Serum ß-klotho is a potential biomarker for the progression of hepatitis B virus-related liver diseases.

INTRODUCTION: Hepatitis B virus (HBV) infection is a global epidemic that can lead to several liver diseases, seriously affecting people's health. This study aimed to investigate the clinical potential of serum ß-klotho (KLB) as a promising biomarker in HBV-related liver diseases. METHODOLOGY: This study enrolled 30 patients with chronic hepatitis B (CHB), 35 with HBV-related cirrhosis, 66 with HBV-related hepatocellular carcinoma (HCC), and 48 healthy individuals. ELISA measured the levels of serum KLB in the four groups. We then compared the differences in serum KLB levels among the groups and analyzed the relationship between serum KLB and routine clinical parameters. RESULTS: The concentrations of serum KLB levels were increased sequentially among the healthy subjects, the HBV-related CHB group, the HBV-related cirrhosis group, and the HBV-related HCC group (p < 0.05). Expression of KLB was positively correlated with alpha-fetoprotein (AFP), total bilirubin, direct bilirubin, alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl-transferase, alkaline phosphatase, total bile acid, serum markers for liver fibrosis, ascites, cirrhosis, splenomegaly, and model for end-stage liver disease sodium, while negatively correlated with platelet count, albumin, and prothrombin activity (p < 0.05). In addition, serum KLB has better sensitivity in diagnosing HCC than AFP, and serum KLB combined with AFP has higher sensitivity and specificity than AFP alone in diagnosing HCC. CONCLUSIONS: Serum KLB level is associated with the severity of HBV-related liver diseases and has important diagnostic value for HCC. Therefore, it could be a predictive biomarker for monitoring disease progression.

Serum klotho associated with thyroid hormone in adults: A population-based cross-sectional research.

BACKGROUND AND STUDY AIM: The klotho protein, a multifunctional protein, has been shown to be associated with a wide range of endocrine diseases and has been linked to thyroid tumourigenesis. However, the relationship between serum klotho levels and thyroid hormones remains poorly understood. This study aimed to explore the correlation between serum klotho levels and thyroid hormones. METHODS: Data was obtained from the NHANES cycles 2007-2008, 2009-2010, and 2011-2012. A total of 4674 participants were recruited for this study. Statistical analysis was using multiple linear regression analyses, and restricted cubic spline plots (RCS) to investigate the association between serum klotho levels and serum levels of thyroid hormones. RESULTS: In the unadjusted covariate model, ln(klotho) significantly positively correlated with tT3, tT4, fT3, tT4/fT4, and tT3/fT3 (all P<0.01) and negatively correlated with TSH, tT4/tT3, and fT4/fT3 (all P<0.05). Furthermore, tT3, tT4, fT3and tT3/fT3 (P < 0.05) were still significant in the adjusted model. And it is worth noting that there is an approximately L-shaped nonlinear relationship between ln(klotho) and fT3,tT3 with a cut-off point of 6.697 (P-non-linear < 0.05). The stratification analysis showed gender and iodine level differences in the relationship between serum Klotho levels and thyroid hormones. CONCLUSION: There is an L-shaped nonlinear relationship between ln(klotho) and fT3, tT3, suggesting that klotho could be involved in the physiological regulation of thyroid function.

Inverse association of the systemic immune-inflammation index with serum anti-ageing protein Klotho levels in individuals with osteoarthritis: A cross-sectional study.

BACKGROUND: The association between the systemic immune-inflammation index (SII) and the serum soluble-Klotho concentration (pg/ml) in osteoarthritis (OA) patients is unknown. This study aimed to investigate the relationship between the SII and serum soluble-Klotho levels in OA patients. METHODS: All study data were obtained from the National Health and Nutrition Examination Survey (NHANES) database (n = 1852 OA patients; age range = 40-79 years). The SII and serum Klotho measurement data are from the NHANES mobile examination centre. The SII values were divided into quartiles (Q1-4: 0.02-3.36, 3.36-4.78, 4.79-6.70, and 6.70-41.75). A multivariate linear regression model was constructed to evaluate the association between the SII and serum Klotho levels in OA patients; interaction tests were conducted to test the stability of the statistical results. RESULTS: Multivariate linear regression revealed a negative linear relationship between the SII and serum Klotho concentration in OA patients (ß = -6.05; 95% CI: -9.72, -2.39). Compared to Q1, Q4 was associated with lower serum Klotho concentrations (ß = -59.93; 95% CI: -96.57, -23.28). Compared with that of Q1, the ß value of Q2-Q4 showed a downwards trend as the SII increased (Ptrend <0.001). The stratified analysis results indicated that the SII had a greater sensitivity in predicting serum Klotho concentrations in OA patients aged 60-79 years (Pinteraction = 0.028). CONCLUSIONS: There was a significant negative linear correlation between the SII and serum Klotho concentration in OA patients. The SII can serve as a predictive indicator of serum Klotho concentrations in OA patients. Klotho may be a potential anti-inflammatory drug for OA treatment.

Patients With Coronary Microvascular Dysfunction Have Less Circulating α-Klotho.

BACKGROUND: Coronary microvascular dysfunction (CMD) represents an early functional characteristic of coronary vascular aging. Klotho (α-klotho) is a circulating protein inversely linked to physiological aging. We examined low klotho as a potential marker for vascular aging in patients with CMD and no coronary artery disease. METHODS AND RESULTS: Patients undergoing nonurgent angiogram for chest pain who had no coronary artery disease underwent invasive coronary microvascular and endothelial function testing. CMD was defined by ≤50% increase in coronary blood flow (percentage change in coronary blood flow) in response to intracoronary acetylcholine or coronary flow reserve ≤2. Fresh arterial whole blood was used to analyze circulating endothelial progenitor cells with flow cytometry. Stored arterial plasma was used for klotho analysis by ELISA. Participants with CMD (n=62) were compared with those without CMD (n=36). Those with CMD were age 55±10 years (versus 51±11 years; P=0.07) and 73% women (versus 81%; P=0.38). Traditional risk factors for coronary artery disease were similar between groups. Patients with CMD had less klotho (0.88±1.50 versus 1.75±2.38 ng/mL; P=0.03), and the odds of low klotho in CMD were significant in a logistic regression model after adjusting for traditional cardiovascular risk factors (odds ratio [OR], 0.80 [95% CI, 0.636-0.996]; P=0.05). Higher klotho was associated with higher numbers of endothelial progenitor cells with vascular regenerative potential (CD34+ and CD34+CD133+KDR+). Among a subgroup of patients with atherosclerotic cardiovascular disease risk <5% (n=58), CMD remained associated with lower klotho (OR, 0.80 [95% CI, 0.636-0.996]; P=0.047). CONCLUSIONS: Klotho may be a biomarker for CMD and may be a therapeutic target for groups of patients without significant traditional cardiovascular risk.

Serum Klotho and insulin resistance: Insights from a cross-sectional analysis.

The prevalence of diabetes has surged globally, posing significant health and economic burdens. Insulin resistance underlies the initiation and development of type 2 diabetes. Klotho is a crucial endogenous antiaging factor, associated with atherosclerotic cardiovascular diseases, cancer, neurological disorders, and renal diseases. It additionally has a function in controlling glucose metabolism and holds promise as a new therapeutic target for diabetes. However, its relationship with insulin resistance remains unclear. This study utilizes the National Health and Nutrition Examination Survey (NHANES) 2007 to 2016 data to investigate the relationship between serum Klotho concentrations and insulin resistance. In this observational study, information from the NHANES spanning 2007 to 2016 was employed. The sample consisted of 6371 participants. Weighted linear regression model and chi-square tests were utilized to assess differences in continuous and categorical variables, respectively, among groups categorized by Klotho quartiles. The relationship between Klotho and HOMA-IR (homeostatic model assessment of insulin resistance) was studied using multiple linear regression. Smooth curve fitting was used to analyze nonlinear relationships and the inflection point was determined through a 2-stage linear regression method. After adjusting for multiple confounding factors, serum Klotho levels were found to be positively correlated with insulin resistance [0.90 (0.68, 1.13)]. This correlation is nonlinear and exhibits a saturation effect, with the inflection point identified at 1.24 pg/µL. When Klotho levels are below 1.24 pg/µL, for every unit increase in Klotho, HOMA-IR increases by 1.30 units. Conversely, when Klotho levels exceed 1.24 pg/µL, there is no correlation between HOMA-IR and Klotho. Subgroup analysis reveals that the relationship between HOMA-IR and Klotho varies depending on diabetes and body mass index (BMI). This positive correlation was most prominent in the obese nondiabetic population. There is a positive correlation between serum Klotho and insulin resistance.

Exercise-induced changes in plasma S-Klotho levels are associated with the obtained enhancements of heart rate variability in sedentary middle-aged adults: the FIT-AGEING study.

The shed form of the Klotho protein (S-Klotho) is considered a biomarker of longevity, but it is still unknown whether the levels are related to heart rate (HR) and heart rate variability (HRV); both of them greatly influenced by the ageing process, physical fitness, exercise, and health status. This study aimed (i) to investigate the association between S-Klotho plasma levels with HR and HRV parameters and (ii) to examine the association of exercise-induced changes in S-Klotho and those obtained in HR and HRV parameters after a 12-week exercise intervention in sedentary middle-aged adults. Sixty-six sedentary middle-aged adults participated in this study (50% women; 45-65 years old). Participants were randomized into 4 groups: (a) a control group (no exercise), (b) a physical activity recommendation from the World Health Organization group, (c) a high-intensity interval training group, and (d) a high-intensity interval training group adding whole-body electromyostimulation. S-Klotho plasma levels, HR, and HRV parameters (SDNN, RMSSD, high frequency, stress score, and sympathetic/parasympathetic ratio) were measured. At baseline, S-Klotho plasma levels were not related to HR and HRV parameters. After the intervention, exercise-induced changes in S-Klotho plasma levels were positively associated with changes in SDNN (ß=0.261; R2=0.102; p=0.014) and negatively related to changes in stress score and sympathetic/parasympathetic ratio (all ß=-0.257; R2 ranges between 0.092 and 0.131; all p<0.020). Our study suggests that higher S-Klotho plasma levels are related to increased vagal influence and reduced sympathetic tone in the autonomic nervous system in sedentary middle-aged adults after different training programs. ClinicalTrials.gov identifier: CT03334357.

HIGH HEPARANASE LEVEL IN SURVIVORS OF COVID-19 - INDICATOR OF VASCULAR AND PULMONARY RECOVERY?

ABSTRACT: Background: Severe progression of coronavirus disease 2019 (COVID-19) causes respiratory failure and critical illness. Recently, COVID-19 has been associated with heparanase (HPSE)-induced endothelial barrier dysfunction and inflammation, so called endothelitis, and therapeutic treatment with heparin or low-molecular-weight heparin (LMWH) targeting HPSE has been postulated. Because, up to this date, clinicians are unable to measure the severity of endothelitis, which can lead to multiorgan failure and concomitant death, we investigated plasma levels of HPSE and heparin-binding protein (HBP) in COVID-19 intensive care patients to render a possible link between endothelitis and these plasma parameters. Therefore, a prospective prolonged cohort study was conducted, including 47 COVID-19 patients from the intensive care unit. Plasma levels of HPSE, and HBP were measured daily by enzyme-linked immunosorbent assay in survivors (n = 35) and nonsurvivors (n = 12) of COVID-19 from admission until discharge or death. All patients were either treated with heparin or LMWH, aiming for an activated partial thromboplastin time of ≥60 seconds or an anti-Xa level of >0.8 IU/mL using enoxaparin, depending on the clinical status of the patient (patients with extracorporeal membrane oxygenation or >0.1 µg/kg/min noradrenaline received heparin, all others enoxaparin). Results: We found significantly higher plasma levels of HPSE and HBP in survivors and nonsurvivors of COVID-19, compared with healthy controls. Still, interestingly, plasma HPSE levels were significantly higher ( P < 0.001) in survivors compared with nonsurvivors of COVID-19. In contrast, plasma HBP levels were significantly reduced ( P < 0.001) in survivors compared with nonsurvivors of COVID-19. Furthermore, when patients received heparin, they had significantly lower HPSE ( P = 2.22 e - 16) and significantly higher HBP ( P = 0.00013) plasma levels as when they received LMWH. Conclusion: Our results demonstrated that patients, who recover from COVID-19-induced vascular and pulmonary damage and were discharged from the intensive care unit, have significantly higher plasma HPSE level than patients who succumb to COVID-19. Therefore, HPSE is not suitable as marker for disease severity in COVID-19 but maybe as marker for patient's recovery. In addition, patients receiving therapeutic heparin treatment displayed significantly lower heparanse plasma level than upon therapeutic treatment with LMWH.

Tumour necrosis factor alpha (TNFα) and alpha-Klotho (αKL) in children and adolescents with chronic kidney disease (CKD).

INTRODUCTION: Chronic kidney disease (CKD) in children, despite the progress in science and technology, is still a serious challenge. Early CKD detection gives a chance of early therapeutic intervention and lowering the progression of the disease. According to several publications indicating the possible use of alpha-Klotho (αKL) and tumour necrosis factor alpha (TNFα) for the early detection of the disease in adults, an attempt was made to evaluate their usefulness in the paediatric population. MATERIAL AND METHODS: The study group consisted of 42 patients with CKD with a mean age of 10.7 years (18 girls and 24 boys). The control group involved 21 healthy children with a mean age of 8.4 years (11 girls and 10 boys). Anthropometrical parameters and blood pressure were taken and routine biochemical tests were performed in the whole group. The concentrations of TNFα and αKL in serum and urine were determined by enzyme immunoassay. RESULTS: Children from the CKD group showed a statistically significant difference in serum TNFα and αKL in comparison to the control group. There was no significant relationship between the evaluated markers and sex, presence of hypertension, or proteinuria in the children. The mean αKL serum concentration was higher in patients on dialysis compared to the group of conservatively treated children, whereas the values of TNFα in serum and urine, as well as the αKL in urine, did not differ significantly in these groups. A significant positive correlation was found between serum αKL concentration and serum creatinine, but there was no other correlation between serum αKL or TNFα concentration and any of the measured anthropometric and laboratory parameters. CONCLUSIONS: Serum TNFα and αKL levels in children with chronic kidney disease, although being statistically different compared to the group of healthy children, except for the correlation of serum aKL and creatinine, showed no other correlations to the most parameters used for chronic kidney disease evaluation including, eGFR. Their usefulness in the early detection of kidney dysfunction in children was not proven.

Associations of serum soluble klotho and fibroblast growth factor 23 with carotid artery calcification in patients undergoing continuous ambulatory peritoneal dialysis: A retrospective study.

ABSTRACT: This study aimed to assess the associations of serum soluble klotho and fibroblast growth factor 23 (FGF-23) with the occurrence of carotid artery calcification. Peritoneal dialysis patients treated from June 2018 to June 2019 were retrospectively analyzed. They were divided into the carotid artery calcification and non-carotid artery calcification groups according to color Doppler ultrasound findings. Basic indicators in both groups were compared, and the influencing factors of carotid artery calcification were analyzed by logistic regression. Among the 73 continuous ambulatory peritoneal dialysis (CAPD) patients enrolled, 40 (54.8%) had carotid artery calcification. Significant differences were found in age (68.85 ±â€Š7.45 vs 46.62 ±â€Š5.51 years), dialysis time (8.15 ±â€Š1.42 vs 6.02 ±â€Š1.14 months), klotho amounts (325.56 ±â€Š41.15 vs 436.65 ±â€Š45.58 pg/mL) and FGF-23 levels (114.45 ±â€Š15.56 vs 70.15 ±â€Š12.23 pg/mL) between the carotid artery calcification and non-carotid artery calcification groups (all P < .001). The above factors were associated with carotid artery calcification occurrence in univariate analysis. Multivariate analysis showed that elevated age (odds ratio [OR] = 1.55, 95% confidence interval [CI] 1.13-1.74; P = .025) and FGF-23 (OR = 2.16, 95% CI 2.01-2.44; P = .042), and lower klotho (OR = 0.66, 95% CI 0.47-0.85; P = .036) were independent risk factors for carotid artery calcification in CAPD. Serum FGF-23 and age are risk factors for carotid artery calcification in patients with CAPD, whereas klotho is a protective factor.

Constitutive transgenic α-Klotho overexpression enhances resilience to and recovery from murine acute lung injury.

Normal lungs do not express α-Klotho (Klotho) protein but derive cytoprotection from circulating soluble Klotho. It is unclear whether chronic supranormal Klotho levels confer additional benefit. To address this, we tested the age-related effects of modest Klotho overexpression on acute lung injury (ALI) and recovery. Transgenic Klotho-overexpressing (Tg-Kl) and wild-type (WT) mice (2 and 6 mo old) were exposed to hyperoxia (95% O2; 72 h; injury; Hx) then returned to normoxia (21% O2; 24 h; recovery; Hx-R). Control mice were kept in normoxia. Renal and serum Klotho, lung histology, and bronchoalveolar lavage fluid oxidative damage markers were assessed. Effects of hyperoxia on Klotho release were tested in human embryonic kidney cells stably expressing Klotho. A549 lung epithelial cells transfected with Klotho cDNA or vector were exposed to cigarette smoke; lactate dehydrogenase and double-strand DNA breaks were measured. Serum Klotho decreased with age. Hyperoxia suppressed renal Klotho at both ages and serum Klotho at 2 mo of age. Tg-Kl mice at both ages and 2-mo-old WT mice survived Hx-R; 6-mo-old Tg-Kl mice showed lower lung damage than age-matched WT mice. Hyperoxia directly inhibited Klotho expression and release in vitro; Klotho transfection attenuated cigarette smoke-induced cytotoxicity and DNA double-strand breaks in lung epithelial cells. Young animals with chronic high baseline Klotho expression were more resistant to ALI. Chronic constitutive Klotho overexpression in older Tg-Kl animals attenuated hyperoxia-induced lung damage and improves survival and short-term recovery despite an acute reduction in serum Klotho during injury. We conclude that chronic enhancement of Klotho expression increases resilience to ALI.

Effect of Lipopolysaccharide-Induced Inflammatory Challenge on ß-Glucuronidase Activity and the Concentration of Quercetin and Its Metabolites in the Choroid Plexus, Blood Plasma and Cerebrospinal Fluid.

Quercetin-3-glucuronide (Q3GA), the main phase II metabolite of quercetin (Q) in human plasma, is considered to be a more stable form of Q for transport with the bloodstream to tissues, where it can be potentially deconjugated by ß-glucuronidase (ß-Gluc) to Q aglycone, which easily enters the brain. This study evaluates the effect of lipopolysaccharide (LPS)-induced acute inflammation on ß-Gluc gene expression in the choroid plexus (ChP) and its activity in blood plasma, ChP and cerebrospinal fluid (CSF), and the concentration of Q and its phase II metabolites in blood plasma and CSF. Studies were performed on saline- and LPS-treated adult ewes (n = 40) receiving Q3GA intravenously (n = 16) and on primary rat ChP epithelial cells and human ChP epithelial papilloma cells. We observed that acute inflammation stimulated ß-Gluc activity in the ChP and blood plasma, but not in ChP epithelial cells and CSF, and did not affect Q and its phase II metabolite concentrations in plasma and CSF, except Q3GA, for which the plasma concentration was higher 30 min after administration (p < 0.05) in LPS- compared to saline-treated ewes. The lack of Q3GA deconjugation in the ChP observed under physiological and acute inflammatory conditions, however, does not exclude its possible role in the course of neurodegenerative diseases.

Circulating α-klotho regulates metabolism via distinct central and peripheral mechanisms.

Emerging evidence implicates the circulating α-klotho protein as a prominent regulator of energy balance and substrate metabolism, with diverse, tissue-specific functions. Despite its well-documented ubiquitous role inhibiting insulin signaling, α-klotho elicits potent antidiabetic and anti-obesogenic effects. α-Klotho facilitates insulin release and promotes ß cell health in the pancreas, stimulates lipid oxidation in liver and adipose tissue, attenuates hepatic gluconeogenesis, and increases whole-body energy expenditure. The mechanisms underlying α-klotho's peripheral functions are multifaceted, including hydrolyzing transient receptor potential channels, stimulating integrin ß1➔focal adhesion kinase signaling, and activating PPARα via inhibition of insulin-like growth factor receptor 1. Moreover, until recently, potential metabolic roles of α-klotho in the central nervous system remained unexplored; however, a novel α-klotho➔fibroblast growth factor receptor➔PI3kinase signaling axis in the arcuate nucleus of the hypothalamus has been identified as a critical regulator of energy balance and glucose metabolism. Overall, the role of circulating α-klotho in the regulation of metabolism is a new focus of research, but accumulating evidence identifies this protein as an encouraging therapeutic target for Type 1 and 2 Diabetes and obesity. This review analyzes the new literature investigating α-klotho-mediated regulation of metabolism and proposes impactful future directions to progress our understanding of this complex metabolic protein.

Association of bone biomarkers with advanced atherosclerotic disease in people with overweight/obesity.

BACKGROUND: A growing body of evidence suggests a potential link between bone metabolism and cardiovascular disease. Aim of this study was to investigate the relationship between levels of circulating bone turnover biomarkers and advanced atherosclerosis. METHODS: Klotho (KL), sclerostin (SOST), osteopontin (OPN) and osteoprotegerin (OPG) were measured in patients undergoing elective coronary angiography and carotid Doppler ultrasound. The primary outcome was the difference in bone biomarkers levels between participants with and without advanced atherosclerosis, defined as the presence of a critical coronary (≥70%) and/or carotid (≥50%) stenosis. RESULTS: A total of 80 subjects (32.5% females) with a mean age of 68 ± 10 years were included. Advanced atherosclerosis was detected in 55 (68.8%) patients. Subjects with advanced atherosclerosis showed higher serum levels of OPG (p = 0.0015) and SOST (p = 0.017) and similar levels of KL (p = 0.62) and OPN (p = 0.06) compared to patients without. After adjustment for age and sex, only elevated levels of OPG remained significantly associated with advanced atherosclerosis (p = 0.011). CONCLUSIONS: Higher serum levels of OPG are independently associated with advanced atherosclerosis confirming a common bond between bone metabolism and vascular disease. Further investigations on the role of selected bone biomarkers in the pathogenesis of cardiovascular disease are needed.

Comparison of serum human Klotho levels and thiol/disulfide homeostasis in women with polycystic ovary syndrome and in healthy women.

OBJECTIVES: Women with polycystic ovary syndrome (PCOS) have an increased cardiometabolic risk. Similarly, it was previously shown that atherosclerotic and cardiovascular risk is increased in the general population with lower serum Klotho levels. The aim of this study was to investigate the lotho and thiol/disulfide levels in women with non-obese PCOS compared to healthy controls and also to investigate the relationship of serum Klotho and thiol/disulfide homeostasis with cardiometabolic risk factors. MATERIALS AND METHODS: In this prospective case control study, human serum alpha Klotho levels and thiol/disulfide homeostasis of women with PCOS aged between 19-33 were compared to their age and BMI matched non - PCOS healthy controls. In addition, the correlation of these molecules with other metabolic markers/measurements were also investigated. RESULTS: Metabolic parameters such as mean waist circumference, lipid accumulation product, visceral adiposity index, fasting insulin, homeostasis model assessment of insulin resistance and triglyceride values were higher in the PCOS group (p = 0.038, p = 0.008, p = 0.001, p = 0.001, p = 0.002 and p = 0.002, respectively) compared to controls. However, mean serum Klotho and native thiol levels (respectively p < 0.0001 and p = 0.038) were lower compared to controls. Correlation analysis revealed that serum Klotho levels were negatively correlated with BMI, waist circumference, disulphide/total thiol, disulphide/native thiol, HOMA-IR and LAP-index. CONCLUSIONS: Findings of decreased serum Klotho and native thiol values of the PCOS group compared to controls and the negative correlation of serum Klotho levels with metabolic markers supports the idea that decreased Klotho may be another mechanism by which cardiovascular risk is increased in women with PCOS.

Soluble Alpha Klotho in Acromegaly: Comparison With Traditional Markers of Disease Activity.

CONTEXT: Soluble alpha klotho (sαKL) has been linked to growth hormone (GH) action, but systematic evaluation and comparisons with traditional biomarkers in acromegaly are lacking. OBJECTIVE: To evaluate the potential of sαKL to aid classification of disease activity. METHODS: This retrospective study at 2 academic centers included acromegaly patients before surgery (A, n = 29); after surgery (controlled, discordant, or uncontrolled) without (B1, B2, B3, n = 28, 11, 8); or with somatostatin analogue treatment (C1, C2, C3, n = 17, 11, 5); nonfunctioning pituitary adenomas (n = 20); and healthy controls (n = 31). sαKL was measured by immunoassay and compared with traditional biomarkers (random and nadir GH, insulin-like growth factor I [IGF-I], IGF binding protein 3). Associations with disease activity were assessed. RESULTS: sαKL was correlated to traditional biomarkers, particularly IGF-I (rs=0.80, P <0.0001). High concentrations before treatment (A, median, interquartile range: 4.04 × upper limit of normal [2.26-8.08]) dropped to normal after treatment in controlled and in most discordant patients. A cutoff of 1548 pg/mL for sαKL discriminated controlled (B1, C1) and uncontrolled (B3, C3) patients with 97.8% (88.4%-99.9%) sensitivity and 100% (77.1%-100%) specificity. sαKL was below the cutoff in 84% of the discordant subjects. In the remaining 16%, elevated sαKL and IGF-I persisted, despite normal random GH. Sex, age, body mass index, and markers of bone and calcium metabolism did not significantly affect sαKL concentrations. CONCLUSION: Our data support sαKL as a biomarker to assess disease activity in acromegaly. sαKL exhibits close association with GH secretory status, large dynamic range, and robustness toward biological confounders. Its measurement could be helpful particularly when GH and IGF-I provide discrepant information.

Low serum klotho concentration is associated with worse cognition, psychological components of frailty, dependence, and falls in nursing home residents.

Serum alpha-klotho (s-klotho) protein has been linked with lifespan, and low concentrations of s-klotho have been associated with worse physical and cognitive outcomes. Although its significance in aging remains unclear, s-klotho has been proposed as a molecular biomarker of frailty and dependence. This study is a secondary analysis of data from a clinical trial performed in a population of 103 older individuals living in 10 nursing homes in Gipuzkoa (Spain). We aimed to elucidate associations between s-klotho (as measured by enzyme-linked immunosorbent assay) and body composition, physical fitness, and cognition, as well as frailty and dependence (determined using validated tests and scales). In addition, we investigated the association of s-klotho concentration with falls in the six months following the initial assessment. Low s-klotho levels were associated with a lower score in the psychological component of the Tilburg Frailty Indicator, a worse score in the Coding Wechsler Adult Intelligence Scale, and a greater dependence in activities of daily living. Moreover, participants with lower s-klotho concentrations suffered more falls during the 6 months after the assessment. Future translational research should aim to validate klotho's putative role as a biomarker that could identify the risk of aging-related adverse events in clinical practice.

No significant association of serum klotho concentration with blood pressure and pulse wave velocity in a Chinese population.

Klotho, an important anti-aging protein, may be related to elevated blood pressure (BP) and arterial stiffness. We aimed to investigate associations between the serum klotho concentration and peripheral/central BP and arterial stiffness based on the carotid-femoral pulse wave velocity (cfPWV) in a Chinese population. We invited all inhabitants aged ≥ 18 years in two Dali communities for participation. The SphygmoCor system was used to record radial arterial waveforms. Aortic waveforms were derived using a generalized transfer function. The central BP was assessed by calibrating the brachial BP, which was measured using an oscillometric device. The serum klotho concentration was measured using an enzyme-linked immunosorbent assay and logarithmically transformed. Of the 716 participants (mean age: 51.9 ± 12.6 years), 467 (65.2%) were women. The median serum klotho concentration was 381.8 pg/mL. The serum klotho concentration did not significantly differ between patients with and without hypertension (P > 0.05) and between those with and without arterial stiffness (cfPWV ≥ 10 m/s) (P > 0.05). After adjusting for confounders, the serum klotho concentration was not significantly associated with the peripheral or central BP (P > 0.05) and cfPWV (P > 0.05). Our data indicated that the serum klotho concentration was not associated with BP or cfPWV in the general Chinese population.

Alpha-Klotho is a novel predictor of treatment responsiveness in patients with heart failure.

Heart failure is a major cause of death with an increasing population of elderly individuals. Several studies have demonstrated the involvement of soluble alpha-Klotho (sαKl) in various diseases. However, the correlation between sαKl and heart failure remains to be understood. The aim of this study is to investigate the levels and role of sαKl in patients with heart failure. Twenty-eight consecutive patients with acute heart failure (19 male, 9 female), admitted to the Osaka University Hospital from 2010 to 2018, were enrolled in this study. Mean NYHA score, left ventricular ejection fraction and BNP were 3.3, 17.0% and 588 pg/mL, respectively. SαKl significantly increased in heart failure patients. SαKl on admission were significantly higher in patients with heart failure who showed improvement after intensive treatment than that in patients who did not show improvement after the treatment. SαKl levels decreased significantly in patients who showed improvement. Interestingly, sαKl levels increased in male patients with heart failure, but not in female patients. Our data suggest that soluble αKl may be a novel biomarker for the responsiveness against treatment in patients with heart failure with reduced ejection fraction. Our findings may help developing a personalized therapy for different patients with heart failure.

A novel antibody for the detection of alternatively spliced secreted KLOTHO isoform in human plasma.

αKlotho is primarily known to express as a transmembrane protein. Proteolytic cleavage results in shedding of the extracellular domain which enters systemic circulation. A truncated form of αKlotho resulting from alternative splicing of the αKLOTHO transcript exists and is believed to be secreted, thereby also entering systemic circulation. Existing ELISA methods fail to distinguish between the two circulating isoforms resulting in inconsistencies in assessing circulating αKlotho levels. We have exploited a unique 15aa peptide sequence present in the alternatively spliced secreted isoform to generate an antibody and show that it is able to specifically detect only the secreted Klotho isoform in human plasma. This finding will facilitate in distinguishing the levels of different circulating Klotho isoforms in health and disease and enhance their potential to serve as a biomarker for CKD and other conditions.

Relationship between dietary factors and S-Klotho plasma levels in young sedentary healthy adults.

OBJECTIVE: To study the associations of dietary factors with S-Klotho plasma levels in young adults. We also aimed to study whether body composition and cardiometabolic risk factors affected the association between dietary factors and S-Klotho plasma levels. METHODS: A total of 139 young adults took part in this study. Dietary factors were measured using a food frequency questionnaire and three non-consecutive 24 h recalls. S-Klotho plasma levels were measured by immunosorbent assay. Body composition was measured by DXA. RESULTS: We observed a direct association of ethanol intake and S-Klotho plasma levels in women. An inverse association was also observed between the dietary inflammatory index (DII) with S-Klotho plasma levels in all sample. No mediation effects of body composition or cardiometabolic risk factors were observed in the relationship between alcohol and S-Klotho plasma levels. Lean mass index (LMI) and uric acid levels mediated the relationship between DII and S-Klotho plasma levels. CONCLUSION: A pro-inflammatory dietary pattern was inversely associated with S-Klotho plasma levels in young adults, which was partially mediated by LMI and uric acid levels.