Редактирование: FGF23

Fibroblast growth factor 23 precursor (FGF-23) (Phosphatonin) (Tumor-derived hypophosphatemia-inducing factor) [Contains: Fibroblast growth factor 23 N-terminal peptide; Fibroblast growth factor 23 C-terminal peptide] [HYPF] [UNQ3027/PRO9828]

==Publications==

{{medline-entry
|title=Phosphate as a Pathogen of Arteriosclerosis and Aging.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33028781
|abstract=During the evolution of skeletons, terrestrial vertebrates acquired strong bones made of calcium-phosphate. By keeping the extracellular fluid in a supersaturated condition regarding calcium and phosphate ions, they created the bone when and where they wanted simply by providing a cue for precipitation. To secure this strategy, they acquired a novel endocrine system to strictly control the extracellular phosphate concentration. In response to phosphate intake, fibroblast growth factor-23 ([[FGF23]]) is secreted from the bone and acts on the kidney through binding to its receptor Klotho to increase urinary phosphate excretion, thereby maintaining phosphate homeostasis. The [[FGF23]]-Klotho endocrine system, when disrupted in mice, results in hyperphosphatemia and vascular calcification. Besides, mice lacking Klotho or [[FGF23]] suffer from complex aging-like phenotypes, which are alleviated by placing them on a low-phosphate diet, indicating that phosphate is primarily responsible for the accelerated aging. Phosphate acquires the ability to induce cell damage and inflammation when precipitated with calcium. In the blood, calcium-phosphate crystals are adsorbed by serum protein fetuin-A and prevented from growing into large precipitates. Consequently, nanoparticles that comprised calcium-phosphate crystals and fetuin-A, termed calciprotein particles (CPPs), are generated and dispersed as colloids. CPPs increase in the blood with an increase in serum phosphate and age. Circulating CPP levels correlate positively with vascular stiffness and chronic non-infectious inflammation, raising the possibility that CPPs may be an endogenous pro-aging factor. Terrestrial vertebrates with the bone made of calcium-phosphate may be destined to age due to calcium-phosphate in the blood.

|keywords=* Aging
* Calciprotein particles (CPPs)
* Fibroblast growth factor-23 (FGF23)
* Inflammation
* Klotho
* Phosphate
* Vascular calcification
|full-text-url=https://sci-hub.do/10.5551/jat.RV17045
}}
{{medline-entry
|title=Plasma Soluble αKlotho, Serum Fibroblast Growth Factor 23, and Mobility Disability in Community-Dwelling Older Adults.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32405607
|abstract=αKlotho is a hormone and co-receptor for fibroblast growth factor 23 ([[FGF23]]), a hormone that downregulates active vitamin D synthesis and promotes phosphate excretion. Low αKlotho and high [[FGF23]] occur in chronic kidney disease (CKD). We aimed to assess the relationships of αKlotho and [[FGF23]] with mobility disability in community-dwelling older adults. We estimated associations of plasma-soluble αKlotho and serum [[FGF23]] concentrations with mobility disability over 6 years. Additional analyses was stratified by CKD. Participants included 2751 adults (25.0% with CKD), aged 71 to 80 years, from the 1998 to 1999 Health, Aging, and Body Composition Study visit. Walking disability and stair climb disability were defined as self-reported "a lot of difficulty" or an inability to walk a quarter mile and climb 10 stairs, respectively. Median (interquartile range [IQR]) serum [[FGF23]] and plasma soluble αKlotho concentrations were 46.6 (36.7, 60.2) pg/mL and 630.4 (478.4, 816.0) pg/mL, respectively. After adjustment, higher αKlotho concentrations were associated with lower walking disability rates (Rate Ratio [RR] highest vs. lowest tertile = 0.74; 95% confidence interval l [CI] = 0.62, 0.89; [i]P[/i] = 0.003). Higher [[FGF23]] concentrations were associated with higher walking disability rates (RR highest vs. lowest tertile = 1.24; 95%CI = 1.03, 1.50; [i]P[/i] = 0.005). Overall, higher αKlotho combined with lower [[FGF23]] was associated with the lowest walking disability rates ([i]P[/i] for interaction = 0.023). Stair climb disability findings were inconsistent. No interactions with CKD were statistically significant ([i]P[/i] for interaction > 0.10). Higher plasma soluble αKlotho and lower serum [[FGF23]] concentrations were associated with lower walking disability rates in community-dwelling older adults, particularly those without CKD.

|keywords=* aging
* chronic kidney disease
* fibroblast growth factor 23
* mobility disability
* αKlotho
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7209777
}}
{{medline-entry
|title=Astragalus improve aging bone marrow mesenchymal stem cells (BMSCs) vitality and osteogenesis through VD-[[FGF23]]-Klotho axis.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32355520
|abstract=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
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7191145
}}
{{medline-entry
|title=Protective effect of Polygonatum sibiricum Polysaccharide on D-galactose-induced aging rats model.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32042011
|abstract=The polysaccharide of Polygonatum sibiricum (PSP)is one of the main active ingredients of Polygonatum Polygonatum in Liliaceae. It has anti-tumor, anti-aging, immune regulation, and anti-oxidative effects. Recent studies have shown that the Klotho gene and fibroblast growth factor-23 (FGF-23) have a common receptor, which is closely related to aging and highly expressed in kidney and meninges. Our study aimed to investigate the anti-aging effect of PSP on D-galactose-induced rats and its mechanism. D-galactose (120 mg Kg ) and PSP (100 mg Kg ) was used to intervene in rats, respectively. Then The changes of indexes of the natural aging-like model rats before and after PSP intervention were observed. We found that PSP could significantly improve the learning and memory abilities of rats and reverse the pathological changes of kidney tissues in rats. At the same time, PSP up-regulated the expression of Klotho mRNA and Klotho protein in the renal cortex, down-regulated the expression of FOXO3a mRNA and p-FOXO3a protein in renal tissue, and inhibited the expression of FGF-23 protein in the femur. Our studies suggest that PSP may play a role by regulating the Klotho-[[FGF23]] endocrine axis, alleviating oxidative stress, and balancing calcium and phosphorus metabolism.
|mesh-terms=* Aging
* Animals
* Calcium
* Dietary Carbohydrates
* Fibroblast Growth Factors
* Galactose
* Glucuronidase
* Male
* Oxidative Stress
* Phosphorus
* Phytochemicals
* Polygonatum
* Polysaccharides
* Protective Agents
* Rats
* Rats, Sprague-Dawley

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7010663
}}
{{medline-entry
|title=[[FGF23]] expression is stimulated in transgenic α-Klotho longevity mouse model.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31801907
|abstract=Observations in transgenic α-Klotho (Kl) mice (KlTg) defined the antiaging role of soluble Klotho (s[[KL]]130). A genetic translocation that elevates s[[KL]] levels in humans is paradoxically associated with increased circulating fibroblast growth factor 23 ([[FGF23]]) levels and the potential of both membrane [[KL]] (m[[KL]]135) and s[[KL]]130 to act as coreceptors for [[FGF23]] activation of fibroblast growth factor receptors (FGFRs). Neither [[FGF23]] expression nor the contributions of [[FGF23]], m[[KL]]135, and s[[KL]]130 codependent and independent functions have been investigated in KlTg mice. In the current study, we examined the effects of Kl overexpression on [[FGF23]] levels and functions in KlTg mice. We found that m[[KL]]135 but not s[[KL]]130 stimulated [[FGF23]] expression in osteoblasts, leading to elevated Fgf23 bone expression and circulating levels in KlTg mice. Elevated [[FGF23]] suppressed 1,25(OH)2D and parathyroid hormone levels but did not cause hypophosphatemic rickets in KlTg mice. KlTg mice developed low aldosterone-associated hypertension but not left ventricular hypertrophy. Mechanistically, we found that m[[KL]]135 and s[[KL]]130 are essential cofactors for [[FGF23]]-mediated ERK activation but that they inhibited [[FGF23]] stimulation of PLC-γ and PI3K/AKT signaling. Thus, increased longevity in KlTg mice occurs in the presence of excess [[FGF23]] that interacts with m[[KL]] and s[[KL]] to bias FGFR pathways.
|mesh-terms=* Aldosterone
* Animals
* Bone and Bones
* Cardiovascular Diseases
* Disease Models, Animal
* Female
* Fibroblast Growth Factors
* Gene Knockout Techniques
* Glucuronidase
* Kidney
* Longevity
* Male
* Mice
* Mice, Inbred C57BL
* Mice, Transgenic
* Osteoblasts
* Protein Isoforms
* Transcriptome
|keywords=* Bone Biology
* Cardiovascular disease
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6962016
}}
{{medline-entry
|title=Fibroblast growth factor 23 and symmetric dimethylarginine concentrations in geriatric cats.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31568615
|abstract=Fibroblast growth factor 23 ([[FGF23]]) is a phosphaturic hormone that is increased in azotemic cats with chronic kidney disease (CKD) and predictive of the onset of azotemia in older cats. The introduction of symmetric dimethylarginine (SDMA) as a biomarker of glomerular filtration rate has led to the identification of cats in which SDMA is increased, but plasma creatinine concentrations remains within reference range. There is currently little understanding of the metabolic changes present in such cats. To examine the relationship between plasma [[FGF23]] and SDMA concentrations in non-azotemic geriatric cats. Records of a cross section of client-owned cats (n = 143) without azotemic CKD. Clinicopathological information was obtained from cats (≥ 9 years) from records of 2 first opinion practices. The relationship between plasma SDMA and [[FGF23]] concentrations was examined using Spearman's correlation and variables compared using the Mann-Whitney U test. Cats with increased SDMA concentrations had significantly higher plasma [[FGF23]] (P < .001) and creatinine (P < .001) concentrations compared to cats with SDMA concentrations within reference range. A weak positive relationship was demonstrated between plasma [[FGF23]] and SDMA concentrations (r = .35, P < .001) and between plasma [[FGF23]] and creatinine (r = .23, P = .005) concentrations. More cats with increased SDMA concentrations had higher [[FGF23]] concentrations than those with SDMA concentrations within the reference range, suggesting the presence of an alteration in phosphate homeostasis. Further studies are warranted to identify influencing factors and to explore the utility of [[FGF23]] concentration to inform management of cats with early stage CKD.
|mesh-terms=* Aging
* Animals
* Arginine
* Biomarkers
* Cats
* Cross-Sectional Studies
* Female
* Fibroblast Growth Factors
* Male
* Reference Values
* Retrospective Moral Judgment
|keywords=* azotemia
* feline
* phosphate
* renal
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6872607
}}
{{medline-entry
|title=Muscle-bone crosstalk and potential therapies for sarco-osteoporosis.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31106446
|abstract=The nature of muscle-bone crosstalk has been historically considered to be only mechanical, where the muscle is the load applier while bone provides the attachment sites. However, this dogma has been challenged with the emerging notion that bone and muscle act as secretory endocrine organs affect the function of each other. Biochemical crosstalk occurs through myokines such as myostatin, irisin, interleukin (IL)-6, IL-7, IL-15, insulin-like growth factor-1, fibroblast growth factor (FGF)-2, and β-aminoisobutyric acid and through bone-derived factors including [[FGF23]], prostaglandin E  , transforming growth factor β, osteocalcin, and sclerostin. Aside from the biochemical and mechanical interaction, additional factors including aging, circadian rhythm, nervous system network, nutrition intake, and exosomes also have effects on bone-muscle crosstalk. Here, we summarize the current research progress in the area, which may be conductive to identify potential novel therapies for the osteoporosis and sarcopenia, especially when they develop in parallel.
|mesh-terms=* Aging
* Bone and Bones
* Circadian Rhythm
* Humans
* Muscle Proteins
* Muscle, Skeletal
* Nervous System Physiological Phenomena
* Osteocalcin
* Protein Binding
* Signal Transduction
|keywords=* bone
* crosstalk
* muscle
* myokines
* osteoporosis
* sarcopenia
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7331460
}}
{{medline-entry
|title=Extraskeletal Calcifications in Hutchinson-Gilford Progeria Syndrome.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31077852
|abstract=Children with Hutchinson-Gilford progeria syndrome (HGPS), a rare premature aging disease, exhibit extraskeletal calcifications detected by radiographic analysis and on physical examination. The aim of this study was to describe the natural history and pathophysiology of these abnormal calcifications in HGPS, and to determine whether medications and/or supplements tested in clinical trials alter their development. Children from two successive clinical trials administering 1) lonafarnib (n = 26) and 2) lonafarnib   pravastatin   zoledronic acid (n = 37) were studied at baseline (pre-therapy), one year on therapy, and at end-of-therapy (3.3-4.3 years after the baseline visit). Calcium supplementation (oral calcium carbonate) was administered during the first year of the second trial and was subsequently discontinued. Information on calcifications was obtained from physical examinations, radiographs, and serum and urinary biochemical measures. The mineral content of two skin-derived calcifications was determined by x-ray diffraction. Extraskeletal calcifications were detected radiographically in 12/39 (31%) patients at baseline. The odds of exhibiting calcifications increased with age (p = 0.045). The odds were unaffected by receipt of lonafarnib, pravastatin, and zoledronate therapies. However, administration of calcium carbonate supplementation, in conjunction with all three therapeutic agents, significantly increased the odds of developing calcifications (p = 0.009), with the odds plateauing after the supplement's discontinuation. Composition analysis of calcinosis cutis showed hydroxyapatite similar to bone. Although serum calcium, phosphorus, and parathyroid hormone ([[PTH]]) were within normal limits at baseline and on-therapy, [[PTH]] increased significantly after lonafarnib initiation (p < 0.001). Both the urinary calcium/creatinine ratio and tubular reabsorption of phosphate (TRP) were elevated at baseline in 22/39 (56%) and 31/37 (84%) evaluable patients, respectively, with no significant changes while on-therapy. The mean calcium × phosphorus product (Ca × Pi) was within normal limits, but plasma magnesium decreased over both clinical trials. Fibroblast growth factor 23 ([[FGF23]]) was lower compared to age-matched controls (p = 0.03). Extraskeletal calcifications increased with age in children with HGPS and were composed of hydroxyapatite. The urinary calcium/creatinine ratio and TRP were elevated for age while [[FGF23]] was decreased. Magnesium decreased and [[PTH]] increased after lonafarnib therapy which may alter the ability to mobilize calcium. These findings demonstrate that children with HGPS with normal renal function and an unremarkable Ca × Pi develop extraskeletal calcifications by an unidentified mechanism that may involve decreased plasma magnesium and [[FGF23]]. Calcium carbonate accelerated their development and is, therefore, not recommended for routine supplementation in these children.
|mesh-terms=* Calcinosis
* Calcium
* Child
* Child, Preschool
* Creatinine
* Female
* Humans
* In Vitro Techniques
* Lamin Type A
* Male
* Parathyroid Hormone
* Piperidines
* Pravastatin
* Progeria
* Pyridines
* Zoledronic Acid
|keywords=* Aging
* Extraskeletal calcifications
* HGPS
* Lamin
* Laminopathy
* Magnesium
* Parathyroid hormone
* Progeria
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6628204
}}
{{medline-entry
|title=Genome-wide associations and detection of potential candidate genes for direct genetic and maternal genetic effects influencing dairy cattle body weight at different ages.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30727969
|abstract=Body weight (BW) at different ages are of increasing importance in dairy cattle breeding schemes, because of their strong correlation with energy efficiency traits, and their impact on cow health, longevity and farm economy. In total, 15,921 dairy cattle from 56 large-scale test-herds with BW records were genotyped for 45,613 single nucleotide polymorphisms (SNPs). This dataset was used for genome-wide association studies (GWAS), in order to localize potential candidate genes for direct and maternal genetic effects on BW recorded at birth (BW0), at 2 to 3 months of age (BW23), and at 13 to 14 months of age (BW1314). The first 20 principal components ([[PC]]) of the genomic relationship matrix ([Formula: see text]) grouped the genotyped cattle into three clusters. In the statistical models used for GWAS, correction for population structure was done by including polygenic effects with various genetic similarity matrices, such as the pedigree-based relationship matrix ([Formula: see text]), the [Formula: see text]-matrix, the reduced [Formula: see text]-matrix LOCO (i.e. exclusion of the chromosome on which the candidate SNP is located), and LOCO plus chromosome-wide [[PC]]. Inflation factors for direct genetic effects using [Formula: see text] and LOCO were larger than 1.17. For [Formula: see text] and LOCO plus chromosome-wide [[PC]], inflation factors were very close to 1.0. According to Bonferroni correction, ten, two and seven significant SNPs were detected for the direct genetic effect on BW0, BW23, and BW1314, respectively. Seventy-six candidate genes contributed to direct genetic effects on BW with four involved in growth and developmental processes: [[FGF6]], [[FGF23]], [[TNNT3]], and [[OMD]]. For maternal genetic effects on BW0, only three significant SNPs (according to Bonferroni correction), and four potential candidate genes, were identified. The most significant SNP on chromosome 19 explained only 0.14% of the maternal de-regressed proof variance for BW0. For correction of population structure in GWAS, we suggest a statistical model that considers LOCO plus chromosome-wide [[PC]]. Regarding direct genetic effects, several SNPs had a significant effect on BW at different ages, and only two SNPs on chromosome 5 had a significant effect on all three BW traits. Thus, different potential candidate genes regulate BW at different ages. Maternal genetic effects followed an infinitesimal model.
|mesh-terms=* Aging
* Animals
* Body Weight
* Cattle
* Extracellular Matrix Proteins
* Female
* Fibroblast Growth Factors
* Genome-Wide Association Study
* Male
* Polymorphism, Single Nucleotide
* Proteoglycans
* Quantitative Trait Loci
* Troponin T

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6366057
}}
{{medline-entry
|title=Age-Related Changes and Effects of Bisphosphonates on Bone Turnover and Disease Progression in Fibrous Dysplasia of Bone.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30645769
|abstract=Fibrous dysplasia (FD) is a mosaic disease in which bone is replaced with fibro-osseous tissue. Lesions expand during childhood, reaching final burden by age 15 years. In vitro data suggest that disease activity decreases in adulthood; however, there is no clinical data to support this concept. Bone turnover markers (BTMs) have been used as markers of disease activity in FD; however, the natural history of BTM changes, the effects of antiresorptive treatment, and their association to clinical outcomes have not been described. The goals of this study are to describe 1) the natural history of FD disease activity and its association with pain; 2) the impact of bisphosphonates on the natural history of BTMs; and 3) the effect of bisphosphonates on progression of FD burden during childhood. Disease burden scores and alkaline phosphatase, osteocalcin, NTx, [[FGF23]], and RANKL levels from 178 subjects in an FD/MAS natural history study were reviewed, including 73 subjects treated with bisphosphonates. BTMs, RANKL, and [[FGF23]] demonstrated a sustained reduction with age. Bisphosphonate treatment did not significantly impact this age-dependent decrease in BTMs. Pain was more prevalent and severe in adults compared with children and was not associated with BTMs. In children, the progression of disease burden was not affected by bisphosphonates. In conclusion, FD is associated with an age-dependent decline in bone turnover and other markers of disease activity. Pain, in contrast, is more frequent and severe in adults with FD and is not related to bone turnover. Bisphosphonate treatment does not significantly impact the age-dependent decrease in bone turnover, nor does it prevent the progression of FD disease burden in children. These findings, in association with the established adverse effects of antiresorptives, should be considered when evaluating use and response to bisphosphonates in patients being treated for FD and in any study using BTMs as surrogate endpoints. © 2019 American Society for Bone and Mineral Research.
|mesh-terms=* Adolescent
* Adult
* Age Factors
* Aged
* Aged, 80 and over
* Aging
* Biomarkers
* Bone Remodeling
* Child
* Child, Preschool
* Diphosphonates
* Female
* Fibrous Dysplasia of Bone
* Humans
* Male
* Middle Aged
* Pain
* Prevalence
|keywords=* ANTIRESORPTIVES
* BIOCHEMICAL MARKERS OF BONE TURNOVER
* FIBROUS DYSPLASIA
* MCCUNE-ALBRIGHT SYNDROME
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6983318
}}
{{medline-entry
|title=Kotho and aging.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30557478
|abstract=Three fibroblast growth factor(FGF) members, [[FGF19]], [[FGF21]], and [[FGF23]], function as endocrine factors that regulate various metabolic processes. The unique feature of these endo- crine FGFs is the fact that they require Klotho proteins to bind to their cognate FGF recep- tors. Defects in Klotho or [[FGF23]] result in disturbed mineral metabolism and accelerated aging. The aging phenotypes can be alleviated by correcting phosphate imbalance, leading us to hypothesize that phosphate accelerates aging. In contrast, overexpression of [[FGF21]] extends life span in mice. Thus, the FGF-Klotho endocrine axes have emerged as key regula- tors of the aging process and are regarded as potential therapeutic targets for the treatment of age-related disorders.
|mesh-terms=* Aging
* Animals
* Fibroblast Growth Factors
* Glucuronidase
* Humans
* Longevity
* Mice


}}
{{medline-entry
|title=The Klotho proteins in health and disease.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30455427
|abstract=The Klotho proteins, αKlotho and βKlotho, are essential components of endocrine fibroblast growth factor (FGF) receptor complexes, as they are required for the high-affinity binding of [[FGF19]], [[FGF21]] and [[FGF23]] to their cognate FGF receptors (FGFRs). Collectively, these proteins form a unique endocrine system that governs multiple metabolic processes in mammals. [[FGF19]] is a satiety hormone that is secreted from the intestine on ingestion of food and binds the βKlotho-[[FGFR4]] complex in hepatocytes to promote metabolic responses to feeding. By contrast, under fasting conditions, the liver secretes the starvation hormone [[FGF21]], which induces metabolic responses to fasting and stress responses through the activation of the hypothalamus-pituitary-adrenal axis and the sympathetic nervous system following binding to the βKlotho-FGFR1c complex in adipocytes and the suprachiasmatic nucleus, respectively. Finally, [[FGF23]] is secreted by osteocytes in response to phosphate intake and binds to αKlotho-FGFR complexes, which are expressed most abundantly in renal tubules, to regulate mineral metabolism. Growing evidence suggests that the FGF-Klotho endocrine system also has a crucial role in the pathophysiology of ageing-related disorders, including diabetes, cancer, arteriosclerosis and chronic kidney disease. Therefore, targeting the FGF-Klotho endocrine axes might have therapeutic benefit in multiple systems; investigation of the crystal structures of FGF-Klotho-FGFR complexes is paving the way for the development of drugs that can regulate these axes.
|mesh-terms=* Aging
* Animals
* Biomarkers
* Birds
* Cardiovascular Diseases
* Endocrine System Diseases
* Fibroblast Growth Factors
* Glucuronidase
* Humans
* Hypothalamo-Hypophyseal System
* Kidney Diseases
* Mammals
* Phosphates
* Pituitary-Adrenal System

|full-text-url=https://sci-hub.do/10.1038/s41581-018-0078-3
}}
{{medline-entry
|title=Wnt signaling in bone, kidney, intestine, and adipose tissue and interorgan interaction in aging.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30101565
|abstract=Over the last two decades, it has become increasingly apparent that Wnt signaling plays a critical role in development and adult tissue homeostasis in multiple organs and in the pathogenesis of many diseases. In particular, a crucial role for Wnt signaling in bone development and bone tissue homeostasis has been well recognized. Numerous genome-wide association studies confirmed the importance of Wnt signaling in controlling bone mass. Moreover, ample evidence suggests that Wnt signaling is essential for kidney, intestine, and adipose tissue development and homeostasis. Recent emerging evidence demonstrates that Wnt signaling may play a fundamental role in the aging process of those organs. New discoveries show that bone is not only the major reservoir for calcium and phosphate storage, but also the largest organ with multiple functions, including mineral and energy metabolism. The interactions among bone, kidney, intestine, and adipose tissue are controlled and regulated by several endocrine signals, including [[FGF23]], klotho, sclerostin, osteocalcin, vitamin D, and leptin. Since the aging process is characterized by structural and functional decline in almost all tissues and organs, understanding the Wnt signaling-related interactions among bone, kidney, intestine, and adipose tissue in aging may shed light on the pathogenesis of age-related diseases.
|mesh-terms=* Adipose Tissue
* Aging
* Animals
* Bone Development
* Bone and Bones
* Humans
* Intestinal Mucosa
* Kidney
* Wnt Signaling Pathway
|keywords=* FGF23-klotho
* Wnt/β-catenin signaling
* aging
* bone
* sclerostin
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6372353
}}
{{medline-entry
|title=Towards frailty biomarkers: Candidates from genes and pathways regulated in aging and age-related diseases.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30071357
|abstract=Use of the frailty index to measure an accumulation of deficits has been proven a valuable method for identifying elderly people at risk for increased vulnerability, disease, injury, and mortality. However, complementary molecular frailty biomarkers or ideally biomarker panels have not yet been identified. We conducted a systematic search to identify biomarker candidates for a frailty biomarker panel. Gene expression databases were searched (http://genomics.senescence.info/genes including GenAge, AnAge, LongevityMap, CellAge, DrugAge, Digital Aging Atlas) to identify genes regulated in aging, longevity, and age-related diseases with a focus on secreted factors or molecules detectable in body fluids as potential frailty biomarkers. Factors broadly expressed, related to several "hallmark of aging" pathways as well as used or predicted as biomarkers in other disease settings, particularly age-related pathologies, were identified. This set of biomarkers was further expanded according to the expertise and experience of the authors. In the next step, biomarkers were assigned to six "hallmark of aging" pathways, namely (1) inflammation, (2) mitochondria and apoptosis, (3) calcium homeostasis, (4) fibrosis, (5) NMJ (neuromuscular junction) and neurons, (6) cytoskeleton and hormones, or (7) other principles and an extensive literature search was performed for each candidate to explore their potential and priority as frailty biomarkers. A total of 44 markers were evaluated in the seven categories listed above, and 19 were awarded a high priority score, 22 identified as medium priority and three were low priority. In each category high and medium priority markers were identified. Biomarker panels for frailty would be of high value and better than single markers. Based on our search we would propose a core panel of frailty biomarkers consisting of (1) [[CXCL10]] (C-X-C motif chemokine ligand 10), IL-6 (interleukin 6), [[CX3CL1]] (C-X3-C motif chemokine ligand 1), (2) [[GDF15]] (growth differentiation factor 15), [[FNDC5]] (fibronectin type III domain containing 5), vimentin (VIM), (3) regucalcin (RGN/SMP30), calreticulin, (4) [[PLAU]] (plasminogen activator, urokinase), [[AGT]] (angiotensinogen), (5) [[BDNF]] (brain derived neurotrophic factor), progranulin (PGRN), (6) α-klotho (KL), [[FGF23]] (fibroblast growth factor 23), [[FGF21]], leptin (LEP), (7) miRNA (micro Ribonucleic acid) panel (to be further defined), [[AHCY]] (adenosylhomocysteinase) and [[KRT18]] (keratin 18). An expanded panel would also include (1) pentraxin (PTX3), sVCAM/ICAM (soluble vascular cell adhesion molecule 1/Intercellular adhesion molecule 1), defensin α, (2) [[APP]] (amyloid beta precursor protein), LDH (lactate dehydrogenase), (3) [[S100B]] (S100 calcium binding protein B), (4) TGFβ (transforming growth factor beta), PAI-1 (plasminogen activator inhibitor 1), [[TGM2]] (transglutaminase 2), (5) sRAGE (soluble receptor for advanced glycosylation end products), [[HMGB1]] (high mobility group box 1), C3/C1Q (complement factor 3/1Q), ST2 (Interleukin 1 receptor like 1), agrin (AGRN), (6) IGF-1 (insulin-like growth factor 1), resistin (RETN), adiponectin (ADIPOQ), ghrelin (GHRL), growth hormone (GH), (7) microparticle panel (to be further defined), GpnmB (glycoprotein nonmetastatic melanoma protein B) and lactoferrin (LTF). We believe that these predicted panels need to be experimentally explored in animal models and frail cohorts in order to ascertain their diagnostic, prognostic and therapeutic potential.
|mesh-terms=* Aged
* Aging
* Amyloid beta-Peptides
* Amyloid beta-Protein Precursor
* Animals
* Apoptosis
* Biomarkers
* Fibronectins
* Frailty
* Genetic Association Studies
* Growth Differentiation Factor 15
* Humans
* Insulin-Like Growth Factor I
* Interleukin-1 Receptor-Like 1 Protein
* Membrane Glycoproteins
* MicroRNAs
* Signal Transduction
|keywords=* Age-related diseases
* Biomarker panel
* Frailty
* Hallmark of aging pathways
|full-text-url=https://sci-hub.do/10.1016/j.arr.2018.07.004
}}
{{medline-entry
|title=New Insights into the Mechanism of Action of Soluble Klotho.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29250031
|abstract=The [i]klotho[/i] gene encodes a type I single-pass transmembrane protein that contains a large extracellular domain, a membrane spanning segment, and a short intracellular domain. Klotho protein exists in several forms including the full-length membrane form (mKl) and a soluble circulating form [soluble klotho (sKl)]. mKl complexes with fibroblast growth factor receptors to form coreceptors for [[FGF23]], which allows it to participate in [[FGF23]]-mediated signal transduction and regulation of phosphate and calcium homeostasis. sKl is present in the blood, urine, and cerebrospinal fluid where it performs a multitude of functions including regulation of ion channels/transporters and growth factor signaling. How sKl exerts these pleiotropic functions is poorly understood. One hurdle in understanding sKl's mechanism of action as a "hormone" has been the inability to identify a receptor that mediates its effects. In the body, the kidneys are a major source of sKl and sKl levels decline during renal disease. sKl deficiency in chronic kidney disease makes the heart susceptible to stress-induced injury. Here, we summarize the current knowledge of mKl's mechanism of action, the mechanistic basis of sKl's protective, [[FGF23]]-independent effects on the heart, and provide new insights into the mechanism of action of sKl focusing on recent findings that sKl binds sialogangliosides in membrane lipid rafts to regulate growth factor signaling.

|keywords=* FGF23
* IGF-1
* TRPC6
* aging
* heart disease
* klotho
* lipid rafts
* sialidase
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5715364
}}
{{medline-entry
|title=The relevance of α-[[KL]]OTHO to the central nervous system: Some key questions.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/28323064
|abstract=α-Klotho is well described as an anti-aging protein, with critical roles in kidney function as a transmembrane co-receptor for [[FGF23]], and as a soluble factor in serum. α-Klotho is also expressed in the choroid plexus, where it is released into the cerebrospinal fluid. Nonetheless, α-Klotho is also expressed in the brain parenchyma. Accumulating evidence indicates that this pool of α-Klotho, which we define as brain α-Klotho, may play important roles as a neuroprotective factor and in promoting myelination, thereby supporting healthy brain aging. Here we summarize what is known about brain α-Klotho before focusing on the outstanding scientific questions related to its function. We believe there is a need for in vitro studies designed to distinguish between brain α-Klotho and other pools of α-Klotho, and for a greater understanding of the basic function of soluble α-Klotho. The mechanism by which the human [[KL]]-VS variant affects cognition also requires further elucidation. To help address these questions we suggest some experimental approaches that other laboratories might consider. In short, we hope to stimulate fresh ideas and encourage new research approaches that will allow the importance of α-Klotho for the aging brain to become clear.
|mesh-terms=* Aging
* Animals
* Brain
* Central Nervous System
* Cognition
* Fibroblast Growth Factors
* Glucuronidase
* Humans
|keywords=* Aging
* CNS
* Cognition
* KLOTHO
* Signaling
|full-text-url=https://sci-hub.do/10.1016/j.arr.2017.03.003
}}
{{medline-entry
|title=Fibroblast Growth Factor 23 and the Risk of Infection-Related Hospitalization in Older Adults.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/28122946
|abstract=Within monocytes, 1,25-dihydroxyvitamin D [1,25(OH) D] is important for production of cathelicidins, which in turn, are critical for antibacterial action. Fibroblast growth factor 23 ([[FGF23]]) decreases 1,25(OH) D production and thus, could increase infection risk. We examined this possibility in 3141 community-dwelling adults ages ≥65 years old at baseline in the Cardiovascular Health Study using Cox proportional hazards models to examine the association between [[FGF23]] concentrations and first infection-related hospitalizations and determine whether associations differed by the presence of CKD (eGFR<60 ml/min per 1.73 m  [[i]n[/i]=832] or urine albumin-to-creatinine ratio >30 mg/g [[i]n[/i]=577]). Mean±SD age of participants was 78±5 years old, 60% of participants were women, and the median plasma [[FGF23]] concentration was 70 (interquartile range, 53-99) relative units per milliliter. In fully adjusted models, higher [[FGF23]] concentrations associated with higher risk of first infection-related hospitalization (hazard ratio [HR], 1.11; 95% confidence interval [95% CI], 1.03 to 1.20 per doubling of [[FGF23]]) during a median follow-up of 8.6 years. In participants with or without CKD (defined by eGFR), [[FGF23]] concentration associated with first infection-related hospitalization with HRs of 1.24 (95% CI, 1.08 to 1.42) and 1.06 (95% CI, 0.97 to 1.17) per doubling of [[FGF23]], respectively ([i]P[/i]=0.13 for interaction). Associations did not differ between groups when stratified by urine albumin-to-creatinine ratio. In sensitivity analyses, the addition of serum calcium, phosphorus, 25-hydroxyvitamin D, intact parathyroid hormone, and 24,25-dihydroxyvitamin D did not meaningfully change the estimates. In conclusion, in community-dwelling older adults, higher plasma [[FGF23]] concentrations independently associated with the risk of first infection-related hospitalization.
|mesh-terms=* Aged
* Bacterial Infections
* Female
* Fibroblast Growth Factors
* Hospitalization
* Humans
* Longitudinal Studies
* Male
* Prospective Studies
* Risk Factors
|keywords=* aging
* chronic kidney disease
* clinical epidemiology
* infection
* mineral metabolism
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5373449
}}
{{medline-entry
|title=Reduction of calprotectin and phosphate during testosterone therapy in aging men: a randomized controlled trial.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/28000180
|abstract=To investigate the effect of testosterone treatment on biomarkers calprotectin, fibroblast growth factor 23 ([[FGF23]]), soluble Klotho, phosphate, calcium, parathyroid hormone, creatinine and estimated glomerular filtration rate. Randomized, double-blinded, placebo-controlled study. Odense Androgen Study-the effect of Testim and training in hypogonadal men. Men aged 60-78 years old with a low normal concentration of free of bioavailable testosterone <7.3 nmol/L and waist circumference >94 cm recruited from 2008 to 2009 (N = 48) by advertisement. Participants were randomized to receive 5-10 g gel/50-100 mg testosterone (Testim , Ipsen, France) or 5-10 g gel/placebo. The plasma levels of calprotectin and phosphate were significantly reduced in the group receiving testosterone therapy (gel) compared to the placebo group (p < 0.05). Testosterone treatment did not have any significant effect on plasma levels of [[FGF23]] or soluble Klotho. The reduction in phosphate levels was inversely associated with bioavailable testosterone. Compared to the placebo group, 6 months of testosterone therapy (gel) reduced calprotectin and phosphate levels suggesting decreased inflammation and decreased cardiovascular risk.
|mesh-terms=* Aged
* Aging
* Androgens
* Double-Blind Method
* Female
* Follow-Up Studies
* Humans
* Leukocyte L1 Antigen Complex
* Male
* Middle Aged
* Phosphates
* Prognosis
* Risk Factors
* Testosterone
|keywords=* Biomarkers
* Calprotectin
* FGF23
* Klotho
* Phosphate
* Testosterone therapy
|full-text-url=https://sci-hub.do/10.1007/s40618-016-0597-3
}}
{{medline-entry
|title=Association between circulating fibroblast growth factor-23 and age-related cardiovascular-renal parameters in a healthy Chinese population.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/27427468
|abstract=Previous studies showed that circulating fibroblast growth factor-23 ([[FGF23]]) is a new biomarker linked to cardiovascular and kidney diseases. Here, we explored the association between serum [[FGF23]] and aging-related cardiovascular-renal parameters in a healthy Chinese population. A total of 314 healthy participants aged 36-87 years were enrolled. Cardiovascular structure and function were assessed by the left ventricular ejection fraction, the ratio of early diastolic peak flow velocity to late diastolic peak flow velocity at the mitral leaflet tips, carotid intima-media thickness, the diameter of the bilateral common carotid artery, blood systolic peak and end diastolic velocities, which were measured by M-mode ultrasonography. Glomerular filtration rate was evaluated using the Chronic Kidney Disease Epidemiology Collaboration equation and Chronic Kidney Disease Epidemiology Collaboration equation for Asians. Serum [[FGF23]], 1, 25-dihydroxy vitamin D  and parathyroid hormone were measured by enzyme-linked immunosorbent assay. For all participants, intima-media thickness/diameter of the bilateral common carotid artery gradually decreased with the progression from low to high [[FGF23]] concentration (P < 0.05). After adjusting for all possible confounders, [[FGF23]] remained significantly associated with intima-media thickness/diameter of the bilateral common carotid artery (P = 0.016). In women, serum [[FGF23]] was significantly associated with serum creatinine, cystatin C and estimated glomerular filtration rate in the Spearman correlation analysis. [[FGF23]] remained significantly associated with serum creatinine (P = 0.046) and estimated glomerular filtration rate (P = 0.034) after full adjustment. However, no such relationship was apparent in men. Serum [[FGF23]] was correlated with aging-related cardiovascular-renal parameters even in healthy people. Measurement of serum [[FGF23]] can provide valuable information to predict cardiovascular-renal function in healthy people, especially in older female adults. Geriatr Gerontol Int 2017; 17: 1221-1231.
|mesh-terms=* Adult
* Aged
* Aged, 80 and over
* Aging
* Biomarkers
* Cardiovascular System
* Carotid Intima-Media Thickness
* China
* Female
* Fibroblast Growth Factors
* Glomerular Filtration Rate
* Healthy Volunteers
* Heart Function Tests
* Humans
* Kidney Function Tests
* Male
* Middle Aged
* Reference Values
|keywords=* age
* cardiovascular
* fibroblast growth factor-23
* parameters
* renal
|full-text-url=https://sci-hub.do/10.1111/ggi.12844
}}
{{medline-entry
|title=The [[FGF23]]/[[KL]]OTHO Regulatory Network and Its Roles in Human Disorders.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/27125741
|abstract=The functions of Klotho ([[KL]]) are multifaceted and include the regulation of aging and mineral metabolism. It was originally identified as the gene responsible for premature aging-like symptoms in mice and was subsequently shown to function as a coreceptor in the fibroblast growth factor (FGF) 23 signaling pathway. The discovery of [[KL]] as a partner for [[FGF23]] led to significant advances in understanding of the molecular mechanisms underlying phosphate and vitamin D metabolism, and simultaneously clarified the pathogenic roles of the [[FGF23]] signaling pathway in human diseases. These novel insights led to the development of new strategies to combat disorders associated with the dysregulated metabolism of phosphate and vitamin D, and clinical trials on the blockade of [[FGF23]] signaling in X-linked hypophosphatemic rickets are ongoing. Molecular and functional insights on [[KL]] and [[FGF23]] have been discussed in this review and were extended to how dysregulation of the [[FGF23]]/[[KL]] axis causes human disorders associated with abnormal mineral metabolism.
|mesh-terms=* Animals
* Calcium
* Fibroblast Growth Factors
* Gene Expression
* Glucuronidase
* Homeostasis
* Humans
* Metabolic Diseases
* Minerals
* Mutation
* Phosphates
* Receptors, Fibroblast Growth Factor
* Renal Insufficiency, Chronic
* Signal Transduction
* Vitamin D
|keywords=* Aging
* FGF23
* Klotho
* Phosphate
* Vitamin D
|full-text-url=https://sci-hub.do/10.1016/bs.vh.2016.02.001
}}
{{medline-entry
|title=Wound healing delays in α-Klotho-deficient mice that have skin appearance similar to that in aged humans - Study of delayed wound healing mechanism.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/27037022
|abstract=Skin atrophy and delayed wound healing are observed in aged humans; however, the molecular mechanism are still elusive. The aim of this study was to analyze the molecular mechanisms of delayed wound healing by aging using α-Klotho-deficient (kl/kl) mice, which have phenotypes similar to those of aged humans. The kl/kl mice showed delayed wound healing and impaired granulation formation compared with those in wild-type (WT) mice. The skin graft experiments revealed that delayed wound healing depends on humoral factors, but not on kl/kl skin tissue. The mRNA expression levels of cytokines related to acute inflammation including IL-1β, IL-6 and [[TNF]]-α were higher in wound lesions of kl/kl mice compared with the levels in WT mice by RT-PCR analysis. LPS-induced [[TNF]]-α production model using spleen cells revealed that [[TNF]]-α production was significantly increased in the presence of [[FGF23]]. Thus, higher levels of [[FGF23]] in kl/kl mouse may have a role to increase [[TNF]]-α production in would lesion independently of α-Klotho protein, and impair granulation formation and delay wound healing.
|mesh-terms=* Aging
* Animals
* Cytokines
* Disease Models, Animal
* Female
* Glucuronidase
* Humans
* Male
* Mice
* Mice, Knockout
* Mice, Transgenic
* Skin
* Species Specificity
* Treatment Outcome
* Wound Healing
|keywords=* FGF23
* Klotho
* TNF-α
* Wound healing
|full-text-url=https://sci-hub.do/10.1016/j.bbrc.2016.03.138
}}
{{medline-entry
|title=Partial Reversal of Tissue Calcification and Extension of Life Span following Ammonium Nitrate Treatment of Klotho-Deficient Mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/26881935
|abstract=Klotho is required for the inhibitory effect of [[FGF23]] on 1,25(OH)2D3 formation and Klotho-hypomorphic mice (kl/kl) suffer from severe tissue calcification due to excessive 1,25(OH)2D3 formation with subsequent increase of Ca2  and phosphate concentrations and stimulation of osteogenic signaling. The excessive tissue calcification dramatically accelerates aging and leads to premature death of the animals. Osteogenic signaling in those mice is disrupted by treatment with NH4Cl, which prevents tissue calcification and early death of kl/kl mice. The present study explored whether the beneficial effects of NH4Cl treatment could be mimicked by NH4NO3 treatment. The kl/kl mice had free access to tap water either without or with addition of NH4NO3 (0.28 M) starting with the mating of the parental generation. Calcification of trachea, lung, kidney, stomach, heart and vessels was visualized by histology with von Kossa staining. Plasma phosphate concentration was determined utilizing photometry, blood gas and electrolytes utilizing a blood Gas and Chemistry Analysis System and plasma 1,25(OH)2D3 concentration with ELISA. In untreated kl/kl mice plasma 1,25(OH)2D3 and phosphate concentrations were elevated, and the mice suffered from marked calcification of all tissues analyzed. Untreated kl/kl mice further suffered from respiratory acidosis due to marked lung emphysema. NH4NO3-treatment decreased both, blood pCO2 and HCO3-, decreased calcification of trachea, lung, kidney, stomach, heart and vessels and increased the life span of kl/kl mice more than 1.7-fold (♂) or 1.6-fold (♀) without significantly affecting extracellular pH or plasma concentrations of 1,25(OH)2D3, Ca2 , phosphate, Na , and K . NH4NO3-treatment turns respiratory acidosis into metabolic acidosis and mitigates calcification thus leading to a substantial extension of kl/kl mice survival.
|mesh-terms=* Animals
* Calcinosis
* Female
* Glucuronidase
* Longevity
* Male
* Mice
* Mice, Knockout
* Nitrates
* Treatment Outcome

|full-text-url=https://sci-hub.do/10.1159/000443411
}}
{{medline-entry
|title=[Regulatory mechanism of circulating inorganic phosphate].
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/26813498
|abstract=Circulating level of phosphate is altered by age and diet, and is also controlled by several hormones such as parathyroid hormone([[PTH]]), 1,25-dihydroxyvitamin D[1,25(OH)2D]and fibroblast growth factor 23([[FGF23]]). The main function of [[PTH]] and 1,25(OH)2D is maintaining calcium homeostasis, while [[FGF23]] plays a central role in phosphate metabolism. [[PTH]] suppresses phosphate reabsorption in the proximal tubules to increase the renal phosphate wasting, while 1,25(OH)2D facilitates the intestinal phosphate absorption. [[FGF23]] increases the renal phosphate wasting and reduces the production of 1,25(OH)2D. Of note, these hormones mutually regulate one another. The production of [[FGF23]] is also regulated by various local factors. The mechanism for sensing the phosphate availability still remains unknown, and further investigation is required. 
|mesh-terms=* Aging
* Animals
* Calcitriol
* Calcium
* Diet
* Fibroblast Growth Factors
* Homeostasis
* Humans
* Intestinal Absorption
* Kidney Tubules
* Parathyroid Hormone
* Phosphates

|full-text-url=https://sci-hub.do/CliCa1602193198
}}
{{medline-entry
|title=Biological Role of Anti-aging Protein Klotho.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/26528423
|abstract=Klotho-deficient mice have accelerated aging phenotypes, whereas overexpression of Klotho in mice extends lifespan. Klotho is an anti-aging single-pass membrane protein predominantly produced in the kidney, with shedding of the amino-terminal extracellular domain into the systemic circulation. Circulating levels of soluble Klotho decrease with age, and the klotho gene is associated with increased risk of age-related diseases. The three forms of Klotho protein have distinct functions. Membrane Klotho forms a complex with fibroblast growth factor (FGF) receptors, functions as an obligatory co-receptor for [[FGF23]], which is involved in aging and the development of chronic diseases via regulation of P i and vitamin D metabolism. Secreted Klotho functions as a humoral factor with pleiotropic activities including regulation of oxidative stress, growth factor signaling, and ion homeostasis. Secreted Klotho is also involved in organ protection. The intracellular form of Klotho suppresses inflammation-mediated cellular senescence and mineral metabolism. Herein we provide a brief overview of the structure and function and recent research about Klotho. 

|keywords=* Age-related diseases
* Aging
* Klotho
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4608225
}}
{{medline-entry
|title=Soluble αKlotho as a candidate for the biomarker of aging.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/26462468
|abstract=Although the Klotho gene has been recognized as an aging-suppressor gene, the significance of its soluble product, soluble αKlotho (sKlotho), in aging remains to be elucidated. To address this issue, we conducted a single-centered cross-sectional study in a region with a high prevalence of aging. We compared sKlotho levels with the patient characteristics from medical records and laboratory measurements, including fibroblast growth factor 23 ([[FGF23]]), intact parathyroid hormone, activated vitamin D3 and factors associated with mineral bone metabolism, in 52 outpatients with a mean age of 78.2 years. Serum sKlotho levels significantly decreased with age, but were not associated with the stage of chronic kidney disease (CKD). Serum [[FGF23]] levels increased as CKD stages advanced, but were not associated with aging. Univariate analyses revealed that sKlotho levels positively correlated with glomerular filtration rate, and negatively with age and serum levels of [[FGF23]] and phosphorus. In a multivariable linear regression analysis, sKlotho significantly correlated with aging and lower [[FGF23]] levels. Only osteoporosis affected sKlotho and [[FGF23]] levels among the various complications and patient status including medication. In summary, serum sKlotho levels inversely correlated with age and [[FGF23]], and were significantly reduced in patients with osteoporosis. sKlotho may serve as a biomarker of aging independent of renal function. 
|mesh-terms=* Aged
* Aged, 80 and over
* Aging
* Biomarkers
* Female
* Glucuronidase
* Humans
* Male
* Solubility
|keywords=* Aging
* Chronic kidney disease
* FGF23
* Klotho
* Osteoporosis
* Soluble αKlotho
|full-text-url=https://sci-hub.do/10.1016/j.bbrc.2015.10.018
}}
{{medline-entry
|title=Acetazolamide sensitive tissue calcification and aging of klotho-hypomorphic mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/26307633
|abstract=Klotho, a protein expressed mainly in the kidney, is required for the inhibitory effect of [[FGF23]] on renal 1,25(OH)2D3 formation. Klotho counteracts vascular calcification and diverse age-related disorders. Klotho-hypomorphic mice (kl/kl) suffer from severe vascular calcification and rapid aging. The calcification is at least in part caused by excessive 1,25(OH)2D3, Ca(2 ), and phosphate concentrations in blood, which trigger osteogenic signaling including upregulation of alkaline phosphatase (Alpl). As precipitation of calcium and phosphate is fostered by alkaline pH, extracellular acidosis could counteract tissue calcification. In order to induce acidosis, acetazolamide was added to drinking water (0.8 g/l) of kl/kl and wild-type mice. As a result, acetazolamide treatment of kl/kl mice partially reversed the growth deficit, tripled the life span, almost completely reversed the calcifications in trachea, lung, kidney, stomach, intestine, and vascular tissues, the excessive aortic alkaline phosphatase mRNA levels and the plasma concentrations of osteoprotegerin, osteopontin as well as fetuin-A, without significantly decreasing [[FGF23]], 1,25(OH)2D3, Ca(2 ), and phosphate plasma concentrations. In primary human aortic smooth muscle cells, acidotic environment prevented phosphate-induced alkaline phosphatase mRNA expression. The present study reveals a completely novel effect of acetazolamide, i.e., interference with osteoinductive signaling and tissue calcification in kl/kl mice. Klotho deficient (kl/kl) mice suffer from hyperphosphatemia with dramatic tissue calcification. Acetazolamide (ACM) treatment partially reversed the growth deficit of kl/kl mice. In kl/kl mice, ACM reversed tissue calcification despite continued hyperphosphatemia. ACM tripled the life span of kl/kl mice. In human aortic smooth muscle cells, low extracellular pH prevented osteogenic signaling.
|mesh-terms=* Acetazolamide
* Acidosis
* Aging
* Alkaline Phosphatase
* Animals
* Calcitriol
* Calcium
* Carbonic Anhydrase Inhibitors
* Cells, Cultured
* Glucuronidase
* Humans
* Hyperphosphatemia
* Mice
* Mice, Knockout
* Osteogenesis
* Phosphates
* Signal Transduction
* Vascular Calcification
|keywords=* 1,25(OH)2D3
* Acetazolamide
* Acidosis
* Calcification
* Calcium
* Phosphate
|full-text-url=https://sci-hub.do/10.1007/s00109-015-1331-x
}}
{{medline-entry
|title=N-ethyl-N-Nitrosourea (ENU) induced mutations within the klotho gene lead to ectopic calcification and reduced lifespan in mouse models.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/25860694
|abstract=Ectopic calcification (EC), which is the pathological deposition of calcium and phosphate in extra-skeletal tissues, may be associated with hypercalcaemic and hyperphosphataemic disorders, or it may occur in the absence of metabolic abnormalities. In addition, EC may be inherited as part of several monogenic disorders and studies of these have provided valuable insights into the metabolic pathways regulating mineral metabolism. For example, studies of tumoural calcinosis, a disorder characterised by hyperphosphataemia and progressive EC, have revealed mutations of fibroblast growth factor 23 ([[FGF23]]), polypeptide N-acetyl galactosaminyltransferase 3 (GALNT3) and klotho (KL), which are all part of a phosphate-regulating pathway. However, such studies in humans are limited by the lack of available large families with EC, and to facilitate such studies we assessed the progeny of mice treated with the chemical mutagen N-ethyl-N-nitrosourea (ENU) for EC. This identified two mutants with autosomal recessive forms of EC, and reduced lifespan, designated Ecalc1 and Ecalc2. Genetic mapping localized the Ecalc1 and Ecalc2 loci to a 11.0 Mb region on chromosome 5 that contained the klotho gene (Kl), and DNA sequence analysis identified nonsense (Gln203Stop) and missense (Ile604Asn) Kl mutations in Ecalc1 and Ecalc2 mice, respectively. The Gln203Stop mutation, located in KL1 domain, was severely hypomorphic and led to a 17-fold reduction of renal Kl expression. The Ile604Asn mutation, located in KL2 domain, was predicted to impair klotho protein stability and in vitro expression studies in COS-7 cells revealed endoplasmic reticulum retention of the Ile604Asn mutant. Further phenotype studies undertaken in Ecalc1 (kl203X/203X) mice demonstrated elevations in plasma concentrations of phosphate, [[FGF23]] and 1,25-dihydroxyvitamin D. Thus, two allelic variants of Kl that develop EC and represent mouse models for tumoural calcinosis have been established. 
|mesh-terms=* Alleles
* Amino Acid Sequence
* Animals
* COS Cells
* Calcinosis
* Chlorocebus aethiops
* Codon, Nonsense
* Disease Models, Animal
* Endoplasmic Reticulum
* Ethylnitrosourea
* Fibroblast Growth Factors
* Genetic Loci
* Genotype
* Glucuronidase
* Humans
* Kidney
* Longevity
* Male
* Mice
* Mice, Inbred C57BL
* Molecular Sequence Data
* Mutation, Missense
* N-Acetylgalactosaminyltransferases
* Phenotype
* Phosphates
* Polymorphism, Single Nucleotide
* Sequence Alignment
* Vitamin D

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4393098
}}
{{medline-entry
|title=Intracellular signaling of the aging suppressor protein Klotho.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/25601466
|abstract=The Klotho protein deficiency is known to participate in premature aging. As an aging suppressor, Klotho is an important molecule in aging processes and its overexpression results in longevity. Due to many reasons, the insulin/insulin-like growth factor-1 (IGF-1) has been considered as a key pathway in aging research. The Klotho gene is closely related to this pathway. The Klotho gene encodes a transmembrane protein that after cleavage is also found as a secreted protein. Importantly, its overexpression suppresses insulin/IGF-1 signaling and thus extends the lifespan. In addition, Klotho participates in the regulation of several other intracellular signaling pathways, including regulation of [[FGF23]] signaling, cAMP, PKC, transforming growth factor-β (TGF-β), p53/p21, and Wnt signaling. The aim of this review is to summarize current literature that shows the involvement of Klotho in the regulation of several intracellular pathways. The results of our review clearly indicate that Klotho participates in several intracellular signaling pathways, and by regulating them, Klotho is involved in aging and longevity. 
|mesh-terms=* Aging, Premature
* Fibroblast Growth Factors
* Glucuronidase
* Humans
* Insulin
* Insulin-Like Growth Factor I
* Longevity
* Transforming Growth Factor beta
* Wnt Signaling Pathway

|full-text-url=https://sci-hub.do/10.2174/1566524015666150114111258
}}
{{medline-entry
|title=Tumour-associated osteomalacia and hypoglycaemia in a patient with prostate cancer: is Klotho involved?
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/25406200
|abstract=Tumour-associated osteomalacia is a paraneoplastic syndrome caused by renal phosphate wasting, leading to severe hypophosphataemia. Excess of circulating fibroblast growth factor 23 ([[FGF23]]) is the likely cause, acting via the [[FGF23]]/α-Klotho coreceptor, a critical regulator of phosphate metabolism. The other possible effects of that complex in humans are still under investigation. We present a case of an 84-year-old Belgian man, presenting prostate cancer with bone metastases. From June 2010 to March 2013, he presented three episodes of disease progression. From January 2012, the patient developed a progressively marked dorsal kyphosis with significant hypophosphataemia. The calculated TRP (tubular reabsorption of phosphate) was decreased and the [[FGF23]] increased. Mid-March 2013, the patient died after a profound unconsciousness due to hypoglycaemia with hypothermia. We hypothesised that the two paraneoplastic manifestations of this patient (tumour-associated osteomalacia and refractory hypoglycaemia) were due to one cause chain with two main nodes-[[FGF23]] and its coreceptor Klotho.. 
|mesh-terms=* Aged, 80 and over
* Aging
* Biomarkers, Tumor
* Blood Glucose
* Fatal Outcome
* Glucuronidase
* Humans
* Hypoglycemia
* Hypophosphatemia
* Male
* Osteomalacia
* Paraneoplastic Syndromes
* Prostatic Neoplasms

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4244358
}}
{{medline-entry
|title=Calpain 1 inhibitor BDA-410 ameliorates α-klotho-deficiency phenotypes resembling human aging-related syndromes.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/25080854
|abstract=Taking good care of elderly is a major challenge of our society, and thus identification of potential drug targets to reduce age-associated disease burden is desirable. α-klotho(-/-) (α-kl) is a short-lived mouse model that displays multiple phenotypes resembling human aging-related syndromes. Such ageing phenotype of α-kl(-/-) mice is associated with activation of a proteolytic enzyme, Calpain-1. We hypothesized that uncontrolled activation of calpain-1 might be causing age-related phenotypes in α-kl-deficient mice. We found that daily administration of BDA-410, a calpain-1 inhibitor, strikingly ameliorated multiple aging-related phenotypes. Treated mice showed recovery of reproductive ability, increased body weight, reduced organ atrophy, and suppression of ectopic calcifications, bone mineral density reduction, pulmonary emphysema and senile atrophy of skin. We also observed ectopic expression of [[FGF23]] in calcified arteries of α-kl(-/-) mice, which might account for the clinically observed association of increased [[FGF23]] level with increased risk of cardiovascular mortality. These findings allow us to propose that modulation of calpain-1 activity is a potential therapeutic option for delaying age-associated organ pathology, particularly caused by the dysregulation of mineral ion homeostasis. 
|mesh-terms=* Aging
* Animals
* Calpain
* Drug Evaluation, Preclinical
* Female
* Fibroblast Growth Factors
* Glucuronidase
* Humans
* Male
* Mice, Knockout
* Phenotype
* Renal Insufficiency, Chronic
* Sulfonamides
* Vascular Calcification

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4118420
}}
{{medline-entry
|title=[Bone metabolism and cardiovascular function update. α-klotho/[[FGF23]] system; a new insight into the field of mineral homeostasis and the pathogeneses of aging-associated syndromes and the complications of chronic kidney disease].
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/24976054
|abstract=α-klotho (α-kl) was first identified as an aging gene and was later shown to be a regulator of mineral homeostasis. α-kl (- / -) mice display multiple aging related phenotypes including atherosclerosis, cardiovascular/soft tissue calcifications, pulmonary emphysema, osteopenia, and senile atrophy of skin ; such age-related organ pathologies are associated with biochemical changes in blood, including severe hyperphosphatemia, elevated serum [[FGF23]] and1,25 (OH) 2 Vitamin D levels. Of significance, advanced stage patients suffering chronic kidney disease (CKD) develop multiple complications quite resembling phenotypes observed in α-kl (- / -) mice, and high serum phosphate, the major cause of abnormalities of α-kl (- / -) mice, has been reported to be closely associated with high levels of cardiovascular disease morbidity and mortality in patients with CKD, particularly in patients with end-stage renal disease. In addition, the expressions of α-kl mRNA and α-Kl protein were severely reduced in these patients. These results suggest the involvement of α-Kl and [[FGF23]] in the pathogeneses of not only aging-associated syndromes but also the complications of CKD. Here, the unveiling of the molecular functions of α-Klotho and [[FGF23]] has recently given new insight into the field of mineral homeostasis and the pathogeneses of aging-associated syndromes and the complications of CKD. 
|mesh-terms=* Aging
* Animals
* Bone Density
* Bone and Bones
* Cardiovascular Diseases
* Fibroblast Growth Factors
* Glucuronidase
* Homeostasis
* Humans
* Renal Insufficiency, Chronic

|full-text-url=https://sci-hub.do/CliCa140710051011
}}
{{medline-entry
|title=[Aging and inflammation: Klotho, diet and the kidney connection].
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/24294726
|abstract=Despite renal replacement therapy mortality among chronic kidney disease patients is 10-1000-fold higher than in age-matched controls. Klotho is a kidney protein with anti-ageing hormonal properties that is also a co-receptor for the [[FGF23]] fosfatonin. There is a bidirectional relationship between Klotho and inflammation. Thus, inflammation decreases renal Klotho and Klotho has anti-inflammatory properties. Mice with genetic defects in Klotho suffer from accelerated aging and early death. Decreasing the phosphate load improves the phenotype and prolongs survival in these mice. Unraveling the Klotho-phosphate-inflammation interaction may open new avenues for research that may improve the outcomes of kidney patients as well as provide new tools to retard aging in the general population.
|mesh-terms=* Aging
* Animals
* Diet
* Glucuronidase
* Humans
* Inflammation
* Mice
* Renal Insufficiency, Chronic


}}
{{medline-entry
|title=Significance of the anti-aging protein Klotho.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/24124751
|abstract=The Klotho gene was identified as an 'aging suppressor' in mice. Overexpression of the Klotho gene extends lifespan and defective Klotho results in rapid aging and early death. Both the membrane and secreted forms of Klotho have biological activity that include regulatory effects on general metabolism and a more specific effect on mineral metabolism that correlates with its effect on aging. Klotho serves as a co-receptor for fibroblast growth factor (FGF), but it also functions as a humoral factor that regulates cell survival and proliferation, vitamin D metabolism, and calcium and phosphate homeostasis and may serve as a potential tumor suppressor. Moreover, Klotho protects against several pathogenic processes in a [[FGF23]]-independent manner. These processes include cancer metastasis, vascular calcification, and renal fibrosis. This review covers the recent advances in Klotho research and discusses novel Klotho-dependent mechanisms that are clinically relevant in aging and age-related diseases.
|mesh-terms=* Aging
* Animals
* Calcium
* Cell Proliferation
* Cell Survival
* Fibroblast Growth Factors
* Glucuronidase
* Homeostasis
* Humans
* Kidney Diseases
* Membrane Proteins
* Mice
* Neoplasm Metastasis
* Neoplasms
* Phosphates
* Signal Transduction
* Vascular Calcification

|full-text-url=https://sci-hub.do/10.3109/09687688.2013.837518
}}
{{medline-entry
|title=[[FGF23]] affects the lineage fate determination of mesenchymal stem cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/24068282
|abstract=[[FGF23]] is a bone-derived hormone that regulates mineral metabolism by inhibiting renal tubular phosphate reabsorption and suppressing circulating 1,25(OH)2D and [[PTH]] levels. These effects are mediated by FGF-receptor binding and activation in the presence of its coreceptor Klotho, which is expressed in the distal tubules of the kidney. Recently, expression of Klotho in skeletal tissues has been reported, indicating a direct, yet unclear, extrarenal effect of [[FGF23]] on cells involved with bone development and remodeling. In the present study, we found that bone marrow stromal cells harvested from Klotho null mice developed fewer osteoblastic but more adipocytic colonies than cells from wild-type mice. The underlying mechanism was explored by experiments on mouse C3H10T1/2 cells. We found that Klotho was weakly expressed and that [[FGF23]] dose-dependently affected the lineage fate determination. The effects of [[FGF23]] on cell differentiation can be diminished by SU 5402, a specific tyrosine kinase inhibitor for FGF receptors. Our results indicate that [[FGF23]] directly affects the differentiation of bone marrow stromal cells. 
|mesh-terms=* Adipocytes
* Aging
* Animals
* Bone and Bones
* Cell Differentiation
* Cell Lineage
* Cell Proliferation
* Dose-Response Relationship, Drug
* Fibroblast Growth Factors
* Gene Expression Regulation
* Glucuronidase
* Kidney Tubules
* Mesenchymal Stem Cells
* Mice
* Mice, Inbred C3H
* Osteoblasts
* Osteoporosis
* Phosphates
* Protein Binding
* Recombinant Proteins

|full-text-url=https://sci-hub.do/10.1007/s00223-013-9795-6
}}
{{medline-entry
|title=Klotho and chronic kidney disease.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/23652549
|abstract=Through alternative splicing, Klotho protein exists both as a secreted and a membrane form whose extracellular domain could be shed from the cell surface by secretases and released into the circulation to act as endocrine factor. Unlike membrane Klotho which functions as a coreceptor for fibroblast growth factor-23 ([[FGF23]]) to modulate [[FGF23]] signal transduction, soluble Klotho is a multifunction protein present in the biological fluids including blood, urine and cerebrospinal fluid and plays important roles in antiaging, energy metabolism, inhibition of Wnt signaling, antioxidation, modulation of ion transport, control of parathyroid hormone and 1,25(OH)2VD3 production, and antagonism of renin-angiotensin-aldosterone system. Emerging evidence from clinical and basic studies reveal that chronic kidney disease is a state of endocrine and renal Klotho deficiency, which may serve as an early biomarker and a pathogenic contributor to chronic progression and complications in chronic kidney disease including vascular calcification, cardiac hypertrophy, and secondary hyperparathyroidism. Supplementation of exogenous Klotho and/or upregulation of endogenous Klotho production by using rennin angiotensin system inhibitors, HMG CoA reductase inhibitors, vitamin D analogues, peroxisome proliferator-activated receptors-gamma agonists, or anti-oxidants may confer renoprotection from oxidation and suppression of renal fibrosis, and also on prevention or alleviation of complications in chronic kidney disease. Therefore, Klotho is a highly promising candidate on the horizon as an early biomarker, and as a novel therapeutic agent for chronic kidney disease.
|mesh-terms=* Aging
* Animals
* Calcinosis
* Calcium
* Cardiomyopathies
* Chronic Kidney Disease-Mineral and Bone Disorder
* Disease Models, Animal
* Disease Progression
* Fibroblast Growth Factors
* Glucuronidase
* Humans
* Hyperparathyroidism, Secondary
* Membrane Proteins
* Nephrosclerosis
* Parathyroid Hormone
* Phosphates
* Renal Insufficiency, Chronic
* Renin-Angiotensin System
* Signal Transduction
* Solubility
* Uremia
* Vitamin D

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3911771
}}
{{medline-entry
|title=Klotho and βKlotho.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/22396160
|abstract=Endocrine fibroblast growth factors (FGFs) have been recognized as hormones that regulate a variety of metabolic processes. [[FGF19]] is secreted from intestine upon feeding and acts on liver to suppress bile acid synthesis. [[FGF21]] is secreted from liver upon fasting and acts on adipose tissue to promote lipolysis and responses to fasting. [[FGF23]] is secreted from bone and acts on kidney to inhibit phosphate reabsorption and vitamin D synthesis. One critical feature of endocrine FGFs is that they require the Klotho gene family of transmembrane proteins as coreceptors to bind their cognate FGF receptors and exert their biological activities. This chapter overviews function of Klotho family proteins as obligate coreceptors for endocrine FGFs and discusses potential link between Klothos and age-related diseases.
|mesh-terms=* Aging
* Animals
* Glucuronidase
* Homeostasis
* Humans
* Membrane Proteins
* Phosphates
* Receptors, Cytoplasmic and Nuclear

|full-text-url=https://sci-hub.do/10.1007/978-1-4614-0887-1_2
}}
{{medline-entry
|title=Vitamin D receptor controls expression of the anti-aging klotho gene in mouse and human renal cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/21982773
|abstract=Isoforms of the mammalian klotho protein serve as membrane co-receptors that regulate renal phosphate and calcium reabsorption. Phosphaturic effects of klotho are mediated in cooperation with fibroblast growth factor receptor-1 and its [[FGF23]] ligand. The vitamin D receptor and its 1,25-dihydroxyvitamin D(3) ligand are also crucial for calcium and phosphate regulation at the kidney and participate in a feedback loop with [[FGF23]] signaling. Herein we characterize vitamin D receptor-mediated regulation of klotho mRNA expression, including the identification of vitamin D responsive elements ([[VDR]]Es) in the vicinity of both the mouse and human klotho genes. In keeping with other recent studies of vitamin D-regulated genes, multiple [[VDR]]Es control klotho expression, with the most active elements located at some distance (-31 to -46 kb) from the klotho transcriptional start site. We therefore postulate that the mammalian klotho gene is up-regulated by liganded [[VDR]] via multiple remote [[VDR]]Es. The phosphatemic actions of 1,25-dihydroxyvitamin D(3) are thus opposed via the combined phosphaturic effects of [[FGF23]] and klotho, both of which are upregulated by the liganded vitamin D receptor.
|mesh-terms=* Aging
* Animals
* Cell Line
* Gene Expression Regulation
* Glucuronidase
* Humans
* Kidney
* Ligands
* Mice
* RNA, Messenger
* Receptors, Calcitriol
* Vitamin D
* Vitamin D Response Element

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3209523
}}
{{medline-entry
|title=Identification of novel small molecules that elevate Klotho expression.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/21939436
|abstract=The absence of Klotho ([[KL]]) from mice causes the development of disorders associated with human aging and decreased longevity, whereas increased expression prolongs lifespan. With age, [[KL]] protein levels decrease, and keeping levels consistent may promote healthier aging and be disease-modifying. Using the [[KL]] promoter to drive expression of luciferase, we conducted a high-throughput screen to identify compounds that activate [[KL]] transcription. Hits were identified as compounds that elevated luciferase expression at least 30%. Following validation for dose-dependent activation and lack of cytotoxicity, hit compounds were evaluated further in vitro by incubation with opossum kidney and Z310 rat choroid plexus cells, which express [[KL]] endogenously. All compounds elevated [[KL]] protein compared with control. To determine whether increased protein resulted in an in vitro functional change, we assayed [[FGF23]] (fibroblast growth factor 23) signalling. Compounds G-I augmented ERK (extracellular-signal-regulated kinase) phosphorylation in FGFR (fibroblast growth factor receptor)-transfected cells, whereas co-transfection with [[KL]] siRNA (small interfering RNA) blocked the effect. These compounds will be useful tools to allow insight into the mechanisms of [[KL]] regulation. Further optimization will provide pharmacological tools for in vivo studies of [[KL]].
|mesh-terms=* Aging
* Animals
* Cell Line
* Cloning, Molecular
* Drug Screening Assays, Antitumor
* Fibroblast Growth Factors
* Gene Expression Regulation
* Glucuronidase
* Kidney
* Mice
* Opossums
* Rats

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3677209
}}
{{medline-entry
|title=The role of cellular senescence during vascular calcification: a key paradigm in aging research.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/21235497
|abstract=Vascular calcification has severe clinical consequences and is considered an accurate predictor of future adverse cardiovascular events. Vascular calcification refers to the deposition of calcium phosphate mineral, most often hydroxyapatite, in arteries. Extensive calcification of the vascular system is a key characteristic of aging. In this article, we outline the mechanisms governing vascular calcification and highlight its association with cellular senescence. This review discusses the molecular mechanisms of cellular senescence and its affect on calcification of vascular cells, the relevance of phosphate regulation and the function of [[FGF23]] and Klotho proteins. The association of vascular calcification and cellular senescence with the rare human aging disorder Hutchison-Gilford Progeria Syndrome (HGPS) is highlighted and the mouse models used to try to determine the underlying pathways are discussed. By understanding the pathways involved in these processes novel drug targets may be elucidated in an effort to reduce the effects of cellular aging as a risk factor in cardiovascular disease.
|mesh-terms=* Aging
* Animals
* Calcinosis
* Cellular Senescence
* Durapatite
* Fibroblast Growth Factors
* Glucuronidase
* Humans
* Models, Animal
* Phosphates
* Vascular Diseases

|full-text-url=https://sci-hub.do/10.2174/1874609811104020128
}}
{{medline-entry
|title=Klotho interferes with a novel FGF-signalling pathway and insulin/Igf-like signalling to improve longevity and stress resistance in Caenorhabditis elegans.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/20844315
|abstract=Klotho exerts anti-aging properties in mammals in two different ways. While membrane-bound Klotho, which is primarily expressed in the kidney, acts as an obligate co-receptor of [[FGF23]] to regulate phosphate homeostasis, secreted Klotho, resulting from the shedding of the KL1-KL2 ectodomain into the bloodstream, inhibits Insulin/IGF1 signalling. However, the underlying molecular mechanisms are not fully understood. Here, we investigated the biological role of Klotho in Caenorhabditis elegans. Two redundant homologues of the klotho gene exist in C. elegans and encode predicted proteins homologous to the  glucosidase-like KL1 domain of mammalian Klotho. We have used a genetic approach to investigate the functional activity of Klotho in C. elegans. Here, we report that whereas Klotho requires EGL-15 (FGFR) and EGL-17 to promote longevity and oxidative stress resistance, it is not involved in the regulation of fluid homeostasis, controlled by LET-756. Besides revealing a new post-developmental role for EGL-17, our data suggest that the KL1 form of Klotho is involved in [[FGF23]]-independent FGF signalling. We also report a genetic interaction between Klotho and the DAF-2 (Ins/IGF1R)/DAF-16 (FOXO) pathway. While the regulation of longevity requires functional DAF-2/DAF-16 signalling, the control of oxidative stress resistance involves a DAF-2- independent, DAF-16-dependent pathway, suggesting that Klotho may target either DAF-2 or DAF-16, depending of environmental conditions. Thus, the predictive KL1 form of Klotho appears to crosstalk with both FGF and Insulin/IGF1/FOXO pathways to exert anti-aging properties in C. elegans.
|mesh-terms=* Aging
* Amino Acid Sequence
* Animals
* Caenorhabditis elegans
* Caenorhabditis elegans Proteins
* Fibroblast Growth Factors
* Glucuronidase
* Insulin
* Insulin-Like Growth Factor I
* Intercellular Signaling Peptides and Proteins
* Longevity
* Models, Animal
* Molecular Sequence Data
* Receptor, Insulin
* Receptors, Fibroblast Growth Factor
* Signal Transduction
* Stress, Physiological
* Water-Electrolyte Balance

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2984606
}}
{{medline-entry
|title=Effect of sirolimus on calcineurin inhibitor-induced nephrotoxicity using renal expression of KLOTHO, an antiaging gene.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/20562737
|abstract=The aim of this study was to observe the effect of sirolimus ([[SRL]]) on calcineurin inhibitor (CNI)-induced nephrotoxicity in the aging process by using renal expression of KLOTHO, an antiaging gene. METHODS.: Mice were treated with vehicle (VH; 1 mL/kg/day of olive oil), cyclosporine A (CsA; 30 mg/kg/day), or tacrolimus (FK; 1 mg/kg/day) with or without [[SRL]] (0.3 mg/kg/day) for 2 weeks. KLOTHO expression was evaluated by using reverse-transcriptase polymerase chain reaction, immunoblotting, and immunohistochemistry. Oxidative stress was evaluated by using immunohistochemistry and urinary excretion of 8-hydroxy-2'-deoxyguanosine (8-OHdG). The calcium metabolism was evaluated by using renal ectopic calcification, serum intact parathyroid hormone level, and renal fibroblast factor 23 ([[FGF23]]) expression. Treatment with CsA or FK alone significantly decreased KLOTHO expression and increased urinary 8-OHdG excretion compared with VH treatment but [[SRL]] treatment did not. Treatment [[SRL]] CsA or [[SRL]] FK further decreased KLOTHO expression and increased urinary 8-OHdG excretion compared with treatment of CsA or FK alone. There was a strong correlation between KLOTHO expression and urinary 8-OHdG excretion (r=-0.893; P<0.001). Treatment of CsA or FK alone increased renal ectopic calcification and serum intact parathyroid hormone level and decreased renal [[FGF23]] expression compared with VH treatment (P<0.05) but [[SRL]] treatment did not. Treatment with [[SRL]] CNI aggravated these parameters compared with CNI alone. [[SRL]] accelerates the CNI-induced oxidative process by down-regulating the renal antioxidant KLOTHO expression in the kidney.
|mesh-terms=* Aging
* Animals
* Calcineurin Inhibitors
* Colforsin
* Cyclosporine
* DNA Primers
* Gene Expression Regulation
* Glucuronidase
* Immunosuppressive Agents
* Kidney
* Mice
* Nephritis, Interstitial
* Oxidative Stress
* RNA
* RNA, Messenger
* Reverse Transcriptase Polymerase Chain Reaction
* Sirolimus
* Tacrolimus

|full-text-url=https://sci-hub.do/10.1097/TP.0b013e3181e117b4
}}
{{medline-entry
|title=Regulation of ion channels by secreted Klotho: mechanisms and implications.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/20375979
|abstract=Klotho is an anti-aging protein predominantly expressed in the kidney, parathyroid glands, and choroid plexus of the brain. It is a single-pass transmembrane protein with a large extracellular domain. The extracellular domain of Klotho is cleaved and released into extracellular fluid, including blood, urine, and cerebrospinal fluid. The membrane-bound full-length Klotho and secreted extracellular domain of Klotho have distinct functions. Membrane Klotho interacts with fibroblast growth factor (FGF) receptors to form high-affinity receptors for [[FGF23]]. Secreted Klotho functions as a humoral factor that regulates several ion channels and transporters, and other processes, including insulin and insulin-like growth factor signaling. This mini-review focuses on the mechanisms of regulation of cell-surface abundance of ion channels by secreted Klotho and the importance of these effects of Klotho in physiology and pathological conditions.
|mesh-terms=* Aging
* Animals
* Cell Membrane
* Insulin
* Ion Channels
* Ions
* Kidney
* Mice
* Receptors, Fibroblast Growth Factor
* Signal Transduction

|full-text-url=https://sci-hub.do/10.1038/ki.2010.73
}}
{{medline-entry
|title=The nuclear vitamin D receptor controls the expression of genes encoding factors which feed the "Fountain of Youth" to mediate healthful aging.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/20227497
|abstract=The nuclear vitamin D receptor ([[VDR]]) binds 1,25-dihydroxyvitamin D3 (1,25D), its high affinity renal endocrine ligand, to signal intestinal calcium and phosphate absorption plus bone remodeling, generating a mineralized skeleton free of rickets/osteomalacia with a reduced risk of osteoporotic fractures. 1,25D/[[VDR]] signaling regulates the expression of [[TRPV6]], BGP, [[SPP1]], [[LRP5]], RANKL and OPG, while achieving feedback control of mineral ions to prevent age-related ectopic calcification by governing [[CYP24A1]], [[PTH]], [[FGF23]], [[PHEX]], and klotho transcription. Vitamin D also elicits numerous intracrine actions when circulating 25-hydroxyvitamin D3, the metabolite reflecting vitamin D status, is converted to 1,25D locally by extrarenal [[CYP27B1]], and binds [[VDR]] to promote immunoregulation, antimicrobial defense, xenobiotic detoxification, anti-inflammatory/anticancer actions and cardiovascular benefits. [[VDR]] also affects Wnt signaling through direct interaction with beta-catenin, ligand-dependently blunting beta-catenin mediated transcription in colon cancer cells to attenuate growth, while potentiating beta-catenin signaling via [[VDR]] ligand-independent mechanisms in osteoblasts and keratinocytes to function osteogenically and as a pro-hair cycling receptor, respectively. Finally, [[VDR]] also drives the mammalian hair cycle in conjunction with the hairless corepressor by repressing [[SOSTDC1]], S100A8/S100A9, and [[PTH]]rP. Hair provides a shield against UV-induced skin damage and cancer in terrestrial mammals, illuminating another function of [[VDR]] that facilitates healthful aging.
|mesh-terms=* Aging
* Animals
* Calcium
* Cell Nucleus
* Gene Expression Regulation
* Humans
* Keratinocytes
* Mice
* Models, Biological
* Osteopontin
* Phosphates
* Receptors, Calcitriol
* Signal Transduction
* Wnt Proteins
* beta Catenin

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2906618
}}
{{medline-entry
|title=A potential link between phosphate and aging--lessons from Klotho-deficient mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/20197072
|abstract=Phosphate homeostasis is maintained primarily by a bone-kidney endocrine axis. When phosphate is in excess, fibroblast growth factor-23 ([[FGF23]]) is secreted from bone and acts on kidney to promote phosphate excretion into urine. [[FGF23]] also reduces serum vitamin D levels to suppress phosphate absorption from intestine. Thus, [[FGF23]] functions as a hormone that induces negative phosphate balance. One critical feature of [[FGF23]] is that it requires Klotho, a single-pass transmembrane protein expressed in renal tubules, as an obligate co-receptor to bind and activate cognate FGF receptors. Importantly, defects in either [[FGF23]] or Klotho not only cause phosphate retention but also a premature-aging syndrome in mice, which can be rescued by resolving hyperphosphatemia. In addition, changes in extracellular and intracellular phosphate concentration affect glucose metabolism, insulin sensitivity, and oxidative stress in vivo and in vitro, which potentially affect aging processes. These findings suggest an unexpected link between inorganic phosphate and aging in mammals.
|mesh-terms=* Aging
* Aging, Premature
* Animals
* Bone and Bones
* Fibroblast Growth Factors
* Homeostasis
* Hyperphosphatemia
* Kidney
* Mice
* Oxidative Stress
* Phosphates
* Receptors, Fibroblast Growth Factor
* Risk Factors
* Vitamin D

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2862786
}}
{{medline-entry
|title=Role of [[FGF19]] induced [[FGFR4]] activation in the regulation of glucose homeostasis.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/20157585
|abstract=[[FGF19]], [[FGF21]], and [[FGF23]] form a unique subfamily of fibroblast growth factors. Because they contain intra-molecular disulfide bonds and show reduced affinity toward heparan sulfate located in the extracellular space, it is thought that, in contrast to other FGFs, they function as endocrine hormones. [[FGF23]] and its co-receptor alphaKlotho are involved in the control of aging, but it is not known if the same holds true for [[FGF19]], which can also signal through alphaKlotho. However, considerable evidence supports a role for [[FGF19]] in controlling various aspects of metabolism. We have recently fully characterized [[FGF19]]/FGFR/co-factor interactions and signaling, and in the current manuscript discuss the contribution of the [[FGF19]]/[[FGFR4]] axis to bile acid and glucose regulation.
|mesh-terms=* Animals
* Bile Acids and Salts
* Blood Glucose
* Fibroblast Growth Factors
* Homeostasis
* Humans
* Mice
* Receptor, Fibroblast Growth Factor, Type 4
|keywords=* FGF19
* FGF21
* FGF23
* aging
* diabetes
* fibroblast growth factors
* insulin
* metabolic diseases
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2815751
}}
{{medline-entry
|title=The influence of glomerular filtration rate and age on fibroblast growth factor 23 serum levels in pediatric chronic kidney disease.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/20157196
|abstract=Fibroblast growth factor 23 ([[FGF23]]) is a phosphaturic factor and a suppressor of 1alpha-hydroxylase activity in the kidney. Although its importance in chronic kidney disease (CKD) has been demonstrated in adults, there is little information in pediatric patients. The aims of this study were: 1) to determine reference values for [[FGF23]] serum levels according to glomerular filtration rate (GFR) (measured by the reference standard, inulin clearance), gender, and age; and 2) to evaluate the effects of different etiologies and treatments on [[FGF23]] serum levels in a prospective single-center cohort of 227 CKD children (119 boys). Age, body weight, height, and GFR (mean  /- sd) values were: 11.3  /- 4.1 yr, 37  /- 16 kg, 140  /- 20 cm, and 98  /- 34 ml/min per 1.73 m(2), respectively. Calcium, phosphate, [[PTH]], 25 hydroxyvitamin D, 1,25 dihydroxyvitamin D, C-terminal [[FGF23]], and intact [[FGF23]] (mean  /- sd) levels were: 2.43  /- 0.11 mmol/liter, 1.41  /- 0.22 mmol/liter, 41  /- 23 pg/ml, 24  /- 10 ng/ml, 152  /- 72 pmol/liter, 76  /- 134 relative units/ml, and 44  /- 37 pg/ml, respectively. There was a wide range of [[FGF23]] serum levels, but [[FGF23]] levels increased when GFR decreased. [[FGF23]] serum levels were not modified by gender, but they increased with age. In univariate analysis, corticosteroid therapy seemed to be associated with increased [[FGF23]] serum levels. A multivariate linear regression analysis found a significant impact of GFR, body mass index, and solid organ transplantation on [[FGF23]] serum levels. Age, GFR, body mass index, and solid organ transplantation seem to influence [[FGF23]] serum levels in a pediatric population. The impact of corticosteroids on [[FGF23]] metabolism should be further investigated; further longitudinal studies will also help to better define the prognostic impact of [[FGF23]] serum levels in pediatric CKD in terms of disease progression, cardiovascular morbidities, and bone disabilities.
|mesh-terms=* Adolescent
* Adrenal Cortex Hormones
* Aging
* Body Height
* Body Weight
* Child
* Child, Preschool
* Circadian Rhythm
* Cohort Studies
* Cross-Sectional Studies
* Female
* Fibroblast Growth Factors
* Glomerular Filtration Rate
* Hormones
* Humans
* Inulin
* Kidney Failure, Chronic
* Kidney Transplantation
* Kidney Tubules
* Male
* Prospective Studies
* Reference Values
* Sex Characteristics
* Vitamins
* Water-Electrolyte Balance
* Young Adult

|full-text-url=https://sci-hub.do/10.1210/jc.2009-1576
}}
{{medline-entry
|title=Klotho.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/19730882
|abstract=The klotho gene was identified as an "aging-suppressor" gene in mice that accelerates aging when disrupted and extends life span when overexpressed. It encodes a single-pass transmembrane protein and is expressed primarily in renal tubules. The extracellular domain of Klotho protein is secreted into blood and urine by ectodomain shedding. The two forms of Klotho protein, membrane Klotho and secreted Klotho, exert distinct functions. Membrane Klotho forms a complex with fibroblast growth factor (FGF) receptors and functions as an obligate co-receptor for [[FGF23]], a bone-derived hormone that induces phosphate excretion into urine. Mice lacking Klotho or [[FGF23]] not only exhibit phosphate retention but also display a premature-aging syndrome, revealing an unexpected link between phosphate metabolism and aging. Secreted Klotho functions as a humoral factor that regulates activity of multiple glycoproteins on the cell surface, including ion channels and growth factor receptors such as insulin/insulin-like growth factor-1 receptors. Potential contribution of these multiple activities of Klotho protein to aging processes is discussed.
|mesh-terms=* Aging
* Animals
* Bone and Bones
* Calcium Channels
* Fibroblast Growth Factors
* Glucuronidase
* Homeostasis
* Humans
* Insulin Resistance
* Kidney
* Longevity
* Mice
* Oxidative Stress
* Phosphates
* Receptors, Fibroblast Growth Factor
* TRPV Cation Channels
* Vitamin D

|full-text-url=https://sci-hub.do/10.1007/s00424-009-0722-7
}}
{{medline-entry
|title=[Aspects of mammalian aging from alphaklotho study].
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/19591273
|abstract=Since the discovery of alphaklotho-mutant mice, it has been questioned whether the responsible gene, alphaklotho, makes any effect on 'intrinsic aging' process. So far we found that alphaKlotho regulates transcellular calcium transport by mediating Na,K-ATPase activity and dominates mineral-regulating hormones such as [[PTH]], vitamin D and [[FGF23]]. A new concept is now emerged that alphaklotho integrates mineral homeostasis. Findings of human cases with mineral disorders revealed impairment of alphaklotho expression as a pathological cause. Mineral metabolic system contributes to health and thus its disruption should result in acceleration of aging and disease.
|mesh-terms=* Aging
* Animals
* Glucuronidase
* Mice
* Mice, Mutant Strains
* Minerals


}}
{{medline-entry
|title=[Fibroblast Growth Factor 23-Klotho: a new axis of phosphate balance control].
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/19480830
|abstract=The kidney is a key player of phosphate balance, it determines serum phosphate levels by coupling phosphate reabsorption in the renal proximal tubule, calcitriol synthesis and consequently intestinal -phosphate absorption. The identification of fibroblast growth factor 23 ([[FGF23]]) as a hormone regulating phosphate and calcitriol metabolism has unveiled the mechanisms that coordinate these renal proximal tubule functions. A bone-kidney axis has emerged that controls bone mineralization. Animal model studies have improved our understanding of phosphate homeostasis and revealed the role of the Klotho protein, which is mandatory to [[FGF23]] action. In this review, we detail [[FGF23]] and Klotho implication in physiology and in genetic or acquired disorders. Phosphate ion is involved in vascular and soft tissue calcification and is important for cell proliferation. Disorders of [[FGF23]]-klotho axis alter life span and are involved in senescence.
|mesh-terms=* Aging
* Animals
* Calcification, Physiologic
* Calcitriol
* Cell Division
* Fibroblast Growth Factors
* Glucuronidase
* Homeostasis
* Humans
* Hyperphosphatemia
* Hypophosphatemia
* Intestinal Absorption
* Kidney Tubules, Proximal
* Longevity
* Mice
* Mice, Knockout
* Phosphates

|full-text-url=https://sci-hub.do/10.1051/medsci/2009255489
}}
{{medline-entry
|title=[Clinical aspect of recent progress in phosphate metabolism. [[FGF23]]; physiological action and molecular mechanism in the regulation of phosphate and vitamin D metabolism].
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/19483273
|abstract=Fibroblast growth factor (FGF) 23 is an endocrine hormone regulating the phosphate and vitamin D metabolism in the normal physiology. Recent studies have revealed that Klotho plays an essential role in [[FGF23]] signaling. Klotho-deficient mice exhibit premature aging-like phenotypes, and therefore, this molecule has provided insights into the molecular mechanism of aging. However, it is suggested that the phenotype of the Klotho-deficient mice results from the disturbance in the phosphate and vitamin D metabolism. The importance of the [[FGF23]]/Klotho system thus is evident, but additional questions arose from this new concept.
|mesh-terms=* Aging
* Amino Acid Sequence
* Animals
* Fibroblast Growth Factors
* Glucuronidase
* Humans
* Mice
* Molecular Sequence Data
* Phosphates
* Signal Transduction
* Vitamin D

|full-text-url=https://sci-hub.do/CliCa0906794801
}}
{{medline-entry
|title=Vitamin D and aging.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/19444937
|abstract=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 apo[[VDR]]-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.
|mesh-terms=* Aging
* Aging, Premature
* Animals
* Calcifediol
* Calcitriol
* Fibroblast Growth Factors
* Glucuronidase
* Humans
* Neoplasms
* Nutrition Disorders
* Vitamin D
* Vitamin D Deficiency

|full-text-url=https://sci-hub.do/10.1016/j.jsbmb.2008.12.020
}}
{{medline-entry
|title=Therapeutic effects of anti-[[FGF23]] antibodies in hypophosphatemic rickets/osteomalacia.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/19419316
|abstract=X-linked hypophosphatemia (XLH), characterized by renal phosphate wasting, is the most common cause of vitamin D-resistant rickets. It has been postulated that some phosphaturic factor plays a causative role in XLH and its murine homolog, the Hyp mouse. Fibroblast growth factor 23 ([[FGF23]]) is a physiological phosphaturic factor; its circulatory level is known to be high in most patients with XLH and Hyp mice, suggesting its pathophysiological role in this disease. To test this hypothesis, we treated Hyp mice with anti-[[FGF23]] antibodies to inhibit endogenous [[FGF23]] action. A single injection of the antibodies corrected the hypophosphatemia and inappropriately normal serum 1,25-dihydroxyvitamin D. These effects were accompanied by increased expressions of type IIa sodium-phosphate cotransporter and 25-hydroxyvitamin-D-1alpha-hydroxylase and a suppressed expression of 24-hydroxylase in the kidney. Repeated injections during the growth period ameliorated the rachitic bone phenotypes typically observed in Hyp mice, such as impaired longitudinal elongation, defective mineralization, and abnormal cartilage development. Thus, these results indicate that excess actions of [[FGF23]] underlie hypophosphatemic rickets in Hyp mice and suggest a novel therapeutic potential of the [[FGF23]] antibodies for XLH.
|mesh-terms=* Aging
* Animals
* Antibodies
* Body Weight
* Familial Hypophosphatemic Rickets
* Female
* Fibroblast Growth Factors
* Genetic Diseases, X-Linked
* Growth Plate
* Immunohistochemistry
* Injections, Subcutaneous
* Male
* Mice
* Osteomalacia
* Tibia
* Time Factors
* Vitamin D

|full-text-url=https://sci-hub.do/10.1359/jbmr.090509
}}
{{medline-entry
|title=Klotho and aging.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/19230844
|abstract=The klotho gene encodes a single-pass transmembrane protein that forms a complex with multiple fibroblast growth factor (FGF) receptors and functions as an obligatory co-receptor for [[FGF23]], a bone-derived hormone that induces negative phosphate balance. Defects in either Klotho or Fgf23 gene expression cause not only phosphate retention but also a premature-aging syndrome in mice, unveiling a potential link between phosphate metabolism and aging. In addition, the extracellular domain of Klotho protein is clipped on the cell surface and secreted into blood stream, potentially functioning as an endocrine factor. The secreted Klotho protein has a putative sialidase activity that modifies glycans on the cell surface, which may explain the ability of secreted Klotho protein to regulate activity of multiple ion channels and growth factors including insulin, IGF-1, and Wnt. Secreted Klotho protein also protects cells and tissues from oxidative stress through a mechanism yet to be identified. Thus, the transmembrane and secreted forms of Klotho protein have distinct functions, which may collectively affect aging processes in mammals.
|mesh-terms=* Aging
* Animals
* Calcium Channels
* Fibroblast Growth Factors
* Glucuronidase
* Humans
* Mice
* Models, Biological
* Mutation
* Vitamin D

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2743784
}}
{{medline-entry
|title=Vitamin D receptor genotype in hypophosphatemic rickets as a predictor of growth and response to treatment.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/18827005
|abstract=Treatment of X-linked hypophosphatemic rickets improves bone mineralization and bone deformities, but its effect on skeletal growth is highly variable. Genetic variants in the promoter region of the vitamin D receptor ([[VDR]]) gene may explain the response to treatment because this receptor mediates vitamin D action. We studied the [[VDR]] promoter haplotype structure in a large cohort of 91 patients with hypophosphatemic rickets including 62 patients receiving 1alpha-hydroxyvitamin D3 derivatives and phosphates from early childhood on. Treatment improved bone deformities and final height, but 39% of treated patients still had short stature at the end of growth (-2 sd score or below). Height was closely associated with [[VDR]] promoter Hap1 genotype. Hap1(-) patients (35% of the cohort) had severe growth defects. This disadvantageous association of Hap1(-) status with height was visible before treatment, under treatment, and on to adulthood. Gender and age at initiation of treatment could not account for the Hap1 effect. No association with growth was found with a polymorphism of the [[PTH]] receptor gene otherwise found to be associated with adult height. Compared with Hap1( ) patients, those who were Hap1(-) had a higher urinary calcium response to 1alpha-hydroxyvitamin D3 and had significantly lower circulating [[FGF23]] levels (C-terminal assay), taking into account their phosphate and 1alpha-hydroxyvitamin D3 intakes. The present work identifies the [[VDR]] promoter genotype as a key predictor of growth under treatment with 1alpha-hydroxyvitamin D3 derivatives in patients with hypophosphatemic rickets, including those with established [[PHEX]] alterations. The [[VDR]] promoter genotype appears to provide valuable information for adjusting treatment and for deciding upon the utility of early GH therapy.
|mesh-terms=* Adolescent
* Adult
* Aging
* Calcitriol
* Child
* Child, Preschool
* Cohort Studies
* DNA
* Familial Hypophosphatemic Rickets
* Female
* Fibroblast Growth Factors
* Genetic Diseases, X-Linked
* Genotype
* Haplotypes
* Humans
* Male
* Middle Aged
* Organophosphates
* Predictive Value of Tests
* Promoter Regions, Genetic
* Receptor, Parathyroid Hormone, Type 1
* Receptors, Calcitriol
* Reverse Transcriptase Polymerase Chain Reaction
* Sex Characteristics
* Young Adult

|full-text-url=https://sci-hub.do/10.1210/jc.2007-2553
}}
{{medline-entry
|title=[Role of kidney in calcium homeostasis and premature aging].
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/18591745
|abstract=The kidney plays a critical role in the calcium (Ca) homeostasis. With advancing age, the kidney function, including glomerular filtration rate and tubular electrolyte reabsorption, is deteriorating without any kidney disease. Disturbed Ca metabolism may be associated with premature aging process, in which various cellular function is impaired by intracellular Ca burden due to increased Ca efflux from bone. Fibroblast growth factor (FGF) 23, a novel phosphate (P) -regulating factor, is involved in disorders of mineral bone metabolism. Recent studies suggest that [[FGF23]] plays a certain role in premature aging process through altered P and vitamin D metabolism.
|mesh-terms=* Aging
* Animals
* Bone and Bones
* Calcium
* Fibroblast Growth Factors
* Homeostasis
* Humans
* Kidney
* Phosphorus
* Vitamin D

|full-text-url=https://sci-hub.do/CliCa0807942946
}}
{{medline-entry
|title=Klotho as a regulator of oxidative stress and senescence.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/18177265
|abstract=The klotho gene functions as an aging-suppressor gene that extends life span when overexpressed and accelerates aging-like phenotypes when disrupted in mice. The klotho gene encodes a single-pass transmembrane protein that binds to multiple fibroblast growth factor (FGF) receptors and functions as a co-receptor for [[FGF23]], a bone-derived hormone that suppresses phosphate reabsorption and vitamin D biosynthesis in the kidney. In addition, the extracellular domain of Klotho protein is shed and secreted, potentially functioning as a humoral factor. The secreted Klotho protein can regulate multiple growth factor signaling pathways, including insulin/IGF-1 and Wnt, and the activity of multiple ion channels. Klotho protein also protects cells and tissues from oxidative stress, yet the precise mechanism underlying these activities remains to be determined. Thus, understanding of Klotho protein function is expected to provide new insights into the molecular basis for aging, phosphate/vitamin D metabolism, cancer and stem cell biology.
|mesh-terms=* Aging
* Animals
* Atrophy
* Bone Density
* Calcinosis
* Cognition Disorders
* Female
* Fibroblast Growth Factors
* Glucuronidase
* Hearing Loss
* Hypogonadism
* Insulin
* Insulin-Like Growth Factor I
* Ion Channels
* Male
* Mice
* Mice, Transgenic
* Nitric Oxide
* Osteoporosis
* Oxidative Stress
* Pulmonary Emphysema
* Signal Transduction
* Skin
* Spinal Cord Diseases
* Wnt Proteins

|full-text-url=https://sci-hub.do/10.1515/BC.2008.028
}}
{{medline-entry
|title=Klotho: an antiaging protein involved in mineral and vitamin D metabolism.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/17332731
|abstract=Klotho gene mutation leads to a syndrome strangely resembling chronic kidney disease patients undergoing dialysis with multiple accelerated age-related disorders, including hypoactivity, sterility, skin thinning, muscle atrophy, osteoporosis, vascular calcifications, soft-tissue calcifications, defective hearing, thymus atrophy, pulmonary emphysema, ataxia, and abnormalities of the pituitary gland, as well as hypoglycemia, hyperphosphatemia, and paradoxically high-plasma calcitriol levels. Conversely, mice overexpressing klotho show an extended existence and a slow aging process through a mechanism that may involve the induction of a state of insulin and oxidant stress resistance. Two molecules are produced by the klotho gene, a membrane bound form and a circulating form. However, their precise biological roles and molecular functions have been only partly deciphered. Klotho can act as a circulating factor or hormone, which binds to a not yet identified high-affinity receptor and inhibits the intracellular insulin/insulin-like growth factor-1 (IGF-1) signaling cascade; klotho can function as a novel beta-glucuronidase, which deglycosylates steroid beta-glucuronides and the calcium channel transient receptor potential vallinoid-5 (TRPV5); as a cofactor essential for the stimulation of fibroblast growth factor (FGF) receptor by [[FGF23]]. The two last functions have propelled klotho to the group of key factors regulating mineral and vitamin D metabolism, and have also stimulated the interest of the nephrology community. The purpose of this review is to provide a nephrology-oriented overview of klotho and its potential implications in normal and altered renal function states.
|mesh-terms=* Aging
* Animals
* Bone and Bones
* Glucuronidase
* Humans
* Kidney
* Minerals
* RNA, Messenger
* Vitamin D

|full-text-url=https://sci-hub.do/10.1038/sj.ki.5002163
}}
{{medline-entry
|title=[Vitamin D and phosphate metabolism; relationship with aging-regulating gene].
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/16816473
|abstract=It has been known that phosphate homeostasis is mainly regulated by parathyroid hormone and vitamin D. Fibroblast growth factor 23 ([[FGF23]]) has been identified as a novel factor that regulates vitamin D and phosphate metabolism. Genetic defect of [[FGF23]] in mice revealed not only abnormal vitamin D and phosphate metabolism, but also premature aging-like phenotype that is quite similar to Klotho mice. Regulation of vitamin D and phosphate metabolism is closely related to aging processes as well as bone and mineral metabolism.
|mesh-terms=* Aging
* Aging, Premature
* Animals
* Bone and Bones
* Fibroblast Growth Factors
* Forkhead Transcription Factors
* Glucuronidase
* Humans
* Insulin-Like Growth Factor I
* Mice
* Phosphates
* Phosphorus, Dietary
* Signal Transduction
* Vitamin D

|full-text-url=https://sci-hub.do/CliCa060711371142
}}
{{medline-entry
|title=Toward a better understanding of Klotho.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/16672727
|abstract=klotho mutant mice were originally described as a short-lived mouse model with premature aging-like disorders. The klotho gene responsible for these phenotypes encodes a type I membrane protein with a considerable similarity to beta-glycosidase. klotho is predominantly expressed in tissues functioning in the regulation of calcium homeostasis. Suggested functions of Klotho are (i) a fundamental regulator of calcium homeostasis, namely, a cofactor for the fibroblast growth factor (FGF) receptor 1c in [[FGF23]] signaling and a regulator of parathyroid hormone secretion; (ii) a hormone that interferes with the intracellular signaling of insulin and insulin-like growth factor-1; and (iii) a beta-glucuronidase that activates the transient receptor potential ion channel [[TRPV5]] by trimming its sugar moiety. How can we reconcile these pleiotropic functions of Klotho? Is there any common mechanism? Further in vivo studies, and biochemical as well as physiological analyses, are required for a better understanding of the molecular aspects of Klotho.
|mesh-terms=* Aging
* Aging, Premature
* Animals
* Calcium
* Fibroblast Growth Factors
* Glucuronidase
* Homeostasis
* Insulin Antagonists
* Mice
* Mutation
* Phenotype
* Signal Transduction

|full-text-url=https://sci-hub.do/10.1126/sageke.2006.8.pe11
}}
{{medline-entry
|title=Loss of renal phosphate wasting in a child with autosomal dominant hypophosphatemic rickets caused by a [[FGF23]] mutation.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/11805436
|abstract=A girl with autosomal dominant hypophosphatemic rickets, presented with clinical, radiological and laboratory signs of rickets at the age of 11 months. She showed a good response to the treatment with low doses of oral phosphate and calcitriol. Surprisingly, she lost her renal phosphate wasting at the age of 8 years, indicating that the disturbed phosphate metabolism can be compensated by hormonal or other factors.
|mesh-terms=* Administration, Oral
* Aging
* Calcitriol
* Calcium Channel Agonists
* Child
* Female
* Fibroblast Growth Factors
* Genes, Dominant
* Humans
* Hypophosphatemia, Familial
* Kidney
* Mutation
* Pedigree
* Phosphates

|full-text-url=https://sci-hub.do/10.1159/000050018
}}