Search Results (84)

Background/Objectives: Chronic kidney disease (CKD) is characterized by accelerated aging and functional decline. Serum α-Klotho levels, an anti-aging biomarker predominantly associated with renal function, have emerged as potential indicators of biological aging and cardiovascular risk. To investigate the association between serum α-Klotho levels and habitual physical activity in hemodialysis patients. Methods: This study combined (1) a prospective case analysis of high-intensity interval training (HIIT) in a hemodialysis patient and (2) a cross-sectional analysis of 24 hemodialysis patients and 18 healthy controls. Serum α-Klotho levels were measured using ELISA, and their association with habitual physical activity was evaluated. Results: Serum α-Klotho levels were significantly lower in hemodialysis patients than in healthy controls (p < 0.001). In hemodialysis patients, physical activity was moderately correlated with serum α-Klotho levels (r = 0.52, p = 0.02), whereas no significant association was observed in healthy controls. The case analysis demonstrated marked improvement in physical function following HIIT. These findings suggest that serum α-Klotho levels may be associated with physical activity status in hemodialysis patients. Conclusions: Serum α-Klotho levels were associated with habitual physical activity in hemodialysis patients and may represent a potential molecular indicator related to physical function and rehabilitation status. These findings support further investigation of biomarker-informed approaches in renal rehabilitation. Full article

Background/Objectives: Sepsis-associated encephalopathy (SAE) is an acute brain dysfunction during sepsis with high mortality. Klotho protein is notable for its identified neuroprotective effects in chronic neurodegenerative diseases. This study evaluated temporal changes in serum soluble Klotho levels and their association with clinical recovery in SAE. Methods: In this prospective observational study, 750 intensive care unit (ICU) patients were screened and 42 patients with SAE were included. Serum soluble Klotho levels, inflammatory markers, and Glasgow Coma Scale (GCS) scores were recorded on days 1 and 3. Associations between changes in Klotho levels and clinical and inflammatory parameters were analyzed. Results: The median GCS score increased from 11 (IQR: 10–13) on day 1 to 12 (IQR: 10–13) on day 3 (p < 0.001). Serum soluble Klotho levels decreased significantly from 8114.5 ± 3515.7 pg/mL on day 1 to 6452.9 ± 3390 pg/mL on day 3 (p < 0.001). Inflammatory markers, including C-reactive protein and procalcitonin, also showed significant reductions over time (p < 0.001). A moderate negative correlation was observed between changes in Klotho levels and GCS scores (r = −0.56, p < 0.001). Changes in inflammatory markers were not significantly correlated with Klotho dynamics. Conclusions: Serum soluble Klotho levels decrease in parallel with neurological improvements in sepsis-associated encephalopathy and are significantly associated with changes in GCS scores. These findings suggest that Klotho may represent a potential biomarker of disease trajectory and neurological recovery. Full article

Cognitive frailty (CF), characterized by concurrent cognitive and motor decline, is a major challenge to healthy aging, yet effective interventions remain limited. Klotho, an anti-aging protein that declines with age, has been implicated in both hippocampal function and skeletal muscle homeostasis. In this study, we investigated whether aerobic exercise combined with multisensory stimulation training (CT) ameliorates age-related CF through systemic Klotho signaling. A 16-month-old mouse model of age-related CF was assigned to aerobic training, multisensory stimulation, or combined training, and behavioral, electrophysiological, histological, and molecular assessments were performed. To examine the mechanistic role of Klotho, dual-route shRNA delivery was used to inhibit systemic Klotho expression. CT significantly improved cognitive and motor performance compared with either intervention alone. CT also increased hippocampal dendritic spine density and long-term potentiation, reduced collagen deposition in gastrocnemius muscle, and upregulated Klotho, FGF19, and FGFR1 expression in both hippocampus and muscle, accompanied by elevated serum Klotho levels. Klotho knockdown attenuated these beneficial effects, reduced PSD95 and GluN2B expression, and increased MuRF3 and TNF-α levels. These findings suggest that CT alleviates cognitive frailty and that systemic Klotho is a key mediator linking hippocampal synaptic function and skeletal muscle homeostasis. Full article

Background/Objectives: Vascular calcification and arterial stiffness are common in chronic kidney disease (CKD). Gla-rich protein (GRP) is a vitamin K-dependent protein implicated in mineral biology, but clinical evidence across CKD stages is limited. We evaluated associations of serum GRP with vascular calcification (VC) burden and arterial stiffness across CKD stages, including hemodialysis, compared with controls. Methods: In this prospective observational study, 185 adults were enrolled: controls (n = 61), individuals with CKD stage IIIb–IV (n = 61), and individuals with CKD stage V on hemodialysis (HD) (n = 63). Abdominal aortic calcification was assessed by the Kauppila score, and arterial stiffness was assessed by oscillometric pulse wave velocity (PWV). Serum GRP, FGF-23, and β-Klotho (KLb) were measured by ELISA. Non-parametric group comparisons and Bonferroni-corrected Spearman correlations were used. Results: GRP differed across groups (p < 0.001), showing a non-linear pattern with the lowest values in CKD IIIb–IV. PWV and Kauppila score increased across CKD stages (both p < 0.001). After Bonferroni correction, GRP correlated with KLb (ρ = 0.720) and FGF-23 (ρ = 0.625), but not with PWV or Kauppila score. In multivariable analyses, GRP showed a statistically significant but modest association with PWV and Kauppila score. Conclusions: In this CKD spectrum cohort, serum GRP was associated with CKD-MBD biochemical markers (KLb and FGF-23) much more strongly than with vascular phenotypes; its associations with vascular calcification burden and arterial stiffness were modest in multivariable modelling, supporting GRP as a marker of the CKD-MBD biochemical profile rather than a strong surrogate of vascular phenotype. Full article

Background: Prenatal vitamin D exposure has been proposed as a potential determinant of immune development and subsequent allergic disease risk in offspring; however, long-term cohort data remain inconsistent. Methods: We analyzed data from the KLOTHO birth cohort, including 98 adolescents with available allergic outcome assessment. A maternal–neonatal sub-cohort of mother–child pairs with available maternal and neonatal serum total 25-hydroxyvitamin D₃ [25(OH)D] measurements at delivery was used for vitamin D analyses. Allergic outcomes included asthma, allergic rhinitis, and eczema in offspring. Associations were evaluated using descriptive statistics, Spearman correlation analyses, and logistic regression models. Results: Maternal 25(OH)D concentrations were not significantly associated with asthma (ρ = 0.075, p = 0.652), allergic rhinitis (ρ = 0.100, p = 0.556), or eczema (ρ = 0.131, p = 0.426). In crude logistic regression models, vitamin D concentrations were not associated with asthma (odds ratio (OR) per 10 nmol/L: 1.07, 95% confidence interval (CI): 0.78–1.48, p = 0.67), allergic rhinitis (OR: 1.05, 95% CI: 0.76–1.45, p = 0.77), or eczema (OR: 1.17, 95% CI: 0.86–1.60, p = 0.31). Adjusted models including maternal age, pre-pregnancy body mass index (BMI), season of delivery, and ultraviolet exposure yielded similar non-significant findings, although analyses were limited by a reduced complete-case sample size. Conclusions: In this prospective cohort with follow-up into early adolescence, vitamin D status at delivery was not associated with asthma, allergic rhinitis, or eczema in offspring. These findings support a lack of statistically significant association; however, potential non-linear relationships should be interpreted cautiously, given the modest sample size. Full article

Patients with chronic kidney disease (CKD) have a markedly increased cardiovascular risk that is not fully explained by traditional risk factors. Gut-derived uremic toxins, indoxyl sulfate (IS), indole-3-acetic acid (IAA), and p-cresyl sulfate (pCS), are poorly cleared by dialysis and may contribute to vascular damage. This cross-sectional observational study included 70 patients with CKD under different clinical conditions (pre-dialysis, peritoneal dialysis, hemodialysis, and kidney transplantation) and 17 healthy controls. Serum levels of IS, IAA, pCS and Klotho were measured, and vascular damage was assessed by carotid intima–media thickness (IMT) using ultrasound. CKD patients showed higher concentrations of IS, IAA, and pCS compared with controls, with the highest levels observed in hemodialysis patients. Peritoneal dialysis was associated with elevated IS and pCS, whereas in kidney transplantation, IS and IAA levels did not differ significantly from controls, and pCS remained elevated. Carotid IMT was higher in patients with diabetes and those undergoing hemodialysis. IAA correlated significantly with left/mean IMT, and mean IMT was the only parameter associated with previous cardiovascular events. These findings suggest that gut-derived uremic toxins, particularly IAA, might be associated with subclinical vascular damage in advanced CKD, although larger studies are needed to confirm these associations. Full article

Background/Objectives: Obstructive sleep apnea (OSA) syndrome is characterized by recurrent upper airway obstruction during sleep and is closely associated with systemic inflammation and cardiometabolic risk. α-Klotho and fibroblast growth factor-23 (FGF-23) are emerging biomarkers with potential roles in vascular homeostasis, inflammation, and metabolic regulation. However, their relevance in OSA remains insufficiently elucidated. The aim of this study was to evaluate serum α-Klotho and FGF-23 levels in patients with OSA and to investigate their associations with disease severity. This represents a novel approach that may provide new insights into the pathophysiological mechanisms linking OSA with cardiometabolic risk. Methods: A total of 133 participants were included in this study and categorized into three groups according to apnea–hypopnea index: 1—simple snoring (n = 44); 2—non-severe OSA (n = 44); and 3—severe OSA (n = 45). Comparisons between two groups were performed using Student’s t-test for normally distributed variables. Comparisons among three or more groups were conducted using one-way ANOVA and the Kruskal–Wallis test. ANCOVA was applied to compare α-Klotho and FGF-23 levels between groups after adjustment for age, BMI, diabetes, hypertension, asthma, COPD, and thyroid disease. The predictive performance of α-Klotho and FGF-23 for severe obstructive sleep apnea was evaluated using ROC curve analysis. Results: Serum α-Klotho levels decreased significantly with increasing OSA severity (p = 0.001). Serum FGF-23 levels increased significantly across AHI groups (p = 0.001). After adjustment for age, BMI, diabetes, hypertension, asthma, thyroid disease, COPD and vitamin D levels, α-Klotho levels were lower in the severe and non-severe OSA group (p = 0.001, both) compared to the simple snoring group, whereas FGF-23 levels were higher in the severe and non-severe OSA group (p = 0.001; both) compared to the simple snoring group. In predicting the risk of severe OSA compared with non-severe OSA, an α-Klotho cut-off value of 280.3 yielded a sensitivity of 84.44% and specificity of 75%, whereas an FGF-23 cut-off value of 75.5 yielded a sensitivity of 62.2% and specificity of 72.7%. Conclusions: Serum α-Klotho levels significantly decrease while FGF-23 levels increase in correlation with OSA severity. α-Klotho exhibited superior predictive performance over FGF-23 in identifying severe OSA, suggesting its potential as a more sensitive biomarker for systemic involvement. These results indicate that the α-Klotho/FGF-23 axis is independently associated with OSA and may play a pivotal role in the pathophysiological mechanisms linking intermittent hypoxia to increased cardiometabolic risk. Full article

Phosphorus is an essential mineral involved in bone mineralization, energy metabolism, and cellular signaling, whose serum concentration is tightly regulated by an endocrine network including fibroblast growth factor 23 (FGF23), parathyroid hormone (PTH), vitamin D and Klotho. Disruption of this balance, particularly in chronic kidney disease (CKD), leads to hyperphosphatemia, which is strongly associated with bone fragility, vascular calcification, and increased mortality. In CKD, impaired phosphorus homeostasis triggers endocrine dysregulation characterized by elevated PTH and FGF23 levels, Klotho deficiency, and altered vitamin D metabolism, resulting in major skeletal and vascular consequences. Experimental and clinical evidence indicates that phosphorus overload contributes directly to skeletal deterioration and early vascular remodeling, even prior to clinically detectable renal impairment. Moreover, high dietary phosphorus intake under conditions of normal renal function reproduces several molecular and structural alterations typically observed in CKD, supporting a pathogenic role for chronic phosphorus excess. The dietary source of phosphorus has gained increasing relevance, as inorganic phosphate additives exhibit high intestinal bioavailability and impose a greater systemic phosphorus burden. Current management strategies rely on dietary restriction, phosphate binders, modulation of intestinal phosphorus transport and optimization of mineral-regulating hormones, although evidence for improved clinical outcomes remains limited. A deeper understanding of the molecular mechanisms linking phosphorus overload to bone and vascular pathology may facilitate the development of more effective preventive and therapeutic strategies. Full article

Exercise-induced fatigue involves oxidative stress and metabolic dysregulation. While the anti-aging protein α-Klotho regulates metabolism and oxidative stress, its role in exercise fatigue is unexplored. This study investigated whether α-Klotho supplementation mitigates cumulative exercise-induced fatigue and elucidated the underlying tissue-specific mechanisms. Male C57BL/6J mice were divided into three groups (n = 10 per group), the control group, fatigue treated with saline, or α-Klotho (0.2 mg/kg, i.p. daily) group. Fatigue was induced by a 6-day exhaustive swimming protocol (5% body weight load). Tissues were collected 24h post-final exercise. Assessments included daily exhaustion time, grip strength, serum creatine kinase (CK), urea nitrogen (BUN), oxidative stress markers (H₂O₂, MDA, SOD, GSH/GSSG), tissue glycogen, and pathway protein expression (Western blot). α-Klotho supplementation prevented exercise-induced weight loss and restored grip strength. While exhaustive exercise markedly increased serum CK and BUN levels, α-Klotho selectively normalized CK without effecting serum BUN. α-Klotho attenuated oxidative damage by reducing hydrogen peroxide levels while enhancing antioxidant capacity, accompanied by activation of the NRF2/HO-1 pathway and further upregulation of PGC-1α. Notably, α-Klotho induced striking hepatic glycogen supercompensation through activation of the AKT/GS signaling pathway and upregulation of GLUT4, whereas muscle glycogen levels remained unchanged. In conclusion, α-Klotho ameliorates cumulative exercise-induced fatigue through dual recovery-phase mechanisms: NRF2/HO-1-mediated antioxidant protection in skeletal muscle and AKT/GS-triggered hepatic glycogen supercompensation, thereby facilitating oxidative stress resolution and enhancing energy reserve restoration. Full article

Phosphate is emerging as an active mediator of oxidative stress and vascular injury in chronic kidney disease (CKD). This emerging pathophysiological framework, referred to as “Phosphatopathy”, describes the systemic syndrome driven by chronic phosphate overload and characterized by oxidative stress, inflammation, endothelial dysfunction, vascular calcification, cellular senescence, and metabolic imbalance. Beyond being a biochemical marker, phosphate overload triggers NOX-derived reactive oxygen species (ROS), activates Wnt/β-catenin and TGF-β signaling, and disrupts the FGF23–Klotho axis, promoting endothelial dysfunction, vascular calcification, and left ventricular hypertrophy (LVH). These pathways converge with systemic inflammation and energy imbalance, contributing to the malnutrition–inflammation–atherosclerosis (MIA) syndrome. Experimental and clinical data reveal that the phosphate/urinary urea nitrogen (P/UUN) ratio is a sensitive biomarker of inorganic phosphate load, while emerging regulators such as microRNA-125b and calciprotein particles integrate phosphate-driven oxidative and inflammatory responses. Therapeutic strategies targeting phosphate burden—rather than serum phosphate alone—include dietary restriction of inorganic phosphate, non-calcium binders, magnesium and zinc supplementation, and activation of important pathways related to the activation of antioxidant defense such as AMP-activated protein kinase (AMPK) and SIRT1. This integrative framework redefines phosphate as a modifiable upstream trigger of oxidative and metabolic stress in CKD. Controlling phosphate load and redox imbalance emerges as a convergent strategy to prevent vascular calcification, improve arterial stiffness, and reduce cardiovascular risk through personalized, mechanism-based interventions. Full article

Background: Maternal vitamin D status during pregnancy has been hypothesized to influence offspring neurodevelopment; however, the evidence remains inconsistent. Methods: We studied 66 mother–child pairs from the KLOTHO cohort with serum 25-hydroxyvitamin D [25(OH)D] measurements at delivery (maternal and umbilical cord). At 10 years of age, neurodevelopment was assessed using standardized questionnaires, generating composite z-scores for cognitive (cognitive, communication, motor) and psychosocial (social–sentimental, special interests) domains. Multivariable models were adjusted for sex, maternal body mass index and education, and neonatal birth weight and gestational age. Results: Maternal 25(OH)D deficiency (<50 nmol/L) was not associated with cognitive composite scores (p = 0.77). The psychosocial composite scores showed a non-significant negative trend (p = 0.29). Neonatal deficiency showed no consistent association with cognition (p = 0.99) or psychosocial outcomes (p = 0.30). Exploratory partial correlations suggested a positive association between maternal 25(OH)D and psychosocial development (r = 0.60, p = 0.038, n = 12). Seasonal variation in maternal vitamin D was observed (autumn: 56.0 ± 24.6 vs. winter: 32.0 ± 18.3 nmol/L; p < 0.0001), but did not translate into differences in 10-year outcomes. Conclusions: In this cohort of 66 pairs, perinatal vitamin D status was not a determinant of global cognition at 10 years of age. A potential link with psychosocial development requires replication in larger longitudinal studies. Due to the limited sample size, all findings should be interpreted as exploratory. Full article

Background/Objectives: Ankylosing Spondylitis (AS) is associated with increased cardiovascular disease risk due to chronic systemic inflammation. The Atherogenic Index of Plasma (AIP) and Systematic Coronary Risk Evaluation (SCORE) are valuable tools for cardiovascular risk assessment, while Klotho, an anti-aging protein with cardioprotective properties, may serve as a potential biomarker for cardiovascular health. Recent studies have shown that soluble α-Klotho contributes to vascular protection by increasing endothelial cell proliferation, reducing apoptosis, and enhancing angiogenic capacity, thereby helping to maintain microvascular integrity. We aimed to assess cardiovascular event risk in AS patients using AIP and SCORE and investigate the relationship between serum Klotho levels and these factors. Methods: A case–control study was conducted between August and September 2019. The study included 24 AS patients and 24 healthy controls aged 18 and above, with 13 females and 11 males. Results: No significant difference was found in serum Klotho levels between the AS and control groups in terms of SCORE and AI classifications. In the high-risk SCORE classification group, AI was found to be elevated at 0.42. In the AS group, Klotho levels were observed as 0.73 in the low-risk group, 0.60 in the moderate-risk group, and 0.61 in the high-risk group (p = 0.974). When evaluating HDL levels, Klotho was determined to be 7.29 ± 6.81 for HDL < 35 and 0.60 [0.33] for HDL ≥ 35 (p = 0.036). Conclusions: An AI exceeding 0.40 in the high-risk SCORE group and in patients with active disease according to the BASDAI score indicated an increased cardiovascular event risk in the AS group. Further studies are warranted regarding serum Klotho levels, HDL, and LDL subclasses in AS patients. Full article

Alterations in the expression of the Klotho gene have been associated with chronic kidney disease (CKD), and its potential as an early diagnostic biomarker is currently under active investigation. In this work, we report the development of a highly sensitive, label-free electrochemical DNA-based biosensor for the detection of a 100 mer DNA fragment corresponding to a partial region of Klotho mRNA. The proposed bioplatform integrates mixed self-assembled monolayers (SAMs) and gold nanoparticles for efficient DNA immobilization within a sandwich-type configuration, coupled with impedimetric detection. Different SAM architectures were evaluated by cyclic voltammetry and electrochemical impedance spectroscopy, with the binary monolayer composed of 1-hexadecanethiol (HDT) and the capture probe (CP) exhibiting the best analytical performance. The use of gold nanoparticle-modified screen-printed carbon electrodes (AuNPs–SPCEs) resulted in a 1.4-fold increase in the signal-to-noise ratio compared to screen-printed gold electrodes. Additionally, the incorporation of a blocking step using bovine serum albumin (BSA–HDT–CP–AuNPs–SPCE) enhanced the sensitivity by 1.6-fold compared to the unblocked system. The genosensor displayed a linear response in the concentration range of 3 × 10⁻¹⁰ to 7.5 × 10⁻⁸ M, achieving a detection limit of 0.09 nM. Relative standard deviations below 7.5% were obtained for different Klotho concentrations, confirming high intra-assay and intermediary precision. Selectivity assays demonstrated negligible signals for non-complementary sequences, while recovery experiments in spiked human serum samples yielded satisfactory values between 96.5% and 103.4%. Full article

Background: This study investigates the levels of fibroblast growth factor 23 (FGF23), Klotho, interleukin-6 (IL-6), interleukin-10 (IL-10), and myostatin (Mstn) in stable kidney transplant recipients undergoing triple immunosuppressive therapy. Chronic kidney disease (CKD) disrupts the balance of several key minerals and hormones, leading to complications such as vascular calcification and cardiac issues. We aim to identify potential biomarkers for monitoring kidney function post-transplantation and to understand the inflammatory response induced by renal transplantation. Methods: A total of 122 renal transplant patients on triple immunosuppression were included. Patients were categorized based on their calcineurin inhibitor usage and compared with 110 healthy individuals in the control group. Body mass index (BMI), serum FGF23, Klotho, IL-6, IL-10, Mstn, C-reactive protein, creatinine, calcium, phosphorus, and albumin levels were analyzed. Results: The study reveals that FGF23, Klotho, and Mstn levels are significantly lower in transplant patients than in the control group, while IL-6 levels show no significant difference. A decrease in IL-10 levels is observed in transplant patients, suggesting a role in post-transplant inflammation. Additionally, a positive correlation is found between BMI and serum Mstn and Klotho levels, but no correlation with other measured parameters. Conclusions: The findings suggest that serum levels of FGF23, Klotho, and Mstn, along with IL-10, could serve as indicators of kidney function and inflammation in kidney transplant recipients, potentially guiding post-transplant care and management. Full article

Contemporary diabetes management is progressively moving away from a glucocentric approach, with growing expectations that novel antidiabetic agents offer benefits beyond glycaemic control. Sodium–glucose cotransporter 2 inhibitors (SGLT2i) have emerged as a cornerstone in the treatment of type 2 diabetes mellitus (T2DM). In addition to reducing blood glucose levels by promoting renal glucose excretion, these agents contribute significantly to cardio–renal–metabolic protection and are associated with improved cardiovascular outcomes and prolonged survival. Although SGLT2 inhibitors do not exhibit a class effect in all clinical aspects, growing evidence suggests their potential in a variety of additional therapeutic areas. We conducted an in-depth review of current scientific literature and clinical studies regarding this class of drugs. SGLT2 inhibitors demonstrate neuroprotective properties and may provide benefits in neurodegenerative disorders such as Alzheimer’s and Parkinson’s disease, potentially through the improvement of mitochondrial function and attenuation of inflammatory responses. Their anti-inflammatory and antioxidative effects are closely linked to reductions in cardiac and renal fibrosis. Other observed benefits include weight loss, improved insulin sensitivity, normalization of serum uric acid, and a reduction in hepatic steatosis—each with important metabolic implications. Furthermore, SGLT2 inhibitors have been shown to positively influence iron metabolism and improve erythrocyte indices. Emerging data also indicate beneficial effects in women with polycystic ovary syndrome. Another promising area of investigation involves the modulation of Klotho protein expression and support of vascular homeostasis. In oncology, SGLT2 inhibitors are gaining attention, with encouraging preclinical results observed in malignancies such as pancreatic, thyroid, breast, and lung cancers. Based on a comprehensive evaluation of the existing body of evidence, it is anticipated that the clinical indications for SGLT2 inhibitors will expand beyond the cardio–renal–metabolic axis in the near future. Full article