructive pulmonary disease, and arthrosis. In conclusion, this study proposes a new scenario in which the variability of the VDR gene is relevant in the aging process and emphasizes the role of VDR genetic background in determining healthy aging.
MeSH Terms
- Age Factors
- Aged
- Aged, 80 and over
- Aging
- Alleles
- Blood Pressure
- Body Mass Index
- Female
- Gene Frequency
- Genotype
- Hand Strength
- Humans
- Male
- Neuropsychological Tests
- Polymorphism, Single Nucleotide
- Receptors, Calcitriol
Keywords
- Biology of aging
- Centenarian
- Co-morbidity
- Longevity
Diabetes mellitus (DM) is a metabolic disorder associated with serious liver complications. As a metabolic chronic disease, DM is very common in the elderly. Recent studies suggest ameliorating effects of vitamin D on metabolic and oxidative stress in the liver tissue in an experimental model of DM. The aim of this study was to investigate the expression of vitamin D receptors (VDRs) and 1α-hydroxylase, the key enzyme for the production of active vitamin D form (calcitriol) in the liver during long-term diabetes mellitus type 1 (DM1) in aging rats. We performed immunohistochemical analysis of liver expression of 1α-hydroxylase and VDRs during aging in long-term streptozotocin-induced DM1. 1α-Hydroxylase was identified in the monocyte/macrophage system of the liver. In addition to the nuclear expression, we also observed the expression of VDR in membranes of lipid droplets within hepatocytes. Aging and long-term DM1 resulted in significant increases in the number of 1α-hydroxylase immunoreactive cells, as well as the percentage of strongly positive VDR hepatocytes. In conclusion, the liver has the capacity for active vitamin D synthesis in its monocyte/macrophage system that is substantially increased in aging and long-term diabetes mellitus. These conditions are also characterized by significant increases in vitamin D receptor expression in hepatocytes. The present study suggests that VDR signaling system could be a potential target in prevention of liver complications caused by diabetes and aging.
MeSH Terms
- 25-Hydroxyvitamin D3 1-alpha-Hydroxylase
- Aging
- Animals
- Diabetes Mellitus
- Disease Models, Animal
- Hepatocytes
- Liver
- Male
- Rats
- Rats, Sprague-Dawley
- Receptors, Calcitriol
- Signal Transduction
Keywords
- 1α-Hydroxylase
- Aging
- Diabetes mellitus
- Liver
- VDR
Health during aging can be improved by genetic, dietary and pharmacological interventions. Many of these increase resistance to various stressors, including xenobiotics. Up-regulation of xenobiotic detoxification genes is a transcriptomic signature shared by long-lived nematodes, flies and mice, suggesting that protection of cells from toxicity of xenobiotics may contribute to longevity. Expression of genes involved in xenobiotic detoxification is controlled by evolutionarily conserved transcriptional regulators. Three closely related subgroups of nuclear hormone receptors (NHRs) have a major role, and these include DAF-12 and NHR-8 in C. elegans, DHR96 in Drosophila and FXR, LXRs, PXR, CAR and VDR in mammals. In the invertebrates, these NHRs have been experimentally demonstrated to play a role in extension of lifespan by genetic and environmental interventions. NHRs represent critical hubs in that they regulate detoxification enzymes with broad substrate specificities, metabolizing both endo- and xeno-biotics. They also modulate homeostasis of steroid hormones and other endogenous cholesterol derivatives and lipid metabolism, and these roles, as well as xenobiotic detoxification, may contribute to the effects of NHRs on lifespan and health during aging, an issue that is being increasingly addressed in C. elegans and Drosophila. Disentangling the contribution of these processes to longevity will require more precise understanding of the molecular mechanisms by which each is effected, including identification of ligands and co-regulators of NHRs, patterns of tissue-specificity and mechanisms of interaction between tissues. The roles of vertebrate NHRs in determination of health during aging and lifespan have yet to be investigated.
MeSH Terms
- Aging
- Animals
- Biotransformation
- Cell Nucleus
- Gene Expression Regulation, Developmental
- Humans
- Ligands
- Models, Biological
- Nuclear Envelope
- Orphan Nuclear Receptors
- Protein Conformation
- Protein Isoforms
- Receptors, Cytoplasmic and Nuclear
- Sterols
- Toxicokinetics
- Xenobiotics
Keywords
- DAF-12
- DHR96
- NHR-8
- longevity
- steroid hormone
- stress resistance
- xenobiotic detoxification
Vitamin D deficiency is associated with muscle weakness, pain, and atrophy. Serum vitamin D predicts muscle strength and age-related muscle changes. However, precise mechanisms by which vitamin D affects skeletal muscle are unclear. To address this question, this study characterizes the muscle phenotype and gene expression of mice with deletion of vitamin D receptor (VDRKO) or diet-induced vitamin D deficiency. VDRKO and vitamin D-deficient mice had significantly weaker grip strength than their controls. Weakness progressed with age and duration of vitamin D deficiency, respectively. Histological assessment showed that VDRKO mice had muscle fibers that were significantly smaller in size and displayed hyper-nuclearity. Real-time PCR also indicated muscle developmental changes in VDRKO mice with dysregulation of myogenic regulatory factors (MRFs) and increased myostatin in quadriceps muscle (>2-fold). Vitamin D-deficient mice also showed increases in myostatin and the atrophy marker E3-ubiqutin ligase MuRF1. As a potential explanation for grip strength weakness, both groups of mice had down-regulation of genes encoding calcium-handling and sarco-endoplasmic reticulum calcium transport ATPase (Serca) channels. This is the first report of reduced strength, morphological, and gene expression changes in VDRKO and vitamin D-deficient mice where confounding by calcium, magnesium, and phosphate have been excluded by direct testing. Although suggested in earlier in vitro work, this study is the first to report an in vivo association between vitamin D, myostatin, and the regulation of muscle mass. These findings support a direct role for vitamin D in muscle function and corroborate earlier work on the presence of VDR in this tissue.
MeSH Terms
- Animals
- Disease Models, Animal
- Hand Strength
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Muscle Fibers, Skeletal
- Myostatin
- Real-Time Polymerase Chain Reaction
- Receptors, Calcitriol
- Vitamin D Deficiency
Keywords
- Aging
- Development
- Skeletal muscle
- Strength
- Vitamin D
- Vitamin D receptor
The active form of vitamin D, 1,25(OH)2D, is a crucial regulator of calcium homeostasis, especially through stimulation of intestinal calcium transport. Lack of intestinal vitamin D receptor (VDR) signaling does however not result in hypocalcemia, because the increased 1,25(OH)2D levels stimulate calcium handling in extra-intestinal tissues. Systemic VDR deficiency, on the other hand, results in hypocalcemia because calcium handling is impaired not only in the intestine, but also in kidney and bone. It remains however unclear whether low intestinal VDR activity, as observed during aging, is sufficient for intestinal calcium transport and for mineral and bone homeostasis. To this end, we generated mice that expressed the Vdr exclusively in the gut, but at reduced levels. We found that ~15% of intestinal VDR expression greatly prevented the Vdr null phenotype in young-adult mice, including the severe hypocalcemia. Serum calcium levels were, however, in the low-normal range, which may be due to the suboptimal intestinal calcium absorption, renal calcium loss, insufficient increase in bone resorption and normal calcium incorporation in the bone matrix. In conclusion, our results indicate that low intestinal VDR levels improve intestinal calcium absorption compared to Vdr null mice, but also show that 1,25(OH)2D-mediated fine-tuning of renal calcium reabsorption and bone mineralization and resorption is required to maintain fully normal serum calcium levels.
MeSH Terms
- Aging
- Animals
- Biological Transport, Active
- Bone Remodeling
- Calcitriol
- Calcium
- Calcium, Dietary
- Cells, Cultured
- Gene Expression
- Homeostasis
- Intestinal Absorption
- Intestinal Mucosa
- Kidney
- Mice
- Mice, Knockout
- Organ Specificity
- Osteoblasts
- Parathyroid Hormone
- RANK Ligand
- Receptors, Calcitriol
Keywords
- Bone
- Calcium homeostasis
- Intestine
- Kidney
- Vitamin D
Circulating microRNAs (miRNAs) are linked to disease and are potential biomarkers. Vitamin D may modulate miRNA profiles, and vitamin D status has been linked to risk of disease, including cardiovascular disease and cancers. We hypothesise that genotypic variance influences these relationships. We examined the correlations between vitamin D intake and circulating levels of the miRNAs let-7a/b, and the involvement of two common vitamin D receptor (VDR) polymorphisms, BsmI and ApaI. Two hundred participants completed food frequency and supplement questionnaires, and were assayed for circulating let-7b expression by qPCR. Polymorphisms were detected using restriction fragment length polymorphism-PCR. let-7b expression negatively correlated with vitamin D intake (rs=-0.20, p=0.005). The magnitude and direction of correlation were maintained in the presence of the BsmI restriction site (rs=-0.27, p=0.0005). However, in the absence of BsmI restriction site, the direction of the correlation was reversed (rs= 0.319, p=0.0497). These correlations were significantly different (z-score=2.64, p=0.0085). The correlation between vitamin D intake and let-7a was only significant in those without the ApaI restriction site. The correlation between vitamin D intake and let-7a/b expression in this cohort varies with VDR genotype. This study highlights the importance of considering underlying genotypic variance in miRNA expression studies and in nutritional epigenetics generally.
MeSH Terms
- Aged
- Aged, 80 and over
- Aging
- Cohort Studies
- Female
- Gene Expression
- Genotype
- Humans
- Male
- MicroRNAs
- Nutrigenomics
- Polymerase Chain Reaction
- Polymorphism, Restriction Fragment Length
- Receptors, Calcitriol
- Vitamin D
Beyond the established effects of muscle loading on bone, a complex network of hormones and growth factors integrates these adjacent tissues. One such hormone, vitamin D, exerts broad-ranging effects in muscle and bone calcium handling, differentiation and development. Vitamin D also modulates muscle and bone-derived hormones, potentially facilitating cross-talk between these tissues. In the clinical setting, vitamin D deficiency or mutations of the vitamin D receptor result in generalized atrophy of muscle and bone, suggesting coordinated effects of vitamin D at these sites. In this review, we discuss emerging evidence that vitamin D exerts specific effects throughout the life of the musculoskeletal system - in development, aging and injury. From this holistic viewpoint, we offer new insights into an old debate: whether vitamin D's effects in the musculoskeletal system are direct via local VDR signals or indirect via its systemic effects in calcium and phosphate homeostasis.
MeSH Terms
- Aging
- Bone Development
- Bone and Bones
- Calcium
- Humans
- Muscle, Skeletal
- Phosphates
- Receptors, Calcitriol
- Vitamin D
Keywords
- Bone
- Muscle
- Osteoporosis
- Sarcopenia
- Vitamin D
- Vitamin D receptor
Vitamin D co-regulates the synthesis of sex hormones in part by interaction with its nuclear receptor. The aim of this study was to determine whether there is an association of vitamin D concentration vs the level of sex hormones in elderly Polish individuals with different genotypes of the vitamin D receptor (VDR) gene. Rs10735810, rs1544410, rs7975232, and rs731236 polymorphisms of VDR, the serum sex hormone level, free estrogen index (FEI) and free androgen index (FAI) as well as vitamin D, were evaluated in 766 persons (362 women and 404 men) selected from 5695 Polish population, aged 65-90years from the PolSenior survey. We observed that women with GG (rs731236), TT (rs7975232), BB (rs1544410) and FF (rs10735810) genotypes were characterized by a significant correlation between vitamin D vs testosterone concentration and FAI value. We found a significant correlation between testosterone level and FAI vs vitamin D concentration in men with heterozygote AG in the rs731236 polymorphism and in the GG (rs7975232), the BB (rs1544410), and the Ff (rs10735810) genotypes. In elderly selected Polish population with different genotypes of VDR polymorphisms, a statistically significant relationship between vitamin D concentration vs testosterone level was observed.
MeSH Terms
- Aged
- Aged, 80 and over
- Estrogens
- Female
- Heterozygote
- Humans
- Male
- Poland
- Polymorphism, Genetic
- Receptors, Calcitriol
- Testosterone
- Vitamin D
Keywords
- Aging
- FAI
- Testosterone level
- VDR polymorphism
- Vitamin D level
Although the association between lead and cardiovascular disease is well established, potential mechanisms are still poorly understood. Calcium metabolism plays a role in lead toxicity and thus, vitamin D receptor (VDR) polymorphisms have been suggested to modulate the association between lead and health outcomes. We investigated effect modification by VDR genetic polymorphisms in the association between cumulative lead exposure and pulse pressure, a marker of arterial stiffness. We examined 727 participants (3,100 observations from follow-ups from 1991 to 2011) from the Normative Aging Study (NAS), a longitudinal study of aging. Tibia and patella bone lead levels were measured using K-x-ray fluorescence. Four single nucleotide polymorphisms (SNPs) in the VDR gene, Bsm1, Taq1, Apa1, and Fok1, were genotyped. Linear mixed effects models with random intercepts were implemented to take into account repeated measurements. Adjusting for potential confounders, pulse pressure was 2.5 mmHg (95% CI: 0.4-4.7) and 1.9 mmHg (95% CI: 0.1-3.8) greater per interquartile range (IQR) increase in tibia lead (15 μg/g) and patella lead (20 μg/g), respectively, in those with at least one minor frequency allele in Bsm1 compared with those with major frequency allele homozygotes. The observed interaction effect between bone lead and the Bsm1 genotype persists over time during the follow-up. Similar results were observed in effect modification by Taq1. This study suggests that subjects with the minor frequency alleles of VDR Bsm1 or Taq1 may be more susceptible to cumulative lead exposure-related elevated pulse pressure.
MeSH Terms
- Adult
- Aged
- Aged, 80 and over
- Aging
- Blood Pressure
- Boston
- Calcium
- Cardiovascular Diseases
- Environmental Exposure
- Female
- Gene Expression Regulation
- Humans
- Lead
- Longitudinal Studies
- Male
- Middle Aged
- Patella
- Polymorphism, Single Nucleotide
- Receptors, Calcitriol
- Tibia
- Vitamin D
- Young Adult
We examined longitudinal associations of vitamin D receptor (VDR) and megalin (LRP2; LDL receptor-related protein-2) gene polymorphisms with central adiposity. We used data from the Baltimore Longitudinal Study of Aging (BLSA), an ongoing prospective open cohort study. Study participants consisted of non-Hispanic white adults residing in Baltimore city, with one or more visits at age ≥50 years, and complete data (n 609-617). Repeated assessments on waist circumference (WC) and waist:hip ratio (WHR) were available. Multiple linear mixed models were used to estimate mid-follow-up age central adiposity level and annual rate of change with cut-points set at the sex-specific 80th percentile. The four binary outcomes were: 'elevated central adiposity' (ECA-WC and ECA-WHR) and 'significant increase in central adiposity' (SICA-WC and SICA-WHR). SNP for VDR (four SNP: (1) rs11568820 (CdX-2:T/C); (2) rs1544410 (BsmI:G/A); (3) rs7975232 (ApaI:A/C); (4) rs731236 (TaqI:G/A)) and Megalin (three SNP: (1) rs3755166:G/A; (2) rs2075252:C/T; (3) rs4668123:C/T) genes were selected. SNP latent classes (SNPLC) and SNP haplotypes (SNPHAP) were created. Multiple logistic regression analyses indicated that, in men, higher ECA-WHR odds were associated with SNPLC Megalin2:rs3755166[-]/rs2075252[TT]/rs4668123[T-] (v. Megalin1:rs3755166[-]/rs2075252[CC]/rs4668123[-]) (OR 2·87; 95 % CI 1·15, 7·12; P = 0·023) and that SNPLC Megalin3:rs3755166[-]/rs2075252[CT]/rs4668123[-] (v. Megalin1) was linked to lower SICA-WC odds (OR 0·48; 95 % CI 0·26, 0·88; P = 0·019) (P > 0·05 for sex × SNPLC). In women, VDR3 SNPHAP (GAA:bAT) was related to lower odds of ECA-WC (OR 0·37; 95 % CI 0·16, 0·87; P = 0·023) (P < 0·05 for sex × SNPHAP), VDR1 SNPHAP (GCA:baT) was associated with greater odds and VDR3 SNPHAP (GAA:bAT) with lower odds of SICA-WC (P > 0·05 for sex × SNPHAP). Vitamin D-related gene polymorphisms were associated with central adiposity status and change. Future mechanistic studies are needed to confirm those polymorphisms' biological significance to central adiposity.
Keywords
- Adults
- BLSA, Baltimore Longitudinal Study of Aging
- Central adiposity
- ECA, elevated central adiposity
- LCA, latent class analysis
- LD, linkage disequilibrium
- Megalin
- SICA, significant increase in central adiposity
- SNP
- SNPHAP, SNP halotype
- SNPLC, SNP latent class
- VDR, vitamin D receptor
- Vitamin D receptor
- WC, waist circumference
- WHR, waist:hip ratio
Muscle mass and strength progressively decrease with age, which results in a condition known as sarcopenia. Sarcopenia would lead to physical disability, poor quality of life, and death. Therefore, much is expected of an effective intervention for sarcopenia. Epidemiologic, clinical, and laboratory evidence suggest an effect of vitamin D on muscle function. However, the precise molecular and cellular mechanisms remain to be elucidated. Recent studies suggest that vitamin D receptor (VDR) might be expressed in muscle fibers and vitamin D signaling via VDR plays a role in the regulation of myoblast proliferation and differentiation. Understanding how vitamin D signaling contributes to myogenesis will provide a valuable insight into an effective nutritional strategy to moderate sarcopenia. Here we will summarize the current knowledge about the effect of vitamin D on skeletal muscle and myogenic cells and discuss the potential for treatment of sarcopenia.
MeSH Terms
- Aging
- Humans
- Muscle Development
- Receptors, Calcitriol
- Sarcopenia
- Signal Transduction
- Vitamin D
Studies examining whether vitamin D supplementation increases muscle mass or muscle-specific vitamin D receptor (VDR) concentration are lacking. Our objective was to determine whether vitamin D₃ 4000 IU/d alters muscle fiber cross-sectional area (FCSA) and intramyonuclear VDR concentration over 4 months. This was a randomized, double-blind, placebo-controlled study in a single center. Participants were 21 mobility-limited women (aged ≥ 65 years) with serum 25-hydroxyvitamin D (25OHD) levels of 22.5 to 60 nmol/L. Baseline and 4-month FCSA and intramyonuclear VDR were measured from vastus lateralis muscle cross-sections probed for muscle fiber type (I/IIa/IIx) and VDR using immunofluorescence. At baseline, mean (±SD) age was 78 ± 5 years; body mass index was 27 ± 5 kg/m², 25OHD was 46.3 ± 9.5 nmol/L, and a short physical performance battery score was 7.95 ± 1.57 out of 12. At 4 months, 25OHD level was 52.5 ± 17.1 (placebo) vs 80.0 ± 11.5 nmol/L (vitamin D [VD]; P < .01), and change in 25OHD level was strongly associated with percent change in intramyonuclear VDR concentration-independent of group (r = 0.87, P < .001). By treatment group, percent change in intramyonuclear VDR concentration was 7.8% ± 18.2% (placebo) vs 29.7% ± 11.7% (VD; P = .03) with a more pronounced group difference in type II vs I fibers. Percent change in total (type I/II) FCSA was -7.4% ± 18.9% (placebo) vs 10.6% ± 20.0% (VD; P = .048). Vitamin D₃ supplementation increased intramyonuclear VDR concentration by 30% and increased muscle fiber size by 10% in older, mobility-limited, vitamin D-insufficient women. Further work is needed to determine whether the observed effect of vitamin D on fiber size is mediated by the VDR and to identify which signaling pathways are involved.
MeSH Terms
- Aged
- Aged, 80 and over
- Aging
- Anatomy, Cross-Sectional
- Calcifediol
- Cholecalciferol
- Cohort Studies
- Dietary Supplements
- Double-Blind Method
- Female
- Geriatric Assessment
- Humans
- Mobility Limitation
- Muscle Development
- Muscle Fibers, Fast-Twitch
- Muscle Fibers, Slow-Twitch
- Muscle Strength
- Pilot Projects
- Quadriceps Muscle
- Receptors, Calcitriol
- Up-Regulation
- Vitamin D Deficiency
{{medline-entry |title=Impact of vitamin D receptor VDR rs2228570 polymorphism in oldest old. |pubmed-url=https://pubmed.ncbi.nlm.nih.gov/24060611 |abstract=Calcitriol, a key player in the regulation of mineral metabolism, influences, directly or by increasing plasma Ca2 and phosphate levels, a multitude of physiological functions, such as bone mineralization, cell proliferation, immune response, carbohydrate metabolism, blood pressure, platelet reactivity, gastric acid secretion, cognitive function and mood. Calcitriol is mainly effective by stimulation of the Vitamin D receptor VDR. The responsiveness of VDR may be affected by gene variants, such as the FokI polymorphism (rs2228570). The GG gene variant is expected to be more active than the GA or AA gene variant. The present study explored the impact of VDR rs2228570 on survival and health of oldest old individuals (> 90 years). 101 individuals > 90 years were examined and genotyped. As a result, the prevalence of GG, GA