Diabetes is a major global health concern, affecting millions and increasing morbidity and mortality. Recent research highlights fibroblast growth factor 23 (FGF23) as a potential contributor to type 2 diabetes and its cardiovascular complications. This review explores the role of FGF23 in metabolic and cardiovascular dysfunction and discusses possible therapeutic interventions.

Deregulated FGF23 is linked to insulin resistance, pancreatic β-cell dysfunction, and systemic inflammation. Studies suggest FGF23 influences glucose metabolism via insulin signaling, oxidative stress, and inflammation. Epidemiological data indicate that elevated FGF23 levels are associated with an increased risk of type 2 diabetes and posttransplant diabetes, independent of traditional risk factors. Higher FGF23 levels have also been linked with an increased cardiovascular risk in patients with diabetes, even without chronic kidney disease.

FGF23 is emerging as a key factor in the cardiovascular-kidney-metabolic syndrome, connecting diabetes and cardiovascular disease. While studies suggest consistent associations, causal mechanisms remain unclear. No therapies specifically target FGF23 to lower diabetes risk, but fibroblast growth factor receptor 4 (FGFR4) inhibitors show promise. Future research should examine the role of FGF23 in individuals with normal kidney function and explore whether modifying its levels could reduce diabetes and cardiovascular risk.

Mutations in Klotho have been associated with premature ageing and cognitive dysfunction. Although highly expressed in specific regions of the brain, the actions of Klotho in the central nervous system (CNS) remain largely unknown. Here, we show that animals with a mutated hypomorphic Klotho gene have altered glycaemic regulation, suggesting higher insulin sensitivity. In the CNS, pathways related to insulin intracellular signalling were found to be up-regulated in the hippocampus, with higher activation of protein kinase B and mammalian target of rapamycin and inactivation of the transcription factors forkhead box O (FOXO)-1 and FOXO-3a. In addition, the present study showed that in the hippocampi of wild-type aged mice, where Klotho is naturally downregulated, the levels of some proteins related to energy metabolism and metabolic coupling between neurones and astrocytes, such as monocarboxylate transporter 2 and 4, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase isoform 3 and lactate dehydrogenase enzymes isoforms A and B were altered. These findings suggest that Klotho plays an essential role in regulating proteins and genes related to metabolic coupling in the brain.

Klotho, named after the youngest of the three Fates in Greek mythology daughters of Zeus and Nyx, who together spin the thread of life, allot destiny, and determine the time of passing for both mortals and immortals, is an important regulatory factor in aging and cancer dynamics. Initially described as an aging-suppressing protein, Klotho is now recognized for its more diverse role in modulating key signaling pathways like Wnt/β-catenin, IGF-1, PI3K/AKT, and TGF-β. Essentially, its various pro-cellular health functions, such as antioxidant, anti-inflammatory, and tumor-suppressive activities, are, in fact, considered that ensures the maintenance of cellular health and reduce complications related to aging. Klotho deficiency is associated with accelerated aging, chronic kidney disease, cardiovascular disorders, neurodegeneration, and various cancers. This review thus covers the twin roles of Klotho as an antiaging and tumor-suppressor protein, on their therapeutic potential, as well as advances in delivery systems and development of biomarkers and challenges for clinical translation.. Moreover, natural strategies like exercise and dietary interventions are explored that could help overcome Klotho deficiency. Further research with Klotho may offer a paradigm shift in the treatment of aging and cancer and add yet another avenue to increase survival of the patients.

Chronic kidney disease (CKD) is a global health challenge marked by progressive renal decline and increased mortality. The interplay between CKD and hypothyroidism, particularly nonthyroidal low-triiodothyronine (T3) syndrome, exacerbates disease progression, driven by HPT axis dysfunction and reduced Klotho levels due to the Wnt/β-catenin pathway activation. This study explored Klotho as a link between CKD and hypothyroidism using an adenine-induced CKD aged mouse model. Exogenous T3 and baicalein (BAI), targeting the Wnt pathway, were used to upregulate Klotho expression. Combined T3 and BAI treatment significantly increased Klotho levels, surpassing individual effects, and suppressed key signaling molecules (TGF, NFκB, GSK3), mitigating renal fibrosis and CKD complications, including cardiovascular disorders and dyslipidemia. This bidirectional approach, enhancing Klotho via T3 and sustained Wnt pathway inhibition, offers a novel and effective strategy for CKD management, particularly in elderly patients with hypothyroidism.

Chronic kidney disease (CKD) and Alzheimer's disease (AD) are two prevalent and debilitating conditions that frequently coexist, with CKD contributing to cognitive decline and potentially exacerbating AD pathology. In CKD, irreversible changes in the structure or function of the kidneys are observed, while AD is primarily marked by amyloid deposition and tau pathology. Both conditions involve complex and multifactorial pathophysiology affecting brain functioning, highlighting the need for comprehensive research to understand their potential crosstalk. This review articulates the possible molecular mechanisms underlying both diseases, focusing on key pathways, including oxidative stress, inflammation, vascular dysfunction, hypertension, and uremic toxin accumulation. These interconnected mechanisms suggest a potential bidirectional relationship where kidney dysfunction accelerates cognitive decline and vice versa. Additionally, we examine critical risk factors implicated in both CKD and AD, for instance, vitamin D deficiency, erythropoietin dysregulation, endothelin action, klotho gene expression, and the role of the extracellular vesicle, which may influence disease progression through their effects on the kidney and brain, influencing cognitive function. Further, we emphasized potential biomarkers that could aid in diagnosing and monitoring disease progression in these comorbid conditions, like amyloid beta, tau, homocysteine, cystatin C, creatinine, proteinuria, and estimated glomerular filtration rate. Lastly, the review highlights treatment strategies for managing CKD and AD concurrently, focusing on therapeutic approaches that address common pathophysiological mechanisms. These strategies not only aim to address the underlying causes of both conditions but also offer the potential to slow or even prevent the progression of cognitive impairment. Moreover, we recommend further research to refine these approaches, execute correlational studies on disease progression, and design clinical trials that address both conditions, aiming to establish effective, tailored treatments for this dual burden of disease.

Phosphorus is one of the most abundant minerals in the body and plays a critical role in numerous cellular and metabolic processes. Most of the phosphate is deposited in bones, 14% is present in soft tissues as various organic phosphates, and only 1% is found in extracellular space, mainly as inorganic phosphate. The plasma inorganic phosphate concentration is closely maintained between 2.5 and 4.5 mg/dL by intertwined interactions between fibroblast growth factor 23 (FGF-23), parathyroid hormone (PTH), and vitamin D, which tightly regulate the phosphate trafficking across the gastrointestinal tract, kidneys, and bones. Disruption of the strict hemostatic control of phosphate balance can lead to altered cellular and organ functions that are associated with high morbidity and mortality. In the past three decades, there has been a steady increase in the prevalence of kidney failure (KF) among populations. Individuals with KF have unacceptably high mortality, and well over half of deaths are related to cardiovascular disease. Abnormal phosphate metabolism is one of the major factors that is independently associated with vascular calcification and cardiovascular mortality in KF. In early stages of CKD, adaptive processes involving FGF-23, PTH, and vitamin D occur in response to dietary phosphate load to maintain plasma phosphate level in the normal range. However, as the CKD progresses, these adaptive events are unable to overcome phosphate retention from continued dietary phosphate intake and overt hyperphosphatemia ensues. As these hormonal imbalances and the associated adverse consequences are driven by the underlying hyperphosphatemic state in KF, it appears logical to strictly control serum phosphate. Conventional dialysis is inadequate in removing phosphate and most patients require dietary restrictions and pharmacologic interventions to manage hyperphosphatemia. However, diet control comes with many challenges with adherence and may place patients at risk for inadequate protein intake and malnutrition. Phosphate binders help to reduce phosphate levels but come with a sizable pill burden and high financial costs and are associated with poor adherence and psychosocial issues. Additionally, long-term use of binders may increase the risk of calcium, lanthanum, or iron overload or promote gastrointestinal side effects that exacerbate malnutrition and affect quality of life. Given the aforesaid challenges with phosphorus binders, novel therapies targeting small intestinal phosphate absorption pathways have been investigated. Recently, tenapanor, an agent that blocks paracellular absorption of phosphate via inhibition of enteric sodium-hydrogen exchanger-3 (NHE3) was approved for the treatment of hyperphosphatemia in KF. While various clinical tools are now available to manage hyperphosphatemia, there is a lack of convincing clinical data to demonstrate improvement in outcomes in KF with the lowering of phosphorus level. Conceivably, deleterious effects associated with hyperphosphatemia could be attributable to disruptions in phosphorus-sensing mechanisms and hormonal imbalance thereof. Further exploration of mechanisms that precisely control phosphorus sensing and regulation may facilitate development of strategies to diminish the deleterious effects of phosphorus load and improve overall outcomes in KF.

Klotho is an anti-aging protein, and obesity and inflammation have been identified as having a relationship with Klotho. This study investigated the correlation between weight-adjusted-waist index(WWI), systemic inflammation index(SII) and soluble Klotho (sKlotho) and explored the potential mediating role of SII.

The association between WWI, SII, and sKlotho was investigated using weighted multivariate linear regression, subgroup analysis, and smoothed curve fitting in this cross-sectional study, which was based on NHANES data. The Bootstrap method was used to test for mediation effects. Covariate selection was validated using the variance inflation factor (VIF).

The study involved a total of 9,506 participants. The results showed that WWI (β=-0.03; 95%CI:-0.04,-0.01; p<0.0001) was associated with SII (β=-0.00, 95%CI:-0.00,-0.00:p<0.001) and Ln-sKlotho.There was a negative correlation between both WWI and SII and sKlotho. Subgroup analysis showed that gender, age, education, marital status, family income, HEI, PA, hypertension, diabetes, CKD, alcohol use, smoking, and SII did not affect the negative correlation between WWI and sKlotho (FDR-corrected p>0.1). The mediation analysis showed that SII played a significant mediating effect in the role of WWI on sKlotho, with SII mediating 6.78% of the relationship between WWI and sKlotho.

There is a negative correlation between WWI and sKlotho, and SII may be an important mediator between WWI and sKlotho. Reducing inflammatory conditions in obese populations may increase sKlotho levels, which in turn may delay organismal aging in middle-aged and elderly people.

Ethylene oxide (EO) is an industrial chemical used in the production of both consumer and non-consumer products.Additionally, it is utilized as a gaseous sterilant for medical devices. As an anti-aging hormone, kloth involved in various physiological processes. At present, the association between EO exposure and klotho remains uncertain. In this retrospective cross-sectional study, 1696 participants aged 40-79 years in the 2013-2016 National Health and Nutrition Examination Survey were included. EO exposure was measured using the hemoglobin adducts of EO (HbEO) in human whole blood or erythrocytes. Klotho levels were also measured in blood samples. Linear regression, smooth curve fitting, and subgroup analyses were used to assess whether HbEO was associated with klotho level. After full adjustment for confounders, the negative association between log2HbEO and klotho was observed after multivariate adjustment (β=-17.29, 95% CI = - 28.42 ~ - 6.17, P = 0.002). When EO was categorized into quintiles, the fifth quintile exhibited significant differences compared to the lowest quintile (β=-70.79, 95% CI = - 122.54 ~ - 19.04, P = 0.007). The curve fitting shows an inverse "L-shaped" relationship between log2HbEO and klotho (P for nonlinearity = 0.04). In summary, a negative and nonlinear relationship was found between log2HbEO and klotho. Further research is required to confirm the causality of this connection and clarify the underlying mechanisms.

Klotho is an anti-aging gene, and the α-klotho protein it encodes reportedly has cardiovascular protective effects. The atherogenic index of plasma (AIP) is a novel and comprehensive lipid index that correlates with atherosclerotic burden and is a critical risk factor for cardiovascular diseases. There are no studies examining the relationship between AIP and α-klotho; thus, we aimed to explore this potential association.

Data were extracted from the National Health and Nutrition Examination Survey 2007-2016 database, and the relationship between AIP and serum α-klotho levels was analyzed using weighted multivariate linear regression.

After adjusting for risk factors, AIP showed a significant negative correlation with the logarithm of serum α-klotho levels in women. The trend analysis and smoothed curve fitting showed a nonlinear dose-response relationship. Threshold effect analysis showed a significant difference in the association between AIP and α-klotho before and after the AIP break point (0.434). Subgroup analyses demonstrated that the negative association of AIP with α-klotho was consistent across subgroups. However, the correlation between AIP and serum α-klotho in men was not significant.

Our study provides new evidence for sex differences in the association between AIP and serum α-klotho levels.

Aging is a major risk factor for the development of cardiovascular diseases (CVD), leading to specific alterations in the heart and vasculature. Besides, the mechanisms and intracellular pathways of aging and the factors affecting it are still not completely clear. Age-related complications such as oxidative stress, decreased autophagy, mitochondrial dysfunction, inflammatory responses, and cardiac dysfunction are associated with relative Klotho deficiency. Klotho, an anti-aging protein, with anti-oxidative and anti-inflammatory properties, has been shown to modulate calcium regulation and autophagy. It also protects against endothelial dysfunction by increasing nitric oxide production. Furthermore, emerging research has revealed that klotho significantly impacts vascular smooth muscle cells (VSMC) energetics and survival. This article has focused on recent advances in using Klotho in age-related CVD and summarizes the pre-clinical evidence supporting this approach. Based on the research, Klotho could provide more therapeutic options for ameliorating aging-related CVD.

Klotho, initially introduced as an anti-aging protein, is expressed in the brain, pancreas, and most prominently in the kidney. The two forms of Klotho (membrane-bound and soluble form) have diverse pharmacological functions such as anti-inflammatory, anti-oxidative, anti-fibrotic, tumour-suppressive etc. The membrane-bound form plays a pivotal role in maintaining kidney homeostasis by regulating fibroblast growth factor 23 (FGF 23) signalling, vitamin D metabolism and phosphate balance. Klotho deficiency has been linked with significantly reduced protection against various kidney pathological phenotypes, including diabetic kidney disease (DKD), which is a major cause of chronic kidney disease leading to end-stage kidney disease. Owing to the pleiotropic actions of klotho, it has shown beneficial effects in DKD by tackling the complex pathophysiology and reducing kidney inflammation, oxidative stress, as well as fibrosis. Moreover, the protective effect of klotho extends beyond DKD in other pathological conditions, including cardiovascular diseases, alzheimer's disease, cancer, inflammatory bowel disease, and liver disease. Therefore, this review summarizes the relationship between Klotho expression and various diseases with a special emphasis on DKD, the distinct mechanisms and the potential of exogenous Klotho supplementation as a therapeutic strategy. Future research into exogenous Klotho could unravel novel treatment avenues for DKD and other diseases.

Allopurinol, a xanthine oxidase inhibitor, recovers histological alterations and renal dysfunction induced during renal ischemic-reperfusion injury. This study investigated the cross-talk between the allopurinol and soluble Klotho.

Rats were randomly divided into three equal groups (n = 8 per group): The sham-operated group without renal ischemia, the BIR (bilateral ischemia-reperfusion) group which underwent renal ischemia, and BIR+Allo (allopurinol) group which was pretreated with allopurinol (100 mg/kg- gavage) 30 min before the renal ischemia. After recovery from the anesthesia, all animals were placed in metabolic cages to collect their urine after 24 h, plasma was extracted from blood samples taken from the tail vein-plasma and urine samples were saved at -20 °C. Kidneys were harvested and weighed. The left kidney was dropped in the buffer of 10 % formalin for H&E staining, and the right kidney was located in liquid nitrogen and saved at -80 °C for the oxidative stress analysis.

After renal ischemia-reperfusion, serum creatinine, blood urea nitrogen, xanthine oxidase, and total oxidative stress levels significantly increased. However, plasma Klotho level and total antioxidative capacity decreased in the BIR group. There was a reverse correlation between Klotho and xanthine oxidase levels. The pre-treatment with allopurinol increased plasma Klotho, induced a protective effect on renal histopathological changes, and corrected functional biomarkers.

Our results showed that allopurinol enhanced the antioxidative effects by increasing Klotho activity. Therefore, Klotho may be involved in the protective effects of allopurinol on the renal injury induced by BIR.

BackgroundThe α-Klotho is known to be involved in longevity and various age-related diseases, including cognitive impairment. BACE1, an important enzyme associated with the pathological process of Alzheimer's disease (AD), serves as a biomarker for predicting changes in cognitive function. Although both proteins are closely linked to age-related cognitive function, the mechanism of their interaction remains unclear.ObjectiveTo identify the enzymatic digestion relation between α-Klotho and BACE1 and the specific cleavage site.MethodsThirty elderly and forty-five young individuals were recruited. The cleavage product was identified by Coomassie blue staining, western blot, and MALDI-TOF mass spectrometry. The concentrations of plasma proteins were measured by ELISA.ResultsA new protein product was identified after the digestion reaction. BACE1 cleaved the α-Klotho peptide 951-981 at the F-T residues. When the F-T residues were replaced with K-K, BACE1 was unable to cleave the mutant peptide. The plasma levels of α-Klotho were significantly lower in elderly participants than in young participants (p < 0.0001). However, there was no significant difference in plasma BACE1 levels between elderly and young participants (p = 0.164). In elderly adults, there was a significant positive correlation between plasma BACE1 and α-Klotho protein levels (p = 0.009, r = 0.469), while this correlation was not observed in young adults (p = 0.170, r = -0.208).ConclusionsThe anti-aging protein α-Klotho is a substrate of BACE1 with a specific cleavage site at F-T. The BACE1/α-Klotho pathway may serve as a common axis for age-related cognitive decline.

Heart failure (HF) is a prominent fatal cardiovascular disorder afflicting 3.4% of the adult population despite the advancement of treatment options. Therefore, a better understanding of the pathogenesis of HF is essential for exploring novel therapeutic strategies. Hypertrophy and fibrosis are significant characteristics of pathological cardiac remodeling, contributing to HF. The mechanisms involved in the development of cardiac remodeling and consequent HF are multifactorial, and in this review, the key underlying mechanisms are discussed. These have been divided into the following categories thusly: (i) mitochondrial dysfunction, including defective dynamics, energy production, and oxidative stress; (ii) cardiac lipotoxicity; (iii) maladaptive endoplasmic reticulum (ER) stress; (iv) impaired autophagy; (v) cardiac inflammatory responses; (vi) programmed cell death, including apoptosis, pyroptosis, and ferroptosis; (vii) endothelial dysfunction; and (viii) defective cardiac contractility. Preclinical data suggest that there is merit in targeting the identified pathways; however, their clinical implications and outcomes regarding treating HF need further investigation in the future. Herein, we introduce the molecular mechanisms pivotal in the onset and progression of HF, as well as compounds targeting the related mechanisms and their therapeutic potential in preventing or rescuing HF. This, therefore, offers an avenue for the design and discovery of novel therapies for the treatment of HF.

Energy metabolism is indispensable for sustaining physiological functions in living organisms and assumes a pivotal role across physiological and pathological conditions. This review provides an extensive overview of advancements in energy metabolism research, elucidating critical pathways such as glycolysis, oxidative phosphorylation, fatty acid metabolism, and amino acid metabolism, along with their intricate regulatory mechanisms. The homeostatic balance of these processes is crucial; however, in pathological states such as neurodegenerative diseases, autoimmune disorders, and cancer, extensive metabolic reprogramming occurs, resulting in impaired glucose metabolism and mitochondrial dysfunction, which accelerate disease progression. Recent investigations into key regulatory pathways, including mechanistic target of rapamycin, sirtuins, and adenosine monophosphate-activated protein kinase, have considerably deepened our understanding of metabolic dysregulation and opened new avenues for therapeutic innovation. Emerging technologies, such as fluorescent probes, nano-biomaterials, and metabolomic analyses, promise substantial improvements in diagnostic precision. This review critically examines recent advancements and ongoing challenges in metabolism research, emphasizing its potential for precision diagnostics and personalized therapeutic interventions. Future studies should prioritize unraveling the regulatory mechanisms of energy metabolism and the dynamics of intercellular energy interactions. Integrating cutting-edge gene-editing technologies and multi-omics approaches, the development of multi-target pharmaceuticals in synergy with existing therapies such as immunotherapy and dietary interventions could enhance therapeutic efficacy. Personalized metabolic analysis is indispensable for crafting tailored treatment protocols, ultimately providing more accurate medical solutions for patients. This review aims to deepen the understanding and improve the application of energy metabolism to drive innovative diagnostic and therapeutic strategies.

As unhealthy diets have proliferated, there has been an increasing trend in the prevalence of obesity along with socioeconomic progress. WWI, mainly representing weight-independent central obesity, is a more accurate indicator of obesity than BMI and WC. Klotho is known to be one of the root causes of several age-related illnesses. There has never been any prior evidence associating WWI and serum α-Klotho levels.

The current cross-sectional investigation used data from the National Health and Nutrition Examination Survey (NHANES) 2013-2016. The calculation of each participant's WWI involved dividing their waist circumference in centimeters by the square root of their weight in kilograms. Using multivariable linear regression models, the association between serum Klotho concentrations and WWI was analyzed. Smoothed curve fitting was utilized to investigate the nonlinear connection. In addition, interaction tests and other subgroup analyses were carried out.

With an average age of 57.57 ± 10.81 years, 13,172 participants were enrolled in this study, of whom 51.45 % were female. After full adjustment, each unit increase in WWI was significantly associated with a decrease in Klotho by 23.18 ng/ml [β(95%CI) = -23.18 (-31.34, -15.02)]. Moreover, we uncovered that WWI had a stronger negative correlation with Klotho than other obesity markers, such as WC, body mass index (BMI), and a body shape index (ABSI).

To sum up, weight-adjusted-waist index levels were negatively associated with serum Klotho protein concentration and showed a stronger correlation than other obesity markers. Our findings indicated that WWI may be a predictor of reduced Klotho levels, and that controlling obesity in accordance with WWI may help lower the Klotho levels.

Cisplatin (Cisp) is a potent cancer drug, but its use is limited by acute kidney injury (AKI). Autophagy, a process that removes damaged proteins and maintains cellular homeostasis, has been shown to alleviate Cisp-induced AKI. The balance between autophagy and apoptosis is crucial to kidney protection. Treatment with Berberine, known for its antioxidant and anti-inflammatory effects in nephrotoxicity models, was studied for its potential to enhance autophagy in Cisp-induced AKI. Treatment with Berberine (Berb) upregulated Klotho gene expression, enhancing autophagy as indicated by elevated protein levels of pS486-AMPK, pS638-ULK1, and Beclin-1, accompanied by a decrease in pS248-mTOR protein expression. Also, Berb mitigated oxidative stress by reducing elevated MDA levels and boosting SOD activity, which in turn suppressed inflammation by down-regulating HMGB1 and RAGE gene expression, as well as reducing pS536-NF-κB and IL-6 protein contents. Additionally, Berb reduced apoptosis by increasing Bcl-2 and decreasing Bax. This coordinated action preserved kidney function, evidenced by reductions in early injury markers (cystatin C, KIM-1, NGAL) and late markers (creatinine, BUN), along with attenuation of histopathological alterations. The use 3-MA, autophagy inhibitor, nullified these protective effects, highlighting Berb's role in promoting autophagy, reducing oxidative stress, inflammation, and apoptosis, and preserving renal health in Cisp-induced AKI.

Klotho, initially identified as an anti-aging gene, has been shown to play significant roles in cancer biology. Alongside α-Klotho, the β-Klotho and γ-Klotho isoforms have also been studied; these studies showed that Klotho functions as a potential tumor suppressor in many different cancers by inhibiting cancer cell proliferation, inducing apoptosis and modulating critical signaling pathways such as the Wnt/β-catenin and PI3K/Akt pathways. In cancers such as breast cancer, colorectal cancer, hepatocellular carcinoma, ovarian cancer, and renal cell carcinoma, reduced Klotho expression often correlates with a poor prognosis. In addition, Klotho's role in enhancing chemotherapy sensitivity and its epigenetic regulation further underscores its potential as a target for cancer treatments. This review details Klotho's multifaceted contributions to cancer suppression and its potential as a therapeutic target, enhancing the understanding of its significance in cancer treatment and prognoses.

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.

Microalbuminuria is the earliest clinical abnormality in diabetic kidney disease. High glucose (HG) concentrations are associated with the induction of oxidative stress in podocytes, leading to disruption of the glomerular filtration barrier. Our recent study revealed a significant decrease in the membrane-bound fraction of Klotho in podocytes that were cultured under HG conditions. Given that disintegrin and metalloproteinase 17 (ADAM17) is responsible for the shedding of Klotho from the cell membrane, the present study investigated the impact of HG on the interplay between ADAM17 and Klotho in human podocytes. We demonstrated that ADAM17 protein levels significantly increased in urine, renal tissue, and glomeruli from diabetic rats, with a concomitant increase in glomerular albumin permeability. High glucose increased ADAM17 extracellular activity, NADPH oxidase activity, and albumin permeability in podocytes. These effects were reversed after treatment with ADAM17 inhibitor, in cells with downregulated ADAM17 expression, or after the addition of Klotho. Additionally, elevations of extracellular ADAM17 activity were observed in podocytes with the downregulation of Klotho expression. Our data indicate a novel mechanism whereby hyperglycemia deteriorates podocyte function via ADAM17 activation. We also demonstrated the ability of Klotho to protect podocyte function under hyperglycemic conditions in an ADAM17-dependent manner.

α-Klotho (KLA) is a type-1 membranous protein that can associate with fibroblast growth factor receptor (FGFR) to form co-receptor for FGF23. The ectodomain of unassociated KLA is shed as soluble KLA (sKLA) to exert FGFR/FGF23-independent pleiotropic functions. The previously determined X-ray crystal structure of the extracellular region of sKLA in complex with FGF23 and FGFR1c suggests that sKLA functions solely as an on-demand coreceptor for FGF23. To understand the FGFR/FGF23-independent pleiotropic functions of sKLA, we investigated biophysical properties and structure of apo-sKLA. Single particle cryogenic electron microscopy (cryo-EM) revealed a 3.3 Å resolution structure of apo-sKLA that overlays well with its counterpart in the ternary complex with several distinct features. Compared to the ternary complex, the KL2 domain of apo-sKLA is more flexible. Three-dimensional variability analysis revealed that apo-sKLA adopts conformations with different KL1-KL2 interdomain bending and rotational angles. Mass photometry revealed that sKLA can form a stable structure with FGFR and/or FGF23 as well as sKLA dimer in solution. Cryo-EM supported the dimeric structure of sKLA. Recent studies revealed that FGF23 contains two KLA-binding sites. Our computational studies revealed that each site binds separate KLA in the dimer. The potential multiple forms and shapes of sKLA support its role as FGFR-independent hormone with pleiotropic functions. The ability of FGF23 to engage two KLA's simultaneously raises a potential new mechanism of action for FGF23-mediated signaling by the membranous klotho.

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.

This is the initial investigation assessing the association between caffeine consumption through diet and circulating Klotho concentrations, with Klotho being recognized as a key biomarker of healthspan and aging.

This cross-sectional analysis utilized data from 11,169 adults who participated in the National Health and Nutrition Examination Survey (NHANES). Caffeine consumption was evaluated using 24-h dietary recall interviews by trained professionals, and serum Klotho concentrations were measured via an enzyme-linked immunosorbent assay (ELISA). Generalized linear models and threshold effect analysis were employed to examine the relationship between caffeine intake and serum Klotho concentrations. Interaction tests and subgroup analyses were conducted to identify potential effect modifiers.

After controlling for covariates, a negative correlation was observed between dietary caffeine consumption and serum Klotho concentrations, with each additional 100 mg of dietary caffeine consumption, Klotho decreased by 3.40 pg./mL (95% confidence interval [CI]: -5.73, -1.07). Participants in the fourth quartile of dietary caffeine consumption showed a 23.00 pg./mL reduction in serum Klotho concentrations (95% CI: -39.41, -6.58) compared to individuals in the first quartile. Threshold effect analysis revealed a threshold point corresponding to natural log-transformed caffeine value >3.74 (equivalent to ~41 mg/day), above which Klotho levels demonstrated a more pronounced decline. Subgroup analyses indicated that this association was more significant in participants with sedentary activity >480 min and without hypertension.

Our study reveals a significant, dose-dependent negative association linking caffeine intake with serum Klotho concentrations in the United States adults aged 40-79 years, with potential thresholds beyond which the effects become more pronounced. Additional studies are required to verify these results and investigate the underlying biological processes involved.

Anticancer chemotherapy (ACT) remains a cornerstone in cancer treatment, despite significant advances in pharmacology over recent decades. However, its associated side effect toxicity continues to pose a major concern for both oncology clinicians and patients, significantly impacting treatment protocols and patient quality of life. Current clinical strategies to mitigate ACT-induced toxicity have proven largely unsatisfactory, leaving a critical unmet need to block toxicity mechanisms without diminishing ACT's therapeutic efficacy. This review aims to document the molecular mechanisms underlying ACT toxicity and highlight research efforts exploring the protective effects of trace elements (TEs) and their nanoparticles (NPs) against these mechanisms. Our literature review reveals that the primary driver of ACT toxicity is redox imbalance, which triggers oxidative inflammation, apoptosis, endoplasmic reticulum stress, mitochondrial dysfunction, autophagy, and dysregulation of signaling pathways such as PI3K/mTOR/Akt. Studies suggest that TEs, including zinc, selenium, boron, manganese, and molybdenum, and their NPs, can potentially counteract ACT-induced toxicity by inhibiting oxidative stress-mediated pathways, including NF-κB/TLR4/MAPK/NLRP3, STAT-3/NLRP3, Bcl-2/Bid/p53/caspases, and LC3/Beclin-1/CHOP/ATG6, while also upregulating protective signaling pathways like Sirt1/PPAR-γ/PGC-1α/FOXO-3 and Nrf2/HO-1/ARE. However, evidence regarding the roles of lncRNA and the Wnt/β-catenin pathway in ACT toxicity remains inconsistent, and the impact of TEs and NPs on ACT efficacy is not fully understood. Further research is needed to confirm the protective effects of TEs and their NPs against ACT toxicity in cancer patients. In summary, TEs and their NPs present a promising avenue as adjuvant agents for preventing non-target organ toxicity induced by ACT.

Although previous studies demonstrated that the ancestral lifestyle can enhance the metabolic health of offspring exposed to an obesogenic diet, the specific connections between these positive effects in redox state and telomere length are unknown. We investigated the impact of paternal resistance training (RT) on stress-responsive signaling and the pathways involved in telomere homeostasis in skeletal muscle. This investigation encompassed both the fathers and first-generation litter exposed to a long-term standard diet (24 weeks) and high fat diet (HFD). Wistar rats were randomized into sedentary or trained fathers (8 weeks of resistance training). The offspring were obtained by mating with sedentary females. Upon weaning, male offspring were divided into four groups: offspring of sedentary or trained fathers exposed to either a control diet or HFD. The gastrocnemius was prepared for reverse transcription-quantitative polymerase chain reaction, immunoblotting, ELISA, and electron paramagnetic resonance spectroscopy. RT upregulated shelterin mRNA levels and antioxidant protein, preserving muscle telomere in fathers. Conversely, HFD induced a disturbance in the redox balance, which may have contributed to the offspring telomere shortening from sedentary fathers. Preconceptional paternal RT downregulates Kelch-like ECH-associated protein 1 (Keap1) mRNA levels in the skeletal muscle of progeny exposed to HFD, driving an increase in Glutathione reductase mRNA levels, Sod1 and Catalase protein levels to mitigate ROS production. Also, paternal exercise upregulates α-Klotho protein levels, mediating antioxidative responses without altering shelterin mRNA levels and telomere length. We provide the first in-depth analysis that the offspring's redox state seems to be directly associated with the beneficial effects of paternal exercise.

Contrast-induced acute kidney injury (CI-AKI) is one of the main causes of hospital-acquired renal failure, and still lacks of effective treatments. Previously, we demonstrated that αKlotho, which is an anti-aging protein that highly expresses in the kidney, has therapeutic activity in CI-AKI through promoting autophagy. However, the specific mechanism underlying αKlotho-mediated autophagy remains unclear. The RNA sequencing analysis of renal cortex revealed that the differentially expressed genes related to autophagy between αKlotho-treated CI-AKI mice and vehicle-treated CI-AKI mice were found to be associated with mitophagy and apoptosis. In the kidney of CI-AKI mice and HK-2 cells exposed to Iohexol, we revealed that αKlotho promoted mitophagy and decreased cell apoptosis. Mechanistically, αKlotho attenuated mitochondria damage, decreased mitochondrial ROS by upregulating BNIP3-mediated mitophagy. BNIP3 deletion abolished the beneficial effects of αKlotho both in vivo and in vitro. Moreover, we further demonstrated that αKlotho upregulated FoxO3 nuclear expression in Iohexol-treated HK-2 cells. Knockdown of FOXO3 gene inhibited αKlotho-promoted BNIP3-mediated mitophagy and subsequently increased the oxidative injury and cell apoptosis. Taken together, our results indicated a critical role of αKlotho in alleviating CI-AKI via mitophagy promotion involving the FoxO3-BNIP3 pathway.

The prevalence of sleep disorders has been reported from 1.6% to 56.0%, worldwide. Sleep deprivation causes cardiovascular diseases (CVDs) including atherosclerosis, vascular aging, hypertension, heart dysfunction, reduced heart rate variability, and cardiac arrhythmia. Reduced tissue oxygen causes various CVDs by activating pro-inflammatory factors and increasing oxidative stress. Sleep disorders are more important and prevalent in older people and cause more severe cardiovascular complications. On the other hand, the reduction of Klotho level, an age-dependent protein whose expression decreases with age, is associated with age-related diseases. Sirtuins, class III histone deacetylases, also are among the essential factors in postponing cellular aging and increasing the lifespan of organisms, and they do this by regulating different pathways in the cell. Sirtuins and Klotho play an important role in the pathophysiology of CVDS and both have anti-oxidative stress and anti-inflammatory activity. Studies have shown that the levels of Klotho and sirtuins are altered in sleep disorders. In this article, alterations of Klotho and sirtuins in sleep disorders and in the development of sleep-related CVDs were reviewed and the possible signaling pathways were discussed. The inclusion criteria were studies with keywords of different types of sleep disorders and CVDs, klotho, SIRT1-7, and sirtuins in PubMed, Scopus, Embase، Science Direct، Web of Sciences and Google Scholar by the end of 2023. The studies revealed there is a bidirectional relationship between sleep disorders and the serum and tissue levels of Klotho and sirtuins and sleep related-CVDs.

Renal αKlotho along with fibroblast growth factor 23 regulates phosphate and vitamin D metabolism. Its cleavage yields soluble Klotho controlling intracellular processes. αKlotho has anti-inflammatory and antioxidant effects and is nephro- and cardioprotective. AMP-dependent kinase (AMPK) is a nephro- and cardioprotective energy sensor. Given that both αKlotho and AMPK have beneficial effects in similar organs, we studied whether AMPK regulates αKlotho gene expression in Madin-Darby canine kidney, normal rat kidney 52E, and human kidney 2 cells. Using quantitative real-time PCR and western blotting, we measured αKlotho expression upon pharmacological manipulation or siRNA-mediated knockdown of AMPKα. AMPK activator 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) enhanced αKlotho expression, an effect reduced in the presence of AMPK inhibitor compound C or siRNA targeting AMPK catalytic α-subunits (α1 and α2). Similarly, AMPK activators metformin and phenformin upregulated αKlotho transcripts. Taken together, our results suggest that AMPK is a powerful inducer of αKlotho and could thereby contribute to the development of future therapeutic interventions.

α-Klotho has been linked to insulin resistance (IR) in basic research. However, experimental evidence is inconsistent, and there is a lack of data from human research. This study seeks to elucidate the association of α-Klotho with IR in a nationwide, multiracial population.

A total of 5289 participants aged 40-79 years were included in the National Health and Nutrition Examination Survey (NHANES) spanning 2007-2016. Serum α-Klotho was measured using enzyme-linked immunosorbent assays (ELISA), and IR was evaluated by the homeostatic model assessment of insulin resistance (HOMA-IR). Weighted multivariate logistic and linear regression analysis, subgroup analysis stratified by demographic characteristics, medical condition or obesity status, and sensitivity analysis using propensity score matching (PSM) were performed. Restricted cubic splines (RCS) were performed to explore the nonlinear relationship.

In the fully adjusted logistic regression model, a significant positive association was observed between log-transformed α-Klotho and IR (OR = 3.63, 95% CI: 1.56, 8.45), particularly in males or nonobese individuals (Pinteraction < 0.05). In the linear regression model, log10(α-Klotho) was associated with fasting blood glucose (FBG, β = 1.25, 95% CI: 0.74, 1.76) and glycosylated hemoglobin (HbA1c, β = 0.49, 95% CI: 0.20, 0.77). RCS revealed an inverse L-shaped dose-response relationship of α-Klotho with FBG and HbA1c (Pnonlinear <0.05). Beyond the inflection point of log10(α-Klotho) at 2.79, β coefficients sharply rose for these glycaemic control indicators.

The study provides clinical evidence supporting a positive association between α-Klotho and IR. Moreover, the inverse L-shaped relationship suggests that α-Klotho should reach a certain level to predict glycaemic changes effectively.

The triglyceride-glucose (TyG) index is recognized as a robust indicator for evaluating insulin resistance (IR). Despite the well-documented anti-aging biological functions of Klotho protein, its correlation with the TyG index remains unexplored.

A cross-sectional analysis was conducted involving participants from the National Health and Nutrition Examination Surveys (NHANES) 2007-2016. The TyG index was computed using laboratory data, while serum Klotho concentrations was determined using ELISA kit. After adjusting potential confounding variables, multivariate regression models were employed to evaluate the association between the TyG index and Klotho protein levels among middle-aged and elderly females and males separately. Additionally, smooth curve fitting and segmented regression model were applied to investigate potential threshold effects and identify the inflection point.

A total of 6,573 adults qualified for inclusion, comprising 3,147 (47.88%) males and 3,426 (52.12%) females. Multivariate regression analysis revealed that females with a higher TyG index exhibited significantly lower serum Klotho concentrations (β=-83.41, 95% CI: -124.23 to -42.60, P < 0.0001). This association was not statistically significant in males (β = 15.40, 95% CI: -19.16 to 49.95, P = 0.3827). Subgroup analyses revealed a significant interaction effect by diabetes status in females (P-interaction = 0.0121), where non-diabetic females showed a stronger negative association between TyG index and serum Klotho levels compared to diabetic females. In the female group, when TyG index was divided into quartiles, individuals in the highest quartile of TyG index exhibited reduced levels of Klotho protein (Q4: -88.77 pg/ml) compared to those in the lowest quartile (Q1) after full adjustment (P = 0.0041). Segmented regression analysis indicated a turning point value of 9.4 in females. Notably, a 1-unit increase in TyG index was significantly associated with a decrease in Klotho levels by -111.43 pg/ml (95% CI: -157.34 to -65.52, P < 0.0001) when TyG index was below 9.4, while above this threshold, the association was not significant (Log likelihood ratio test: 0.009).

The findings highlight a non-linear correlation between the TyG index and serum Klotho concentrations among females, indicative of a saturation effect. This relationship was particularly pronounced in non-diabetic women. In contrast, no statistically significant association was observed in male participants.

Klotho deficiency may affect clinical outcomes in chronic kidney disease (CKD) through fibroblast growth factor-23 (FGF23)-dependent and -independent pathways. However, the association between circulating Klotho and clinical outcomes in CKD remains unresolved and was the focus of this study.

Prospective observational study.

1,088 participants in the Chronic Renal Insufficiency Cohort (CRIC) Study with an estimated glomerular filtration rate (eGFR) of 20-70mL/min/1.73m2.

Plasma Klotho level at the year-1 study visit.

5-year risks of all-cause mortality, heart failure hospitalization, atherosclerotic cardiovascular events, and a composite kidney end point that comprised a sustained 50% decrease in eGFR, dialysis, kidney transplant, or eGFR<15mL/min/1.73m2.

We divided Klotho into 6 groups to account for its nonnormal distribution. We used Cox proportional hazards regression and subdistribution hazards models to compare survival and clinical outcomes, respectively, between Klotho groups. We sequentially adjusted for demographic characteristics, kidney function, cardiovascular risk factors, sample age, and FGF23.

Mean eGFR was 42mL/min/1.73m2, and median Klotho concentration was 0.31ng/mL (IQR, 0.10-3.27ng/mL). When compared with the lowest Klotho group, survival (HR, 0.77; 95% CI, 0.32-1.89), heart failure hospitalization (HR, 1.10; 95% CI, 0.38-3.17), atherosclerotic cardiovascular events (HR, 1.19; 95% CI, 0.57-2.52), and CKD progression (HR, 1.05; 95% CI, 0.58-1.91) did not differ in the high Klotho group. In contrast, FGF23 was significantly associated with mortality and heart failure hospitalization independent of Klotho levels.

Despite adjustments, we cannot exclude the potential influence of residual confounding or sample storage on the results. A single measurement of plasma Klotho concentration may not capture Klotho patterns over time.

In a large, diverse, well-characterized CKD cohort, Klotho was not associated with clinical outcomes, and Klotho deficiency did not confound the association of FGF23 with mortality or heart failure hospitalization.

Klotho is a protein that is vital to mineral metabolism and aging and may protect against cardiovascular disease. Klotho levels decrease in chronic kidney disease (CKD), but the association between Klotho and clinical outcomes in CKD remains uncertain. In a prospective cohort study of more than 1,000 people with CKD, circulating Klotho levels were not associated with kidney disease progression, cardiovascular outcomes, or mortality. These results suggest that the decrease in circulating Klotho levels in CKD does not play a prominent role in the development of poor clinical outcomes.

Chronic kidney disease (CKD) represents a significant and escalating global health challenge, with morbidity and mortality rates rising steadily. Evidence increasingly implicates perirenal adipose tissue (PRAT) deposition as a contributing factor in the pathogenesis of CKD. This review explores how PRAT deposition may exert deleterious effects on renal structure and function. The anatomical proximity of PRAT to the kidneys not only potentially causes mechanical compression but also leads to the dysregulated secretion of adipokines and inflammatory mediators, such as adiponectin, leptin, visfatin, tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and exosomes. Additionally, PRAT deposition may contribute to renal lipotoxicity through elevated levels of free fatty acids (FFA), triglycerides (TAG), diacylglycerol (DAG), and ceramides (Cer). PRAT deposition is also linked to the hyperactivation of the renin-angiotensin-aldosterone system (RAAS), which further exacerbates CKD progression. Recognizing PRAT deposition as an independent risk factor for CKD underscores the potential of targeting PRAT as a novel strategy for the prevention and management of CKD. This review further discusses interventions that could include measuring PRAT thickness to establish a baseline, managing metabolic risk factors that promote its deposition, and inhibiting key PRAT-induced signaling pathways.

Premature vascular aging and endothelial cell senescence are major risk factors for cardiovascular diseases and atherothrombotic disturbances, which are main complications of both acute and long COVID-19. The S protein of SARS-CoV2, which acts as the receptor binding protein for the viral infection, is able to induce endothelial cells inflammation and it has been found as an isolated element in the circulation and in human tissues reservoirs months after infection. Here, we investigated whether the S protein is able to directly induce endothelial cell senescence and deciphered some of the mechanisms involved. In primary cultures of human umbilical vein endothelial cells (HUVEC), SARS-CoV-2 S protein enhanced in a concentration-dependent manner the cellular content of senescence and DNA damage response markers (senescence-associated-β galactosidase, γH2AX), as well as growth-arrest effectors (p53, p21, p16). In parallel, the S protein reduced the availability of cytoprotective proteins, such as the anti-aging protein klotho, Nrf2 or heme oxygenase-1, and caused functional harm by impairing ex vivo endothelial-dependent vasorelaxation in murine microvessels. These effects were prevented by the pharmacological inhibition of the NLRP3 inflammasome with MCC950. Furthermore, the supplementation with either recombinant klotho or angiotensin-(1-7), equally protected against the pro-senescence, pro-inflammatory and pro-oxidant action of the S protein. Globally, this study proposes novel mechanisms of disease in the context of COVID-19 and its vascular sequelae and provides pharmacological clues in order to prevent such complications.

As individuals age, the prevalence of osteoarthritis tends to increase gradually. α-Klotho is a hormone renowned for its anti-aging properties. However, the precise role of serum α-Klotho in osteoarthritis is still not fully comprehended.

We conducted a cross-sectional study utilizing data from the National Health and Nutrition Examination Survey (NHANES) spanning from 2007 to 2016. Serum α-Klotho levels were measured using an enzyme-linked immunosorbent assay (ELISA). Osteoarthritis was assessed through self-reported questionnaires. Through univariate and multivariate logistic regression analyses, smooth curve fitting, threshold effect analysis, and subgroup analyses, we delved into the potential association between them.

The study encompassed a cohort of 10,265 participants. In fully adjusted models of multivariate logistic regression analysis, we identified a negative correlation between serum ln α-Klotho and OA (OR = 0.77, 95% CI: 0.65-0.91, p = 0.003). When stratifying serum α-Klotho levels into tertiles, individuals in the highest tertile exhibited a 26% reduced risk of OA compared to those in the lowest tertile (OR = 0.84, 95% CI: 0.73-0.97, p = 0.014). Subsequent analyses indicated a linearly negative association. In subgroup analyses, we explored the relationship between serum ln α-Klotho and osteoarthritis across diverse populations, revealing the persistence of this association in the majority of subgroups.

Serum α-Klotho levels exhibit a significant negative linear correlation with the prevalence of osteoarthritis in middle-aged and elderly populations in the United States.

In critically ill patients, overweight and obesity are associated with acute respiratory distress syndrome and acute kidney injury (AKI). However, the effect of obesity on ischemia-reperfusion injury (IRI)-induced AKI is unknown. We hypothesized that obesity would aggravate renal IRI in mice. We fed mice a standard or high-fat diet for eight weeks. The mice were divided into four groups and submitted to sham surgery or IRI: obese, normal, normal + IRI, obese, and obese + IRI. All studies were performed 48 h after the procedures. Serum glucose, cholesterol, and creatinine clearance did not differ among the groups. Survival and urinary osmolality were lower in the obese + IRI group than in the normal + IRI group, whereas urinary neutrophil gelatinase-associated lipocalin levels, tubular injury scores, and caspase 3 expression were higher. Proliferating cell nuclear antigen expression was highest in the obese + IRI group, as were the levels of oxidative stress (urinary levels of thiobarbituric acid-reactive substances and renal heme oxygenase-1 protein expression), whereas renal Klotho protein expression was lowest in that group. Expression of glutathione peroxidase 4 and peroxiredoxin 6, proteins that induce lipid peroxidation, a hallmark of ferroptosis, was lower in the obese + IRI group. Notably, among the mice not induced to AKI, macrophage infiltration was greater in the obese group. In conclusion, greater oxidative stress and ferroptosis might aggravate IRI in obese individuals, and Klotho could be a therapeutic target in those with AKI.

Myotendinous junction (MTJ) injuries are prevalent in clinical practice, yet the treatment approaches are limited to surgical suturing and conservative therapy, exhibiting a high recurrence rate. Current research on MTJ tissue engineering is scarce and lacks in vivo evaluation of repair efficacy. Here, we developed a three-dimensional-printed bioactive fiber-reinforced hydrogel containing mesenchymal stem cells (MSCs) and Klotho for structural and functional MTJ regeneration. In a rat MTJ defect model, the bioactive fiber-reinforced hydrogel promoted the structural restoration of muscle, tendon, and muscle-tendon interface and enhanced the functional recovery of injured MTJ. In vivo proteomics and in vitro cell cultures elucidated the regenerative mechanisms of the bioactive fiber-reinforced hydrogel by modulating oxidative stress and inflammation, thus engineering an optimized microenvironment to support the survival and differentiation of transplanted MSCs and maintain the functional phenotype of resident cells within MTJ tissues, including tendon/muscle cells and macrophages. This strategy provides a promising treatment for MTJ injuries.

Being involved in various physiological and pathophysiological mechanisms (ageing, kidney damage, cardiovascular diseases, etc.), Klotho is a parameter of increasing interest. Studies in veterinary medicine are still rare, but it is exciting to find out whether the findings obtained can be transferred to animals. The aim of this study was therefore to investigate Klotho in cats. This study addressed α-Klotho concentrations in the serum of two groups of cats: one diseased group affected by hypertrophic cardiomyopathy (n = 27) and one healthy control group (n = 35). α-Klotho concentrations in serum were measured using an ELISA. The results were evaluated in the context of several echocardiographic measurement parameters in the diseased group. No significant difference between α-Klotho concentrations in the two groups was found. A slight negative correlation was found between α-Klotho concentrations and the relation of left atrium/aorta (La/Ao) in the diseased group. Gaining initial information on α-Klotho in cats, it was not possible to draw definite conclusions concerning cardiomyopathies in this species. The assessment of Klotho should be considered in terms of its broad implications in disease processes, but it is also recommended to focus on specific disease features. Both approaches might be promising as possible applications of Klotho in veterinary medicine.

Compelling evidence suggests that calcium/phosphorus homeostasis-related parameters may be linked to diabetes mellitus and cardiovascular events. However, few studies have investigated the association of fibroblast growth factor 23 (FGF23), α-klotho and FGF23/α-klotho ratio with atherosclerosis in patients with type 2 diabetes mellitus (T2DM).

This study was designed to evaluate whether FGF23, α-klotho and FGF23/α-klotho ratio are associated with T2DM and further to explore the relationships between these three factors and atherosclerosis in Chinese patients with T2DM.

Serum FGF23 and α-klotho levels were measured via an enzyme-linked immunosorbent assay (ELISA) kit, and the carotid intima-media thickness (CIMT) was assessed via high-resolution color Doppler ultrasonography. The associations of serum FGF23, α-klotho and FGF23/α-klotho ratio with atherosclerosis in T2DM patients were evaluated using multivariable logistic regression models.

This cross-sectional study involved 403 subjects (207 with T2DM and 196 without T2DM), 41.7% of the patients had atherosclerosis, and 67.2% of the carotid intima were thickened to a thickness greater than 0.9 mm. Compared with those in the lowest tertile, higher tertiles of FGF23 levels and FGF23/α-klotho ratio were positively associated with T2DM after adjusting for covariates, and serum α-klotho concentration was inversely correlated with T2DM (all P values < 0.01). Moreover, elevated serum FGF23 levels and FGF23/α-klotho ratio were positively associated with CIMT and carotid atherosclerosis in T2DM patients (all P values < 0.01). Further spline analysis similarly revealed linear dose‒response relationship (all P values < 0.01). And there was still significant differences in CIMT and carotid atherosclerosis between the highest group of α-klotho and the reference group in T2DM patients (P values = 0.05).

T2DM was positively linearly related to serum FGF23 concentration and FGF23/α-klotho ratio, and negatively correlated with serum α-klotho concentration. Furthermore, both FGF23 and FGF23/α-klotho ratio were positively correlated with CIMT and atherosclerosis in T2DM patients, while α-klotho was inversely correlated with both CIMT and atherosclerosis, although the associations were not completely significant. Prospective exploration and potential mechanisms underlying these associations remain to be further elucidated.