Search Results (37)

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

Atherosclerosis is a complex, multifactorial disease that progresses through distinct stages: initiation, progression, and complication, ultimately leading to acute coronary syndromes (ACS). Endothelial cells (ECs), vascular smooth muscle cells (VSMCs), and macrophages are central players in this process, influencing plaque stability and vulnerability. Insulin-Like Growth Factor 1 (IGF-1), soluble-Klotho (S-Klotho), and the Growth Hormone Receptor exon 3 deletion polymorphism (GHRd3) have emerged as key modulators of vascular health, impacting these cellular components through various mechanisms. IGF-1 supports endothelial function, enhances VSMC survival and migration, and mitigates inflammation by inhibiting macrophage recruitment and activation, ultimately reducing the risk of plaque destabilization. S-Klotho, an anti-aging protein with potent anti-inflammatory and antioxidant properties, has been linked to vascular protection, with its deficiency associated with endothelial dysfunction, vascular calcification, and impaired VSMC survival. Evidence suggests that IGF-1 may enhance Klotho shedding, indicating a potential synergistic role in maintaining vascular integrity. This narrative review aims to outline the fundamental stages of atherosclerosis progression, consolidate current evidence on the roles of IGF-1 and S-Klotho in modulating key cellular components of atherosclerosis, and shed light on their potential involvement in plaque healing—an area that remains largely unexplored. By integrating established molecular mechanisms, we explore how these factors may contribute to endothelial integrity, VSMC survival, and macrophage activation and polarization, potentially shaping a more stable plaque phenotype and influencing future therapeutic strategies in cardiovascular disease. 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

Management of secondary hyperparathyroidism (SHPT) in chronic kidney disease (CKD) has evolved dramatically over the past five decades, driven by discoveries that have fundamentally reshaped our understanding of the vitamin D endocrine system and its role in disease progression. This review synthesizes the key pathophysiological insights and clinical evidence underlying three critical paradigm shifts. The first shift moved beyond simple calcitriol replacement with the development of selective vitamin D receptor activators (VDRAs) designed to minimize hypercalcemia while maximizing PTH suppression. Crucially, these analogs revealed unexpected survival benefits, suggesting protective VDR actions extending beyond mineral metabolism. The second shift recognized the profound prevalence and independent mortality risk associated with nutritional vitamin D (25(OH)D) deficiency in CKD. This highlighted the kidney’s complex role in maintaining systemic 25(OH)D supply and the importance of extrarenal vitamin D activation, although optimal assessment, targets, and supplementation strategies remain highly controversial due to CKD-specific pathophysiology (e.g., megalin loss, impaired uptake, obesity effects) and complex dosing paradoxes. The third, and most impactful, shift centers on the FGF23-Klotho axis. Pathologically high FGF23 is now established as a direct cardiovascular and skeletal toxin, acting via Klotho-independent pathways in CKD, while the profound deficiency of the protective, anti-aging hormone Klotho exacerbates systemic damage (inflammation, oxidative stress, impaired autophagy). This creates a major therapeutic dilemma, as VDRAs induce protective Klotho but worsen toxic FGF23, while calcimimetics do not increase FGF23 but offer no Klotho benefit. Furthermore, this complex interplay is obscured by significant limitations in accurately measuring FGF23 isoforms, soluble Klotho, and true vitamin D status. These paradigm shifts reveal a complex pathophysiology far beyond simple PTH control, demanding a move towards nuanced, potentially combined therapeutic strategies that balance FGF23 burden with Klotho preservation. Overcoming the profound diagnostic limitations to accurately monitor this axis and guide personalized therapy represents the critical next frontier in improving outcomes for patients with CKD. Full article

Aging is driven by interconnected genetic, metabolic, and environmental factors that manifest as hallmarks including genomic instability, telomere attrition, epigenetic drift, and altered intercellular signaling. The Klotho-FGF23 axis has emerged as a critical regulator linking mineral metabolism to systemic aging processes. Membrane-bound Klotho, primarily in the kidney and parathyroid, acts as an obligate co-receptor for FGF23 to regulate phosphate and vitamin D homeostasis, while soluble Klotho exerts hormone-like effects that modulate Wnt, IGF-1, NF-κB, and TGF-β pathways, influencing oxidative stress, inflammation, and tissue regeneration. Deficiency of Klotho or FGF23 in animal models results in hyperphosphatemia, vascular calcification, and premature aging phenotypes, whereas Klotho overexpression or supplementation extends lifespan and enhances stress resilience. Beyond its renal role, FGF23 can activate Klotho-independent FGFR4 signaling in cardiomyocytes, promoting hypertrophy and contributing to cardiovascular risk. This review integrates current mechanistic insights on Klotho-FGF23 signaling within the framework of aging hallmarks, differentiating protective Klotho-dependent pathways from maladaptive Klotho-independent effects. We evaluate therapeutic strategies including recombinant Klotho protein, gene therapy, dietary phosphate restriction, FGFR4 inhibition, and senolytics approaches that restore Klotho expression. Key translational challenges remain assay variability and poor standardization of soluble Klotho measurement, limited longitudinal human data, and differences between murine models and human aging. Addressing these barriers will be essential to advancing Klotho-FGF23 targeted interventions as a viable strategy to extend health span and delay age-related pathologies. Full article

The anti-aging protein α-Klotho has several therapeutic effects on different pathophysiological conditions, mainly its anti-inflammatory and antioxidant effects. Experimental evidence and observational studies suggest that there are several strategies to increase α-Klotho in the brain and enhance its beneficial effects, thus contributing to improving its neuroprotective and neuroplasticity mechanisms in brain aging, Alzheimer’s, Parkinson’s, and ischemic stroke diseases. In this article, we summarize the relevant information on α-Klotho, brain aging, Alzheimer’s, Parkinson’s, and ischemic stroke diseases and analyze the role of α-Klotho in each of these alterations, as well as the effect of physical exercise, exogenous application of α-klotho, and various drugs approved for different human diseases on α-Klotho production. Full article

Background/Objectives: Chronic kidney disease–mineral and bone disorder (CKD-MBD) and systemic inflammation contribute to mortality in hemodialysis (HD) patients. The primary aim of this study was to determine whether specific CKD-MBD markers and inflammatory biomarkers are associated with increased mortality risk in HD patients. Methods: We conducted a retrospective cohort study on 63 stage 5D CKD patients undergoing maintenance HD. Serum intact parathyroid hormone (iPTH), soluble Klotho, calcium, phosphorus, 25(OH)D (25-hydroxyvitamin D), transforming growth factor-beta (TGF-β), vascular endothelial growth factor (VEGF), C-reactive protein (CRP), and interleukin-6 (IL-6) were analyzed. A Cox regression analysis assessed mortality predictors, and linear regression analysis evaluated CKD-MBD–inflammation correlations. Results: Lower iPTH (<329.3 pg/mL) levels were the only significant mortality predictor (p = 0.042). Other CKD-MBD markers (calcium, phosphorus, 25(OH)D, VEGF, TGF-β) did not impact survival. Soluble Klotho correlated positively with IL-6 (r = 0.57, p < 0.001), suggesting a compensatory inflammatory response. Conclusions: Our findings demonstrate that low iPTH levels and advanced age are independent predictors of mortality in hemodialysis patients. The positive association between soluble Klotho and IL-6 suggests a potential compensatory inflammatory response. These results highlight the need for further research to clarify underlying mechanisms and to explore novel therapeutic strategies. Full article

Background/Objectives: Cardiovascular disease is the main cause of morbidity and mortality in Chronic Kidney Disease (CKD), so it is of great importance to find simple and non-invasive tools to detect vascular damage in pre-dialysis CKD patients. This study aimed to assess the applicability of non-invasive techniques to evaluate vascular damage in stages CKD-2 to CKD-5 and its progression after an 18-month follow-up using (A) carotid–femoral pulse wave velocity (PWV) to assess aortic stiffness and (B) Superb Microvascular Imaging (SMI) ultrasound to assess adventitial neovascularization compared with other traditional techniques to evaluate vascular damage, such as carotid intima–media thickness and Kauppila index. Methods: The study involved 43 CKD patients in stages CKD-2 to CKD-5 and a group of 38 sex- and age-matched controls, studied at baseline and at an 18-month follow-up. Age, sex, body mass index, arterial pressure, pharmacological treatments, and blood and urinary parameters were collected. Aortic stiffness was determined by carotid–femoral PWV and abdominal aortic calcification was assessed in lateral lumbar X-rays and quantified by the Kauppila index. Carotid intima–media thickness (cIMT), the number of carotid plaques, and adventitial neovascularization were evaluated by SMI. Results: Vascular impairment was mostly detected in CKD-4 and CKD-5 stages, with increased aortic stiffness measured by PWV and increased carotid plaques and adventitial neovascularization measured by SMI ultrasound. Furthermore, CKD-5 patients showed greater abdominal aortic calcification. Interestingly, CKD patients displayed a negative correlation between serum soluble Klotho (sKlotho) and cIMT. Finally, CKD patients showed no progression of vascular impairment after the 18-month follow-up, with the exception of carotid plaques. Conclusions: Performing non-invasive PWV and SMI ultrasound might be useful to evaluate vascular damage in CKD before entering dialysis, possibly helping to prevent cardiovascular events, although future studies should clarify the use of these techniques in clinical practice. Full article

Background/Objectives: Soluble αKlotho (sαKlotho) and fibroblast growth factor 23 (FGF-23) are increased in acute heart failure (AHF). This study aimed to assess changes in serum sαKlotho and FGF-23 concentrations during an episode of AHF as well as the usefulness of both biomarkers for predicting long-term prognosis. Methods: The study included 104 consecutive patients hospitalized in t he intensive cardiac care unit due to AHF (mean age, 65.8 ± 14.6 years; mean ejection fraction, 31.4% ± 14). New-onset AHF was reported in 43.3% of the population. Blood samples were measured at entry and on discharge from hospital. The main clinical outcomes assessed in this study were all-cause mortality or rehospitalization due to HF during a 3-year follow-up. Results: At admission sαKlotho, FGF-23, and NT-pro BNP levels, compared with discharge, were significantly higher at p < 0.001, p < 0.001, and p < 0.001 respectively. The 3-year Kaplan–Meier analysis, based on tertiles, revealed, for sαKlotho levels from Tertile 1 on admission and at discharge, a 2-fold higher rate of all-cause mortality or rehospitalization for HF compared with Tertile 3 (p = 0.006 and p = 0.028, respectively). One-third of patients showed an increase in FGF-23 and sαKlotho levels during hospitalization. Patients with the highest percentage increase in the levels of both biomarkers had an elevated risk of all-cause morality or hospitalization for HF (hazard ratio, 2.75; confidence interval, 1.19–6.35; p = 0.02). Conclusions: sαKlotho and FGF-23 levels are elevated during an episode of AHF. Low sαKlotho levels are associated with an increased risk of all-cause mortality or rehospitalization for HF. Increases in sαKlotho and FGF-23 values during hospitalization identify patients with poor prognosis. Full article

Aging and pregnancy are often considered opposites in a woman’s biological timeline. Aging is defined by a gradual decline in the functional capabilities of an organism over its lifetime, while pregnancy is characterized by the presence of the transient placenta, which fosters the cellular fitness necessary to support fetal growth. However, in the context of preeclampsia, pregnancy and aging share common hallmarks, including clinical complications, altered cellular phenotypes, and heightened oxidative stress. Furthermore, women with pregnancies complicated by preeclampsia tend to experience age-related disorders earlier than those with healthy pregnancies. Klotho, a gene discovered fortuitously in 1997 by researchers studying aging mechanisms, is primarily expressed in the kidneys but also to a lesser extent in several other tissues, including the placenta. The Klotho protein is a membrane-bound protein that, upon cleavage by ADAM10/17, is released into the circulation as soluble Klotho (sKlotho) where it plays a role in modulating oxidative stress. This review focuses on the involvement of sKlotho in the development of preeclampsia and age-related disorders, as well as the expression of the recently discovered Mytho gene, which has been associated with skeletal muscle atrophy. Full article

Gliomas are the most common and lethal forms of malignant brain tumors. We attempted to identify the role of the aging-suppressor Klotho gene and Klotho protein in the immunopathogenesis of gliomas. We examined Klotho genetic variants by PCR-RFLP and measured serum Klotho levels using the ELISA method. We found a statistically significantly increased frequency of rs1207568A allele and rs1207568 GA genotypes in co-dominant, dominant and over-dominant models in grade IV as compared to grade II and III glioma patients. The levels of soluble α Klotho (sαKL) were significantly lower in grade III and IV glioma patients than in healthy controls (p = 0.034; 0.0083). Patients with sαKL levels above 2500 pg/mL survived significantly longer than patients with sαKL below 2500 pg/mL (p = 0.038). We also found a positive correlation of the serum levels of sαKL with seven biomarkers, like angiogenic vascular endothelial growth factor (p = 0.0008), chemokine fractalkine (p = 0.0009), interferon γ (p = 0.003), glial derived neurotrophic factor (p = 0.0268), pro-inflammatory and pro-Th1 cytokine IL-6 (p = 0.0347), anti-inflammatory, pro-Th2 cytokines IL-4 (p = 0.0037) and IL-13 (p = 0.0004). Our results suggest the impact of Klotho genetic variants and Klotho levels on advanced-grade glioma. Full article

Aging is a natural process that is also influenced by some factors like the food someone eats, lifestyle decisions, and impacts on general health. Despite the recognized role of nutrition in modulating the molecular and cellular mechanisms underlying aging, there is a lack of comprehensive exploration into potential interventions that can effectively mitigate these effects. In this study, we investigated the potential anti-aging properties of vitamin D by examining its interactions with key molecular targets involved in aging-related pathways. By using molecular docking and dynamics techniques, we evaluate the interactions and stability of vitamins D2 and D3 with key proteins involved in aging pathways, such as SIRT1, mTOR, AMPK, Klotho, AhR, and MAPK. Our results reveal promising binding affinities between vitamin D and SIRT1 forms, with energy values of −48.33 kJ/mol and −45.94 kJ/mol for vitamins D2 and D3, respectively, in aqueous environments. Moreover, molecular dynamics simulations revealed that the vitamin D3–SIRT1 complex exhibited greater stability compared with the vitamin D2–SIRT1 complex. The study calculated the solvation free energy to compare the solubility of vitamins D2 and D3 in water and various organic solvents. Despite their strong interactions with water, both vitamins exhibited low solubility, primarily due to the high energy cost associated with cavity formation in the aqueous environment. Compared with other solvents, water demonstrated particularly low solubility for both vitamins. This suggested that vitamins D2 and D3 preferred binding to aging receptors over dissolving in bulk aqueous environments, supporting their strong therapeutic interactions with these receptors. These findings shed light on the molecular mechanisms underlying vitamin D’s potential anti-aging effects and lay the groundwork for developing nutraceuticals targeting aging and associated diseases. Understanding these mechanisms holds promise for future interventions aimed at promoting healthy aging and enhancing overall well-being. Full article

The α-Klotho protein (hereafter Klotho) is an obligate coreceptor for fibroblast growth factor 23 (FGF23). It is produced in the kidneys, brain and other sites. Klotho insufficiency causes hyperphosphatemia and other anomalies. Importantly, it is associated with chronic pathologies (often age-related) that have an inflammatory component. This includes atherosclerosis, diabetes and Alzheimer’s disease. Its mode of action in these diseases is not well understood, but it inhibits or regulates multiple major pathways. Klotho has a membrane form and a soluble form (s-Klotho). Cytosolic Klotho is postulated but not well characterized. s-Klotho has endocrine properties that are incompletely elucidated. It binds to the FGF receptor 1c (FGFR1c) that is widely expressed (including endothelial cells). It also attaches to soluble FGF23, and FGF23/Klotho binds to FGFRs. Thus, s-Klotho might be a roaming FGF23 coreceptor, but it has other functions. Notably, Klotho (cell-bound or soluble) counteracts inflammation and appears to mitigate related aging (inflammaging). It inhibits NF-κB and the NLRP3 inflammasome. This inflammasome requires priming by NF-κB and produces active IL-1β, membrane pores and cell death (pyroptosis). In accord, Klotho countered inflammation and cell injury induced by toxins, damage-associated molecular patterns (DAMPs), cytokines, and reactive oxygen species (ROS). s-Klotho also blocks the TGF-β receptor and Wnt ligands, which lessens fibrotic disease. Low Klotho is associated with loss of muscle mass (sarcopenia), as occurs in aging and chronic diseases. s-Klotho counters the inhibitory effects of myostatin and TGF-β on muscle, reduces inflammation, and improves muscle repair following injury. The inhibition of TGF-β and other factors may also be protective in diabetic retinopathy and age-related macular degeneration (AMD). This review examines Klotho functions especially as related to inflammation and potential applications. Full article

Background/Objectives: The survival rate among pediatric cancer patients has reached 80%; however, these childhood cancer survivors (CCSs) are at a heightened risk of developing chronic conditions in adulthood, particularly kidney and cardiovascular diseases. The aims of this study were to assess the serum α-Klotho and FGF23 levels in CCSs and to determine their association with nephro- and cardiotoxicity. Methods: This study evaluated a cohort of 66 CCSs who remained in continuous remission, with a mean follow-up of 8.41 ± 3.76 years. Results: The results of this study revealed that CCSs exhibited significantly higher levels of soluble α-Klotho compared to healthy peers (1331.4 ± 735.5 pg/mL vs. 566.43 ± 157.7 pg/mL, p < 0.0001), while no significant difference was observed in their FGF23 levels. Within the participant cohort, eight individuals (12%) demonstrated a reduced estimated glomerular filtration rate (eGFR) below 90 mL/min/1.73 m². The relationship between treatment with abdominal radiotherapy and reduced eGFR was confirmed (p < 0.05). No correlations were found between potential treatment-related risk factors, such as chemotherapy or radiation therapy, serum levels of α-Klotho and FGF23, and nephro- and cardiotoxicity. Conclusions: In conclusion, this preliminary cross-sectional study revealed elevated levels of α-Klotho among childhood cancer survivors but did not establish a direct association with anticancer treatment. The significance of elevated α-Klotho protein levels among CCSs warrants further investigation. Full article

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