Correlation of serum Klotho, fetuin-A, and MGP levels with coronary artery calcification in maintenance hemodialysis patients.

OBJECTIVE: This study was to investigate the role of serum Klotho, fetuin-A, and Matrix Gla Protein (MGP) in Coronary Artery Calcification (CAC) in patients with Maintenance Hemodialysis (MHD) and their predictive value for CAC. METHODS: 100 patients receiving MHD were selected. Serum Klotho, fetuin-A, and MGP levels were detected by ELISA. CAC scores were assessed by coronary CT scan. Multifactor analysis was used to evaluate the risk factors affecting CAC. The ability of serum Klotho, fetuin-A, and MGP levels to diagnose CAC was evaluated by receiver operating characteristic curves. RESULTS: Serum Klotho, fetuin-A, and MGP were independent risk factors for CAC. Serum Klotho, fetuin-A, and MGP were valuable in the diagnosis of CAC in MHD patients. CONCLUSION: There is a close relationship between Klotho, fetuin-A, and MGP levels in MHD patients and CAC.

Association between α-klotho levels and adults with COPD in the United States.

Purpose: Chronic obstructive pulmonary disease (COPD) is accompanied by increased inflammation, persistent lung function decline, and extensive lung injury. Klotho, a well-known antiaging protein, has anti-inflammatory and antioxidative effects. However, the effects of klotho on COPD have yet to be thoroughly elucidated. This study examined the association among COPD adults and their α-klotho level. Patients and methods: Data were collected from the 2007 to 2012 National Health and Nutrition Examination Survey (NHANES). A total of 676 participants were analyzed and divided into COPD (n = 403) and non-COPD (n = 273) groups. The two groups were compared with respect to clinical characteristics. Logistic regression analysis and a generalized additive model were used to estimate the association between COPD incidence and serum α-klotho concentration. All COPD participants were stratified according to the levels of α-klotho (Q1: <687 pg./mL; Q2: 687-900 pg./mL; Q3: ≥900 pg./mL), and clinical characteristics were compared. Results: Non-COPD individuals had higher α-klotho levels than did COPD individuals (863.09 ± 267.13 vs. 817.51 ± 302.20, p < 0.05). Logistic regression analysis revealed that the Q2 and Q3 layers had a lower risk of COPD than did the Q1 layer, with odds ratios (ORs) of 0.73 (0.50, 0.99) for Q2 and 0.58 (0.41, 0.86) for Q3 (p < 0.001). The generalized additive model showed that the risk of COPD gradually decreased with increasing α-klotho concentration when the α-klotho concentration < 1,500 pg./mL, while the risk of COPD increased as the α-klotho concentration increased to ≥1,500 pg./mL. Compared with individuals in the Q2 or Q3 groups, individuals with COPD in the Q1 group were more likely to be current smokers, have lower levels of erythrocytes, and have higher levels of creatinine and leukocytes. Conclusion: Increased α-klotho levels were negatively correlated with the risk of COPD in participants over 40 years old with α-klotho <1,500 pg./mL. When α-klotho was ≥1,500 pg./mL, the risk of COPD increased as α-klotho levels increased. Pulmonary ventilation function and the number of hemocytes differed among COPD patients with different levels of α-klotho.

Association of elevated cerebrospinal fluid levels of the longevity protein α-Klotho with a delayed onset of cognitive impairment in Parkinson's disease patients.

BACKGROUND AND PURPOSE: Parkinson's disease (PD) is an age-related condition characterized by substantial phenotypic variability. Consequently, pathways and proteins involved in biological aging, such as the central aging pathway comprising insulin-like growth factor 1-α-Klotho-sirtuin 1-forkhead box O3-peroxisome proliferator-activated receptor γ, may potentially influence disease progression. METHODS: Cerebrospinal fluid (CSF) levels of α-Klotho in 471 PD patients were examined. Of the 471 patients, 96 carried a GBA1 variant (PD GBA1), whilst the 375 non-carriers were classified as PD wild-type (PD WT). Each patient was stratified into a CSF α-Klotho tertile group based on the individual level. Kaplan-Meier survival curves and Cox regression analysis stratified by tertile groups were conducted. These longitudinal data were available for 255 patients. Follow-up times reached from 8.4 to 12.4 years. The stratification into PD WT and PD GBA1 was undertaken to evaluate potential continuum patterns, particularly in relation to CSF levels. RESULTS: Higher CSF levels of α-Klotho were associated with a significant later onset of cognitive impairment. Elevated levels of α-Klotho in CSF were linked to higher Montreal Cognitive Assessment scores in male PD patients with GBA1 mutations. CONCLUSIONS: Our results indicate that higher CSF levels of α-Klotho are associated with a delayed cognitive decline in PD. Notably, this correlation is more prominently observed in PD patients with GBA1 mutations, potentially reflecting the accelerated biological aging profile characteristic of individuals harboring GBA1 variants.

Association of Klotho with Neuropsychiatric Disorder: A Meta-Analysis.

Neuropsychiatric disorders are mainly concerned with the behavioural, emotional and cognition symptoms that may be due to disturbed cerebral functions or extracerebral disease. Klotho protein is an antiaging protein that is mostly associated with cognitive changes in these disorders and thus this meta-analysis is conducted in order to find Klotho proteins association with these disorders. We searched related topics in pubmed, by using the key word i.e. Klotho and related disorder from neuropsychiatry e.g. Klotho levels and schizophrenia, Klotho levels and parkinsonism etc. Total 82 studies were found till 9th February 2021 after extensive search and 10 studies were selected for further analysis. The meta-analysis of studies was performed using the Random effect model. The forest plot represented each study in the meta-analysis, so as to make the comparison of SMD value across studies. The meta-analysis outcome demonstrated that overall schizophrenia had higher klotho levels as compared with bipolar disorder, psychosocial stress, parkinsonism, multiple sclerosis, depression, Alzheimer's disease, and healthy controls, followed by MS. The meta-analysis also found that bipolar disorder and Alzheimer's disease were associated with low klotho levels as compared to schizophrenia. The results indicate a significant association of the klotho levels and schizophrenia. Further studies are needed to characterize the potential biological roles of klotho levels in psychiatric disorders.

Molecular Interaction of Soluble Klotho with FGF23 in the Pathobiology of Aortic Valve Lesions Induced by Chronic Kidney Disease.

Chronic kidney disease (CKD) is linked to greater prevalence and rapid progression of calcific aortic valve disease (CAVD) characterized by valvular leaflet fibrosis and calcification. Fibroblast growth factor 23 (FGF23) level is elevated, and anti-aging protein Klotho is reduced in CKD patients. However, the roles of FGF23 and Klotho in the mechanism of aortic valve fibrosis and calcification remain unclear. We hypothesized that FGF23 mediates CKD-induced CAVD by enhancing aortic valve interstitial cell (AVIC) fibrosis and calcification, while soluble Klotho inhibits FGF23 effect. Methods and Results: In an old mouse model of CKD, kidney damages were accompanied by aortic valve thickening and calcification. FGF23 levels in plasma and aortic valve were increased, while Klotho levels were decreased. Recombinant FGF23 elevated the inflammatory, fibrogenic, and osteogenic activities in AVICs. Neutralizing antibody or shRNA targeting FGF23 suppressed the pathobiological activities in AVICs from valves affected by CAVD. FGF23 exerts its effects on AVICs via FGF receptor (FGFR)/Yes-associated protein (YAP) signaling, and inhibition of FGFR/YAP reduced FGF23's potency in AVICs. Recombinant Klotho downregulated the pathobiological activities in AVICs exposed to FGF23. Incubation of FGF23 with Klotho formed complexes and decreased FGF23's potency. Further, treatment of CKD mice with recombinant Klotho attenuated aortic valve lesions. Conclusion: This study demonstrates that CKD induces FGF23 accumulation, Klotho insufficiency and aortic valve lesions in old mice. FGF23 upregulates the inflammatory, fibrogenic and osteogenic activities in AVICs via the FGFR/YAP signaling pathway. Soluble Klotho suppresses FGF23 effect through molecular interaction and is capable of mitigating CKD-induced CAVD.

Deciphering the Biological Ageing Impact on Alveolar Bone Loss: Insights from α-Klotho and Renal Function Dynamics.

Alveolar bone loss is generally considered as a chronological age-related disease. As biological ageing process is not absolutely determined by increasing age, whether alveolar bone loss associated with increasing chronological age or biological ageing remains unclear. Accurately distinguishing whether alveolar bone loss is chronological age-related or biological ageing-related is critical for selecting appropriate clinical treatments. This study aimed to identify the relationship between alveolar bone loss and body ageing. 3635 participants from National Health and Nutrition Examination Survey and 71 living kidney transplant recipients from Gene Expression Omnibus Datasets were enrolled. Multivariate regression analysis, smooth curve fittings and generalized additive models were used to explore the association among alveolar bone loss, age, serum α-Klotho level, renal function markers, as well as between preoperative creatinine and renal cortex related α-Klotho gene expression level. Meanwhile, a two-sample Mendelian randomization study was conducted to assess the causal relationship between α-Klotho and periodontal disease (4,376 individuals versus 361,194 individuals). As biological ageing related indicator, α-Klotho level was negatively correlated with impaired renal function and alveolar bone loss. Correspondingly, accompanied by decreasing renal function, it was manifested with down-regulated expression level of α-Klotho in renal cortex and aggravated alveolar bone loss. The MR analysis further identified the negative association between higher genetically predicted α-Klotho concentrations with alveolar bone loss susceptibility using the IVW (OR=0.999, P=0.005). However, an inversely U-shaped association was observed between chronological age and alveolar bone loss, which especially stable in men (the optimal cut-off values were both 62 years old). For male above 62 years old, increasing age converted to protective factor and accompanied by alleviated alveolar bone loss. Alveolar bone loss which directly associated to decreased renal function and α-Klotho level was related to biological ageing rather than chronological age. The renal-alveolar bone axis could provide new sight of clinical therapy in alveolar bone loss.

U-shaped association between serum Klotho and all-cause mortality in US cardiovascular patients: a prospective cohort study.

Background: Increased levels of serum Klotho have been associated with a reduced risk of several cardiovascular diseases (CVD). However, limited studies exist on the association between serum Klotho and mortality in patients with CVD. Methods: We collected data from CVD patients in the National Health and Nutrition Examination Survey (NHANES) spanning 2007 to 2016. We linked NHANES data with the National Death Index to determine the survival status of participants. Univariate and multivariable Cox regression models were used to investigate the relationship between serum Klotho levels and mortality in CVD patients. The relationship between serum Klotho quartiles and mortality in CVD patients was visualized using Kaplan-Meier (KM) curves and restricted cubic spine. Finally, subgroup analyses were used to examine the association between serum Klotho and all-cause mortality in different populations. Results: 1905 patients with CVD were finally enrolled in our study with a mean follow-up of 7.1 years. The average age of the participants was 63.4 years, with 58.40% being male. KM showed that lower Klotho levels were associated with lower survival rates. After adjusting for potential confounders, patients with higher serum Klotho levels had lower all-cause mortality (Q1: 1.00, Q2: 0.58 (0.42-0.80), Q3: 0.69 (0.47-1.01), and Q4:0.64 (0.45-0.92). However, the relationship between serum Klotho levels and cardiovascular mortality was not statistically significant. Dose-response analysis shows a U-shaped relationship between serum Klotho levels and all-cause mortality in patients with CVD (P nonlinear=0.002). Subgroup analysis indicated that participants with a history of hypertension had a higher risk of all-cause mortality in serum Klotho Q4 compared to Q1 (P trend <0.05). Conclusion: The relationship between serum Klotho levels and all-cause mortality in CVD patients exhibits a U-shaped association. The underlying mechanisms of this association need further investigation.

Polystyrene microplastics facilitate renal fibrosis through accelerating tubular epithelial cell senescence.

Microplastics (MPs), emerging contaminants, are easily transported and enriched in the kidney, suggesting the kidney is susceptible to the toxicity of MPs. In this study, we explored the toxicity of MPs, including unmodified polystyrene (PS), negative-charged PS-SO3H, and positive-charged PS-NH2 MPs, in mice models for 28 days at a human equivalent concentration. The results showed MPs significantly increased levels of UREA, urea nitrogen (BUN), creatinine (CREA), and uric acid (UA) levels in serum and white blood cells, protein, and microalbumin in urine. In the kidney, MPs triggered persistent inflammation and renal fibrosis, which was caused by the increased senescence of tubular epithelial cells. Moreover, we identified the critical role of the Klotho/Wnt/ß-catenin signaling pathway in the process of MPs induced senescence of tubular epithelial cells, promoting the epithelial-mesenchymal transformation of epithelial cells. MPs supported the secretion of TGF-ß1 by senescent epithelial cells and induced the activation of renal fibroblasts. On the contrary, restoring the function of Klotho can alleviate the senescence of epithelial cells and reverse the activation of fibroblasts. Thus, our study revealed new evidence between MPs and renal fibrosis, and adds an important piece to the whole picture of the plastic pollution on people's health.

Fibroblast growth factor 23-mediated regulation of osteoporosis: Assessed via Mendelian randomization and in vitro study.

Despite numerous investigations on the influence of fibroblast growth factor 23 (FGF23), α-Klotho and FGF receptor-1 (FGFR1) on osteoporosis (OP), there is no clear consensus. Mendelian randomization (MR) analysis was conducted on genome-wide association studies (GWASs)-based datasets to evaluate the causal relationship between FGF23, α-Klotho, FGFR1 and OP. The primary endpoint was the odds ratio (OR) of the inverse-variance weighted (IVW) approach. Furthermore, we stably transfected FGF23-mimic or siRNA-FGF23 into human bone marrow mesenchymal stem cells (hBMSCs) in culture and determined its cell proliferation and the effects on osteogenic differentiation. Using MR analysis, we demonstrated a strong correlation between serum FGF23 levels and Heel- and femoral neck-BMDs, with subsequent ORs of 0.919 (95% CI: 0.860-0.983, p = 0.014) and 0.751 (95% CI: 0.587-0.962; p = 0.023), respectively. The expression levels of FGF23 were significantly increased in femoral neck of patients with OP than in the control cohort (p < 0.0001). Based on our in vitro investigation, after overexpression of FGF23, compared to the control group, the BMSC's proliferation ability decreased, the expression level of key osteogenic differentiation genes (RUNX2, OCN and OSX) significantly reduced, mineralized nodules and ALP activity significantly decreased. After silencing FGF23, it showed a completely opposite trend. Augmented FGF23 levels are causally associated with increased risk of OP. Similarly, FGF23 overexpression strongly inhibits the osteogenic differentiation of hBMSCs, thereby potentially aggravating the pathological process of OP.

Association between serum Klotho and major depression: Results from the NHANES 2007-2016 and Mendelian randomization studies.

BACKGROUND: Major depression is a public health problem facing the world. This study aimed to identify the risk factors for major depression and clarify their causal effects. METHODS: Data from the National Health and Nutrition Examination Survey (NHANES). Multifactorial logistic regression analysis was used to calculate the effect of each variable on major depression. Subgroup analyses and interaction tests were conducted to observe the stability of the association between them. Nonlinear correlations were explored using restricted cubic spline plots. The causal effects of serum Klotho on major depression were assessed using Mendelian randomization (MR) analysis. RESULTS: A total of 8359 participated in the study. After adjusting for all covariates, the risk of having major depression was 1.47 times higher for each unit rise in serum Klotho (OR = 1.47, 95 % CI = 1.07-2.02; P = 0.0183). MR analysis showed no causal relationship between serum Klotho levels and risk of major depression (OR = 1.09, 95 % CI = 0.91-1.30; P = 0.4120). Sensitivity analysis verified the reliability of the results. CONCLUSIONS: Serum Klotho is positively associated with an increased risk of major depression in the U.S. population, but MR analyses did not show genetic causality between Klotho and major depression in individuals of European ancestry. Based on the results of the current study, no indication maintaining high levels of Klotho may increase the risk of major depression. LIMITATIONS: The main limitation of this study is the inconsistency of the cross-sectional study and the MR population.

Dietary folate intake and serum klotho levels in adults aged 40-79 years: a cross-sectional study from the national health and nutrition examination survey 2007-2016.

Objective: This study aims to explore the relationship between dietary folate intake and serum Klotho levels in adults from aged 40 to 79 years in the United States, seeking to elucidate the intricacies of their interaction. Methods: Analyzing data from the National Health and Nutrition Examination Survey (NHANES) spanning 2007 to 2016. The survey research determined folate intake through a 24-h dietary recall and nutrient density modeling, and assessed Klotho levels using enzyme-linked immunosorbent assay (ELISA). The relationship between folate intake and Klotho levels was evaluated using weighted linear regression, and complemented by analysis via smoothed curve models for nuanced understanding. Results: The study encompassed 10,278 participants, with an average age of 57.64 years, revealing a noteworthy positive correlation between dietary folate and serum Klotho levels. The regression coefficient stood at 0.11 (95% confidence interval, 0.05, 0.18) post-adjustment for various covariates. When dietary folate intake was categorized into quartiles, the second, third, and fourth quartiles exhibited statistically significant differences compared to the lowest quartile. This indicates that higher folate intake correlates with increased serum Klotho levels. These findings underscore the potential benefits of elevating folate intake to enhance serum Klotho levels. Stratified analysis indicated that this association was more pronounced among males aged 60 years or older and individuals with hypertension. Conclusion: The findings suggest a significant correlation between increased dietary folate intake and elevated serum Klotho levels in adults aged 40-79 years. Hinting at the potential nutritional influences on the aging process and associated health conditions. This calls for further exploration into the mechanisms and broader implications of this association.

Local vascular Klotho mediates diabetes-induced atherosclerosis via ERK1/2 and PI3-kinase-dependent signaling pathways.

BACKGROUND AND AIMS: Diabetes is one of the major causes of cardiovascular disease (CVD). As high as 29 % of patients with diabetes develop atherosclerosis. Vascular Smooth Muscle Cells (VSMCs) are a key mediator in the pathogenesis of atherosclerosis, generating pro-inflammatory and proliferative characteristics in atherosclerotic lesions. METHODS: We used human atherosclerotic samples, developed diabetes-induced atherosclerotic mice, and generated loss of function and gain of function in Klotho human aortic smooth muscle cells to investigate the function of Klotho in atherosclerosis. RESULTS: We found that Klotho expression is decreased in smooth muscle actin-positive cells in patients with diabetes and atherosclerosis. Consistent with human data, we found that Apoe knockout mice with streptozotocin-induced diabetes fed on a high-fat diet showed decreased expression of Klotho in SMCs. Additionally, these mice showed increased expression of TGF-ß, MMP9, phosphorylation of ERK and Akt. Further, we utilized primary Human Aortic Smooth Muscle Cells (HASMCs) with d-glucose under dose-response and in time-dependent conditions to study the role of Klotho in these cells. Klotho gain of function and loss of function studies showed that Klotho inversely regulated the expression of atherosclerotic markers TGF-ß, MMP2, MMP9, and Fractalkine. Further, High Glucose (HG) induced Akt, and ERK1/2 phosphorylation were enhanced or mitigated by endogenous Klotho deficiency or its overexpression respectively. PI3K/Akt and MAPK/ERK inhibition partially abolished the HG-induced upregulation of TGF-ß, MMP2, MMP9, and Fractalkine. Additionally, Klotho knockdown increased the proliferation of HASMCs and enhanced α-SMA and TGF-ß expression. CONCLUSIONS: Taken together, these results indicate that local vascular Klotho is involved in diabetes-induced atherosclerosis, which is via PI3K/Akt and ERK1/2-dependent signaling pathways.

Klotho enhances diastolic function in aged hearts through Sirt1-mediated pathways.

Aging leads to a progressive decline in cardiac function, increasing the risk of heart failure with preserved ejection fraction (HFpEF). This study elucidates the impact of α-Klotho, an anti-aging hormone, on cardiac diastolic dysfunction and explore its downstream mechanisms. Aged wild-type and heterozygous Klotho-deficient mice received daily injection of soluble α-Klotho (sKL) for 10 weeks, followed by a comprehensive assessment of heart function by echocardiography, intracardiac pressure catheter, exercise tolerance, and cardiac pathology. Our findings show that klotho deficiency accentuated cardiac hypertrophy, diastolic dysfunction, and exercise intolerance, while sKL treatment ameliorates these abnormalities and improves cardiac capillary densities. Downstream of klotho, we focused on the Sirtuin1 (Sirt1) signaling pathway to elucidate the potential underlying mechanism by which Klotho improves diastolic function. We found that decreased Klotho levels were linked with Sirt1 deficiency, whereas sKL treatment restored Sirt1 expression in aged hearts and mitigated the DNA damage response pathway activation. Through tandem mass tag proteomics and unbiased acetylomics analysis, we identified 220 significantly hyperacetylated lysine sites in critical cardiac proteins of aged hearts. We found that sKL supplementation attenuated age-dependent DNA damage and cardiac diastolic dysfunction. In contrast, Klotho deficiency significantly increased hyperacetylation of several crucial cardiac contractile proteins, potentially impairing ventricular relaxation and diastolic function, thus predisposing to HFpEF. These results suggest the potential benefit of sKL supplementation as a promising therapeutic strategy for combating HFpEF in aging.

Inhibition of EZH2 Reduces Aging-Related Decline in Interstitial Cells of Cajal of the Mouse Stomach.

BACKGROUND & AIMS: Restricted gastric motor functions contribute to aging-associated undernutrition, sarcopenia, and frailty. We previously identified a decline in interstitial cells of Cajal (ICC; gastrointestinal pacemaker and neuromodulator cells) and their stem cells (ICC-SC) as a key factor of gastric aging. Altered functionality of the histone methyltransferase enhancer of zeste homolog 2 (EZH2) is central to organismal aging. Here, we investigated the role of EZH2 in the aging-related loss of ICC/ICC-SC. METHODS: klotho mice, a model of accelerated aging, were treated with the most clinically advanced EZH2 inhibitor, EPZ6438 (tazemetostat; 160 mg/kg intraperitoneally twice a day for 3 weeks). Gastric ICC were analyzed by Western blotting and immunohistochemistry. ICC and ICC-SC were quantified by flow cytometry. Gastric slow wave activity was assessed by intracellular electrophysiology. Ezh2 was deactivated in ICC by treating KitcreERT2/+;Ezh2fl/fl mice with tamoxifen. TRP53, a key mediator of aging-related ICC loss, was induced with nutlin 3a in gastric muscle organotypic cultures and an ICC-SC line. RESULTS: In klotho mice, EPZ6438 treatment mitigated the decline in the ICC growth factor KIT ligand/stem cell factor and gastric ICC. EPZ6438 also improved gastric slow wave activity and mitigated the reduced food intake and impaired body weight gain characteristic of this strain. Conditional genomic deletion of Ezh2 in Kit-expressing cells also prevented ICC loss. In organotypic cultures and ICC-SC, EZH2 inhibition prevented the aging-like effects of TRP53 stabilization on ICC/ICC-SC. CONCLUSIONS: Inhibition of EZH2 with EPZ6438 mitigates aging-related ICC/ICC-SC loss and gastric motor dysfunction, improving slow wave activity and food intake in klotho mice.

L-shaped association of systemic immune-inflammation index (SII) with serum soluble α-Klotho in the prospective cohort study from the NHANES database.

The systemic immune-inflammation index (SII), an integrated and ground-breaking inflammatory measure, has been widely used in various fields. We aimed to assess the association between the systemic immune-inflammation index (SII) and α-Klotho (a new anti-aging biomarker). In this cross-sectional investigation, people with complete information on SII and α-Klotho from the National Health and Nutrition Examination Survey (NHANES) between 2007 and 2016 were the study's subject population. SII was calculated by platelet count × neutrophil count/lymphocyte count. The association between SII and α-Klotho was investigated using multivariable linear regression and a generalized additive model. In order to explore the non-linear connection, we employed smoothed curve fitting. Subgroup analysis were also performed. A total of 13,701 participants with an average age of 57.73 ± 10.86 years were enrolled, of whom 51.53% were female. After fully adjustment, SII was negatively associated with serum soluble α-Klotho [ß(95% CI) = - 0.07 (- 0.08, - 0.05)]. Furthermore, we found L-shaped association between SII and klotho protein level, with the inflection point at 255 pg/ml. Subgroup analysis and interaction test revealed that there was no discernible dependence on gender, age, race, smoking, alcohol, diabetes and hypertension (all p for interaction > 0.05). SII level was negatively associated with serum klotho protein concentration in American adults. To verify our findings, more large-scale prospective investigations are still required.

High serum klotho levels are inversely associated with the risk of low muscle mass in middle-aged adults: results from a cross-sectional study.

Objective: Muscle mass gradually declines with advancing age, and as an anti-aging protein, klotho may be associated with muscle mass. This study aims to explore the relationship between klotho levels and muscle mass in the middle-aged population. Methods: Utilizing data from the National Health and Nutrition Examination Survey (NHANES) spanning 2011 to 2018, we conducted a cross-sectional analysis on a cohort of individuals aged 40-59. Weighted multivariable analysis was employed to assess the correlation between klotho and low muscle mass, with stratified and Restricted Cubic Spline (RCS) analyses. Results: The cross-sectional investigation revealed a significant negative correlation between klotho levels and the risk of low muscle mass (Model 3: OR = 0.807, 95% CI: 0.712-0.915). A notable interaction between klotho and sex was observed, with a significant interaction effect (P for interaction = 0.01). The risk association was notably higher in females. The risk association was notably higher in females. Additionally, RCS analysis unveiled a significant linear relationship between klotho and low muscle mass (P for nonlinear = 0.9495, P for overall<0.0001). Conclusion: Our observational analysis revealed a noteworthy inverse relationship between klotho and low muscle mass, particularly prominent among female participants. This discovery provides crucial insights for the development of more effective intervention strategies and offers a new direction for enhancing muscle quality in the middle-aged population.

Attenuation of osteoarthritis progression via locoregional delivery of Klotho-expressing plasmid DNA and Tanshinon IIA through a stem cell-homing hydrogel.

BACKGROUND: Osteoarthritis (OA) is an aging-related degenerative joint disorder marked by joint discomfort and rigidity. Senescent chondrocytes release pro-inflammatory cytokines and extracellular matrix-degrading proteins, creating an inflammatory microenvironment that hinders chondrogenesis and accelerates matrix degradation. Targeting of senescent chondrocytes may be a promising approach for the treatment of OA. Herein, we describe the engineering of an injectable peptide-hydrogel conjugating a stem cell-homing peptide PFSSTKT for carrying plasmid DNA-laden nanoparticles and Tanshinon IIA (pPNP + TIIA@PFS) that was designed to attenuate OA progression by improving the senescent microenvironment and fostering cartilage regeneration. RESULTS: Specifically, pPNP + TIIA@PFS elevates the concentration of the anti-aging protein Klotho and blocks the transmission of senescence signals to adjacent healthy chondrocytes, significantly mitigating chondrocyte senescence and enhancing cartilage integrity. Additionally, pPNP + TIIA@PFS recruit bone mesenchymal stem cells and directs their subsequent differentiation into chondrocytes, achieving satisfactory chondrogenesis. In surgically induced OA model rats, the application of pPNP + TIIA@PFS results in reduced osteophyte formation and attenuation of articular cartilage degeneration. CONCLUSIONS: Overall, this study introduces a novel approach for the alleviation of OA progression, offering a foundation for potential clinical translation in OA therapy.

The interaction between klotho protein and epigenetic alteration in diabetes and treatment options.

Introduction: Klotho is a membrane protein predominantly expressed in the kidneys, and its discovery was serendipitously made through gene-targeting experiments conducted on mice. Klotho has a favorable role in the regulation of multiple cellular processes, such as aging, oxidative stress, inflammation, and apoptosis. This regulation occurs through the targeting of diverse signaling molecules, cell membrane receptors, and ion channels, achieved by physical contacts or enzymatic activities of Klotho. This review examines the role of Klotho in the epigenetic regulation of molecules associated with diabetes. Methods: Authors conducted a thorough literature search using the PubMed®, Web of Science™, and Scopus®. Relevant articles up to September 2023, published in the English language were considered. We reviewed research databases searching for studies that included keywords klotho, epigenetic, and diabetes. Results: 14 related papers about epigenetic modification of proteins involved in diabetes pathogenesis were selected to be included in this narrative review. In the studies, the kidney was the most investigated organ regarding this correlation. Also, phosphorylation and methylation were the common epigenetic modifications of proteins by Klotho. Conclusion: Klotho has a significant role in the maturation of adipocytes and the regulation of systemic glucose metabolism, exhibiting a strong association with the pathogenesis of diabetes. Both epigenetic alterations and the modulation of protein phosphorylation by Klotho play significant roles in the regulation of Klotho expression and the modulation of other molecules implicated in the etiology of diabetes.

Elevated Serum Copper, Zinc, Selenium, and Lowered α-Klotho Associations: Findings from NHANES 2011-2016 Dataset.

The α-Klotho is crucial for human health and longevity. However, the relationship between trace elements and α-Klotho levels needs further investigation. We aimed to explore the relationship between serum levels of selenium (Se), copper (Cu), and zinc (Zn), and serum α-Klotho levels. We analyzed 2138 samples from the 2011-2016 National Health and Nutrition Examination Survey, and the weighted linear regression, WQS, and qgcomp models were utilized to evaluate the effects of these elements on serum α-Klotho levels, individually and combined. A negative correlation was observed between serum Cu concentration and serum α-Klotho levels (ß = - 0.128, 95% CI - 0.196, - 0.059), with each increase in Cu concentration grade showing a gradual decrease in serum α-Klotho levels (Ptrend = 0.002). The WQS model exhibited a negative correlation between the combined effect of Se, Cu, and Zn and serum α-Klotho levels (ß = - 0.035, 95%CI - 0.060, - 0.010), consistently in males (ß = - 0.038 (- 0.059, - 0.017)) and in the 40-49 age group (ß = - 0.059, 95% CI - 0.119, - 0.012). The qgcomp model mirrored these findings, showing a negative correlation in the combined effect index of Se, Cu, and Zn with serum α-Klotho levels (ß = - 0.027, 95% CI - 0.047, - 0.006), consistent in females (ß = - 0.032, 95% CI - 0.061, - 0.004) and in individuals with BMI ≥ 25 (ß = - 0.030, 95% CI - 0.054, - 0.006), and in the 40-49 age group (ß = - 0.047, 95% CI - 0.088, - 0.006). Elevated serum Cu levels may be associated with lower serum α-Klotho levels. The combined effect of serum Se, Cu, and Zn shows a negative correlation with serum α-Klotho levels, with Cu contributing the most. Our findings provide significant insights into assessing the role of trace nutrients in maintaining human health.

Klotho accelerates the progression of polycystic ovary syndrome through promoting granulosa cell apoptosis and inflammation.

The morbidity of polycystic ovary syndrome (PCOS) is in highly increasing rate nowadays. PCOS not only affects the fertility in women, but also threatens the health of whole life. Hence, to find the prognostic risk factors is of great value. However, the effective predictors in clinical practice of PCOS are still in blackness. In this study, we found Klotho was increased in FF (Follicular Fluid) and primary luteinized granulosa cells (GCs) from PCOS patients with hyperandrogenism. Furthermore, we found follicular Klotho was negatively correlated with numbers of mature oocytes, and positively correlated with serum testosterone, LH, and LH/FSH levels menstrual cycle and number of total antral follicles in PCOS patients. In primary luteinized GCs, the increased Klotho was accompanied with upregulation of cell apoptosis and inflammation-related genes. In ovaries of PCOS mice and cultured human KGN cell line, Klotho was up-regulated and accompanied by apoptosis, inflammation and mitochondrial dysfunction. Therefore, our findings suggest new mechanisms for granulosa cell injury and revealed to target inhibit Klotho maybe a new therapeutic strategy for treatment of PCOS.