Association between Serum Klotho and All-Cause Mortality in Chronic Kidney Disease: Evidence from a Prospective Cohort Study.

INTRODUCTION: This study aimed to investigate the relationship between circulating soluble Klotho concentration and all-cause mortality in individuals with chronic kidney disease (CKD). METHODS: We conducted a prospective cohort study involving 2,456 participants with CKD from the National Health and Nutrition Examination Survey (NHANES) cycles spanning from 2007 to 2016. Complex sampling-weighted multivariate Cox proportional hazards models were used to estimate the association between serum Klotho level and all-cause mortality, presenting hazard ratios (HRs) and 95% confidence intervals (CIs). Additionally, a restricted cubic spline analysis was performed to explore potential nonlinear associations. RESULTS: During a median of 82 months of follow-up, 550 (22.40%) all-cause deaths were recorded. The median serum Klotho concentration was 760 pg/mL (interquartile ranges, 624, 958). After adjusting for potential covariates, the risk of all-cause mortality decreased by 4% for every 100 pg/mL increase in Klotho (HR = 0.96, 95% CI, 0.92, 0.99). The HR for the fourth quartile of Klotho compared to the first quartile was 0.73 (95% CI, 0.56, 0.96). The restricted cubic spline model revealed a distinctive "L"-shaped association between serum Klotho and all-cause mortality among patients with CKD, with a Klotho concentration of 760 pg/mL at the inflection point. When Klotho concentration was less than 760 pg/mL, a significant negative correlation between Klotho and all-cause mortality was observed (HR per 100 pg/mL increase in Klotho = 0.86, 95% CI, 0.78, 0.95). CONCLUSION: This study documented a distinctive "L"-shaped association between serum Klotho levels and all-cause mortality among individuals with CKD. Further research is needed to validate these findings.

Gender differences in the relationship between the triglyceride-glucose index and serum Klotho concentrations among the middle-aged and elderly: a cross-sectional analysis.

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 (ß=-83.41, 95% CI: -124.23 to -42.60, P < 0.0001). This association was not statistically significant in males (ß = 15.40, 95% CI: -19.16 to 49.95, P = 0.3827). Subgroup analyses revealed a significant interaction effect by diabetes status in females (P-interaction = 0.0121), where non-diabetic females showed a stronger negative association between TyG index and serum Klotho levels compared to diabetic females. In the female group, when TyG index was divided into quartiles, individuals in the highest quartile of TyG index exhibited reduced levels of Klotho protein (Q4: -88.77 pg/ml) compared to those in the lowest quartile (Q1) after full adjustment (P = 0.0041). Segmented regression analysis indicated a turning point value of 9.4 in females. Notably, a 1-unit increase in TyG index was significantly associated with a decrease in Klotho levels by -111.43 pg/ml (95% CI: -157.34 to -65.52, P < 0.0001) when TyG index was below 9.4, while above this threshold, the association was not significant (Log likelihood ratio test: 0.009). CONCLUSIONS: The findings highlight a non-linear correlation between the TyG index and serum Klotho concentrations among females, indicative of a saturation effect. This relationship was particularly pronounced in non-diabetic women. In contrast, no statistically significant association was observed in male participants.

Associations between the TyG index and the ɑ-Klotho protein in middle-aged and older population relevant to diabetes mellitus in NHANES 2007-2016.

BACKGROUND: The anti-aging protein Klotho has diverse functions in antioxidative stress and energy metabolism through several pathways. While it has been reported that α-Klotho is downregulated in patients with insulin resistance (IR), the association between Klotho and IR is complex and controversial. The triglyceride-glucose (TyG) index has provided a practical method for assessing IR. With this in mind, our study aimed to investigate the relationship between the TyG index and soluble α-Klotho protein levels in US populations, both with and without diabetes mellitus. METHODS: This cross-sectional study analyzed data from middle-aged and older participants in the National Health and Nutrition Examination Survey (NHANES) conducted between 2007 and 2016. The participants were divided into two groups based on their diabetes mellitus status: those with diabetes and those without diabetes. To evaluate the relationship between the TyG index and the concentration of the α-Klotho protein in each group, a series of survey-weighted multivariable linear regression models were employed. Furthermore, to examine the association between these two variables, multivariable-adjusted restricted cubic spline curves and subgroup analysis were generated. RESULTS: The study involved 6,439 adults aged 40 years or older, with a mean age of 57.8 ± 10.9 years. Among them, 1577 (24.5%) had diabetes mellitus. A subgroup analysis indicated that the presence of diabetes significantly affected the relationship between the TyG index and the α-Klotho level. After considering all covariables, regression analysis of the participants without diabetes revealed that the α-Klotho concentration decreased by 32.35 pg/ml (95% CI: -50.07, -14.64) with each one unit increase in TyG (p < 0.001). The decline in α-Klotho levels with elevated TyG was more pronounced in the female population. In patients with diabetes mellitus, a non-linear association between the TyG index and α-Klotho was observed. There was no significant correlation observed between the two when TyG index were below 9.7. However, there was an increase in klotho levels of 106.44 pg/ml for each unit increase in TyG index above 9.7 (95% CI: 28.13, 184.74) (p = 0.008). CONCLUSION: Our findings suggested that the presence of diabetes may influence the relationship between the TyG index and soluble α-Klotho. Furthermore, there seem to be sex differences in individuals without diabetes. Further studies are necessary to validate these findings.

Serum klotho levels and mortality patterns in frail individuals: unraveling the u-shaped association.

BACKGROUND: Frailty, a clinical syndrome intricately linked with the aging process, stands as a harbinger of numerous adverse outcomes, most notably mortality. This study aimed to elucidate the association between serum α-klotho concentration and mortality patterns, including all-cause and cause-specific mortality, in patients with frailty. METHODS: The study employed Cox proportional hazard models, smoothed curve fitting, and supplementary analyses, encompassing threshold effect analysis, subgroup and sensitivity analyses, to explore the relationship between α-klotho levels and mortality, including all-cause, CVD, and cancer-related mortality. RESULTS: Among the 2,608 frail individuals (mean age: 60.78 [SD 10.48] years; 59.89% female), the mortality stood at 25.35% during a median follow-up period of 6.95 years. Both unadjusted and adjusted models revealed a significant inverse association between higher serum α-klotho levels and the risk of all-cause and CVD-related mortality ([mean(95% CI) 0.68 (0.55, 0.83)] for all-cause mortality; [mean(95% CI) 0.48 (0.32, 0.74)] for CVD-related mortality, all P for trend < 0.001). Notably, log2-klotho displayed a U-shaped correlation with all-cause mortality and cancer mortality, characterized by thresholds of 9.48 and 9.55, respectively. The robustness of these findings was consistently supported by subgroup and sensitivity analyses. CONCLUSION: This study unveils a U shaped association between serum α-klotho levels and both all-cause and cancer-related mortality among middle-aged and elderly individuals with frailty in the United States. The identified serum α-klotho thresholds, at 714.8 pg/ml for all-cause mortality and 750.6 pg/ml for cancer-related mortality, hold promise as potential targets for interventions aimed at mitigating the risks of premature death and cancer within this vulnerable population.

Soluble Klotho, a Potential Biomarker of Chronic Kidney Disease-Mineral Bone Disorders Involved in Healthy Ageing: Lights and Shadows.

Shortly after the discovery of Klotho, interest grew in its potential role in chronic kidney disease (CKD). There are three isoforms of the Klotho protein: αKlotho, ßKlotho and γKlotho. This review will focus on αKlotho due to its relevance as a biomarker in CKD. αKlotho is synthesized mainly in the kidneys, but it can be released into the bloodstream and urine as soluble Klotho (sKlotho), which undertakes systemic actions, independently or in combination with FGF23. It is usually accepted that sKlotho levels are reduced early in CKD and that lower levels of sKlotho might be associated with the main chronic kidney disease-mineral bone disorders (CKD-MBDs): cardiovascular and bone disease. However, as results are inconsistent, the applicability of sKlotho as a CKD-MBD biomarker is still a matter of controversy. Much of the inconsistency can be explained due to low sample numbers, the low quality of clinical studies, the lack of standardized assays to assess sKlotho and a lack of consensus on sample processing, especially in urine. In recent decades, because of our longer life expectancies, the prevalence of accelerated-ageing diseases, such as CKD, has increased. Exercise, social interaction and caloric restriction are considered key factors for healthy ageing. While exercise and social interaction seem to be related to higher serum sKlotho levels, it is not clear whether serum sKlotho might be influenced by caloric restriction. This review focuses on the possible role of sKlotho as a biomarker in CKD-MBD, highlighting the difference between solid knowledge and areas requiring further research, including the role of sKlotho in healthy ageing.

Parishin alleviates vascular ageing in mice by upregulation of Klotho.

Senescence of vascular endothelial cells is the major risk of vascular dysfunction and disease among elderly people. Parishin, which is a phenolic glucoside derived from Gastrodia elata, significantly prolonged yeast lifespan. However, the action of parishin in vascular ageing remains poorly understood. Here, we treated human coronary artery endothelial cells (HCAEC) and naturally aged mice by parishin. Parishin alleviated HCAEC senescence and general age-related features in vascular tissue in naturally aged mice. Network pharmacology approach was applied to determine the compound-target networks of parishin. Our analysis indicated that parishin had a strong binding affinity for Klotho. Expression of Klotho, a protein of age-related declines, was upregulated by parishin in serum and vascular tissue in naturally aged mice. Furthermore, FoxO1, on Klotho/FoxO1 signalling pathway, was increased in the parishin-intervened group, accompanied by the downregulated phosphorylated FoxO1. Taken together, parishin can increase Klotho expression to alleviate vascular endothelial cell senescence and vascular ageing.

Randomized Trial of Etelcalcetide for Cardiac Hypertrophy in Hemodialysis.

[Figure: see text].

Association between anemia and serum Klotho in middle-aged and older adults.

BACKGROUND: The role of Klotho as a multifunctional protein in anemia is unclear. This study aimed to determine the association between anemia and serum Klotho concentrations in middle-aged and elderly populations. METHODS: In this cross-sectional study, we used data collected from the National Health and Nutrition Examination Survey (NHANES) 2007-2016. A total of 13,357 individuals who received serum Klotho measurements, biochemical tests, and demographic surveys were analyzed. Multivariate linear regression models adjusting for covariates were used to investigate the associations between anemia and serum Klotho. RESULTS: Multivariable regression showed that serum Klotho correlates positively with hemoglobin and red blood cells and inversely with red cell distribution width. After adjusting for all covariates, compared with Q4, there was a significantly increased risk of anemia in serum Klotho quartiles 1 to 2 (OR=1.54, 95% CI:1.21-1.95, P=0.002; OR=1.30, 95% CI:1.02-1.64, P=0.042,respectively). Segmented regression showed that for every 100 pg/mL increase in serum Klotho <9.746 pg/mL, the risk of anemia was reduced by 10.9%, and this reduction was significant (P<0.001). Furthermore, stratified analyses yielded a stronger association between reduced anemia and high levels of Klotho in men and those with diabetes (P< 0.05 for interaction). However, this association was not found to be significantly altered by chronic kidney disease. CONCLUSIONS: In summary, we indicated that low serum Klotho is associated with an increased likelihood of anemia using a nationally representative sample of middle-aged and older adults.

Klotho Level as a Marker of Low Bone Mineral Density in Egyptian Sickle Cell Disease Patients.

Bone involvement of sickle cell disease (SCD) patients varies from acute clinical manifestations of painful vaso-occlusive crises or osteomyelitis to more chronic affection of bone mineral density (BMD) and debilitating osteonecrosis and osteoporosis. Secreted klotho protein is involved in calcium (Ca) reabsorption in the kidney. This study aimed to measure serum klotho levels in children with SCD to determine the possibility of using it as a marker of low BMD in children with SCD in correlation with a dual-energy radiograph absorptiometry scan. This study included 60 sickle disease patients and 30 age-matched and sex-matched control participants without SCD. A highly statistically significant difference was found between patients with normal BMD and those with low BMD, with serum Ca and klotho levels being lower in the latter group. Klotho serum level correlated positively with both serum Ca and BMD. Serum klotho level showed 94.9% sensitivity and 95.2% specificity in the detection of low BMD. Both serum Ca and klotho serum levels may be useful markers for detection of low BMD related to SCD with high sensitivity and specificity; however, klotho may be a better indicator as it is less affected by the nutritional and endocrinal status of patients or by intake of Ca supplements.

Gender-specific soluble α-klotho levels as marker of GH deficiency in children: a case-control study.

PURPOSE: To evaluate circulating soluble α-klotho (sαKL) levels in GHD children before and after 12 months of GH treatment (GHT). METHODS: Auxological and basal metabolic parameters, oral glucose tolerance test for glucose and insulin levels, insulin sensitivity indices and klotho levels were evaluated before and after 12 months of follow-up in 58 GHD children and 56 healthy controls. RESULTS: At baseline, GHD children showed significantly lower growth velocity standard deviation score (SDS) (p < 0.001), bone/chronological age ratio (p < 0.001), GH peak and area under the curve (AUC) after arginine test (ARG) (both p < 0.001) and glucagon stimulation test (GST) (p < 0.001 and 0.048, respectively), IGF-1 (p < 0.001), with higher BMI (SDS) (p < 0.001), WC (SDS) (p = 0.003) and sαKL (p < 0.001) than controls. After 12 months of GHT, GHD children showed a significant increase in height (SDS) (p < 0.001), growth velocity (SDS) (p < 0.001), bone/chronological age ratio (p < 0.001) IGF-1 (p < 0.001), fasting insulin (p < 0.001), Homa-IR (p < 0.001) and sαKL (p < 0.001) with a concomitant decrease in BMI (SDS) (p = 0.002) and WC (SDS) (p = 0.038) than baseline. At ROC curve analysis, we identified a sαKL cut-off to discriminate controls and GHD children of 1764.4 pg/mL in females and 1339.4 pg/mL in males. At multivariate analysis, the independent variables significantly associated with sαKL levels after 12 months of GHT were the oral disposition index (p = 0.004, ß = 0.327) and IGF-1 (p = 0.019, ß = 0.313). CONCLUSIONS: Gender-related sαKL may be used as a marker of GHD combined to GH and IGF-1. Insulin and IGF-1 are independently associated with sαKL values after 12 months of GHT.

Association between testosterone and serum soluble α-klotho in U.S. males: a cross-sectional study.

PURPOSE: Testosterone plays a crucial role in males, and the deficiency of testosterone leads to multiple adverse health conditions. Klotho is a recently discovered protein encoded by antiaging gene klotho. Both the levels of testosterone and klotho change with aging, so the relationship between them is worth exploring. The purpose of this study was to investigate whether total testosterone is associated with serum klotho levels in U.S. males aged 40-79 years. METHODS: Included in this study were 3750 male participants from the 2011 to 2016 National Health and Nutrition Examination Survey, aged 40-79 years with included information on klotho and sex hormones. The sex steroid hormone levels and klotho concentrations were assayed in laboratories using the recommended methods according to Nutrition Examination Survey guidelines. The association between sex hormones and klotho was calculated using multivariate linear regression models after adjustment for several possible confounding variables. RESULTS: Among the 3750 participants, the total testosterone concentration was 399.048 ± 184.780 ng/dL, and the testosterone deficiency prevalence was 1160 (30.942%). The geometric mean of serum klotho levels was 791.000 pg/mL. In the adjusted models, klotho increased 0.165 pg/mL for every 1 ng/dL increase of total testosterone (p = 0.004). In addition, estradiol (ß 2.232; 95% CI 0.588-3.876; p = 0.032) and sex hormone-binding globulin (ß 2.013; 95% CI 1.173-2.583; p = 0.002) were also positively associated with klotho concentrations. CONCLUSION: This study reported a significant association between klotho and sex hormones in the U.S. male population. The levels of klotho in men increased with total testosterone, estradiol and sex hormone-binding globulin levels, which may have implications for future research and clinical practice.

Klotho, FOXO1 and cytokines associations in patients with coronary artery disease.

INTRODUCTION: Atherosclerosis is one of the main reasons for adult mortality in advanced populations and countries with high stress levels. Klotho family are single-pass trans-membrane proteins that involve in the genesis and progression of various diseases, including acardiovascular disease, apoptosis and stress oxidative imbalance. Present study, investigates the pattern of changes in Klotho and FOXO1 gene expressions and levels in atherosclerosis. METHODS: Present case control study consisted of 79 patients with atherosclerosis and 78 healthy controls. PBMC (peripheral mono-nuclear blood cells) expression levels of Klotho and FOXO1 were assayed, using qPCR method. Serum concentration of Klotho and FOXO1 were measured by ELISA method. RESULTS: A significant reduction was found in PBMC genes expression levels of Klotho (P < 0.01) of patients as comparison with controls. PBMC Gene expression of FOXO1 in patients was increased significantly (P < 0.01) when compared with controls. Pearson analysis showed a positive correlation between PBMC Klotho gene expression and Klotho levels of patients (P < 0.01). The correlation between serum concentrations of Klotho and FOXO1 of patients was also positive significantly (P < 0.01). AUC of ROC for gene expression and serum concentration of Klotho in patients were 0.701 and 0.737 respectively. CONCLUSION: Investigating the PBMC gene expression and serum concentration of Klotho in patients with atherosclerosis is suggested could be a convenient novel biomarker for predicting, prognosis, monitoring the disease progression and designing a suitable drug for patients with atherosclerosis.

Post-kidney transplant soluble Klotho levels are determined by pretransplant soluble Klotho levels in both living donors and recipients.

BACKGROUND: Soluble Klotho (sKl), the free form of membrane-bound Klotho predominantly expressed in the kidney, is detectable in serum and may have multiple pleiotropic effects. Patients with end-stage kidney disease are possibly sKl deficient, and kidney transplantation is the treatment of choice in these patients; however, little is known about changes in posttransplant sKl level and the factors influencing these changes. METHODS: We conducted a prospective longitudinal study to examine changes in posttransplant sKl level in recipients for 12 months after living-donor kidney transplantation and analyzed correlations between posttransplant changes in sKl levels and various influencing factors in both recipients and donors. RESULTS: 29 kidney transplant recipients and their living donors were included for analysis. The results showed that sKl levels transiently decreased at 1 week posttransplant but progressively increased thereafter for 12 months. Multivariable linear regression analysis showed that body surface area-adjusted donor sKl levels were associated with posttransplant increases in recipient sKl levels at 12 months. In addition, pretransplant recipient sKl levels and body surface area-adjusted donor sKl levels were identified as an independent predictor of 12-month posttransplant sKl levels. CONCLUSION: Pretransplant sKl levels in both kidney recipients and living donors are a strong determinant of sKl levels after kidney transplantation.

Association of fibroblast growth factor 23 and α-klotho in hemodialysis patients during administration of ferric citrate hydrate: post hoc analysis of ASTRIO study.

BACKGROUND: Fibroblast growth factor-23 (FGF23) and α-klotho are associated with anemia in patients with chronic kidney disease. In this post hoc analysis of the ASTRIO study (UMIN000019176), we investigated the relationship between FGF23 and α-klotho during treatment with an iron-based phosphate binder, ferric citrate hydrate (FC), compared with non-iron-based phosphate binders in hemodialysis (HD) patients. We examined the effect of iron absorption by FC on the relationship between FGF23 and α-klotho. There have been few clinical studies evaluating these biomarkers simultaneously in HD patients. METHODS: The ASTRIO study was a 24-week, randomized, open-label, multicenter trial. HD patients taking non-iron-based phosphate binder(s) were randomized at a 1:1 ratio to continue other binder(s) (control group) or switch to FC (FC group). Serum phosphate (P) and hemoglobin (Hb) were maintained within 3.5-6.0 mg/dL and 10-12 g/dL, respectively. Plasma levels of intact FGF23 (i-FGF23), C-terminal FGF23 (c-FGF23), and α-klotho were measured, as were iron-related parameters. Association analyses of FGF23 and α-klotho were conducted. RESULTS: Patients were randomized to FC (n = 48) and control (n = 45) groups. Serum ferritin significantly increased from baseline to end-of-treatment (EOT) in the FC group, compared with the control group (adjusted mean difference [95% confidence interval]: 79.5 [44.7, 114.4] ng/mL; p <  0.001). The mean change from baseline to EOT in c-FGF23 was significantly different between the FC and control groups (mean ± standard deviation (SD): - 0.2 ± 0.8 loge pg/mL vs. 0.2 ± 0.8 loge pg/mL, respectively; p = 0.04). The mean change from baseline to EOT in i-FGF23 and α-klotho were not significantly different between the FC and control groups (mean ± SD: - 0.1 ± 0.8 loge pg/mL vs. 0.1 ± 0.9 loge pg/mL; p = 0.33, and 2.0 ± 91.5 pg/mL vs. - 8.9 ± 145.3; p = 0.58, respectively). However, both forms of FGF23 and α-klotho were not significantly associated with each other in both groups. CONCLUSIONS: Iron absorbed via FC administration in HD patients did not influence the correlation relationship between plasma levels of FGF23 and α-klotho under the condition of serum P and Hb were maintained. TRIAL REGISTRATION: ASTRIO study ( UMIN000019176 , registered at UMIN Clinical Trials Registry on October 1, 2015).

Dominant factors of the phosphorus regulatory network differ under various dietary phosphate loads in healthy individuals.

BACKGROUND: The purpose of this study was to explore the contribution of each factor of the phosphorus metabolism network following phosphorus diet intervention via Granger causality analysis. METHODS: In this study, a total of six healthy male volunteers were enrolled. All participants sequentially received regular, low-, and high-phosphorus diets. Consumption of each diet lasted for five days, with a 5-day washout period between different diets. Blood and urinary samples were collected on the fifth day of consumption of each diet at 9 time points (00:00, 04:00, 08:00, 10:00, 12:00, 14:00, 16:00, 20:00, 24:00) for measurements of serum levels of phosphate, calcium, PTH, FGF23, BALP, α-Klotho, and 1,25 D and urinary phosphorus excretion. Granger causality and the centrality of the above variables in the phosphorus network were analyzed by pairwise panel Granger causality analysis using the time-series data. RESULTS: The mean age of the participants was 28.5 ± 2.1 years. By using Granger causality analysis, we found that the α-Klotho level had the strongest connection with and played a key role in influencing the other variables. In addition, urinary phosphorus excretion was frequently regulated by other variables in the network of phosphorus metabolism following a regular phosphorus diet. After low-phosphorus diet intervention, serum phosphate affected the other factors the most, and the 1,25 D level was the main outcome factor, while urinary phosphorus excretion was the most strongly associated variable in the network of phosphorus metabolism. After high-phosphorus diet intervention, FGF23 and 1,25 D played a more critical role in active regulation and passive regulation in the Granger causality analysis. CONCLUSIONS: Variations in dietary phosphorus intake led to changes in the central factors involved in phosphorus metabolism.

Relationship of fibroblast growth factor 21, Klotho, and diabetic retinopathy: a meta-analysis.

Background: Diabetic retinopathy (DR) is a serious microvascular complication of diabetes mellitus. Research has identified a close relationship between fibroblast growth factor 21 (FGF21) and DR. FGF21 is a member of the FGF subfamily, which is activated by the Klotho coenzyme involved in the occurrence of DR. However, the association between FGF21, Klotho, and DR remains controversial. Aim: To assess FGF21 and Klotho levels in patients with DR. Methods: A literature search of the Web of Science, Wiley Online Library, PubMed, China National Knowledge Infrastructure and Wanfang databases was performed. The title or abstract search terms "diabetic retinopathy" and "DR" were used in combination with "fibroblast growth factor 21", "FGF21", and "Klotho". Meta-analysis results are presented as standardized mean difference (SMD) with corresponding 95% confidence interval (CI). Results: Fifteen studies were included in this meta-analysis. FGF21 levels in patients with DR were significantly higher than in non-DR patients with diabetes (SMD: 2.12, 95% CI [1.40, 2.84]). Klotho levels in patients with DR were significantly lower than in non-DR patients with diabetes (SMD: -0.63, 95% CI [-1.22, - 0.04]). Conclusions: This systematic review is the first to evaluate the relationship between FGF21, Klotho levels, and DR. FGF21 levels were significantly higher in patients with DR. Fully elucidating the role of FGF21 will significantly contribute to the treatment of DR.

Testosterone does not mediate the correlation between dietary inflammation and serum klotho levels among males: insights from NHANES database.

Introduction: Serum Klotho (S-Klotho) is a transmembrane protein holds pivotal roles in anti-aging. The Dietary Inflammation Index (DII), a meticulously dietary tool, quantifies the inflammatory potential of an individual's diet. The existing research strongly suggests that a low DII diet plays a significant role in delaying aging and reducing aging-related symptoms in males. Testosterone could potentially act as a mediating intermediary between DII and S-Klotho. However, this aspect remains unexplored. This study aims to investigate the potential causal link of testosterone between DII and S-Klotho in males. Methods: We utilized data from National Health and Nutrition Examination Survey (NHANES) which focused on male participants from 2013-2016. Mediation analyses were used to investigate the effects of testosterone (TT), free testosterone (FT), and free androgen index (FAI) on the DII-S-Klotho relationship, using three modes adjusting for covariates. Results: Mediation analysis unveiled a significant inverse correlation between DII and S-Klotho levels (model 1: c = -14.78, p = 0.046). The interaction between DII and S-Klotho was modulated by TT in model 1 (ab = -1.36; 95% CI: -5.59, -0.55; p = 0.008), but lost significance after adjustments (model 2: ab = -0.39; 95% CI: -4.15, 1.66; p = 0.378; model 3: ab = -0.59; 95% CI: -4.08, 2.15; p = 0.442). For FT, the mediating impact was not statistically significant (model 1: ab = 0.43; 95% CI: -0.51, 5.44; p = 0.188; model 2: ab = 0.72; 95% CI: -0.26, 5.91; p = 0.136; model 3: ab = 0.84; 95% CI: -0.02, 8.06; p = 0.056). Conversely, FAI consistently influenced the DII-S-Klotho relationship (model 1: ab = 2.39; 95% CI: 0.69, 9.42; p = 0.002), maintaining significance after adjustments (model 2: ab = 3.2; 95% CI: 0.98, 11.72; p = 0.004; model 3: ab = 3.15; 95% CI: 0.89, 14.51; p = 0.026). Discussion: This study observed no mediating influence of TT or FT on the correlation between DII and S-Klotho after covariate control. Remarkably, FAI continued to significantly mediate the DII-S-Klotho connection even following covariate adjustment, although its significance in males warrants careful consideration.

The association between testosterone and serum soluble klotho in the females: evidence from the NHANES database.

Objective: This research aimed to elucidate the relationship between testosterone levels and serum soluble klotho (S-klotho) concentrations in females aged 40-79 years using the National Health and Nutrition Examination Survey (NHANES) dataset. Design: Associations between testosterone and S-klotho were assessed through multivariable linear regression methodologies, spanning nonadjusted, minimally adjusted, and fully adjusted models. Settings: The investigation was conducted as a cross-sectional analysis utilizing the NHANES database. Participants: From 20,146 NHANES participants between 2013 and 2016, 2,444 females met the stipulated inclusion and exclusion criteria. Results: Free androgen index (FAI) showcased a negative correlation with S-klotho levels across all regression models (nonadjusted: ß -7.08, 95% CI -13.39- -0.76; minimally adjusted: ß -9.73, 95% CI -16.6- -2.84; fully adjusted: ß -7.63, 95% CI -14.75-0.51). Conversely, total testosterone did not exhibit significant associations with S-klotho across the models. In the nonadjusted model, estradiol was positively associated with S-klotho concentrations (ß 0.14, 95% CI 0.05-0.23), but this significance was not retained in subsequent regression models. Conclusion: Findings suggest that in U.S. females aged 40-79 years, FAI negatively correlates with S-klotho concentrations, while there is the lack of significant associations for total testosterone and estradiol.

Positive association of the anti-aging protein α-Klotho with insulin resistance and its inverse L-shaped relationship with glycaemic control in the middle-aged and elderly population.

PURPOSE: α-Klotho has been linked to insulin resistance (IR) in basic research. However, experimental evidence is inconsistent, and there is a lack of data from human research. This study seeks to elucidate the association of α-Klotho with IR in a nationwide, multiracial population. METHODS: A total of 5289 participants aged 40-79 years were included in the National Health and Nutrition Examination Survey (NHANES) spanning 2007-2016. Serum α-Klotho was measured using enzyme-linked immunosorbent assays (ELISA), and IR was evaluated by the homeostatic model assessment of insulin resistance (HOMA-IR). Weighted multivariate logistic and linear regression analysis, subgroup analysis stratified by demographic characteristics, medical condition or obesity status, and sensitivity analysis using propensity score matching (PSM) were performed. Restricted cubic splines (RCS) were performed to explore the nonlinear relationship. RESULTS: In the fully adjusted logistic regression model, a significant positive association was observed between log-transformed α-Klotho and IR (OR = 3.63, 95% CI: 1.56, 8.45), particularly in males or nonobese individuals (Pinteraction < 0.05). In the linear regression model, log10(α-Klotho) was associated with fasting blood glucose (FBG, ß = 1.25, 95% CI: 0.74, 1.76) and glycosylated hemoglobin (HbA1c, ß = 0.49, 95% CI: 0.20, 0.77). RCS revealed an inverse L-shaped dose-response relationship of α-Klotho with FBG and HbA1c (Pnonlinear <0.05). Beyond the inflection point of log10(α-Klotho) at 2.79, ß coefficients sharply rose for these glycaemic control indicators. CONCLUSION: The study provides clinical evidence supporting a positive association between α-Klotho and IR. Moreover, the inverse L-shaped relationship suggests that α-Klotho should reach a certain level to predict glycaemic changes effectively.

Fibroblast growth factor-23 and Alpha-Klotho concentrations in dogs with canine Leishmaniasis.

This study aimed to assess the concentrations of Fibroblast Growth Factor-23 (FGF-23) and α-Klotho in healthy dogs and dogs at different stages of Canine Leishmaniasis (CanL), and investigate the changes of these parameters in relation to renal function and calcium­phosphorus metabolism. A total of 74 dogs (22 healthy and 52 with CanL) of varying ages, sexes, and medium-sized breeds were included. Dogs with CanL were categorized into different stages (Stage I-IV) based on Leishvet recommendations. In addition to routine hematological parameters, plasma FGF-23, serum α-Klotho, urea, creatinine, phosphorus, calcium, parathormone, vitamin D concentrations, and urine protein/creatinine ratio were measured. Data from healthy dogs were compared to dogs with CanL overall and by stage. Dogs with CanL exhibited higher concentrations of FGF-23 (p < 0.05), α-Klotho, and parathormone (p < 0.001), as well as lower concentrations of vitamin D and calcium (p < 0.001). FGF-23 concentration was particularly elevated in Stage IV compared to other stages. However, no significant differences in α-Klotho levels were observed among the stages. FGF-23 levels showed a weak positive correlation with urea and creatinine concentrations and a moderate positive correlation with urine protein/creatinine ratio. This study demonstrated increased levels of FGF-23 and α-Klotho in dogs with CanL for the first time. The increase in FGF-23 levels was more prominent in advanced stages of the disease and correlated with higher urea and creatinine concentrations. These findings may serve as a basis for future diagnostic and therapeutic investigations, contributing to the understanding of the pathophysiology of kidney disease in CanL.