α-Klotho Levels Research Articles

Sex differences in the association between serum α-Klotho and depression in middle-aged and elderly individuals: A cross-sectional study from NHANES 2007–2016

BackgroundKlotho is a well-known anti-aging protein that exerts pleiotropic effects; however, little is known regarding serum α-Klotho in the context of depression. Here, we evaluated the association between serum α-Klotho levels and depression in middle-aged and older individuals. MethodsIn this cross-sectional study, data were collected from the National Health and Nutrition Examination Survey (NHANES) from 2007 to 2016 with a total of 5272 participants who were ≥40 years of age. Depression was evaluated using the 9-item Patient Health Questionnaire (PHQ-9). The association between serum α-Klotho levels and depression was determined on the basis of multivariable logistic regression models. ResultsThe mean age of the enrolled adults was 58.94 ± 10.54 years, of which 49.5 % were female. When serum α-Klotho was log10-transformed, it was significantly inversely associated with depression in females in the final adjusted model (odds ratio [OR], 0.32; 95 % confidence interval [CI], 0.12–0.85). In the contrast, serum α-Klotho (log10) was significantly positively associated with depression in males in one of the adjusted models (OR, 3.71; 95 % CI, 1.17–11.8), and this disappeared after adjusting other covariates (all P > 0.05). Based on further stratified respective analyses of females and males, the results were stable. LimitationsThe cross-sectional study could not yield any conclusions regarding causality. ConclusionsIn the present study, serum α-Klotho levels were negatively related to the prevalence of depression in middle-aged and elderly women. This study provides new evidence of sex differences in the association between serum α-Klotho levels and depression.

Relationships between blood bone metabolic biomarkers and anemia in patients with chronic kidney disease

Introduction Blood bone metabolic biomarkers are noninvasive indices for evaluating metabolic bone diseases. We investigated the relationships between blood bone metabolic biomarkers and anemia in chronic kidney disease (CKD) patients and analyzed the effects of parathyroidectomy (PTX) on the above indices. Methods In this cross-sectional study, 100 healthy controls and 239 CKD patients, including 46 secondary hyperparathyroidism (SHPT) patients with PTX, were enrolled. Moreover, a prospective study was conducted in which 28 PTX patients were followed up. The degree of anemia was classified as mild, moderate, or severe based on the tertiles of hemoglobin (Hb) levels of the anemic CKD patients, with cutoff values of 83 g/L and 102 g/L. Bone metabolic biomarkers, including calcium (Ca), phosphorus (P), intact parathyroid hormone (iPTH), fibroblast growth factor 23 (FGF23), and α-klotho, were tested. Results The mean estimated glomerular filtration rate (eGFR) in CKD patients was 25.7 ± 36.0 ml/min/1.73 m2, and 84.10% of CKD patients had anemia. The baseline Hb levels in the mild, moderate, and severe anemia subgroups were 110.86 ± 5.99 g/L, 92.71 ± 5.96 g/L, and 67.38 ± 10.56 g/L, respectively. CKD patients had higher adjusted Ca, P, alkaline phosphatase (ALP), iPTH, and FGF23 levels and lower α-klotho levels than controls. Baseline adjusted Ca, P, iPTH, and α-klotho levels were associated with Hb levels in CKD patients. Blood adjusted Ca, P, and iPTH levels were correlated with anemia severity. After PTX (median interval: 6.88 months), anemia and high blood adjusted Ca, P, iPTH, and FGF23 levels were ameliorated, while α-klotho levels were increased. Conclusions Blood adjusted Ca, P, iPTH, and α-klotho levels were correlated with Hb levels in CKD patients. Correction of bone metabolic disorders may be a therapeutic strategy for anemia treatment.

Association between perfluoroalkyl and polyfluoroalkyl internal exposure and serum α-Klotho levels in middle-old aged participants.

Exposure to perfluoroalkyl and polyfluoroalkyl substances causes oxidative stress, which is strongly associated with adverse health effects. Klotho protein plays an anti-aging role via antioxidation activity. We investigated the levels of serum α-Klotho and PFAS exposure in adults who participated in the National Health and Nutrition Examination Survey from 2013 to 2016. A nationally representative subsample of 1,499 adults aged 40-79 years was analyzed for the associations of serum α-Klotho levels with serum PFAS exposures by correlation analysis and multiple general linear models. Of note, the potential confounding factors including age and gender were adjusted. Quantile-based g-computation models were used to assess the effects of mixed PFAS exposure on serum α-Klotho levels. The weighted geometric mean of serum α-Klotho was 791.38 pg/mL for the subjects during 2013-2016. After adjusting for potential confounders, serum Klotho levels showed a statistically significant downward trend with increasing quartiles of PFOA and PFNA. Multivariate adjusted general linear regression analysis showed that increased exposure to PFNA was substantially associated with lower serum levels of α-Klotho, and each 1-unit increase in PFNA concentration was accompanied by a 20.23 pg/mL decrease in α-Klotho level; while no significant association was observed between other PFAS exposures and serum α-Klotho levels. It was negatively correlated between α-Klotho and Q4 for PFNA relative to the lowest quartile (Q1) of exposure (P = 0.025). It was found that the strongest negative correlation between PFNA exposure and serum α-Klotho levels was in the middle-aged (40-59 years) female participants. Furthermore, the mixture of the four PFAS substances showed an overall inverse association with serum α-Klotho concentrations, with PFNA being the major contributor. Taken together, in a representative sample of the U.S. middle-aged and elderly populations, serum concentrations of PFAS, especially PFNA, have been negatively associated with serum levels of α-Klotho, which is strongly associated with cognition and aging. It was important to note that the majority of associations were limited to middle-aged women. It will be meaningful to clarify the causal relationship and the pathogenic mechanisms of PFAS exposure and α-Klotho levels, which is helpful to aging and aging-related diseases.

Branched Multimeric Peptides as Affinity Reagents for the Detection of α-Klotho Protein.

α-Klotho, an aging-related protein found in the kidney, parathyroid gland, and choroid plexus, acts as an essential co-receptor with the fibroblast growth factor 23 receptor complex to regulate serum phosphate and vitamin D levels. Decreased levels of α-Klotho are a hallmark of age-associated diseases. Detecting or labeling α-Klotho in biological milieu has long been a challenge, however, hampering the understanding of its role. Here, we developed branched peptides by single-shot parallel automated fast-flow synthesis that recognize α-Klotho with improved affinity relative to their monomeric versions. These peptides were further shown to selectively label Klotho for live imaging in kidney cells. Our results demonstrate that automated flow technology enables rapid synthesis of complex peptide architectures, showing promise for future detection of α-Klotho in physiological settings.

The impact of SGLT2 inhibitors on αKlotho in renal MDCK and HK-2 cells.

αKlotho is a transmembrane protein predominantly expressed in the kidney serving as a co-receptor for phosphate homeostasis-regulating hormone FGF23 and has an extracellular domain that can be cleaved off and is a hormone. αKlotho deficiency results in accelerated aging and early onset of aging-associated diseases while its overexpression strongly expands the lifespan of mice. Moreover, αKlotho exerts health-beneficial anti-inflammatory, anti-neoplastic, anti-fibrotic, and anti-oxidant effects. Higher αKlotho levels are associated with better outcomes in renal and cardiovascular diseases. SGLT2 inhibitors are novel drugs in the treatment of diabetes by inhibiting renal glucose transport and have additional nephro- and cardioprotective effects. We explored whether SGLT2 inhibitors affect αKlotho gene expression and protein secretion. Experiments were performed in renal MDCK and HK-2 cells, and αKlotho transcripts were determined by qRT-PCR and Klotho protein by ELISA. SGLT2 inhibitors canagliflozin, sotagliflozin, and dapagliflozin enhanced whereas empagliflozin reduced αKlotho gene expression in MDCK cells. By the same token, canagliflozin, sotagliflozin, dapagliflozin, but not empagliflozin down-regulated p65 subunit of pro-inflammatory NFκB. In HK-2 cells, all SGLT2 inhibitors reduced αKlotho transcripts. Canagliflozin and sotagliflozin, however, increased Klotho protein concentration in the cell culture supernatant, an effect paralleled by up-regulation of ADAM17. Taken together, our investigations demonstrate complex effects of different SGLT2 inhibitors on αKlotho gene expression and protein secretion in renal MDCK and HK-2 cells.

Association of α-klotho levels with serum copper and cadmium levels in schizophrenia

IntroductionSchizophrenia is associated with harmful health effects such as oxidative stress from heavy metal exposure. We considered the relationship between genes and heavy metals in association with oxidative stress and then investigated the association between serum α- klotho and copper and cadmium exposure among schizophrenia patients in western India.ObjectivesTo investigated the association between serum α- klotho and copper and cadmium exposure among schizophrenia patients in western India.Methods100 individuals participated out of which 50 were diagnosed with schizophrenia, severity was assessed by using PANSS score and 50 were taken as controls using General health questionnaire. Serum Klotho levels were estimated using ELISA. Serum Cadmium (Cd) and Serum Copper (Cu) was estimated using Atomic Absorption Spectrophotometry.ResultsThe mean ± SD levels of Serum Cd, Serum Cu and serum Klotho were 1.05 ± 0.55 μg/dl, 135.5 ± 51.25 μg/ml and 62.9 ± 35.1 ng/ml respectively in the patients and 0.23 ± 0.17 μg/dl, 147.9 ± 25.42 μg/ml and 78.6 ± 34.6 ng/ml respectively in controls. The differences in Serum Cd, Serum Cu levels and Klotho levels among the study group were highly significant (p <0.05).ConclusionsBoth Cu and Cd levels were significantly raised in schizophrenic patients compared with controls. Serum klotho levels showed a statistically significant decreasing trend with increasing cadmium levels. These results suggest that cadmium levels may be associated with the serum klotho levels which may be associated with decreased cognition in schizophrenia.Disclosure of InterestNone Declared

Association between Serum α-Klotho Levels and Behçet Disease.

Endothelial dysfunction (ED) has a well-known role in promoting vascular inflammation in Behçet disease (BD). α-klotho is involved in regulation of endothelial function, and its reduction has been reported to be associated with ED. To assess serum α-klotho in patients with BD, compared with healthy control individuals. In a cross-sectional study, 55 patients with BD and 30 age- and sex-matched healthy controls were enrolled, and their serum levels of α-klotho were measured. Common clinical symptoms in patients with BD were oral aphthous ulcers, uveitis, and genital ulcers. Median (IQR) serum α-klotho levels in the BD and control groups were 0.30 (0.20-0.70) and 1.00 (0.70-2.52) ng/mL, respectively. The difference was statistically significant (P = .005). No significant correlation was observed between serum α-klotho and age (r = 0.194; P = .14). Serum α-klotho levels in patients with uveitis were significantly lower. α-klotho may have a role in the pathogenesis of ED and is a potential biomarker for uveitis in BD.

Effect of cigarette smoking on serum methylarginine and α-klotho levels

Background and aimsSmoking causes many diseases such as cardiovascular, lung diseases, stroke and premature aging. However, the role of smoking in the pathogenesis of these diseases is unclear. Increasing evidence suggests that methylarginine pathway metabolites and α-klotho may be strong markers for pathologies such as premature aging, endothelial dysfunction, and oxidant damage. Therefore, the study aimed to measure the serum levels of arginine, asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA), N-monomethyl-l-arginine (L-NMMA), and α-klotho levels in smokers. Methods and resultsThis case-control analytical study included 65 smokers and 71 non-smokers. Sociodemographic characteristics, routine biochemistry parameters, Framingham risk scores and Fagerström Nicotine Dependence Test (FTND) were recorded. Serum methylarginine and α-klotho levels were analyzed by tandem mass spectrometry and enzyme-linked immunosorbent assay (ELISA), respectively. Serum ADMA (p < 0.001), L-NMMA (p = 0.024), SDMA (p < 0.001) levels of smokers were higher than non-smokers, and serum α-klotho (p < 0.001) and arginine levels (p < 0.001) were lower. There was a positive correlation between serum ADMA levels with FNDT, age and pack/year in smokers, while there was a negative correlation between klotho levels and age. A positive correlation was found between serum ADMA levels, Framingham risk score and age in non-smokers. ConclusionSmoking is related to premature aging and is a strong risk factor for various diseases such as cardiovascular, inflammatory, and renal diseases. Elevated serum methylarginine and decreased serum klotho levels were found in smokers. Therefore, our findings suggest that smoking may be involved in the pathogenesis of these diseases by affecting α-klotho and methylarginine-related pathways.

Reduced levels of α-Klotho are associated with increase in oxidative stress and immune response in MDD patients

Reduced levels of α-Klotho are associated with increase in oxidative stress and immune response in MDD patients

Fibroblast growth factor 23-Klotho and mineral metabolism in the first year after pediatric kidney transplantation: A single-center prospective study.

The role of fibroblast growth factor 23 (FGF23) levels in mineral metabolism before and after kidney transplantation in pediatric patients is poorly understood. We prospectively evaluated 24 patients under 18 years of age (4.5 [3.3-9.8]years) who underwent living kidney transplantation between July 2016 and March 2018, and measured intact FGF23 and serum αKlotho levels, and other parameters of mineral metabolism before and after transplantation (Day 7, 1 and 4 months, and 1 year). Relationships between parameters were examined by linear analysis. FGF23 level was 440.8 [63.4-5916.3]pg/ml pre-transplant and decreased significantly to 37.1 [16.0-71.5]pg/ml at Day 7 post-transplant (-91.6%, p < .001). Thereafter, it remained at normal levels until 1 year. αKlotho level was 785 [568-1292]pg/ml pre-transplant and remained low at Day 7 and 1 month post-transplant, with an increasing trend at 4 months. Post-transplant phosphorus levels were significantly decreased compared with pre-transplant, with a lowest level of 1.7 [1.3-2.9]mg/dl, -5.7 [-6.8, -3.8] SD at Day 4, followed by gradual recovery. Phosphorus levels and the ratio of tubular maximum phosphate reabsorption were significantly and negatively associated with pre-transplant FGF23 until 4 months of post-transplant. Pre-transplant αKlotho was negatively associated with pre-transplant FGF23 but not FGF23 or other parameters after transplantation. FGF23 in pediatric kidney transplant patients decreased rapidly after transplantation and associated with post-transplant hypophosphatemia and increased phosphorus excretion. Post-transplant αKlotho was low early post-transplant but tended to increase subsequently. Post-transplant αKlotho was unaffected by pre-transplant FGF23 or other factors, suggesting pre-transplant chronic kidney disease status has no effect.

Treatment of early borderline lesions in low immunological risk kidney transplant patients: a Spanish multicenter, randomized, controlled parallel-group study protocol: the TRAINING study

BackgroundSubclinical inflammation, including borderline lesions (BL), is very common (30–40%) after kidney transplantation (KT), even in low immunological risk patients, and can lead to interstitial fibrosis/tubular atrophy (IFTA) and worsening of renal function with graft loss. Few controlled studies have analyzed the therapeutic benefit of treating these BL on renal function and graft histology. Furthermore, these studies have only used bolus steroids, which may be insufficient to slow the progression of these lesions. Klotho, a transmembrane protein produced mainly in the kidney with antifibrotic properties, plays a crucial role in the senescence-inflammation binomial of kidney tissue. Systemic and local inflammation decrease renal tissue expression and soluble levels of α-klotho. It is therefore important to determine whether treatment of BL prevents a decrease in α-klotho levels, progression of IFTA, and loss of kidney function.MethodsThe TRAINING study will randomize 80 patients with low immunological risk who will receive their first KT. The aim of the study is to determine whether the treatment of early BL (3rd month post-KT) with polyclonal rabbit antithymocyte globulin (Grafalon®) (6 mg/kg/day) prevents or decreases the progression of IFTA and the worsening of graft function compared to conventional therapy after two years post-KT, as well as to analyze whether treatment of BL with Grafalon® can modify the expression and levels of klotho, as well as the pro-inflammatory cytokines that regulate its expression.DiscussionThis phase IV investigator-driven, randomized, placebo-controlled clinical trial will examine the efficacy and safety of Grafalon® treatment in low-immunological-risk KT patients with early BL.Trial registrationclinicaltrials.gov: NCT04936282. Registered June 23, 2021, https://clinicaltrials.gov/ct2/show/NCT04936282?term=NCT04936282&draw=2&rank=1. Protocol Version 2 of 21 January 2022. Sponsor: Canary Isles Institute for Health Research Foundation, Canary Isles (FIISC). mgomez@fciisc.org.

Serum Levels of α-Klotho, Inflammation-Related Cytokines, and Mortality in Hemodialysis Patients.

It has been hypothesized that α-Klotho deficiency might contribute to chronic inflammation in patients with end-stage renal disease (ESRD), especially those on hemodialysis (HD). Serum Klotho levels by some authors are considered a potential predictor of cerebrovascular events. Therefore, we analyzed serum levels of α-Klotho with ELISA and inflammation-related cytokines in HD patients. Sixty-seven HD patients and 19 healthy people were recruited between November 2017 and June 2021. A Cytometric Bead Array (CBA) was used to determine the level of different cytokines: IL-12p70, TNF, IL-10, IL-6, IL-1β, and IL-8. A human Klotho ELISA kit was used to determine the level of α-Klotho in the plasma samples of HD patients. There was no difference in serum levels of α-Klotho between HD patients and healthy people. Patients had increased serum IL-6 and IL-8. Significant positive correlations existed between the concentration of α-Klotho and the serum concentrations of IL-12p70, IL-10, and IL-1β. However, in a multivariable linear regression analysis, only patients' age was associated independently with α-Klotho level. Serum α-Klotho was not associated with higher mortality risk in HD patients. While these results draw attention to potential relationships between α-Klotho proteins and inflammatory markers in HD patients, our cross-sectional study could not confirm the pathogenic link between α-Klotho, inflammation, and cardiovascular mortality.

Exposure to p-dichlorobenzene and serum α-Klotho levels among US participants in their middle and late adulthood

P-dichlorobenzene (p-DCB) is a volatile compound commonly used as pest repellent and air deodorant in the home and public buildings, leading to a widespread exposure in indoor environments. There has been an increasing concern about its metabolic and endocrine effects. In this study, we explored the relation between p-DCB exposure and serum levels of soluble α-Klotho, an anti-aging hormone, in US adults. A nationally representative subsample of 1485 adults 40–79 ages in the 2013–2016 National Health and Nutrition Examination Survey was analyzed for the association between p-DCB exposure, measured as urinary concentrations of 2,5-dichlorophenol (2,5-DCP), the major metabolite of p-DCB, and serum α-Klotho levels using multiple general linear models, adjusting for potential confounders. Age- and sex-specific analyses were further conducted. The weighted geometric mean of urinary 2,5-DCP was 2.43 μg/L and the weighted mean of serum α-Klotho was 831.97 pg/mL in the study participants during 2013–2016. After adjusting for potential confounders and urinary creatinine, urinary 2,5-DCP was significantly associated with decreased serum levels of α-Klotho (regression coefficient β = −9.88; p = 0.0133) in the total study population. When age- and sex-specific analyses being conducted, a significantly inverse association was found in older adults aged 60–79 years (β = −20.40; p = 0.0001) and in males (β = −13.81; p = 0.0097), but not in the middle ages (40–59 years) and in females. The strongest association was observed in older (60–79 years) male participants, with a 25.43 pg/mL reduction of α-Klotho levels per 1-unit increase of 2,5-DCP concentrations (p = 0.0008). This is the first study demonstrating a relation between p-DCB exposure, measured as 2,5-DCP, and decreased α-Klotho levels in older males. Additional studies would further explore these interactions and elucidate the pathogenesis of the potential effects of p-DCB exposure on aging.

New mechanisms for the kidney-protective effect of alkali in chronic kidney disease.

Worldwide, more than one in ten adults are estimated to have chronic kidney disease (CKD). As CKD progresses, both the cost of treatment and associated risk of morbidity and mortality increase exponentially. As such, there is a great need for therapies that effectively slow CKD progression. Evidence from several small clinical trials indicates that alkali therapy may slow the rate of CKD progression. The biological mechanisms underlying this protective effect, however, remain unknown. In their recently published manuscript, Pastor Arroyo et al. (Clin Sci (Lond) (2022) 136(8): https://doi.org/10.1042/CS20220095) demonstrate that the alkali sodium bicarbonate protects against loss of renal function in a crystal nephropathy model in mice. Using unbiased approaches in both mice and human tissue, the authors go on to identify two novel mechanisms that may underly this protection. The first pathway is through promoting pathways of cell metabolism, which they speculate helps the remaining functional nephrons adapt to the greater metabolic needs required to maintain kidney filtration. The second pathway is by restoration of α-Klotho levels, which may limit the expression of adhesion molecules in the injured kidney. This, the authors speculate, may prevent inflammation from driving the functional decline of the kidney. Identifying these novel pathways represents an important step forward harnessing the potential benefits of alkali therapy in CKD.

The association between serum soluble Klotho and chronic kidney disease among us adults ages 40 to 79 years: Cross-sectional study.

BackgroundChronic kidney disease (CKD) is diagnosed in more than 26 million U.S. people, which increases the risk of many adverse events. α-Klotho was reported to have potential effects on kidney function. The purpose of this study was to investigated whether CKD prevalence is associated with α-Klotho levels in the U.S. people aged 40–79 years.MethodsThirteen thousand five hundred eighty-nine participates in the National Health and Nutrition Examination Survey 2007–2016 aged 40–79 with information of Klotho and kidney function were included. The association between CKD and Klotho was calculated using multivariate linear or logistic regression models with adjustment of several possibly confounding variables. Subgroup analyses stratified by age, BMI, and diabetes mellitus were conducted. The non-linear relationship between Klotho and dependent variables with a non-normality of residues was assessed using smooth curve fitting and the segmented regression (also known as piece-wise regression) models.ResultsAmong 13,589 participants, the median of Klotho levels was 803.10 pg/mL, mean eGFR of all participants was 86.96 (SD = 19.88) mL/min/1.73 m2, and CKD was diagnosed in 20.11% of them (N = 2733). In the fully adjusted model, eGFR was positively associated with Klotho (β = 5.14, 95%CI 4.13-6.15, p < 0.001), while CKD was negatively associated with Klotho (stage ≧ 1, OR = 0.62, 95% CI 0.50–0.76, p < 0.001; stage ≧ 3, OR = 0.31, 95% CI 0.24–0.41, p < 0.001). The non-linear relationship showed that occurrence of CKD stage> 1 and albuminuria were negatively associated with Klotho when Klotho smaller than turning point (for whether CKD stage> 1, turning point K = 6.85, Klotho < K, OR = 0.44, p < 0.001; for albuminuria, turning point K = 6.84, Klotho < K, OR = 0.59, p < 0.001).ConclusionSerum soluble Klotho levels were positively associated with eGFR and negatively associated with the prevalence of CKD, especially in elderly, obese, and diabetic patients.

Serum α-Klotho associated with oral health among a nationally representative sample of US adults.

BackgroundLow klotho is associated with aging-related traits. However, no study has assessed the association between klotho and oral health in a large sample of population. This study aimed to explore the association between serum α-klotho and oral health in US Adults.MethodsData were from the National Health and Nutrition Examination Survey. Oral health parameters included periodontitis, self-rated oral health, and tooth loss. Logistic regression and restricted cubic spline models were adopted to evaluate the associations.ResultsA total of 6187 participants were included in the study. The median of the α-klotho level was 815.2 pg/mL. Serum α-Klotho was significantly lower in participants with poor oral health (all P <0.01). Compared with the highest tertile, the lowest tertile of α-klotho was associated with moderate/severe periodontitis, poor-rated oral health, and tooth loss, with OR (95% CI) being 1.21 (1.01, 1.48), 1.26 (1.01, 1.56) and 1.38 (1.05, 1.84), respectively. An increment of per 1 standard deviation in the α-klotho concentration was associated with lower odds of moderate/severe periodontitis (OR: 0.93; 95% CI: 0.87, 0.99). Linear dose-response relationships were found between α-klotho and the odds of moderate/severe periodontitis (P for non-linearity=0.88) and poor-rated oral health (P for non-linearity=0.66). An L-shaped dose-response relationship was found between levels of α-klotho and the odds of tooth loss (P for non-linearity=0.04).ConclusionsSerum α-klotho was associated with oral health. Further studies are necessary to clarify the potential mechanisms and demonstrate the predictive ability of klotho in oral diseases.

Para-dichlorobenzene exposure and serum α-Klotho levels among US participants in their middle and late adulthood

Para-dichlorobenzene exposure and serum α-Klotho levels among US participants in their middle and late adulthood

Association between environmental exposure to perchlorate, nitrate, and thiocyanate and serum α-Klotho levels among adults from the National Health and nutrition examination survey (2007–2014)

Background & aimsAging is a pathophysiological process driven by a diverse set of complex biological processes, and environmental pollution plays an important role in this process. This study aimed to explore the association between serum α-Klotho levels and urinary perchlorate, nitrate, and thiocyanate levels.MethodsThis secondary dataset analysis included 4875 participants (mean age, 57.69 year; male, 49.58%; non-Hispanic White, 47.67%) from the US National Health and Nutrition Examination Survey (2007–2014). Enzyme-linked immunosorbent assay was used to quantify α-Klotho levels, and ion chromatography coupled with electrospray tandem mass spectrometry was used to quantify thiocyanate, nitrate, and perchlorate levels. Multivariate linear regression models were applied to estimate the association between perchlorate, nitrate, and thiocyanate levels and serum α-Klotho levels.ResultsUrinary thiocyanate levels were negatively associated with α-Klotho levels (β = − 0.006; 95% confidence interval, − 0.010 to − 0.003; P = 0.0004) after adjusting for age, sex, body mass index, race, alcohol consumption, estimated glomerular filtration rate, underlying disease, physical activity, smoking status, usual energy intake, and urinary creatinine and serum cotinine levels and mutual adjustment of urinary perchlorate, urinary nitrate, and urinary thiocyanate levels. The α-Klotho level in participants in the highest quartile was higher by 50.567 ng/mL (β = 50.567; 95% confidence interval, 14.407 to 86.726; P = 0.009) than that in participants in the lowest quartile of urinary perchlorate. A linear relationship was observed between urinary thiocyanate and α-Klotho levels.ConclusionsUrinary thiocyanate levels were negatively associated with serum α-Klotho levels. Urinary thiocyanate should be further investigated as a potential mediator of aging and age-related diseases.

Association of pre- and postoperative αKlotho levels with long-term remission after pituitary surgery for acromegaly

Soluble αKlotho (sKl) is a disease-specific biomarker that is elevated in patients with acromegaly and declines after surgery for pituitary adenoma. Approximately 25% of patients do not achieve remission after surgery, therefore a risk stratification for patients early in the course of their disease may allow for the identification of patients requiring adjuvant treatment. Growth hormone (GH) and insulin-like growth factor-1 (IGF-1) have been assessed as biomarker for disease activity, however the value of sKl as a predictive biomarker of surgical success has not been evaluated yet. In this study, we measured serum biomarkers before and after transsphenoidal pituitary surgery in 55 treatment-naïve patients. Based on biochemical findings at follow-up (7–16 years), we divided patients into three groups: (A) long-term cure (defined by normal IGF-1 and random low GH (< 1 μg/l) or a suppressed GH nadir (< 0.4/μg/l) on oral glucose testing); (B) initial remission with later disease activity; (C) persistent clinical and/or biochemical disease activity. sKl levels positively related to GH, IGF-1 levels and tumor volume. Interestingly, there was a statistically significant difference in pre- and postoperative levels of sKl between the long-term cure group and the group with persistent disease activity. This study provides first evidence that sKl may serve as an additional marker for surgical success, decreasing substantially in all patients with initial clinical remission while remaining high after surgery in patients with persistent disease activity.

Association of α-klotho and lead and cadmium: A cross-sectional study

Epigenetic aging is associated with harmful health effects such as oxidative stress from heavy metal exposure. We considered the relationship between genes and heavy metals in association with oxidative stress and then investigated the association between serum α- klotho and lead and cadmium exposure among adults in the United States from 2007 to 2016 participating in the National Health and Nutrition Examination Survey (NHANES). Samples included 9800 adults aged 40 to 79 years with measurements of serum α-klotho, lead and cadmium, and complete covariate data. Lead and cadmium levels were measured by inductively coupled plasma mass spectrometry and serum α-klotho levels were measured using enzyme-linked immunosorbent assay (ELISA). Multivariate linear regression analysis was used to estimate the association between serum α-klotho and blood lead, blood cadmium, and urinary cadmium. A percent increase in blood lead, blood cadmium, and urinary cadmium was associated with a statistically significant 4.0 % (p < 0.001), 2.0 %, (p = 0.003) and 1.0 % (p = 0.020) decrease in serum klotho. After adjustment, a percent increase in blood lead was associated with a statistically significant 4.0 % (p < 0.001) decrease in serum klotho; blood and urinary cadmium did not show any statistically significant associations after adjustment (β (95 % CI), p-value for blood cadmium: 0.00 (−0.02–0.01), p = 0.573; urinary cadmium: −0.01 (−0.03–0.01), p = 0.210). Mean serum klotho levels showed a statistically significant decreasing trend with increasing blood lead quartiles (unadjusted and all-adjusted geometric means and 95 % confidence intervals of serum klotho (in pg/mL) for Q1, Q2, Q3, and Q4: unadjusted: 827.49 (814.20–840.92), 811.92 (794.73–829.48), 791.48 (775.11–808.19), and 772.01 (754.23–790.29); adjusted: 830.64 (805.53–856.45), 816.07 (789.18–843.87), 800.71 (773.71–828.57), and 784.31 (757.94–811.59)). Blood lead and levels were negatively associated with serum α-klotho levels in a representative population of US adults. These results suggest that blood lead levels may be associated with the serum levels of a protein associated with cognition and aging. Further research is recommended to investigate the causality behind such relationship.