Klotho

human studyNo significant differences in soluble α-Klotho (sαKl) levels were found between study groups⁵

human studySoluble α-Klotho levels did not associate with memory performance⁵

human studyKL-VS heterozygosity association with memory might be specific to the aMCI stage of AD⁵

human studyIn progressive CKD, rising circulating FGF23 levels in combination with decreasing kidney expression of klotho results in klotho-independent effects of FGF23 on the heart that promote left ventricular hypertrophy, heart failure, atrial fibrillation and death⁶

human studyNo differences were found in α-Klotho levels between SLE patients and controls, both in univariable and multivariable analyses⁷

human studyDisease-related data like SLE duration, acute phase reactants, activity, severity and damage indices, and autoantibodies profile were not significantly associated with serum levels of α-Klotho⁷

human studyThe use of prednisone and the presence of musculoskeletal manifestations were significantly related to higher α-Klotho serum levels⁷

human studyα-Klotho protein serum levels do not differ between patients with SLE and controls⁷

human studySoluble Klotho protein concentration was inversely correlated with the presence of metabolic syndromes⁹

human studySoluble Klotho protein concentration was inversely correlated with numbers of components that met the definition of metabolic syndrome⁹

human studyThe concentration of Soluble Klotho protein was negatively associated with abdominal obesity in the adjusted model⁹

human studyThe concentration of Soluble Klotho protein was negatively associated with high triglyceride (TG) in the adjusted model⁹

human studyThere was no association between klotho and prevalent hypertension or baseline systolic BP¹⁰

human studyHigher klotho was associated with higher baseline diastolic BP (fully adjusted=0.92 mmHg, 95% confidence interval, 0.24 to 1.60 mmHg, higher per two-fold higher klotho)¹⁰

human studyHigher baseline serum klotho levels were significantly associated with a lower rate of incident hypertension (fully adjusted hazard ratio, 0.80; 95% confidence interval, 0.69 to 0.93 for every two-fold higher klotho)¹⁰

human studyHigher klotho was associated with lower subsequent systolic BP and diastolic BP (-0.16 mmHg lower systolic BP per year and -0.10 mmHg lower diastolic BP per year, for each two-fold higher klotho)¹⁰

human studyKlotho deficiency has been linked with significantly reduced protection against various kidney pathological phenotypes, including diabetic kidney disease (DKD)¹³

human studyLow Klotho levels correlate with an increase in the death rate from all causes¹⁵

human studyDeclining Klotho levels increase risk of age-related diseases¹⁷

human studyLow Klotho levels correlate with an increase in the death rate from all causes¹⁸

human studyAlcohol consumption in non-alcoholics is inversely related to sKl²⁰

human studyAlcoholic cirrhotics showed higher-than-normal sKl values in association with liver function derangement²⁰

human studyAmong severe alcoholic cirrhotics sKl is directly related to serum TNF-α levels²⁰

human studyAmong severe alcoholic cirrhotics sKl is inversely related to brain atrophy²⁰

human studyAcute kidney injury (AKI) and chronic kidney disease (CKD) are states of systemic Klotho deficiency²³

human studyHigher Klotho is associated with cognitive reserve and a lower rate of dementia²⁵

human studyKlotho levels decline with age²⁵

human studyHigher levels of Klotho circulating in plasma or CSF are associated with higher cognitive function and lower incidence of dementia during aging²⁵

animalA single administration of low-dose, but not high-dose, klotho enhanced memory in aged nonhuman primates¹

animalKP1 preserved kidney function, repressed TGF-β signaling, ameliorated renal fibrosis and restored endogenous Klotho expression in mouse models⁸

animalKlotho-deficient mutant mice display shortened lifespan, multiple organ degeneration, vascular calcification, cardiovascular disease and frailty¹²

animalKlotho-deficient murine models displayed accelerated aging phenotype and abnormal phosphate and mineral regulation¹²

animalExcessive production of Klotho rescued mice against kidney disease and longer their existence by approximately 30%¹³

animalExogenous Klotho protein supplementation inhibits oxidative stress production and hyperglycemia, correlating with different kidney injury studies¹³

animalkl/kl mice have shortened lifespan, stunted growth, renal disease, hyperphosphatemia, hypercalcemia, vascular calcification, cardiac hypertrophy, hypertension, pulmonary disease, cognitive impairment, multi-organ atrophy and fibrosis¹⁵

animalPreclinical Klotho therapy ameliorated renal, cardiovascular, diabetes-related and neurodegenerative diseases, as well as cancer¹⁵

animalPreclinical Klotho therapy ameliorated renal, cardiovascular, diabetes-related and neurodegenerative diseases, as well as cancer¹⁸

animalOverexpression of the Klotho gene is associated with longevity²²

animalKlotho deficiency exacerbates decreases in glomerular filtration rate in both AKI and CKD²³

animalKlotho repletion or excess preserves glomerular filtration rate in both AKI and CKD²³

animalalpha-kl(-/-) mouse (alpha-Klotho mouse with defect of alpha-klotho gene expression) shows various phenotypes resembling human aging²⁴

in vitroPretreatment with sKL significantly attenuated morphological, molecular, and functional changes induced by TGFβ1, preserving the endothelial phenotype and mitigating myofibroblast-like contractile activity¹⁶

in vitroIn hepatoma cells, the intensity of Klotho staining was related to faster tumor progression and a shortened life span²⁰

expert opinionNo studies examining effects of Klotho supplementation in humans²⁵

theoreticalKlotho and follistatin plasmid gene therapy have the potential to improve physical function, cognitive function, kidney function, body composition, epigenetic age, and subjective well being³

human trialα-klotho implements FGF23-FGFR1c proximity and confers stability¹¹

human trialDimerization of stabilized ternary complexes and receptor activation remain dependent on the binding of heparan sulfate¹¹

human trialThe structure of α-klotho is incompatible with its purported glycosidase activity¹¹

human trialShed α-klotho functions as an on-demand non-enzymatic scaffold protein that promotes FGF23 signalling¹¹

human studyKlotho is a longevity factor that declines in aging¹

human studyKlotho was initially identified as an anti-ageing protein expressed mainly in renal distal tubular cells and the choroid plexus⁴

human studyThe Klotho family comprises several members, including α-Klotho (αKl), β-Klotho (βKl), Klotho-LPH related protein (KLPH; lactase-phlorizin hydrolase), and Klotho-related protein (KlrP)⁴

human studyKlotho has antiapoptotic effects⁴

human studyKlotho reduces oxidative stress⁴

human studyKlotho has anti-inflammatory effects⁴

human studyKlotho expression is closely correlated with insulin secretion, insulin signaling pathways, and insulin sensitivity⁴

human studyα-Klotho shows neuroprotective potential against Alzheimer's disease (AD)⁵

human studyFibroblast growth factor 23 (FGF23) regulates mineral homeostasis by activating complexes of FGF receptors and transmembrane klotho co-receptors⁶

human studyA soluble form of klotho acts as a 'portable' FGF23 co-receptor in tissues that do not express klotho⁶

human studyLoss of Klotho, an anti-aging protein, plays a critical role in the pathogenesis of chronic kidney diseases⁸

human studyKlotho deficiency is both the result and the driving force of chronic kidney disease⁸

human studyIn aging or after kidney injury, expression of Klotho is severely downregulated⁸

human studyKlotho protein is an anti-aging protein⁹

human studyKlotho plays multiple roles in ion-regulation, anti-oxidative stress, and energy metabolism through various pathways⁹

human studyFGF23-independent soluble Klotho protein may act on multiple signal pathways in different organs and tissue in roles of anti-aging and protection from metabolic syndrome⁹

human studyIn humans, Klotho levels decline with age, chronic kidney disease, diabetes, Alzheimer's disease and other conditions¹⁵

human studySoluble Klotho levels in blood decline with age¹⁷

human studyKlotho may mitigate the effects of ApoE4 on AD risk²⁵

human studyKlotho expression is induced by aerobic exercise²⁵

animalElevating klotho boosts cognitive functions in mice through transgenic overexpression and acute peripheral administration¹

animalKlotho (secreted α-klotho) circulates as a hormone following cleavage from its transmembrane form and impacts insulin and fibroblastic growth factor (FGF) signaling, Wnt and N-methyl-d-aspartate receptor (NMDAR) functions¹

animalSystemic elevation of klotho in mice increases synaptic plasticity, cognition and neural resilience to aging, Alzheimer's and Parkinson disease-related toxicities¹

animalRhesus macaques undergo age-induced cognitive decline with synaptic changes, without significant neuronal loss, impairing brain regions including the hippocampus and prefrontal cortex¹

animalSoluble klotho is a circulating protein that in preclinical studies is protective against the development of hypertension¹⁰

animalPhosphate toxicity is a hallmark of mammalian aging and correlates with diminution of Klotho levels with increasing age¹²

animalKlotho protein was functionally identified as a receptor for Fibroblast Growth Factor-23 (FGF23) following discovery of fgf23 deficient mice displaying identical aging phenotype to Klotho deficient mice¹²

animalKlotho safeguards the pancreatic islets of Langerhans activity, also boosting insulin production and decreasing blood glucose levels¹³

animalα-Klotho protein has antiaging properties, as first observed in mice homozygous for a hypomorphic Klotho gene (kl/kl)¹⁵

animalOverexpression of Klotho extends lifespan¹⁵

animalKlotho gene silencing or deficiency causes shorter lifespan¹⁷

animalKlotho gene overexpression results in longer lifespan¹⁷

animalα-Klotho protein has antiaging properties, as first observed in mice homozygous for a hypomorphic Klotho gene (kl/kl)¹⁸

animalOverexpression of Klotho extends lifespan¹⁸

animalPhosphate toxicity is a hallmark of mammalian aging and correlates with diminution of Klotho levels with increasing age¹⁹

animalExperimental animals lacking the Klotho gene develop multiple disorders resembling human aging and present a shortened lifespan²²

animalKlotho protects against soft tissue calcification via phosphaturia, preservation of renal function and a direct effect on vascular smooth muscle cells by inhibiting phosphate uptake and dedifferentiation²³

animalalpha-klotho is a gene related to aging²⁴

in vitroKP1 (Klotho-derived peptide 1) repressed fibroblast activation by binding to TGF-β receptor 2 (TβR2) and disrupting the TGF-β/TβR2 engagement⁸

in vitroKP1 blocked TGF-β-induced activation of Smad2/3 and mitogen-activated protein kinases⁸

in vitroSoluble form of α-Klotho (sKL) hormone has been shown to counteract fibrotic processes in multiple organs¹⁶

in vitrosKL inhibits transforming growth factor β1 (TGFβ1)-induced endothelial-to-mesenchymal transition (EndMT) in human dermal microvascular endothelial cells¹⁶

in vitroTGFβ1-treated H-dMVECs underwent significant changes in cell morphology with loss of endothelial markers (CD31 and VE-cadherin) and increase in mesenchymal/myofibroblast markers (α-smooth muscle actin, type I collagen, and S100A4/fibroblast-specific protein 1)¹⁶

in vitroFGF23 is a bone-derived phosphotropic hormone that regulates phosphate and vitamin D metabolism²¹

in vitroFGF23 mainly affects kidney function via the FGF receptor (FGFR)/α-Klotho complex²¹

in vitroThe physiological roles of FGF23 and α-Klotho in the regulation of mineral homeostasis have been well established²¹

in vitroFGF23 has various effects on many other tissues, sometimes in an α-Klotho-independent manner, especially under pathological conditions²¹

in vitroFGF23 can work in tissues without α-Klotho²¹

in vitroKlotho is a single-pass transmembrane protein that exerts its biological functions through multiple modes²³

in vitroMembrane-bound Klotho acts as coreceptor for the major phosphatonin fibroblast growth factor-23 (FGF23)²³

in vitroSoluble Klotho functions as an endocrine substance²³

in vitroKlotho is present in the proximal tubule lumen where it inhibits renal Pi excretion by modulating Na-coupled Pi transporters via enzymatic glycan modification of the transporter proteins²³

in vitroKlotho modulates Na-coupled Pi transporters via an effect completely independent of its role as the FGF23 coreceptor²³

expert opinionSoluble klotho might mitigate some of the klotho-independent effects of FGF23 via several candidate mechanisms⁶

expert opinionAlpha-Klotho protein (α-Klotho) is an essential component of endocrine fibroblast growth factor receptor complexes that governs multiple metabolic processes including aging-related disorders, diabetes, cancer, arteriosclerosis, and chronic kidney disease⁷

expert opinionα-Klotho protein regulates phosphate homeostasis and the activity of members of the fibroblast growth factor (FGF) family¹²

expert opinionThe α-Klotho protein is the receptor for Fibroblast Growth Factor-23 (FGF23), regulating phosphate homeostasis and vitamin D metabolism¹²

expert opinionβ-Klotho is mainly expressed in the liver, but is also found in the kidney, gut and spleen and regulates FGF-21 and FGF-19¹²

expert opinionγ-Klotho is expressed in the skin and the kidney¹²

expert opinionKlotho is required for high affinity binding of FGF23 to its receptor FGFR1¹²

expert opinionKlotho is expressed mainly on the cell surface membrane of proximal and distal renal tubules and in the choroid plexus in the brain¹²

expert opinionKlotho is a gene involved in the aging process in mammals recognized for over 30 years¹⁹

expert opinionα-Klotho protein is the receptor for Fibroblast Growth Factor-23 (FGF23)¹⁹

expert opinionα-Klotho regulates phosphate homeostasis and vitamin D metabolism¹⁹

expert opinionExercise plays a key role on the secreted form of the α-Klotho gene (S-Klotho) in animal models as well as in humans²²

expert opinionThe relationship between aging and alpha-klotho protein function is gradually becoming clear²⁴

expert opinionThere is a lack of knowledge regarding upregulation and degradation mechanisms of Klotho²⁶

theoreticalKlotho is expressed in the brain, pancreas, and most prominently in the kidney¹³

theoreticalKlotho exists in three subfamilies, including α-Klotho, β-Klotho, and γ-Klotho, where α-Klotho has two distinct forms (membrane-bound and soluble form)¹³

theoreticalThe membrane-bound form serves a role in kidney fibroblast growth factor 23 (FGF 23) signalling, which in turn regulates phosphate homeostasis and vitamin D metabolism¹³

theoreticalThe soluble form acts as a circulating hormone exhibiting diverse activities, such as anti-inflammatory, anti-oxidative stress, tumour-suppressive, and proteolytic cleavage activity¹³

theoreticalKlotho acts as an obligate coreceptor for fibroblast growth factor 23 (FGF23)¹⁵

theoreticalKlotho acts as a soluble pleiotropic endocrine hormone (s-Klotho)¹⁵

theoreticalKlotho is mainly produced in the kidneys, but also in the brain, pancreas and other tissues¹⁵

theoreticalOn renal tubular-cell membranes, Klotho associates with FGF receptors to bind FGF23¹⁵

theoreticalFGF23 regulates renal excretion of phosphate and vitamin D metabolism¹⁵

theoreticalLack of Klotho or FGF23 results in hyperphosphatemia and hypervitaminosis D¹⁵

theoreticalKlotho inhibits TGF-β, IGF-1, Wnt and NF-κB pathways linked to aging¹⁵

theoreticalKlotho increases cell-protective antioxidant enzymes through Nrf2 and FoxO¹⁵

theoreticalKlotho gene is found on chromosome 13q12¹⁷

theoreticalKlotho is involved in vitamin D metabolism¹⁷

theoreticalKlotho is involved in cardiovascular, renal, musculoskeletal, and skin diseases¹⁷

theoreticalKlotho is involved in cancer biology¹⁷

theoreticalKlotho causes higher representation of useful longevity genes¹⁷

theoreticalKlotho prevents neuronal damage and offers neuroprotection¹⁷

theoreticalKlotho acts either as an obligate coreceptor for fibroblast growth factor 23 (FGF23), or as a soluble pleiotropic endocrine hormone (s-Klotho)¹⁸

theoreticalKlotho is mainly produced in the kidneys, but also in the brain, pancreas and other tissues¹⁸

theoreticalKlotho inhibits four pathways linked to aging: TGF-β, IGF-1, Wnt and NF-κB¹⁸

theoreticalKlotho increases cell-protective antioxidant enzymes through Nrf2 and FoxO¹⁸

theoreticalModulation of foodome and gut microbiota can indirectly influence Klotho expression¹⁹

theoreticalAlpha Klotho is a transmembrane protein that serves as co-receptor for FGF23²⁰

theoreticalEctodomain of membrane bound α Klotho may be shed by membrane bound proteases (activated, among other factors, by tumor necrosis factor (TNF)-α) generating the soluble form of the protein (sKl)²⁰

theoreticalsKl functions as a hormone by itself²⁰

theoreticalKlotho modulates calcium influx into cells²⁰

theoreticalKlotho blunts IGF-1/Insulin signaling²⁰

theoreticalKlotho promotes synthesis of antioxidants²⁰

theoreticalKlotho generally slows down tumor progression²⁰

theoreticalKlotho delays cell senescence²⁰

theoreticalKlotho is neuroprotective²⁰

theoreticalKlotho promotes oligodendrocyte maturation and myelin synthesis²⁰

theoreticalKlotho promotes muscle rejuvenation²⁰

theoreticalKlotho may be involved in inflammation and exerts antifibrogenic effects²⁰

theoreticalThree Klotho-related genes have been identified: α-Klotho, β-Klotho, and γ-Klotho²²

theoreticalEffects may be mediated by antioxidant, anti-inflammatory, and lipid homeostatic activities²⁵

human trialRenin-angiotensin system inhibitors (losartan, valsartan) increased circulating Klotho levels in clinical trials¹⁸

human trialStatin (fluvastatin) increased circulating Klotho levels in clinical trials¹⁸

human trialmTOR inhibitors (rapamycin, everolimus) increased circulating Klotho levels in clinical trials¹⁸

human trialVitamin D increased circulating Klotho levels in clinical trials¹⁸

human trialPentoxifylline increased circulating Klotho levels in clinical trials¹⁸

human studyKlotho levels decline with age, chronic kidney disease, diabetes, Alzheimer's disease and other conditions¹⁸

animalSystemic administration of klotho does not cross the blood–brain barrier as measured by autoradiography and His-tagged protein studies¹

animalIn mouse models of renal fibrosis, intravenous injection of KP1 resulted in its preferential accumulation in injured kidneys⁸

animalIn preclinical work, antidiabetic drugs (metformin, GLP-1-based, GABA, PPAR-γ agonists) enhance Klotho¹⁵

animalAntidiabetic drugs (metformin, GLP-1-based, GABA, PPAR-γ agonists) enhanced Klotho in preclinical work¹⁸

animalAstaxanthin, curcumin, ginseng, ligustilide and resveratrol increased Klotho in rodents¹⁸

expert opinionSoluble Klotho is the main functional form in the circulation and is detected in the blood, urine, and cerebrospinal fluid¹²

animalKlotho-deficient mice have shortened lifespan, stunted growth, renal disease, hyperphosphatemia, hypercalcemia, vascular calcification, cardiac hypertrophy, hypertension, pulmonary disease, cognitive impairment, multi-organ atrophy and fibrosis¹⁸

animals-Klotho protein injection was effective¹⁸

in vitrosKL effectively prevented TGFβ1-induced EndMT in H-dMVECs, highlighting its potential as a novel therapeutic agent against dermal fibrosis¹⁶

expert opinionSystemic low-dose klotho treatment may prove therapeutic in aging humans¹

expert opinionModulation of Klotho activity is an attractive target for therapeutic intervention in aging and chronic kidney disease¹²

expert opinionSenotherapeutic strategies to influence Klotho expression include administration of exogenous Klotho, synthetic and natural Klotho agonists and indirect approaches via modulation of the foodome and gut microbiota¹²

expert opinionModulation of Klotho activity is an attractive target for therapeutic intervention in aging¹⁹

expert opinionKlotho has been implicated directly in the pathophysiology of chronic kidney disease (CKD)¹⁹

theoreticalKlotho has shown beneficial effects in DKD by tackling the complex pathophysiology and reducing kidney inflammation, oxidative stress, as well as fibrosis¹³

theoreticalThe protective effect of klotho extends beyond DKD in other pathological conditions, including cardiovascular diseases, alzheimer's disease, cancer, inflammatory bowel disease, and liver disease¹³

theoreticalKlotho has been linked to beneficial anti-aging effects¹⁷

theoreticalKlotho has positive benefits on the neurological system¹⁷

theoreticalKlotho has potential to treat age-related dementia, multiple sclerosis, Alzheimer's disease, and Parkinson's disease¹⁷

theoreticalAdministration of exogenous Klotho is a senotherapeutic strategy to influence Klotho expression¹⁹

theoreticalSynthetic and natural Klotho agonists are senotherapeutic strategies developed to influence Klotho expression¹⁹

theoreticalKlotho maintenance may extend lifespan²⁵

theoreticalKlotho may preserve metabolic flexibility²⁵