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The effects of apolipoprotein E (APOE) and Klotho genes, both implicated in aging, on human cognition as a function of sex and age are yet to be definitively established. Here, we showed in the largest cohort studied to date (N = 320,861) that APOE homozygous e4 carriers had a greater decline in cognition with aging compared to e3 carriers (e3/e4 and e3/e3) as well as smaller hippocampi and amygdala (N = 29,510). Critically, sex and age differentially affected the decline in cognition. Younger (40 to 50 y) female homozygous e4 carriers showed a cognitive advantage over female e3 carriers, but this advantage was not present in males. By contrast, Klotho-VS heterozygosity did not affect cognition or brain volume, regardless of APOE genotype, sex, or age. These cognitive trajectories with aging demonstrate clear sex-dependent antagonistic pleiotropy effects of APOE e4, but no effects of Klotho genotype on cognition and brain volume. [ABSTRACT FROM AUTHOR]

Aging and pregnancy are often considered opposites in a woman's biological timeline. Aging is defined by a gradual decline in the functional capabilities of an organism over its lifetime, while pregnancy is characterized by the presence of the transient placenta, which fosters the cellular fitness necessary to support fetal growth. However, in the context of preeclampsia, pregnancy and aging share common hallmarks, including clinical complications, altered cellular phenotypes, and heightened oxidative stress. Furthermore, women with pregnancies complicated by preeclampsia tend to experience age-related disorders earlier than those with healthy pregnancies. Klotho, a gene discovered fortuitously in 1997 by researchers studying aging mechanisms, is primarily expressed in the kidneys but also to a lesser extent in several other tissues, including the placenta. The Klotho protein is a membrane-bound protein that, upon cleavage by ADAM10/17, is released into the circulation as soluble Klotho (sKlotho) where it plays a role in modulating oxidative stress. This review focuses on the involvement of sKlotho in the development of preeclampsia and age-related disorders, as well as the expression of the recently discovered Mytho gene, which has been associated with skeletal muscle atrophy. [ABSTRACT FROM AUTHOR]

Elevated serum soluble alpha Klotho (s-αKlotho) levels are early biomarkers for overwork-related health risks, allowing timely intervention. This finding supports healthcare policies to limit work hours and promote a healthy work-life balance, reducing overwork-related diseases. Further research is needed for validation and intervention development. Objective: This study evaluates the utility of serum s-αKlotho levels as a quantifiable biomarker for overwork. Methods: Frontline medical workers aged 20–55 years from Yiling People's Hospital of Yichang were recruited. Criteria included nonsmokers, non-heavy drinkers, no chronic medication use, and no acute illnesses recently. Participants worked over 10 hours per day, 60 hours weekly, and had at least 3 years of experience. A control group was matched except for work conditions. Data were collected through surveys, and serum levels were measured. Results: Significant differences in serum Klotho were found between overwork and control groups. The overwork group had higher median s-αKlotho levels (49.99 pg/mL) compared to controls (27.88 pg/mL). Conclusion: Overworked medical workers exhibited elevated serum s-αKlotho, suggesting s-αKlotho as a potential biomarker for overwork. Future research should use multicenter designs with larger samples to validate findings. [ABSTRACT FROM AUTHOR]

Microalbuminuria is the earliest clinical abnormality in diabetic kidney disease. High glucose (HG) concentrations are associated with the induction of oxidative stress in podocytes, leading to disruption of the glomerular filtration barrier. Our recent study revealed a significant decrease in the membrane-bound fraction of Klotho in podocytes that were cultured under HG conditions. Given that disintegrin and metalloproteinase 17 (ADAM17) is responsible for the shedding of Klotho from the cell membrane, the present study investigated the impact of HG on the interplay between ADAM17 and Klotho in human podocytes. We demonstrated that ADAM17 protein levels significantly increased in urine, renal tissue, and glomeruli from diabetic rats, with a concomitant increase in glomerular albumin permeability. High glucose increased ADAM17 extracellular activity, NADPH oxidase activity, and albumin permeability in podocytes. These effects were reversed after treatment with ADAM17 inhibitor, in cells with downregulated ADAM17 expression, or after the addition of Klotho. Additionally, elevations of extracellular ADAM17 activity were observed in podocytes with the downregulation of Klotho expression. Our data indicate a novel mechanism whereby hyperglycemia deteriorates podocyte function via ADAM17 activation. We also demonstrated the ability of Klotho to protect podocyte function under hyperglycemic conditions in an ADAM17-dependent manner. [ABSTRACT FROM AUTHOR]

Soluble, circulating Klotho (sKlotho) is essential for normal health and renal function. sKlotho is shed from the renal distal convoluted tubule (DCT), its primary source, via enzymatic cleavage. However, the physiologic mechanisms that control sKlotho production, trafficking, and shedding are not fully defined. We previously found that the G protein‐coupled calcium‐sensing receptor (CaSR) co‐localizes with membrane‐bound αKlotho and the disintegrin/metalloprotease ADAM10 in the DCT and controls sKlotho in response to CaSR ligands and pHo by activating ADAM10. Here, we advance understanding of this process by showing that tetraspanin 5 (Tspan5), a scaffolding and chaperone protein, contributes to the cell surface expression and specificity of a protein complex that includes Tspan5, ADAM10, Klotho, and CaSR. These results support a model of multiprotein complexes that confer signaling specificity beyond CaSR on G protein‐coupled processes. Impact statement Systemic circulating sKlotho is a determinant for normal physiology. Studies of knockout animals established its role as an anti‐aging protein. The regulatory mechanisms for Klotho production and secretion are largely unknown. We report that Tspan 5 contributes to CaSR‐ and ADAM10‐dependent Klotho shedding from the kidney, its primary source. Systemic circulating sKlotho is a determinant for normal physiology. Studies of knockout animals established its role as an anti‐aging protein. The regulatory mechanisms for Klotho production and secretion are largely unknown. We report that Tspan 5 contributes to CaSR‐ and ADAM10‐dependent Klotho shedding from the kidney, its primary source. [ABSTRACT FROM AUTHOR]

Objective To explore the clinical value of apolipoprotein C1 (APOC1) and Klotho expression levels in predicting the prognosis of patients with renal cancer after laparoscopic partial nephrectomy. Methods Eighty patients diagnosed as renal cell carcinoma and underwent laparoscopic partial nephrectomy were collected as the study subjects. According to the prognosis, patients were separated into the good prognosis group (61 cases) and the poor prognosis group (19 cases). Seventy-eight healthy individuals underwent physical examination were collected as the control group. The general clinical data of the subjects were collected, and serum levels of APOC1 and Klotho were tested and analyzed in three groups. Pearson method was applied to analyze the correlation between serum APOC1 and Klotho levels in patients. Cox regression was applied to analyze factors affecting the prognosis of patients. Receiver operating characteristic (ROC) curve was applied to analyze the predictive efficacy of APOC1 and Klotho levels on the prognosis of patients. Results There were significant differences in clinical stage and pathological grade between the poor prognosis group and the good prognosis group (P＜ 0.05). Compared with the control group, the serum APOC1 levels were significantly increased in the good prognosis group and the poor prognosis group (P＜0.05), while the Klotho expression levels were obviously reduced (P＜0.05). And the serum APOC1 level in the control group, the poor prognosis group and the good prognosis group was increased successively (P＜ 0.05), while the serum Klotho level was obviously decreased successively (P＜0.05). The serum APOC1 expression level of patients was negatively correlated with Klotho level (r=-0.577, P＜0.001). The Cox regression results showed that decreased expression level of Klotho and elevated expression level of APOC1, pathologic grading 2 and clinical staging stage Ⅱ were all independent risk factors for poor prognosis (P＜0.05). The area under the curve (AUC) of serum APOC1 and Klotho levels, and their combined application in predicting poor postoperative prognosis in renal cancer patients was 0.863, 0.850 and 0.953, respectively, and the clinical value of combination of the two in predicting the prognosis of patients was superior to that of APOC1 and Klotho alone. Conclusion Patients with poor prognosis after retroperitoneal laparoscopic partial nephrectomy have a obvious increase in serum levels of APOC1 and a obvious decrease in serum level of Klotho. The combination of the two has high clinical significance in predicting the prognosis of patients with retroperitoneal laparoscopic partial nephrectomy. [ABSTRACT FROM AUTHOR]

Background. Inflammation-induced apoptosis of alveolar type II epithelial cells is a primary contributor to sepsis-induced acute respiratory distress syndrome (ARDS). Klotho is a single-pass transmembrane protein with anti-inflammatory and anti-apoptotic effects. However, the role and mechanism of Klotho in the development of ARDS remains unknown. Objectives. This study aimed to investigate the effect of Klotho on sepsis-induced apoptosis in human pulmonary alveolar epithelial cells (HPAEpiCs) together with the potential mechanism. Materials and methods. Cecal ligation and puncture (CLP) were performed to generate an in vivo sepsis model, and HPAEpiCs were treated with lipopolysaccharide (LPS) to mimic sepsis in vitro. Both models were administered recombinant Klotho protein. The morphology of the lung tissue was observed, and apoptotic cells and cell viability were detected. Interleukin (IL)-1β, IL-6, and tumor necrosis factor alpha (TNF-α) levels were detected using enzyme-linked immunosorbent assay (ELISA), while the expression of Bcl-2, Bax and cleaved caspase-3 was detected with western blotting. Results. Klotho reversed the CLP-induced decrease in mouse survival in vivo (p < 0.001) and increased inflammatory cell infiltration and inflammatory substance exudation in the lung tissue of mice with sepsis (both p < 0.001). Klotho also suppressed apoptosis (p < 0.001) as demonstrated by IL-1β, IL-6 and TNF-α expression (all p < 0.001), and Bcl-2/Bax/caspase-3 pathway activation (p < 0.001). Klotho pretreatment significantly prevented LPS-induced apoptosis in vitro (p < 0.001), as demonstrated by IL-1β, IL-6 and TNF-α upregulation (all p < 0.001); and Bcl-2/Bax/caspase-3 pathway activation in HPAEpiCs (p < 0.001). Conclusions. This study demonstrated that Klotho can ameliorate acute lung injury (ALI) induced by sepsis by inhibiting inflammatory responses and exerting anti-apoptotic effects by suppressing Bcl-2/Bax/caspase-3 pathway activation. [ABSTRACT FROM AUTHOR]

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Klotho has been importantly linked to atherosclerosis, but little is known about its specific role. This study investigates the mechanism by which Klotho enhances the stability of atherosclerotic plaques in chronic kidney disease. apoE-/- knockout mice and C57BL/6 mice underwent 5/6 nephrectomy and then klotho-NC and klotho-mimic groups were set up to be fed a high-fat chow diet and a dummy group was created to be fed a normal chow diet. qPCR detected relative mRNA expression of klotho. Oil Red O and HE staining assessed lipid proportion in the aorta. Masson staining evaluated renal failure pathology in mice. Immunohistochemistry measured MAC-2 and α-SMA expression in the aorta. ELISA quantified urea, cholesterol, calcium ions, and triglycerides in mouse plasma. Western blotting detected associated protein expression, followed by cell-based experiments for validation. Compared with the Klotho-NC group, the plaque area and aortic lipid and renal fibrosis area were reduced in the Klotho-mimic group. Klotho-mimic reduced macrophage area, plasma urea, cholesterol, calcium ions, and triglyceride levels, and decreased the expression of p-PERK, NOX2, NOX4, Caspase-3, Caspase-9, Bax, p-GRK2, p-PLCβ, p-Src, and p-IP3R. Without ox-LDL stimulation, Klotho expression increased in the Klotho-mimic group, with no significant differences in NOX2, p-SHP1, p-Src, p-PERK, p-GRK2, and p-PLCβ. With ox-LDL in high-calcium medium, Klotho and p-SHP1 increased, while NOX2, p-Src, p-PERK, p-GRK2, and p-PLCβ decreased in the Klotho-mimic group. After ox-LDL and TPI-1 treatment, Klotho increased, NOX2 decreased, and other proteins showed no significant changes. Adding shRNA-GRK2 reduced NOX2, p-Src, and p-PERK, increased p-SHP1, with no changes in p-GRK2 and p-PLCβ. Differences in NOX2, p-GRK2, p-PLCβ, and p-PERK between groups were reduced in high-calcium medium, while p-SHP1 differences increased. Klotho enhances chronic kidney disease atherosclerotic plaque stability by inhibiting GRK2/PLC-β-mediated endoplasmic reticulum stress in macrophages via the ROS/SHP1 pathway. [ABSTRACT FROM AUTHOR]

The relationship between the weight-adjusted waist circumference index (WWI) and the senescence-inhibitory protein Klotho remains unknown. Therefore, this study aimed to investigate the relationship between WWI and soluble Klotho (s-Klotho). This study analyzed 9,928 participants based on the 2007–2016 National Health and Nutrition Examination Survey (NHANES). Three multiple linear regression models and a restricted cubic spline (RCS) were constructed to assess the association between WWI and s-Klotho levels. Further stratified analyses and interaction tests were performed to evaluate the stability of this association. Piecewise multivariate regression modeling was applied to detect threshold effects. The fully adjusted model showed a negative correlation between continuous WWI and s-Klotho levels (β = −23.65, 95% CI: −36.55, −10.76, P < 0.001). When WWI was grouped into quartiles, participants in the highest quartile had significantly lower circulating s-Klotho levels than those in the lowest quartile (β = −40.65, 95% CI: −64.20, −17.10, P = 0.001). The RCS curves showed a linear negative correlation between WWI and s-Klotho. Further stratified analyses showed that the correlation between WWI and s-Klotho remained stable in most conditions, except for gender. A nonlinear relationship and saturation effect were observed between WWI and s-Klotho in females, with an inflection point of 11.38 cm/√kg (P for overall < 0.001; P for non-linearity = 0.013). However, no significant correlation was observed in males. There is a significant negative correlation between WWI and s-Klotho levels. Proper management of central obesity in middle-aged and older women may be beneficial in delaying senescence. [ABSTRACT FROM AUTHOR]

Background: The relationship between serum klotho level and albuminuria is unknown in middle-aged and elderly participants without diabetes mellitus (DM). Therefore, we will investigate the association between serum klotho level and albuminuria in middle-aged and elderly participants without DM. Methods: Participants (aged 40–79) were from the five continuous cycles (2007–2016) of the National Health and Nutrition Examination Survey (NHANES). Multiple logistic regression was performed to investigate the association between serum klotho level and albuminuria. Results: 9217 participants were included in the present study. 47.6% of the participants were male. The average age of the overall participants was 56.3 years (40–79 years). Overall, 823 participants with albuminuria were identified. After adjusted confounders (age, gender, marital status, ethnicity, family income to poverty ratio, education, body mass index, smoke, charlson comorbidity index, hypertension, hyperlipidemia, angiotensin converting enzyme inhibitor/angiotonin receptor blocker, and estimated glomerular filtration rate), participants with a high serum klotho level had a decreased risk for albuminuria. Compared with the lowest serum klotho level (Tertile 1), participants in Tertile 2 (odds ratio [OR] 0.83, 95% CI 0.70–0.99, P = 0.044) and Tertile 3 (OR 0.76, 95% CI 0.63–0.91, P = 0.003) had a lower risk of albuminuria (P for trend = 0.002). The stratified analysis showed that serum klotho level was still negatively associated with albuminuria in the subgroups, and statistically significant interactions were not observed in the subgroups (all P values for interactions > 0.05, except for the hypertension subgroup). Conclusions: In middle-aged and elderly participants without DM, a high serum klotho level is associated with a decreased risk of albuminuria. In the future, the mechanism of the interaction between klotho and albuminuria needs to be elucidated to find new treatment targets for individuals without DM who suffer from albuminuria. [ABSTRACT FROM AUTHOR]

The retinal pigment epithelium (RPE) contributes to retinal homeostasis, and its metabolic dysfunction is implied in the development of retinal degenerative disease. The isoform M2 of pyruvate kinase (PKM2) is a key factor in cell metabolism, and its function may be affected by insulin-like growth factor 1 (IGF-1). This study aims to investigate the effect of IGF-1 on PKM2 modulation of RPE cells and whether co-treatment with klotho may preserve it. ARPE-19 cells, an ex vivo model of human pigmented epithelium, were exposed to IGF-1. Then, we evaluated PKM2 expression, dimerization and subcellular localization, energy metabolism, and redox balance, and whether pre-treatment with Klotho may antagonize the effects of IGF-1. The results show that IGF-1 favors PKM2 dimerization, thus reducing the activity of PKM2 and leading to an altered cellular energy status coupled with reduced oxidative stress. In conclusion, PKM2 plays a pivotal role in the modulation of RPE metabolism and redox balance and could explain the mechanisms through which IGF-1 participates in the pathogenesis of some retinal diseases. Klotho may exert protective effects by mitigating the IGF-1 signal and its effect on mitochondrial function. [ABSTRACT FROM AUTHOR]

Objectives: The ketogenic diet (KD) has long been used as an alternative nonpharmacological therapy to manage pharmacoresistant epilepsy. The anticonvulsant mechanisms of KD have yet to be fully elucidated. The present study explored whether a KD could exert antioxidative effects by altering brain Klotho (Kl) gene expression.Methods: Thirty male rats were divided into three groups: the normal diet (ND) group received standard rat chow; the calorie-restricted diet (CRD) group was maintained at 90% of the calculated energy need; and the KD group received a diet composed of 8% protein, 2% carbohydrates, and 90% fat (per calorie macronutrient). The levels of β-hydroxybutyrate (BHB) in the serum, Kl gene expression in the brain, and Kl protein, malondialdehyde (MDA), and protein carbonyl (PC) levels in the serum and brain were evaluated by standard methods.Results: The serum BHB levels in the KD group were significantly greater than those in the ND and CRD groups (p < 0.001). The Kl expression in the brain was significantly greater in the KD group than in the ND group (p = 0.028). The brain MDA levels in the KD group were significantly lower than those in the ND group (p = 0.006). Elevated BHB was positively correlated with brain Kl expression (r = 0.668, p < 0.001). The brain MDA levels were negatively correlated with brain Kl expression (r = −0.531, p = 0.003) and serum BHB levels (r = 0.472, p = 0.020).Discussion: KD might exert antioxidative effects by increasing BHB and upregulating Kl in the brain. This could be considered a possible anticonvulsant mechanism of KD. [ABSTRACT FROM AUTHOR]

Background: Klotho, an anti-aging protein, is linked to energy metabolism. There is limited research on the association of serum klotho and triglyceride glucose (TyG) index-related indicators. Our research aims to investigate the relationship of serum klotho with TyG-BMI (body mass index), TyG-WC (waist circumference), and TyG-WHtR (waist-to-height ratio). Methods: From 2007 to 2016, we examined 6,370 participants in the National Health and Nutrition Examination Survey (NHANES). The enzyme-linked immunosorbent assay (ELISA) was utilized to measure serum klotho. We calculated the TyG-BMI, TyG-WC, and TyG-WHtR based on fasting triglycerides, fasting glucose, BMI, WC, and WHtR. Multiple linear regression analysis was used to evaluate the association of serum klotho with TyG-BMI, TyG-WC, and TyG-WHtR. Additionally, generalized additive model (GAM) and smoothing curves were used to evaluate the linear and nonlinear relationships. A piecewise regression model was also utilized to test for threshold effects and determine the breakpoints. Finally, the potential independent associations of serum klotho with TyG-BMI, TyG-WC, and TyG-WHtR were further explored using subgroup analysis. Results: We observed a statistically significant difference in serum klotho levels across different quartiles of the population. Based on the multiple linear regression analysis, serum klotho levels were negatively associated with TyG-related indicators. There was a nonlinear relationship between the serum klotho and TyG-BMI, TyG-WC, and TyG-WHtR. The segmented regression analysis revealed that the breakpoints of TyG-BMI, TyG-WC, and TyG-WHtR were 5.42, 6.67, and 1.89, respectively. Subgroup analysis showed that TyG-related indicators interacted with gender and diabetes. Conclusions: In this study, a negative and nonlinear relationship was identified between serum klotho and TyG-related indicators. Further research is needed to clarify the potential mechanisms that may link serum klotho to TyG-BMI, TyG-WC, and TyG-WHtR. [ABSTRACT FROM AUTHOR]

Introduction: This study investigated the role of fibroblast growth factor 23 (FGF23)/Klotho in the mortality of patients hospitalized with coronavirus disease 2019 (COVID-19), excluding those with chronic kidney disease (CKD). Methodology: A prospective cross-sectional study was conducted from April 2021 to May 2022. Patients who tested positive for COVID-19 via polymerase chain reaction and were hospitalized, were classified into two groups (survivors and non-survivors) at the end of their hospital follow-up. Demographic data, clinical status, and prognosis were analyzed. Results: A total of 66 patients (age 58.8 ± 17.0 years, 60.6% male) were included. The mean age of non-survivors (67.2 ± 1 years) was significantly higher than the survivors (49.2 ± 1 years; p < 0.0001). FGF23 was significantly elevated in non-survivors (301 ± 20 pg/mL), compared to survivors (160 ± 36 pg/mL; p < 0.0001). Factors with significant differences (p < 0.001) between the two groups were investigated as independent mortality predictors using logistic regression analysis. FGF23 (p = 0.01), age (p = 0.045), and oxygen saturation at admission (p = 0.02) were independent predictors of mortality. High serum FGF23 levels were associated with COVID-19-related mortality; Klotho levels were lower (p = 0.028). Vitamin D was not significantly different between the groups. Conclusions: Elevated serum FGF23 and parathyroid hormone (PTH), and lower Klotho levels, were associated with COVID-19-related mortality in patients without CKD. There was no association with serum vitamin D levels. Further studies are required to establish the relationship between mortality and FGF23/Klotho, PTH, and vitamin D levels. [ABSTRACT FROM AUTHOR]

Anemia and mineral and bone disorder (MBD) are significant complications of chronic kidney disease (CKD). The erythropoietin (Epo) pathway plays a key role in both of these processes in CKD. Another molecule that plays an important role in CKD-MBD is fibroblast growth factor (FGF)-23, whose main role is to maintain serum phosphate levels in the normal range, acting via its co-receptor Klotho; however, its activity may also be related to anemia and inflammation. In this review, the regulation of Epo and FGF-23 and the molecular mechanisms of their action are outlined. Furthermore, the complex interaction between EPO and FGF-23 is discussed, as well as their association with other anemia-related factors and processes such as Klotho, vitamin D, and iron deficiency. Together, these may be part of a "kidney–bone marrow–bone axis" that promotes CKD-MBD. [ABSTRACT FROM AUTHOR]

Salivary gland branching morphogenesis is regulated by the functional integration of neuronal signaling, but the underlying mechanisms are not fully understood in aging accelerated klotho‐deficient (Kl−/−) mice. Here, we investigated whether the neuropeptides substance P (SP) and neuropeptide Y (NPY) affect the branching morphogenesis of embryonic salivary glands in aging Kl−/− mice. In the salivary glands of embryonic Kl−/− mice, morphological analysis and immunostaining revealed that epithelial bud formation, neuronal cell proliferation/differentiation, and the expression of the salivary gland functional marker ZO‐1 were decreased in embryonic ductal cells. Incubation with SP/NPY at E12‐E13d promoted branching morphogenesis, parasympathetic innervation, and epithelial proliferation in salivary glands of embryonic Kl−/− mice. The ERK inhibitor U0126 specifically inhibited neuronal substance‐induced epithelial bud formation in the embryonic salivary gland. RNA‐seq profiling analysis revealed that the expression of fibroblast growth factors/fibroblast growth factors (FGFs/FGFRs) and their receptors was significantly regulated by SP/NPY treatment in the embryonic salivary gland (E15). The FGFR inhibitor BGJ389 inhibited new branching formation induced by SP and NPY treatment and ERK1/2 expression. These results showed that aging may affect virtually the development of salivary gland by neuronal dysfunction. The neuropeptides SP/NPY induced embryonic salivary gland development through FGF/FGFR/ERK1/2‐mediated signaling. [ABSTRACT FROM AUTHOR]

COVID-19 is characterized by a striking similarity to premature aging. Its clinical manifestations range from asymptomatic to critical illness. No single central agent has been demonstrated so far. We present Klotho, an antiaging protein, as a key factor in COVID-19 pathophysiology. There is epidemiological evidence that both acute and chronic uses of Klotho agonists have a beneficial effect in reducing COVID-19 severity and mortality. A review of the PubMed epidemiological, clinical, and mechanistic evidence supports a role for Klotho deficit as a central determinant of severe COVID-19. Clinical data support the idea that chronic use of Klotho agonists protects against severe COVID-19 and that its acute use may be beneficial. We propose a unifying hypothesis that low Klotho levels play a key role in severe COVID-19, while increasing Klotho levels can have a beneficial effect through the prevention of acute kidney injury (AKI) and potential antiviral effects. Further research is needed. [ABSTRACT FROM AUTHOR]

Phosphate is essential for numerous biological processes, and serum levels are tightly regulated to accomplish these functions. The regulation of serum phosphate in a narrow physiological range is a well-orchestrated process and involves the gastrointestinal (GI) tract, bone, kidneys, and several hormones, namely, parathyroid hormone, fibroblast growth factor 23 (FGF23), and 1,25-dihydroxyvitamin D (1,25 Vitamin D). Although primarily synthesized in the bone, FGF23, an endocrine FGF, acts on the kidney to regulate phosphate and Vitamin D homeostasis by causing phosphaturia and reduced levels of 1,25 Vitamin D. Recent studies have highlighted the complex regulation of FGF23 including transcriptional and post-translational modification and kidney-bone cross talk. Understanding FGF23 biology has led to the identification of novel therapeutic agents to treat diseases that disrupt phosphate metabolism secondary to FGF23. The focus of this review is to provide an overview of phosphate homeostasis, FGF23 biology, and the role of FGF23 in phosphate balance. [ABSTRACT FROM AUTHOR]

Treatment of multiple sclerosis (MS) remains a major challenge. The aim of this study was to evaluate the therapeutic potential of mesenchymal stem cells (MSCs) engineered with secreted Klotho (SKL) in an experimental autoimmune encephalomyelitis (EAE) mouse model of MS. EAE was induced in mice. MSCs or MSCs engineered with SKL (SKL-MSCs) were administered to EAE mice at the onset of disease. Hematoxylin-eosin and luxol fast blue staining were performed to evaluate histopathological changes. Expression of pro-inflammatory (TNF-α, IFN-γ, and IL-17) and anti-inflammatory (IL-10) cytokines was determined in the spinal cord using real-time PCR. Spinal cords were then processed for immunohistochemistry of the aforementioned cytokines. The frequencies of Th1, Th17, and regulatory T (Treg) cells were evaluated by flow cytometry of the spleen. The results showed that SKL-MSCs decreased clinical scores and reduced demyelination and inflammatory infiltration in the spinal cord more significantly than MSCs. Compared to MSCs, SKL-MSCs also exhibited a more profound capability of decreasing expression of TNF-α, IFN-γ, and IL-17 and increasing expression of IL-10 in the spinal cord with an enhanced homing to the inflamed tissue. Moreover, SKL-MSCs decreased the frequencies of Th1 and Th17 cells and increased the frequency of Treg cells in the spleen more potently than MSCs. Taken together, these findings demonstrate that SKL overexpression enhances the therapeutic potential of MSCs, as evidenced by significantly improved disease severity, decreased inflammation and tissue damage in the spinal cord, and a promoted shift in the Th17/Treg balance towards the anti-inflammatory Treg side in the EAE mice. [ABSTRACT FROM AUTHOR]

Abstract Background The relationship between serum klotho level and albuminuria is unknown in middle-aged and elderly participants without diabetes mellitus (DM). Therefore, we will investigate the association between serum klotho level and albuminuria in middle-aged and elderly participants without DM. Methods Participants (aged 40–79) were from the five continuous cycles (2007–2016) of the National Health and Nutrition Examination Survey (NHANES). Multiple logistic regression was performed to investigate the association between serum klotho level and albuminuria. Results 9217 participants were included in the present study. 47.6% of the participants were male. The average age of the overall participants was 56.3 years (40–79 years). Overall, 823 participants with albuminuria were identified. After adjusted confounders (age, gender, marital status, ethnicity, family income to poverty ratio, education, body mass index, smoke, charlson comorbidity index, hypertension, hyperlipidemia, angiotensin converting enzyme inhibitor/angiotonin receptor blocker, and estimated glomerular filtration rate), participants with a high serum klotho level had a decreased risk for albuminuria. Compared with the lowest serum klotho level (Tertile 1), participants in Tertile 2 (odds ratio [OR] 0.83, 95% CI 0.70–0.99, P = 0.044) and Tertile 3 (OR 0.76, 95% CI 0.63–0.91, P = 0.003) had a lower risk of albuminuria (P for trend = 0.002). The stratified analysis showed that serum klotho level was still negatively associated with albuminuria in the subgroups, and statistically significant interactions were not observed in the subgroups (all P values for interactions > 0.05, except for the hypertension subgroup). Conclusions In middle-aged and elderly participants without DM, a high serum klotho level is associated with a decreased risk of albuminuria. In the future, the mechanism of the interaction between klotho and albuminuria needs to be elucidated to find new treatment targets for individuals without DM who suffer from albuminuria.

In this study, the potential role and interaction of the APOε and KLOTHO genes on the penetrance of fragile X-associated tremor/ataxia syndrome (FXTAS) and on the IQ trajectory were investigated. FXTAS was diagnosed based on molecular, clinical and radiological criteria. Males with the premutation (PM) over 50 years, 165 with and 34 without an FXTAS diagnosis, were included in this study and were compared based on their APO (ε2-ε3-ε4) and KLOTHO variant (KL-VS) genotypes. The effect of APOε4 on FXTAS stage and on diagnosis did not differ significantly by KL-VS genotype with interaction effect p = 0.662 and p = 0.91, respectively. In the FXTAS individuals with an APOε2 allele, a marginal significance was observed towards a larger decline in verbal IQ (VIQ) in individuals with an APOε4 allele compared to those without an APOε4 allele (p = 0.071). In conclusion, our findings suggest that the APOε4 and KL-VS genotypes alone or through their interaction effect do not appear to predispose to either FXTAS diagnosis or stage in male carriers of the PM allele. A further study is needed to establish the trend of IQ decline in the FXTAS individuals who carry APOε4 with APOε2 compared to those without APOε4.

Background: Neurodegenerative diseases (NDs) have become a significant public health problem, and oxidative stress (OS) serves as a pivotal factor in the pathological progression of NDs. Pharmacological research indicates that Astragalus polysaccharide (APS, extract of Astragalus membranaceus) has antioxidant and antiaging effects, closely related to NDs. Objectives: The potential of APS in treating NDs remains uncertain. Herein, the neuroprotective effect of APS was evaluated. Materials and Methods: The H2O2-induced PC12 cell damage model was established to assess the neuroprotection of APS. Cell viability was determined by MTT. Cell images were observed using ImageXpress Micro Confocal analysis. Apoptosis of the cells and intracellular levels of reactive oxygen species (ROS) were detected using flow cytometry. The expression of Klotho, nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), thioredoxin reductase 1 (TrxR1), and NAD(P)H quinone oxidoreductase 1 (NQO1) was determined by Western blot (WB). Results: APS exerted significant protection against H2O2-caused cell death dose-dependently, and APS could significantly reduce the intracellular ROS and relieve cell apoptosis. Furthermore, we found that APS could upregulate the expression of Klotho and Nrf2 dose-dependently, and the expression levels of Nrf2-mediated antioxidant proteins increased significantly, including HO-1, TrxR1, and NQO1. Moreover, we found that APS upregulated Klotho and Nrf2-mediated antioxidant proteins time-dependently. The expression of klotho peaked at 6 hours after treatment with APS (400 mg/L). Subsequently, the protein level of Nrf2 reached the maximum at 12 hours, and the downstream NQO1, HO-1, and TrxR1 levels peaked at 24 hours. Conclusion: This study demonstrates that APS is promising for further development against oxidative stress-related NDs. [ABSTRACT FROM AUTHOR]

Background and objective: In acute kidney injury (AKI), a strong inflammatory component is activated in response to the renal damage, and one of the main mediators behind this process is the pro-inflammatory interleukin 6 or IL-6. Beside to this phenomenon, there are also alterations in different components of mineral metabolism, such as those dependent on fibroblast growth factor (FGF)23 and the anti-ageing cofactor klotho. The aim of this work was to explore the association between renal function and systemic levels of IL-6, as well as FGF23 and klotho in the early stages of AKI, analysing the predictive capacity of IL-6 in early mortality associated with AKI. Material and methods: Plasma levels of IL-6, klotho and FGF23 were analysed in samples from 28 patients with AKI and related to renal function on hospital admission, and after 24 and 72 h. In addition, the predictive capacity of IL-6 on AKI-associated mortality was analysed at the three study time points. In an experimental nephrotoxic -AKI mouse model, systemic IL-6 and FGF23 values were also analysed 24 and 72 h after induction of kidney damage, as well as in mice overexpressing the anti-ageing protein, klotho. Results: Systemic IL-6 levels increased in AKI patients, especially in hospital admission time, and decreased in parallel with improving renal function. At the same time as IL-6 values increased, there was an increase in FGF23 and a decrease in klotho levels, with a significant and positive correlation between IL-6 and FGF23 levels. In addition, we obtained that systemic IL-6 levels were a good predictor of mortality in these patients, with an area under the curve equal to one at 72 h after AKI. In the experimental mouse AKI model, we also observed an increase in plasma levels in both IL-6 and FGF23 after 24 h of kidney damage. Nevertheless, in transgenic mice overexpressing klotho, there was no such increase in any of them. Conclusions: There is an association between renal damage and increased levels of IL-6 and FGF23 in patients with AKI, especially on hospital admission time. Moreover, IL-6 levels are able to predict mortality in these patients, being a promising prognostic biomarker at any study time with a strong prediction at 72 h after patient admission. Maintaining adequate klotho levels could prevent the IL-6 mediated inflammatory response and therefore also reduce the degree and severity of renal damage after AKI. Resumen: Antecedentes y objetivo: En un fracaso renal agudo (FRA) se activa un fuerte componente inflamatorio como respuesta al daño renal, y uno de los principales mediadores de este proceso es la interleuquina pro-inflamatoria 6 o IL-6. A su vez, ligado a este fenómeno también se producen alteraciones en los distintos componentes del metabolismo mineral como son aquellos dependientes del factor de crecimiento de fibroblasto (FGF)23 y el cofactor anti-envejecimiento klotho. El objetivo de este trabajo fue explorar la asociación entre la función renal y los niveles sistémicos tanto de IL-6, así como de FGF23 y klotho, en las etapas tempranas de un FRA, analizando la capacidad predictora de IL-6 en la mortalidad temprana asociada al FRA. Materiales y métodos: Se analizaron los niveles plasmáticos de IL-6, klotho y FGF23 en muestras procedentes de 28 pacientes con FRA, y se relacionaron con la función renal en el momento del ingreso hospitalario, y después de 24 y 72 horas. Además, se analizó la capacidad predictora de IL-6 sobre la mortalidad asociada al FRA en los tres tiempos del estudio. En un modelo experimental de FRA nefrotóxico en ratón, se analizaron también los valores sistémicos de IL-6 y FGF23 tras las 24 y 72 horas desde la inducción del daño renal, así como en ratones que sobreexpresan la proteína anti-envejecimiento, klotho. Resultados: Los niveles de IL-6 aumentaron en los pacientes con FRA, especialmente en el momento del ingreso hospitalario, y fueron disminuyendo en paralelo a la mejora de la función renal. Al mismo tiempo que el aumento de IL-6, se produjo el incremento sistémico de FGF23 y el descenso de klotho, existiendo una correlación significativa y positiva entre los niveles de IL-6 y FGF23. Además, obtuvimos que los niveles sistémicos de IL-6 son un buen predictor de la mortalidad en los pacientes, con un área bajo la curva igual a uno tras las 72 horas desde el diagnóstico de FRA. En el modelo de FRA experimental en ratón, observamos también un incremento en los niveles plasmáticos tanto de IL-6 como de FGF23, tras las 24 horas del daño renal. Sin embargo, en los ratones transgénicos con sobreexpresión de klotho, no se produjo tal incremento en ninguna de ellas. Conclusiones: Existe una asociación entre el daño renal, el incremento de la IL-6 y de FGF23 en pacientes con FRA, especialmente en el momento del diagnóstico. Además, los niveles elevados de IL-6 predicen la mortalidad de estos pacientes a corto y medio plazo, considerándose un buen biomarcador pronóstico con una predicción total tras las 72 horas desde el diagnóstico del FRA. Mantener unos niveles adecuados de klotho podría prevenir la respuesta inflamatoria mediada por la IL-6 y por lo tanto también aminorar el grado y severidad del daño renal tras un FRA.

Abstract Urinary incontinence (UI) in females is a prevailing condition that affects individuals across various age groups and is not limited to older females. The presence of serum alpha-Klotho (α-klotho) serves as a reliable biomarker to indicate the effects of antiaging. Nevertheless, the scientific research on the association between α-klotho and UI remains limited. Therefore, the purpose of this study is to investigate and evaluate the connection between α-klotho levels and the UI among females in the US. We utilized data from the National Health and Nutrition Examination Survey 2007–2016 to investigate the potential connection between α-klotho levels and the UI among females aged 40 to 79. Weighted linear regression models and sensitivity tests were conducted to explore the correlation. 2628 females were involved in this study, representing 22,492,348 non-institutionalized residents in the US. The mean age was 53.9 ± 0.2 years and the mean level of α-klotho was 873.0 ± 8.9 pg/mL. After adjusting for relevant covariables, weighted linear regression models revealed that individuals with severe UI exhibited significantly lower serum α-klotho levels (β = − 100.66; 95% CI: − 156.31, − 45.01; P

Abstract Background This study utilized large-scale population data from the National Health and Nutrition Examination Survey (NHANES) to elucidate the relationship between the Klotho protein and metabolic syndrome along with its components. We further investigated the possible mediating effect of inflammation on these relationships. Our objective was to identify biomarkers for risk stratification and potential therapeutic targets for metabolic syndrome. Methods This study enrolled 13,119 participants aged 40–79 years, spanning five NHANES cycles from 2007 to 2016, with complete information on metabolic syndrome and the Klotho protein. The definition of metabolic syndrome followed the criteria of the National Cholesterol Education Program-Adult Treatment Panel III. Survey-weighted logistic regression and subgroup analysis were used to explore the associations between serum Klotho protein levels and metabolic syndrome, along with its components. Mediation analysis was performed to investigate the mediating effects of inflammation-related markers, including white blood cells, neutrophils, lymphocytes, monocytes, the neutrophil-to-lymphocyte ratio (NLR), the platelet-to-lymphocyte ratio (PLR), the systemic immune-inflammation index (SII) and the monocyte-to-HDL ratio (MHR), with the aim of elucidating how the Klotho protein influences the onset and progression of metabolic syndrome. Results The study participants had an average age of 56.06 years (95% CI: 55.76–56.37), with a Klotho protein concentration of 798.10 pg/ml (95% CI: 656.50–980.50) and a 43.77% prevalence of metabolic syndrome (n = 5742). In the crude model, Klotho was negatively correlated with metabolic syndrome and its components, including central obesity, hypertension, and hypertriglyceridemia. After adjusting for all confounding factors, Klotho was demonstrated to be negatively associated only with metabolic syndrome (OR: 0.82, 95% CI: 0.70–0.97), hypertension (OR: 0.83, 95% CI: 0.70–0.98), and hypertriglyceridemia (OR: 0.78, 95% CI: 0.67–0.91). Subgroup and interaction analyses revealed significant interactions between age, sex, race/ethnicity, body mass index, and Klotho. Additionally, mediation analysis demonstrated that leukocytes, neutrophils and monocytes accounted for 34.78%, 31.91% and 7.13%, respectively, of the associations between Klotho and metabolic syndrome. Conclusion The serum concentration of Klotho protein was negatively associated with metabolic syndrome, with the relationship being partly mediated by systemic immune inflammation. The findings of this research revealed that the Klotho protein may be a valuable biomarker for risk stratification and a potential therapeutic target for metabolic syndrome.

Abstract Background The triglyceride-glucose (TyG) index is recognized as a robust indicator for evaluating insulin resistance (IR). Despite the well-documented anti-aging biological functions of Klotho protein, its correlation with the TyG index remains unexplored. Methods A cross-sectional analysis was conducted involving participants from the National Health and Nutrition Examination Surveys (NHANES) 2007–2016. The TyG index was computed using laboratory data, while serum Klotho concentrations was determined using ELISA kit. After adjusting potential confounding variables, multivariate regression models were employed to evaluate the association between the TyG index and Klotho protein levels among middle-aged and elderly females and males separately. Additionally, smooth curve fitting and segmented regression model were applied to investigate potential threshold effects and identify the inflection point. Results A total of 6,573 adults qualified for inclusion, comprising 3,147 (47.88%) males and 3,426 (52.12%) females. Multivariate regression analysis revealed that females with a higher TyG index exhibited significantly lower serum Klotho concentrations (β=-83.41, 95% CI: -124.23 to -42.60, P

Objective To explore the correlation between the expression levels of serum Klotho and uromodulin （UMOD） and immunoglobulin A （IgA） nephropathy complicated with hyperuricemia. Methods From January 1, 2018 to January 1, 2022, 97 hospitalized IgA nephropathy were selected as study subjects. Based upon blood uric acid level before renal puncture, they were assigned into two groups of IgA nephropathy complicated with hyperuricemia （n=42） and normal blood uric acid （n=55）. Additionally, 97 healthy individuals during the same period were designated as control group. Serum levels of Klotho and UMOD and basic profiles of three groups were compared. Pearson’s method was applied for examining the correlation between serum levels of Klotho and UMOD, estimated glomerular filtration rate （eGFR）, uric acid and creatinine levels in patients with IgA nephropathy complicated by hyperuricemia. Multivariate Logistic regression was utilized for analyzing the influencing factors of IgA nephropathy complicated with hyperuricemia. Receiver operating characteristic （ROC） curve was employed for examining the diagnostic value of serum levels of Klotho and UMOD for IgA nephropathy complicated with hyperuricemia. Results Serum Klotho was （151.66±27.29） ng/L and serum UMOD （39.65±8.67） g/L in IgA nephropathy complicated with hyperuricemia group; serum Klotho was （185.34±38.17） ng/L and serum UMOD （51.13±12.32） g/L in normal blood uric acid group; serum Klotho was （211.53±50.63） ng/L and serum UMOD （62.39±16.86） g/L in control group. Statistically significant differences existed in serum levels of Klotho and UMOD among three groups （P＜0.05）. Systolic blood pressure was （152.62±18.82） mmHg（1mmHg=0.133 kPa）, diastolic blood pressure （98.37±13.65）mmHg, proportion of hypertension 27（64.29）, 24-hour urine protein quantification （2.55±0.69）g, blood uric acid （435.26±113.25）μmol/L, creatinine （352.55±58.62） μmol/L and eGFR （72.28±13.53）mL·min−1·（1.73m2）−1 in IgA nephropathy complicated with hyperuricemia group; systolic blood pressure was （112.58±15.97）mmHg, diastolic blood pressure （72.43±10.34）mmHg, proportion of hypertension 21（38.18）, 4-hour urine protein quantification （1.62±0.31）g, blood uric acid （342.59±84.64）μmol/L, creatinine （103.11±27.47）μmol/L and eGFR （102.96±35.68）mL·min−1·（1.73m2）−1 in normal blood uric acid group. The inter-group differences of the above parameters were statistically significant （P＜0.05）. Pearson’s correlation analysis results indicated that serum levels of Klotho and UMOD in patients with IgA nephropathy complicated by hyperuricemia were correlated negatively with blood uric acid and creatinine and positively with eGFR（P＜0.05）; hypertension, 24-hour urine protein quantification, eGFR, blood uric acid and serum levels of Klotho and UMOD were independent influencing factors for IgA nephropathy complicated with hyperuricemia （P＜0.05）. ROC curve showed that area under the curve （AUC） of serum Klotho and UMOD for diagnosing IgA nephropathy complicated by hyperuricemia alone and in combination was 0.947, 0.882 and 0.961 respectively and combined diagnostic value of the two was higher than that of single diagnosis（Zcombination-Klotho=0.887,P=0.375; Zcombination-UMOD=2.423, P=0.015）. Conclusion Serum levels of Klotho and UMOD are down-regulated in patients with IgA nephropathy complicated by hyperuricemia. Correlation exists between IgA nephropathy and hyperuricemia and a combined diagnosis has an excellent effect. Close monitoring of serum levels of Klotho and UMOD has some reference value for diagnosing IgA nephropathy complicated by hyperuricemia.

Objective To investigate the impact of total parathyroidectomy with autotransplantation (tPTx+AT) on bone mineral density and serum soluble Klotho (sKlotho) level in patients with secondary hyperparathyroidism (SHPT). Methods A total of 86 patients undergoing tPTx+AT in the Second Affiliated Hospital of Anhui Medical University from June 2019 to May 2022 were recruited in this study. Their demographic characteristics were collected before surgery, along with serum levels of corrected calcium, phosphorus, intact parathyroid hormone (iPTH), alkaline phosphatase (ALP), fibroblast growth factor 23 (FGF23), and sKlotho before and at 5 d, and 1, 3, 6, 12 and 24 months after surgery. Dual energy X-ray absorptiometry was used to determine the BMD values of the lumbar spine L1-L4 before surgery and at 3, 6, 12 and 24 months after surgery. The changes in BMD and serum FGF23 and sKlotho levels before and after tPTx+AT were observed. Results Surgical treatment was successfully completed in all 86 patients, with their clinical symptoms such as bone pain and skin itching significantly improved postoperatively, and markedly decreased serum calcium, phosphorus, iPTH, ALP and FGF23 levels. The sKlotho level was significantly lower at 5 d postoperatively than that preoperatively, with that at 1 month after surgery increased by approximately 24.5% than the preoperative level, and then the level was in a stable trend. The BMD values at the lumbar spine L1-L4 were increased postoperatively, and reached the highest levels at 12 months postoperatively. Further analyses showed that dialysis vintage, duration of SHPT, and ALP, iPTH and FGF23 levels were negatively correlated with the Z-scores of the lumbar spine L1-L4, while sKlotho level was positively correlated with the Z-scores. Conclusion tPTx+AT can significantly improve the clinical symptoms of SHPT patients, regulate the balance of calcium and phosphorus metabolism, increase sKlotho level and reduce FGF23 level. It is an effective method to improve BMD.

Abstract Background Klotho plays a pivotal role in human aging. Metabolic syndrome (MetS) is composed of multiple conditions that are also risk factors for cardiovascular disease and diabetes. We try to discuss gender-specific differences in Klotho and the associations between Klotho and MetS components. Materials and methods The National Health and Nutrition Examination Survey database from cycle 2015–2016 was analyzed. MetS was defined according to the 2005 updated criteria by the American Heart Association and National Heart Lung and Blood Institute. Gender-specific differences in serum Klotho, and associations between Klotho level and MetS components were examined. Results A total of 2475 participants (40–79 years old) with comprehensive data were included (52% women). In general, lower Klotho was associated with advanced age, male sex, tobacco use, elevated triglycerides, renal insufficiency, inflammation, low estradiol, and low sex hormone-binding globulin (SHBG). The correlation between MetS and Klotho was more obvious in women, mainly in waist circumference and triglyceride. There were no gender-specific differences in the associations between Klotho and renal dysfunction, but multivariate linear regression analysis showed gender differences in other factors associated with Klotho. Estradiol, SHBG, high-density lipoprotein cholesterol (HDL), and high-sensitivity C-reactive protein (CRP) were associated with Klotho levels independent of age and renal function in men, whereas in women, Klotho was independently associated with triglycerides and white blood cell count. Conclusion Klotho levels had gender disparities regardless of age, renal function, and sex hormones. In the current cohort, triglycerides were the major component of MetS that was independently associated with serum Klotho levels, and the association was particularly seen in women. However, HDL was found to be the male-specific MetS component independently associated with Klotho.

Background: Klotho, encoded by the KLOTHO gene, is an anti-aging and neuroprotective protein. KLOTHO KL-VS heterozygosity (KL-VSHET) is hypothesized to be protective against the accumulation of Alzheimer's disease (AD) neuropathological hallmarks (amyloid-β (Aβ) and tau). Objective: We examine whether being positive for Aβ (A+) or tau (T+), or A/T joint status [positive for Aβ (A + T-), tau (A-T+), both (A + T+) or neither (A-T-)] vary by KL-VS and whether serum klotho protein levels vary based on A+, T+, or A/T status in a cohort enriched for AD risk. Methods: The sample consisted of 704 cognitively unimpaired, late middle-aged, and older adults; MeanAge(SD) = 64.9(8.3). Serum klotho was available for a sub-sample of 396 participants; MeanAge(SD) = 66.8(7.4). Covariate-adjusted logistic regression examined whether A + or T+, and multinomial regression examined whether A/T status, vary by KL-VS genotype. Covariate-adjusted linear regression examined whether serum klotho levels differ based on A+, T+, or A/T status. Results: A+ prevalence was lower in KL-VSHET (p = 0.05), with no differences in T + prevalence (p = 0.52). KL-VSHET also had marginally lower odds of being A + T- (p = 0.07). Serum klotho levels did not differ based on A+, T+, or A/T status (all ps ≥ 0.40). Conclusions: KL-VSHET is associated with lower odds of being positive for Aβ, regardless of whether one is also positive for tau. Conversely, the likelihood of being tau positive did not differ based on KL-VS genotype. Our findings add to the growing KLOTHO literature and suggests the need for further research focused on understanding the mechanisms underlying KL-VS-related putative resilience to AD. [ABSTRACT FROM AUTHOR]

Background: The Klotho gene is implicated in suppressing aging phenotypes and influencing age-related diseases. Previous studies have delved into its connection with different diseases, yet the association between Klotho and hearing loss has rarely been examined. A recent population study explored the relationship between serum Klotho and hearing loss, but it had certain limitations. This study aims to analyze the link between serum α-Klotho levels and hearing thresholds, as well as the risk of hearing loss. Methods: A total of 1,762 adults aged 40–69 years were selected from the 2011–2012 National Health and Nutrition Examination Survey (NHANES). Data on audiometry, serum α-Klotho levels, and relevant covariates were gathered. Statistical analyses, including linear and logistic regression, assessed the relationships of serum α-Klotho levels with hearing outcomes. Results: Increased serum α-Klotho levels were correlated with diminished hearing thresholds and a lower risk of hearing loss. Quartile analysis revealed a significant trend, where elevated α-Klotho levels were linked to better auditory outcomes. Adjusted models controlled for various covariates, affirming the robustness of the findings. Non-linear associations were not observed. Conclusion: This study provided novel evidence of a negative association between serum α-Klotho and hearing impairment in adults aged 40–69. Our results suggested a protective role of serum α-Klotho on adults with hearing loss. [ABSTRACT FROM AUTHOR]

Introduction: This study investigated the potential link between serum klotho levels and cognitive function in patients with non-alcoholic fatty liver disease (NAFLD). Materials and Methods: Utilizing NHANES data from 2011 to 2014, the research included 356 eligible participants. NAFLD was identified with the United States Fatty Liver Index (US-FLI), and cognition was measured by various tests including the Animal Fluency Test (AFT), Digit Symbol Substitution Test (DSST), Immediate Recall Test (IRT), and Delayed Recall Test (DRT). Weighted logistic regression and restricted cubic splines were employed to analyze the relationship between klotho levels and cognitive scores. Results: A significant nonlinear association was observed between klotho levels and the performance in DSST and Delayed Recall Test (DRT). After controlling for confounding factors, the study found a positive association between higher serum klotho levels and improved cognitive performance in both AFT and DSST. However, there was no significant relationship between klotho levels and the IRT or DRT, regardless of whether the natural logarithm or quartile was considered. Discussion: The findings suggest that a higher serum klotho level may be positively correlated with better cognitive performance in NAFLD patients. [ABSTRACT FROM AUTHOR]

Contrast-induced acute kidney injury (CI-AKI) is one of the main causes of hospital-acquired renal failure, and still lacks of effective treatments. Previously, we demonstrated that αKlotho, which is an anti-aging protein that highly expresses in the kidney, has therapeutic activity in CI-AKI through promoting autophagy. However, the specific mechanism underlying αKlotho-mediated autophagy remains unclear. The RNA sequencing analysis of renal cortex revealed that the differentially expressed genes related to autophagy between αKlotho-treated CI-AKI mice and vehicle-treated CI-AKI mice were found to be associated with mitophagy and apoptosis. In the kidney of CI-AKI mice and HK-2 cells exposed to Iohexol, we revealed that αKlotho promoted mitophagy and decreased cell apoptosis. Mechanistically, αKlotho attenuated mitochondria damage, decreased mitochondrial ROS by upregulating BNIP3-mediated mitophagy. BNIP3 deletion abolished the beneficial effects of αKlotho both in vivo and in vitro. Moreover, we further demonstrated that αKlotho upregulated FoxO3 nuclear expression in Iohexol-treated HK-2 cells. Knockdown of FOXO3 gene inhibited αKlotho-promoted BNIP3-mediated mitophagy and subsequently increased the oxidative injury and cell apoptosis. Taken together, our results indicated a critical role of αKlotho in alleviating CI-AKI via mitophagy promotion involving the FoxO3-BNIP3 pathway. [ABSTRACT FROM AUTHOR]

Background and Objectives: Soluble alpha Klotho (s.Klotho) is an emerging marker for chronic kidney disease (CKD) prognosis. The objective was to study the association between s.Klotho and CKD‐related decrease in glomerular filtration rate (GFR), bone and vascular damage. Method: A total of 118 patients with CKD stage 2–4 were enrolled and 107 patients continued in the study. Clinical and laboratory parameters were recorded at time of enrollment and 12 months. A double sandwich ELISA for s.Klotho was recorded in controls (n = 25) and patients' serum samples at 6 months (n = 107) and 12 months (n = 102). Primary endpoints like 40% or more fall in GFR, a requirement for renal replacement therapy (RRT), and death with different grades of s.Klotho deficiency were studied. Results: Of the 107 patients (80 male and 27 female), mean s.Klotho was 3.46 ng/mL (02.3–04.2). The GFR fall was significantly different (p value < 0.0001) in the different grades of s.Klotho deficiency with Grade 4 s.Klotho deficiency (0.1–2.99 ng/mL) having the maximum fall of GFR at 9.2 mL/min/1.73 m2 (04.8–12.0) and minimum in Grade 2 (3–5.99 ng/mL) at 1.35 mL/min/1.73 m2 (03.0–02.75). The Ankle Brachial Pressure Index positively correlated with s.Klotho and the correlation coefficient was 0.536 (0.382–0.662) (p < 0.001). The carotid intimal medial thickness negatively correlated with s.Klotho and the correlation coefficient was −0.712 (95% CI: −0.797–−0.601, p < 0.001). All five deaths had s.Klotho Grade 4 (severe) deficiency. The event‐free survival rate was maximum (100%) in Grade 2 Klotho deficiency and lowest (55%) in Grade 4 s.Klotho deficiency. Conclusions: s.Klotho levels decreased significantly in patients with progressive kidney failure. s.Klotho levels significantly correlated with the presence of vascular disease. Death and need for RRT were significantly more in patients with severe s.Klotho deficiency. [ABSTRACT FROM AUTHOR]

Background: Age-related cataract (ARC) is a common eye disease and represents a common contributing factor to visual damage and loss. Klotho is a longevity gene and has been reported to participate in aging-related disorders. This work aims to investigate the potential role of klotho in ARC. Methods: In human lens epithelial cells (HLECs) induced by varying concentrations of hydrogen peroxide (H2O2), CCK-8 assay was used to detect cell viability. DCFH-DA probe was used to detect reactive oxygen species (ROS) level. Western blot was used to detect klotho expression. JC-1 fluorochrome assay was used to detect mitochondrial membrane potential (MMP). The concentrations of oxidative stress markers malondialdehyde (MDA) and superoxide dismutase (SOD) were detected by related assay kits. Flow cytometry analysis, immunofluorescence staining and western blot were used to detect cell apoptosis. SA-β-gal staining and western blot were used to detect cell senescence. Results: Klotho expression was decreased in HLECs induced by increasing concentrations of H2O2. Overexpression of klotho significantly inhibited ROS generation, decreased MDA content, increased SOD content, promoted cell viability and suppressed cell apoptosis and senescence in H2O2-induced HLECs. Furthermore, klotho down-regulated NOX4 expression and NOX4 elevation partially reversed the effects of klotho on H2O2-induced HLECs. Conclusions: To sum up, klotho may down-regulate NOX4 to protect against H2O2-induced HLECs damage. This finding suggested the potential therapeutic use of klotho in ARC, which needs further investigation. [ABSTRACT FROM AUTHOR]

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Background: This study utilized large-scale population data from the National Health and Nutrition Examination Survey (NHANES) to elucidate the relationship between the Klotho protein and metabolic syndrome along with its components. We further investigated the possible mediating effect of inflammation on these relationships. Our objective was to identify biomarkers for risk stratification and potential therapeutic targets for metabolic syndrome. Methods: This study enrolled 13,119 participants aged 40–79 years, spanning five NHANES cycles from 2007 to 2016, with complete information on metabolic syndrome and the Klotho protein. The definition of metabolic syndrome followed the criteria of the National Cholesterol Education Program-Adult Treatment Panel III. Survey-weighted logistic regression and subgroup analysis were used to explore the associations between serum Klotho protein levels and metabolic syndrome, along with its components. Mediation analysis was performed to investigate the mediating effects of inflammation-related markers, including white blood cells, neutrophils, lymphocytes, monocytes, the neutrophil-to-lymphocyte ratio (NLR), the platelet-to-lymphocyte ratio (PLR), the systemic immune-inflammation index (SII) and the monocyte-to-HDL ratio (MHR), with the aim of elucidating how the Klotho protein influences the onset and progression of metabolic syndrome. Results: The study participants had an average age of 56.06 years (95% CI: 55.76–56.37), with a Klotho protein concentration of 798.10 pg/ml (95% CI: 656.50–980.50) and a 43.77% prevalence of metabolic syndrome (n = 5742). In the crude model, Klotho was negatively correlated with metabolic syndrome and its components, including central obesity, hypertension, and hypertriglyceridemia. After adjusting for all confounding factors, Klotho was demonstrated to be negatively associated only with metabolic syndrome (OR: 0.82, 95% CI: 0.70–0.97), hypertension (OR: 0.83, 95% CI: 0.70–0.98), and hypertriglyceridemia (OR: 0.78, 95% CI: 0.67–0.91). Subgroup and interaction analyses revealed significant interactions between age, sex, race/ethnicity, body mass index, and Klotho. Additionally, mediation analysis demonstrated that leukocytes, neutrophils and monocytes accounted for 34.78%, 31.91% and 7.13%, respectively, of the associations between Klotho and metabolic syndrome. Conclusion: The serum concentration of Klotho protein was negatively associated with metabolic syndrome, with the relationship being partly mediated by systemic immune inflammation. The findings of this research revealed that the Klotho protein may be a valuable biomarker for risk stratification and a potential therapeutic target for metabolic syndrome. [ABSTRACT FROM AUTHOR]