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 studyThe human KLOTHO gene variant KL-VS is associated with enhanced cognition in heterozygous carriers¹⁴

human studyLow Klotho levels correlate with an increase in the death rate from all causes¹⁶

human studyDeclining Klotho levels increase risk of age-related diseases¹⁸

human studyLow Klotho levels correlate with an increase in the death rate from all causes¹⁹

human studyAlcohol consumption in non-alcoholics is inversely related to sKl²¹

human studyAlcoholic cirrhotics showed higher-than-normal sKl values in association with liver function derangement²¹

human studyAmong severe alcoholic cirrhotics sKl is directly related to serum TNF-α levels²¹

human studyAmong severe alcoholic cirrhotics sKl is inversely related to brain atrophy²¹

human studyAcute kidney injury (AKI) and chronic kidney disease (CKD) are states of systemic Klotho deficiency²⁴

human studyHigher Klotho is associated with cognitive reserve and a lower rate of dementia²⁶

human studyKlotho levels decline with age²⁶

human studyHigher levels of Klotho circulating in plasma or CSF are associated with higher cognitive function and lower incidence of dementia during aging²⁶

human studyHigher circulating Klotho levels are associated with better cognitive performance, even independent of age²⁹

human studyLow Klotho levels correlate strongly with hypertension, coronary artery disease, heart failure, and increased cardiovascular mortality²⁹

human studyLower Klotho levels associate with increased mortality and chronic disease risk in observational studies³⁰

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

animalKP1 ameliorated kidney fibrosis in mouse UUO models¹⁴

animalChronic KP6 infusion reversed proteinuria and kidney damage in both type 1 and type 2 diabetic mouse models¹⁴

animalScrambled-sequence KP6 control was inactive¹⁴

animalA single systemic injection of low-dose klotho protein (KL1 domain) enhanced memory in aged rhesus macaques¹⁴

animalEffects of KL1 domain injection on memory were observed within 4 hours and persisted for approximately 2 weeks¹⁴

animalTransgenic mice overexpressing klotho performed better in learning and memory tests, with enhanced long-term potentiation and enriched synaptic GluN2B¹⁴

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 fibrosis¹⁶

animalPreclinical Klotho therapy ameliorated renal, cardiovascular, diabetes-related and neurodegenerative diseases, as well as cancer¹⁶

animalPreclinical Klotho therapy ameliorated renal, cardiovascular, diabetes-related and neurodegenerative diseases, as well as cancer¹⁹

animalOverexpression of the Klotho gene is associated with longevity²³

animalKlotho deficiency exacerbates decreases in glomerular filtration rate in both AKI and CKD²⁴

animalKlotho repletion or excess preserves glomerular filtration rate in both AKI and CKD²⁴

animalalpha-kl(-/-) mouse (alpha-Klotho mouse with defect of alpha-klotho gene expression) shows various phenotypes resembling human aging²⁵

animalMice without Klotho age extremely rapidly³⁰

animalMice with extra Klotho live up to 30% longer³⁰

animalMice lacking Klotho develop multi-organ ageing — atherosclerosis, osteoporosis, skin atrophy, cognitive decline — within weeks of birth³⁰

in vitroPretreatment with sKL significantly attenuated morphological, molecular, and functional changes induced by TGFβ1, preserving the endothelial phenotype and mitigating myofibroblast-like contractile activity¹⁷

in vitroIn hepatoma cells, the intensity of Klotho staining was related to faster tumor progression and a shortened life span²¹

expert opinionNo studies examining effects of Klotho supplementation in humans²⁶

expert opinionEnhances cognitive function and neural protection²⁸

expert opinionProtects cardiovascular tissue from calcification²⁸

expert opinionNatural Klotho levels decline with age²⁸

expert opinionDeficiency is linked to aging, cognitive decline, kidney disease, and vascular stiffness²⁸

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

theoreticalAll klotho peptide research remains preclinical with no human intervention trials¹⁴

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 conditions¹⁶

human studySoluble Klotho levels in blood decline with age¹⁸

human studyKlotho may mitigate the effects of ApoE4 on AD risk²⁶

human studyKlotho expression is induced by aerobic exercise²⁶

human studyEndogenous Klotho levels correlate with cognitive function³⁰

human studyCirculating Klotho levels decline with age³⁰

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

animalKP1, a 30-amino-acid klotho-derived peptide, was identified through systematic screening of KL1 domain peptides¹⁴

animalKP1 blocked TGF-beta/TbetaR2 engagement and repressed fibroblast activation¹⁴

animalKP6, a klotho-derived peptide, ameliorates diabetic kidney disease by binding Wnt ligands and disrupting Wnt/LRP6 engagement¹⁴

animalKP1 binds directly to TGF-beta receptor type 2 (TbetaR2), physically blocking TGF-beta ligand engagement¹⁴

animalKP1 prevents downstream Smad2/3 phosphorylation and MAPK activation¹⁴

animalKP1 inhibits cellular senescence in the fibrotic kidney by restoring klotho expression via posttranscriptional regulation mediated by miR-223-3p and lncRNA-TUG1¹⁴

animalKP1 residues 57-86 emerged as the most potent inhibitor of fibroblast activation¹⁴

animalα-Klotho protein has antiaging properties, as first observed in mice homozygous for a hypomorphic Klotho gene (kl/kl)¹⁶

animalOverexpression of Klotho extends lifespan¹⁶

animalKlotho gene silencing or deficiency causes shorter lifespan¹⁸

animalKlotho gene overexpression results in longer lifespan¹⁸

animalα-Klotho protein has antiaging properties, as first observed in mice homozygous for a hypomorphic Klotho gene (kl/kl)¹⁹

animalOverexpression of Klotho extends lifespan¹⁹

animalPhosphate toxicity is a hallmark of mammalian aging and correlates with diminution of Klotho levels with increasing age²⁰

animalExperimental animals lacking the Klotho gene develop multiple disorders resembling human aging and present a shortened lifespan²³

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 dedifferentiation²⁴

animalalpha-klotho is a gene related to aging²⁵

animalAnimals deficient in Klotho developed accelerated aging, while those with higher Klotho expression demonstrated extended lifespan and resistance to age-related decline²⁹

animalAnimal models with Klotho deficiency exhibit osteoporosis, vascular calcification, cognitive impairment, sarcopenia, skin atrophy, and shortened lifespan²⁹

animalAnimals with enhanced Klotho expression show increased lifespan, improved cognition, resistance to oxidative stress, preserved kidney function, and reduced fibrosis and inflammation²⁹

animalKlotho counters the majority of the 12 hallmarks of ageing — reducing cellular senescence, oxidative damage, fibrosis, and inflammation³⁰

animalKlotho inhibits TGF-beta signalling, mitigating organ fibrosis in animal models³⁰

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 organs¹⁷

in vitrosKL inhibits transforming growth factor β1 (TGFβ1)-induced endothelial-to-mesenchymal transition (EndMT) in human dermal microvascular endothelial cells¹⁷

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)¹⁷

in vitroFGF23 is a bone-derived phosphotropic hormone that regulates phosphate and vitamin D metabolism²²

in vitroFGF23 mainly affects kidney function via the FGF receptor (FGFR)/α-Klotho complex²²

in vitroThe physiological roles of FGF23 and α-Klotho in the regulation of mineral homeostasis have been well established²²

in vitroFGF23 has various effects on many other tissues, sometimes in an α-Klotho-independent manner, especially under pathological conditions²²

in vitroFGF23 can work in tissues without α-Klotho²²

in vitroKlotho is a single-pass transmembrane protein that exerts its biological functions through multiple modes²⁴

in vitroMembrane-bound Klotho acts as coreceptor for the major phosphatonin fibroblast growth factor-23 (FGF23)²⁴

in vitroSoluble Klotho functions as an endocrine substance²⁴

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 proteins²⁴

in vitroKlotho modulates Na-coupled Pi transporters via an effect completely independent of its role as the FGF23 coreceptor²⁴

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 years²⁰

expert opinionα-Klotho protein is the receptor for Fibroblast Growth Factor-23 (FGF23)²⁰

expert opinionα-Klotho regulates phosphate homeostasis and vitamin D metabolism²⁰

expert opinionExercise plays a key role on the secreted form of the α-Klotho gene (S-Klotho) in animal models as well as in humans²³

expert opinionThe relationship between aging and alpha-klotho protein function is gradually becoming clear²⁵

expert opinionThere is a lack of knowledge regarding upregulation and degradation mechanisms of Klotho²⁷

expert opinionKlotho is a powerful anti-aging signaling protein that regulates inflammation, oxidative stress, stem cell activity, and mineral balance²⁸

expert opinionActs as a co-receptor for fibroblast growth factors (especially FGF23)²⁸

expert opinionRegulates phosphate and vitamin D metabolism²⁸

expert opinionReduces inflammation and oxidative stress²⁸

expert opinionPreserves telomere length and mitochondrial health²⁸

expert opinionSuppresses fibrosis and cellular senescence²⁸

expert opinionIts effects on cellular signaling and transcription may last for days or weeks²⁸

expert opinionIt is expressed by the kidney, brain (choroid plexus), parathyroid glands, and vascular tissue²⁸

expert opinionAlso produced in low levels in the placenta and skin²⁸

expert opinionKlotho acts as a co-receptor for FGF23, regulating phosphate homeostasis²⁸

expert opinionIt inhibits Wnt signaling to reduce fibrosis²⁸

expert opinionIt attenuates inflammation via NF-κB suppression²⁸

expert opinionKlotho is recognized as a master regulator of aging biology, influencing kidney function, cardiovascular health, brain aging, mineral metabolism, oxidative stress, and inflammation²⁹

expert opinionα-Klotho is a transmembrane protein primarily expressed in the kidneys (distal convoluted tubules), the choroid plexus of the brain, and parathyroid tissue²⁹

expert opinionKlotho exists in two biologically active forms: membrane-bound Klotho and soluble Klotho, which is cleaved and released into circulation²⁹

expert opinionKlotho acts as a co-receptor for FGF-23, allowing proper regulation of phosphate excretion, vitamin D metabolism, and calcium balance²⁹

expert opinionWithout Klotho, phosphate accumulates, driving vascular calcification and tissue aging²⁹

expert opinionKlotho reduces renal fibrosis, protects against oxidative damage, preserves tubular function, and slows progression of chronic kidney disease²⁹

expert opinionLoss of Klotho is recognized as a key driver of CKD progression²⁹

expert opinionIn the brain, Klotho enhances synaptic plasticity, supports learning and memory, reduces neuroinflammation, and protects against oxidative neuronal injury²⁹

expert opinionKlotho inhibits vascular smooth muscle calcification, endothelial dysfunction, and arterial stiffness²⁹

expert opinionKlotho suppresses NF-κB signaling, pro-inflammatory cytokine release, and oxidative stress pathways²⁹

expert opinionKlotho is a natural anti-ageing protein your body produces³⁰

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)¹⁶

theoreticalKlotho acts as a soluble pleiotropic endocrine hormone (s-Klotho)¹⁶

theoreticalKlotho is mainly produced in the kidneys, but also in the brain, pancreas and other tissues¹⁶

theoreticalOn renal tubular-cell membranes, Klotho associates with FGF receptors to bind FGF23¹⁶

theoreticalFGF23 regulates renal excretion of phosphate and vitamin D metabolism¹⁶

theoreticalLack of Klotho or FGF23 results in hyperphosphatemia and hypervitaminosis D¹⁶

theoreticalKlotho inhibits TGF-β, IGF-1, Wnt and NF-κB pathways linked to aging¹⁶

theoreticalKlotho increases cell-protective antioxidant enzymes through Nrf2 and FoxO¹⁶

theoreticalKlotho gene is found on chromosome 13q12¹⁸

theoreticalKlotho is involved in vitamin D metabolism¹⁸

theoreticalKlotho is involved in cardiovascular, renal, musculoskeletal, and skin diseases¹⁸

theoreticalKlotho is involved in cancer biology¹⁸

theoreticalKlotho causes higher representation of useful longevity genes¹⁸

theoreticalKlotho prevents neuronal damage and offers neuroprotection¹⁸

theoreticalKlotho acts either as an obligate coreceptor for fibroblast growth factor 23 (FGF23), or as a soluble pleiotropic endocrine hormone (s-Klotho)¹⁹

theoreticalKlotho is mainly produced in the kidneys, but also in the brain, pancreas and other tissues¹⁹

theoreticalKlotho inhibits four pathways linked to aging: TGF-β, IGF-1, Wnt and NF-κB¹⁹

theoreticalKlotho increases cell-protective antioxidant enzymes through Nrf2 and FoxO¹⁹

theoreticalModulation of foodome and gut microbiota can indirectly influence Klotho expression²⁰

theoreticalAlpha Klotho is a transmembrane protein that serves as co-receptor for FGF23²¹

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)²¹

theoreticalsKl functions as a hormone by itself²¹

theoreticalKlotho modulates calcium influx into cells²¹

theoreticalKlotho blunts IGF-1/Insulin signaling²¹

theoreticalKlotho promotes synthesis of antioxidants²¹

theoreticalKlotho generally slows down tumor progression²¹

theoreticalKlotho delays cell senescence²¹

theoreticalKlotho is neuroprotective²¹

theoreticalKlotho promotes oligodendrocyte maturation and myelin synthesis²¹

theoreticalKlotho promotes muscle rejuvenation²¹

theoreticalKlotho may be involved in inflammation and exerts antifibrogenic effects²¹

theoreticalThree Klotho-related genes have been identified: α-Klotho, β-Klotho, and γ-Klotho²³

theoreticalEffects may be mediated by antioxidant, anti-inflammatory, and lipid homeostatic activities²⁶

theoreticalKlotho inhibits NF-kB and NLRP3 inflammasome — directly targets inflammaging³⁰

theoreticalAlpha-Klotho is the obligate co-receptor for fibroblast growth factor 23 (FGF23)³⁰

theoreticalSoluble Klotho inhibits the IGF-1/insulin signalling pathway³⁰

theoreticalKlotho enhances expression of antioxidant enzymes via FoxO transcription factor activation³⁰

theoreticalKlotho suppresses Wnt signalling, reducing stem cell exhaustion³⁰

human trialRenin-angiotensin system inhibitors (losartan, valsartan) increased circulating Klotho levels in clinical trials¹⁹

human trialStatin (fluvastatin) increased circulating Klotho levels in clinical trials¹⁹

human trialmTOR inhibitors (rapamycin, everolimus) increased circulating Klotho levels in clinical trials¹⁹

human trialVitamin D increased circulating Klotho levels in clinical trials¹⁹

human trialPentoxifylline increased circulating Klotho levels in clinical trials¹⁹

human studyKlotho levels decline with age, chronic kidney disease, diabetes, Alzheimer's disease and other conditions¹⁹

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

animalIV-administered KP1 showed preferential accumulation in injured kidneys¹⁴

animalIn preclinical work, antidiabetic drugs (metformin, GLP-1-based, GABA, PPAR-γ agonists) enhance Klotho¹⁶

animalAntidiabetic drugs (metformin, GLP-1-based, GABA, PPAR-γ agonists) enhanced Klotho in preclinical work¹⁹

animalAstaxanthin, curcumin, ginseng, ligustilide and resveratrol increased Klotho in rodents¹⁹

animalRecombinant alpha-Klotho: approximately 10-15 hours half-life (estimated from primate studies)³⁰

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

expert opinionDosing, bioavailability, and delivery mechanisms are still under investigation²⁸

expert opinionThe protein has a short plasma half-life (~30 minutes)²⁸

expert opinionIt is preserved in cryopreserved biologics without denaturation²⁸

theoreticalKlotho may have a number of potential adverse effects at high dose levels¹⁵

theoreticalExcessively high levels may increase FGF23 and alter phosphate and calcium mineral balance²⁶

theoreticalTheoretical risk of altering phosphate and calcium homeostasis due to Klotho's role in FGF23 signalling³⁰

theoreticalUnknown effects on cancer biology in long-term use³⁰

theoreticalAllergic reactions to recombinant protein possible³⁰

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 fibrosis¹⁹

animals-Klotho protein injection was effective¹⁹

in vitrosKL effectively prevented TGFβ1-induced EndMT in H-dMVECs, highlighting its potential as a novel therapeutic agent against dermal fibrosis¹⁷

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 aging²⁰

expert opinionKlotho has been implicated directly in the pathophysiology of chronic kidney disease (CKD)²⁰

expert opinionPlays essential roles in cellular longevity, vascular health, neuroprotection, and tissue regeneration²⁸

expert opinionKlotho is present in FDA IND-approved products, such as ViX001, as part of the native perinatal proteome²⁸

expert opinionKlotho is naturally produced in amniotic fluid and Wharton's Jelly from full-term pregnancies²⁸

expert opinionKlotho-Engineered MSCs used in trials for attenuating osteoarthritis progression²⁸

expert opinionRecombinant human Klotho is in early clinical trials³⁰

expert opinionRecombinant alpha-Klotho is in early clinical development for chronic kidney disease, cognitive decline, and age-related diseases³⁰

expert opinionNo therapeutic Klotho product is yet approved for human use³⁰

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 effects¹⁸

theoreticalKlotho has positive benefits on the neurological system¹⁸

theoreticalKlotho has potential to treat age-related dementia, multiple sclerosis, Alzheimer's disease, and Parkinson's disease¹⁸

theoreticalAdministration of exogenous Klotho is a senotherapeutic strategy to influence Klotho expression²⁰

theoreticalSynthetic and natural Klotho agonists are senotherapeutic strategies developed to influence Klotho expression²⁰

theoreticalKlotho maintenance may extend lifespan²⁶

theoreticalKlotho may preserve metabolic flexibility²⁶