Search Results (47)

According to the World Health Organization (WHO), a healthy lifestyle is defined as a way of living that lowers the risk of becoming seriously ill or dying prematurely. Physical activity, as a well-known contributor to overall health, plays a vital role in supporting such a lifestyle. Exercise induces complex molecular responses that mediate both acute metabolic stress and long-term physiological adaptations. FGF21 (fibroblast growth factor 21) and GDF15 (growth differentiation factor 15) are recognized as metabolic stress markers, while their receptors play critical roles in cellular signaling. However, the differential gene expression patterns of these molecules in trained and untrained individuals following exhaustive exercise remain poorly understood. This study aimed to examine the transcriptional and protein-level responses in trained and untrained individuals performed a treadmill maximal exercise test to voluntary exhaustion. Blood samples were collected at six time points (pre-exercise, immediately post-exercise, and 0.5 h, 6 h, 24 h, and 48 h post-exercise). Gene expression of FGF21, GDF15, FGFR1 (fibroblast growth factor receptors), FGFR3, FGFR4, KLB (β-klotho), and GFRAL (glial cell line-derived neurotrophic factor receptor alpha-like) was analyzed using RT-qPCR, while plasma protein levels of FGF21 and GDF15 were quantified via ELISA. The results obtained were statistically analyzed by using Shapiro–Wilk, Mann–Whitney U, and Wilcoxon tests in Statistica 13 software. Untrained individuals demonstrated significant post-exercise upregulation of FGFR3, FGFR4, KLB, and GFRAL. FGF21 and GDF15 protein levels were consistently lower in trained individuals (p < 0.01), with no significant correlations between gene and protein expression. Trained individuals showed more stable expression of genes, while untrained individuals exhibited transient upregulation of genes after exercise. 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

Klotho, an anti-aging protein, has been extensively studied in systemic conditions such as chronic kidney disease and cardiovascular disorders. In recent years, its pivotal protective role and clinical significance in various oral and maxillofacial diseases have been increasingly demonstrated. It has been demonstrated that Klotho regulates oxidative stress, apoptosis, inflammation, and fibrosis via multiple molecular signaling pathways, including Nrf2, NF-κB, PI3K/Akt/FoxO1, insulin/IGF-1, FGF/FGFR, and Wnt/β-catenin. Consequently, these regulatory effects have been observed in conditions such as periodontitis, oral squamous cell carcinoma, malignant salivary gland tumors, oral submucous fibrosis, etc. Moreover, the decreased expression or dysfunctional activity of Klotho is frequently associated with the onset and progression of these diseases. This study provides a comprehensive review of the underlying mechanisms and recent advances in Klotho research within the realm of oral and maxillofacial diseases, offering novel perspectives for future basic and clinical investigations. Full article

The Klotho gene is recognized for its anti-aging properties. Its downregulation leads to aging-like phenotypes, whereas overexpression can extend lifespan. Klotho protein exists in three forms: α-klotho, β-klotho and γ-klotho. The α-klotho has two isoforms: a membrane-bound form, primarily in the kidney and brain, and a secreted klotho protein present in blood, urine, and cerebrospinal fluid. Klotho functions as a co-receptor for fibroblast growth factor-23 (FGF23), regulating phosphate metabolism. The membrane-bound form controls various ion channels and receptors, while the secreted form regulates endocrine FGFs, including FGF19 and FGF21. The interaction between β-klotho and FGF21 in muscle is critical in the development of sarcopenic obesity. This systematic review, registered in PROSPERO and conducted following PRISMA guidelines, evaluates klotho levels in individuals with obesity or sarcopenic obesity. The study includes overweight, obese, and sarcopenic obese adults compared to those with a normal body mass index. After reviewing 713 articles, 20 studies were selected, including observational, cross-sectional, cohort studies, and clinical trials. Significant associations between klotho levels and obesity, metabolic syndrome (MS), and cardiovascular risk were observed. Exercise and dietary interventions positively influenced klotho levels, which were linked to improved muscle strength and slower decline. Klotho is a potential biomarker for obesity, MS, and sarcopenic obesity. Further research is needed to explore its mechanisms and therapeutic potential. Full article

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. 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: This study sought to assess the effect of statin therapy on myocardial inflammation in a White New Zealand rabbit model of atherogenesis. Methods: The mRNA expression levels of pro-inflammatory, pluripotency, and aging-related markers were quantified following a controlled feeding protocol and statin treatments. Results: Following high-cholesterol diet induction, we observed significant upregulation in the myocardial mRNA levels of MYD88, NF-κB, chemokines (CCL4, CCL20, and CCR2), IFN-γ, interleukins (IL-1β, IL-2, IL-4, IL-8, IL-10, and IL-18), and novel markers (klotho, KFL4, NANOG, and HIF1α). In contrast, HOXA5 expression was diminished following a hyperlipidemic diet. Both statin treatments significantly influenced the markers studied. Nevertheless, rosuvastatin administration resulted in a greater reduction in MYD88, NF-kB, chemokines (CCL4, CCL20, and CCR2), and interleukins IL-1β, IL-8, KLF4, NANOG, and HIF1α than fluvastatin. Fluvastatin, on the other hand, led to a stronger decrease in IL-4. Downregulation of IL-2 and IL-18 and upregulation of IFNβ and HOXA5 were comparable between the two statins. Notably, rosuvastatin had a stronger effect on the upregulation of klotho and IL-10. Conclusion: Overall, statin therapy significantly attenuated inflammatory, pluripotency, and klotho expression in myocardial tissue under atherogenic conditions. Our findings also highlight the differential efficacy of rosuvastatin over fluvastatin in curtailing proatherogenic inflammation, which could have profound implications for the clinical management of cardiovascular disease. Full article

Type 2 diabetes mellitus (T2DM) is a critical health problem, with 700 million diagnoses expected worldwide by 2045. Uncontrolled high blood glucose levels can lead to serious complications, including diabetic cardiomyopathy (DCM). Diabetes induces cardiovascular aging and inflammation, increasing cardiomyopathy risk. DCM is characterized by structural and functional abnormalities in the heart. Growing evidence suggests that cellular senescence and macrophage-mediated inflammation participate in the pathogenesis and progression of DCM. Evidence indicates that growth differentiation factor-15 (GDF-15), a protein that belongs to the transforming growth factor-beta (TGF-β) superfamily, is associated with age-related diseases and exerts an anti-inflammatory role in various disease models. Although further evidence suggests that GDF-15 can preserve Klotho, a transmembrane antiaging protein, emerging research has elucidated the potential involvement of GDF-15 and Klotho in the interplay between macrophages-induced inflammation and cellular senescence in the context of DCM. This review explores the intricate relationship between senescence and macrophages in DCM while highlighting the possible contributions of GDF-15 and Klotho. Full article

D-galactose has been widely used as an inducer of cellular senescence and pathophysiological processes related to aging because it induces oxidative stress. On the other hand, the consumption of antioxidants such as curcumin can be an effective strategy to prevent phenotypes related to the enhanced production of reactive oxygen species (ROS), such as aging and senescence. This study aimed to evaluate the potential protective effect of curcumin on senescence and oxidative stress and endoplasmic reticulum stress induced by D-galactose treatment in Lilly Laboratories Culture-Porcine Kidney 1 (LLC-PK1) and human kidney 2 (HK-2) proximal tubule cell lines from pig and human, respectively. For senescence induction, cells were treated with 300 mM D-galactose for 120 h and, to evaluate the protective effect of the antioxidant, cells were treated with 5 µM curcumin for 24 h and subsequently treated with curcumin + D-galactose for 120 h. In LLC-PK1 cells, curcumin treatment decreased by 20% the number of cells positive for senescence-associated (SA)-β-D-galactosidase staining and by 25% the expression of 8-hydroxy-2′-deoxyguanosine (8-OHdG) and increased by 40% lamin B1 expression. In HK-2 cells, curcumin treatment increased by 60% the expression of proliferating cell nuclear antigen (PCNA, 50% Klotho levels, and 175% catalase activity. In both cell lines, this antioxidant decreased the production of ROS (20% decrease for LLC-PK1 and 10 to 20% for HK-2). These data suggest that curcumin treatment has a moderate protective effect on D-galactose-induced senescence in LLC-PK1 and HK-2 cells. Full article

Tissue engineering approaches aim to provide biocompatible scaffold supports that allow healing to progress often in healthy tissue. In diabetic foot ulcers (DFUs), hyperglycemia impedes ulcer regeneration, due to complications involving accumulations of cellular methylglyoxal (MG), a key component of oxidated stress and premature cellular aging which further limits repair. In this study, we aim to reduce MG using a collagen-chondroitin sulfate gene-activated scaffold (GAS) containing the glyoxalase-1 gene (GLO-1) to scavenge MG and anti-fibrotic β-klotho to restore stem cell activity in diabetic adipose-derived stem cells (dADSCs). dADSCs were cultured on dual GAS constructs for 21 days in high-glucose media in vitro. Our results show that dADSCs cultured on dual GAS significantly reduced MG accumulation (−84%; p < 0.05) compared to the gene-free controls. Similar reductions in profibrotic proteins α-smooth muscle actin (−65%) and fibronectin (−76%; p < 0.05) were identified in dual GAS groups. Similar findings were observed in the expression of pro-scarring structural proteins collagen I (−62%), collagen IV (−70%) and collagen VII (−86%). A non-significant decrease in the expression of basement membrane protein E-cadherin (−59%) was noted; however, the dual GAS showed a significant increase in the expression of laminin (+300%). We conclude that dual GAS-containing Glo-1 and β-klotho had a synergistic MG detoxification and anti-fibrotic role in dADSC’s. This may be beneficial to provide better wound healing in DFUs by controlling the diabetic environment and rejuvenating the diabetic stem cells towards improved wound healing. 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

High hepcidin is linked to low-grade inflammation and lower iron levels. The consequences of testosterone replacement therapy (TRT) on inflammation and the risk of cardiovascular disease (CVD) are undetermined. We investigate the effect of TRT on the inflammatory cardiovascular risk markers hepcidin-iron, fibroblast growth factor 23 (FGF23)-phosphate-klotho, and calprotectin pathways. Methods: A randomized, placebo-controlled, double-blinded study at an academic tertiary-care medical center. Interventions were testosterone gel (TRT, n = 20) or placebo gel (n = 19) for 24 weeks. We included 39 men (50–70 years) with type 2 diabetes (T2D) on metformin monotherapy with bioavailable testosterone levels <7.3 nmol/L. Body composition was assessed with DXA- and MRI-scans; the main study outcomes were serum hepcidin-iron, FGF23, phosphate, klotho, and calprotectin. Results: Hepcidin levels decreased during TRT (β = −9.5 ng/mL, p < 0.001), lean body mass (β = 1.9 kg, p = 0.001) increased, and total fat mass (β = −1.3 kg, p = 0.009) decreased compared to placebo. Delta hepcidin was not associated with changes in lean body mass or fat mass. Iron and the pathways of FGF23-phosphate-klotho and calprotectin were unchanged during TRT. Conclusions: During TRT, the reduction in hepcidin was not associated with circulating iron levels, lean body mass, or fat mass; these findings suggested a direct anti-inflammatory effect of TRT and no indirect effect mediated through these factors. Full article

The farnesoid X receptor (FXR)/βKlotho/fibroblast growth factors (FGFs) pathway is crucial for maintaining the intestinal barrier and preventing colorectal cancer (CRC). We used an FXR agonist, GW4064, and FXR-knockout (FXR-KO) mice to investigate the role of FXR/Klothos/FGFs pathways in lipopolysaccharide (LPS)-induced intestinal barrier dysfunction and colon carcinogenesis. The results showed that upregulation of FXR in enterocytes effectively ameliorated intestinal tight-junction markers (claudin1 and zonula occludens-1), inflammation, and bile acid levels, thereby protecting mice from intestinal barrier dysfunction and colon carcinogenesis. GW4064 treatment increased FXR, αKlotho, βKlotho, FGF19, FGF21, and FGF23 in wild-type mice exposed to LPS, while FXR-KO mice had decreased levels. FXR-KO mice exhibited elevated colon cancer markers (β-catenin, LGR5, CD44, CD34, and cyclin D1) under LPS, underscoring the pivotal role of FXR in inhibiting the development of colon tumorigenesis. The varying gut microbiota responses in FXR-KO mice versus wild-type mice post LPS exposure emphasize the pivotal role of FXR in preserving intestinal microbial health, involving Bacteroides thetaiotaomicron, Bacteroides acidifaciens, and Helicobacter hepaticus. Our study validates the effectiveness of GW4064 in alleviating LPS-induced disruptions to the intestinal barrier and colon carcinogenesis, emphasizing the importance of the FXR/αKlotho/βKlotho/FGFs pathway and the interplay between bile acids and gut microbiota. Full article

Mitochondrial degeneration in various neurodegenerative diseases, specifically in Alzheimer’s disease, involves excessive mitochondrial fission and reduced fusion, leading to cell damage. P110 is a seven-amino acid peptide that restores mitochondrial dynamics by acting as an inhibitor of mitochondrial fission. However, the role of P110 as a neuroprotective agent in AD remains unclear. Therefore, we performed cell culture studies to evaluate the neuroprotective effect of P110 on amyloid-β accumulation and mitochondrial functioning. Human SH-SY5Y neuronal cells were incubated with 1 µM and 10 µM of P110, and Real-Time PCR and Western blot analysis were done to quantify the expression of genes pertaining to AD and neuronal health. Exposure of SH-SY5Y cells to P110 significantly increased APP mRNA levels at 1 µM, while BACE1 mRNA levels were increased at both 1 µM and 10 µM. However, protein levels of both APP and BACE1 were significantly reduced at 10 µM of P110. Further, P110 treatment significantly increased ADAM10 and Klotho protein levels at 10 µM. In addition, P110 exposure significantly increased active mitochondria and reduced ROS in live SH-SY5Y cells at both 1 µM and 10 µM concentrations. Taken together, our results indicate that P110 might be useful in attenuating amyloid-β generation and improving neuronal health by maintaining mitochondrial function in neurons. Full article

Klotho proteins, αKlotho, βKlotho, and γKlotho, exert tumor-suppressive activities via the fibroblast growth factor receptors and multiple cell-signaling pathways. There is a growing interest in Klotho proteins as potential diagnostic and prognostic biomarkers for multiple diseases. However, recent advances regarding their roles and potential applications in cancer remain disperse and require an integrated analysis. The present review analyzed research articles published between 2012 and 2022 in the Cochrane and Scopus scientific databases to study the role of Klotho in cancer and their potential as tools for diagnosing specific cancer types, predicting tumor aggressiveness and prognosis. Twenty-six articles were selected, dealing with acute myeloid leukemia and with bladder, breast, colorectal, esophageal, gastric, hepatocellular, ovarian, pancreatic, prostatic, pulmonary, renal, and thyroid cancers. αKlotho was consistently associated with improved prognosis and may be useful in estimating patient survival. A single study reported the use of soluble αKlotho levels in blood serum as a tool to aid the diagnosis of esophageal cancer. γKlotho was associated with increased aggressiveness of bladder, breast, and prostate cancer, and βKlotho showed mixed results. Further clinical development of Klotho-based assays will require careful identification of specific tumor subtypes where Klotho proteins may be most valuable as diagnostic or prognostic tools. Full article