Klotho Gene Research Articles

Amyloid-β positivity is less prevalent in cognitively unimpaired KLOTHO KL-VS heterozygotes.

Klotho, encoded by the KLOTHO gene, is an anti-aging and neuroprotective protein. KLOTHO KL-VS heterozygosity (KL-VSHET) is hypothesized to be protective against the accumulation of Alzheimer's disease (AD) neuropathological hallmarks (amyloid-β (Aβ) and tau). We examine whether being positive for Aβ (A+) or tau (T+), or A/T joint status [positive for Aβ (A + T-), tau (A-T+), both (A + T+) or neither (A-T-)] vary by KL-VS and whether serum klotho protein levels vary based on A+, T+, or A/T status in a cohort enriched for AD risk. The sample consisted of 704 cognitively unimpaired, late middle-aged, and older adults; MeanAge(SD) = 64.9(8.3). Serum klotho was available for a sub-sample of 396 participants; MeanAge(SD) = 66.8(7.4). Covariate-adjusted logistic regression examined whether A + or T+, and multinomial regression examined whether A/T status, vary by KL-VS genotype. Covariate-adjusted linear regression examined whether serum klotho levels differ based on A+, T+, or A/T status. A+ prevalence was lower in KL-VSHET (p = 0.05), with no differences in T + prevalence (p = 0.52). KL-VSHET also had marginally lower odds of being A + T- (p = 0.07). Serum klotho levels did not differ based on A+, T+, or A/T status (all ps ≥ 0.40). KL-VSHET is associated with lower odds of being positive for Aβ, regardless of whether one is also positive for tau. Conversely, the likelihood of being tau positive did not differ based on KL-VS genotype. Our findings add to the growing KLOTHO literature and suggests the need for further research focused on understanding the mechanisms underlying KL-VS-related putative resilience to AD.

Induction of chronic asthma up regulated the transcription of senile factors in male rats

BackgroundThe main characteristic of asthma is chronic inflammation. We examined cellular senescence by histology and molecular assay in the lungs of a rat model of asthma. This model comprises sensitization by several intraperitoneal injections of ovalbumin with aluminium hydroxide, followed by aerosol challenges every other day.ResultsData showed that asthma induction caused histological changes including, hyperemia, interstitial pneumonia, fibrinogen clots, and accumulation of inflammatory cells in the pleura. There is an elevation of IL-1β and NF-kB proteins in the asthmatic group (P < 0.001) compared to the control group. The expression of ß-galactosidase increased (P < 0.01), while the expression of Klotho and Sox2 genes was decreased in the lung tissue of the asthmatic group (P < 0.01).ConclusionTaken together, these findings suggest that asthmatic conditions accelerated the cellular senescence in the lung tissue.

Pentoxifylline ameliorates subclinical atherosclerosis progression in patients with type 2 diabetes and chronic kidney disease: a randomized pilot trial

BackgroundDiabetic kidney disease (DKD) is associated with a higher risk of cardiovascular disease (CVD). Pentoxifylline (PTF), a nonselective phosphodiesterase inhibitor with anti-inflammatory, antiproliferative, and antifibrotic actions, has demonstrated renal benefits in both clinical trials and meta-analyses. The present work aimed to study the effects of PTF on the progression of subclinical atherosclerosis (SA) in a population of patients with diabetes and moderate to severe chronic kidney disease (CKD).MethodsIn this open-label, randomized controlled, prospective single-center pilot study the evolution of carotid intima-media thickness (CIMT) and ankle-brachial index (ABI) were determined in 102 patients with type 2 diabetes mellitus and CKD assigned to PTF, aspirin or control groups during 18 months. We also determined the variations in the levels of inflammatory markers and Klotho (KL), a protein involved in maintaining cardiovascular health, and their relationship with the progression of SA.ResultsPatients treated with PTF presented a better evolution of CIMT, increased KL mRNA levels in peripheral blood cells (PBCs) and reduced the inflammatory state. The progression of CIMT values was inversely related to variations in KL both in serum and mRNA expression levels in PBCs. Multiple regression analysis demonstrated that PTF treatment and variations in mRNA KL expression in PBCs, together with changes in HDL, were significant determinants for the progression of CIMT (adjusted R2 = 0.24, P < 0.001) independently of traditional risk factors. Moreover, both variables constituted protective factors against a worst progression of CIMT [OR: 0.103 (P = 0.001) and 0.001 (P = 0.005), respectively].ConclusionsPTF reduced SA progression assessed by CIMT variation, a beneficial effect related to KL gene expression in PBCs.Trial registrationThe study protocol code is PTF-AA-TR-2009 and the trial was registered on the European Union Drug Regulating Authorities Clinical Trials (EudraCT #2009–016595–77). The validation date was 2010-03-09.

A Heuristic Approach to Analysis of the Genetic Susceptibility Profile in Patients Affected by Airway Allergies.

Allergic respiratory diseases such as asthma might be considered multifactorial diseases, having a complex pathogenesis that involves environmental factors and the activation of a large set of immune response pathways and mechanisms. In addition, variations in genetic background seem to play a central role. The method developed for the analysis of the complexities, as association rule mining, nowadays may be applied to different research areas including genetic and biological complexities such as atopic airway diseases to identify complex genetic or biological markers and enlighten new diagnostic and therapeutic targets. A total of 308 allergic patients and 205 controls were typed for 13 single nucleotide polymorphisms (SNPs) of cytokine and receptors genes involved in type 1 and type 2 inflammatory response (IL-4 rs2243250 C/T, IL-4R rs1801275A/G, IL-6 rs1800795 G/C, IL-10 rs1800872 A/C and rs1800896 A/G, IL-10RB rs2834167A/G, IL-13 rs1800925 C/T, IL-18 rs187238G/C, IFNγ rs 24030561A/T and IFNγR2 rs2834213G/A), the rs2228137C/T of CD23 receptor gene and rs577912C/T and rs564481C/T of Klotho genes, using KASPar SNP genotyping method. Clinical and laboratory data of patients were analyzed by formal statistic tools and by a data-mining technique-market basket analysis-selecting a minimum threshold of 90% of rule confidence. Formal statistical analyses show that IL-6 rs1800795GG, IL-10RB rs2834167G positive genotypes, IL-13 rs1800925CC, CD23 rs2228137TT Klotho rs564481TT, might be risk factors for allergy. Applying the association rule methodology, we identify 10 genotype combination patterns associated with susceptibility to allergies. Together these data necessitate being confirmed in further studies, indicating that the heuristic approach might be a straightforward and useful tool to find predictive and diagnostic molecular patterns that might be also considered potential therapeutic targets in allergy.

Apolipoproteine and KLOTHO Gene Variants Do Not Affect the Penetrance of Fragile X-Associated Tremor/Ataxia Syndrome.

In this study, the potential role and interaction of the APOε and KLOTHO genes on the penetrance of fragile X-associated tremor/ataxia syndrome (FXTAS) and on the IQ trajectory were investigated. FXTAS was diagnosed based on molecular, clinical and radiological criteria. Males with the premutation (PM) over 50 years, 165 with and 34 without an FXTAS diagnosis, were included in this study and were compared based on their APO (ε2-ε3-ε4) and KLOTHO variant (KL-VS) genotypes. The effect of APOε4 on FXTAS stage and on diagnosis did not differ significantly by KL-VS genotype with interaction effect p = 0.662 and p = 0.91, respectively. In the FXTAS individuals with an APOε2 allele, a marginal significance was observed towards a larger decline in verbal IQ (VIQ) in individuals with an APOε4 allele compared to those without an APOε4 allele (p = 0.071). In conclusion, our findings suggest that the APOε4 and KL-VS genotypes alone or through their interaction effect do not appear to predispose to either FXTAS diagnosis or stage in male carriers of the PM allele. A further study is needed to establish the trend of IQ decline in the FXTAS individuals who carry APOε4 with APOε2 compared to those without APOε4.

KLOTHO KL-VS heterozygosity is associated with diminished age-related neuroinflammation, neurodegeneration, and synaptic dysfunction in older cognitively unimpaired adults.

We examined whether the aging suppressor KLOTHO gene's functionally advantageous KL-VS variant (KL-VS heterozygosity [KL-VSHET]) confers resilience against deleterious effects of aging indexed by cerebrospinal fluid (CSF) biomarkers of neuroinflammation (interleukin-6 [IL-6], S100 calcium-binding protein B [S100B], triggering receptor expressed on myeloid cells [sTREM2], chitinase-3-like protein 1 [YKL-40], glial fibrillary acidic protein [GFAP]), neurodegeneration (total α-synuclein [α-Syn], neurofilament light chain protein), and synaptic dysfunction (neurogranin [Ng]). This Alzheimer disease risk-enriched cohort consisted of 454 cognitively unimpaired adults (Mage=61.5±7.75). Covariate-adjusted multivariate regression examined relationships between age (mean-split[age ≥ 62]) and CSF biomarkers (Roche/NeuroToolKit), and whether they differed between KL-VSHET (N=122) and non-carriers (KL-VSNC; N=332). Older age was associated with a poorer biomarker profile across all analytes (Ps ≤ 0.03). In age-stratified analyses, KL-VSNC exhibited this same pattern (Ps ≤ 0.05) which was not significant for IL-6, S100B, Ng, and α-Syn (Ps ≥ 0.13) in KL-VSHET. Although age-related differences in GFAP, sTREM2, and YKL-40 were evident for both groups (Ps ≤ 0.01), the effect magnitude was markedly stronger for KL-VSNC. Higher levels of neuroinflammation, neurodegeneration, and synaptic dysfunction in older adults were attenuated in KL-VSHET. Older age was associated with poorer profiles across all cerebrospinal fluid biomarkers of neuroinflammation, neurodegeneration, and synaptic dysfunction. KLOTHO KL-VS non-carriers exhibit this same pattern, which is does not significantly differ between younger and older KL-VS heterozygotes for interleukin-6, S100 calcium-binding protein B, neurogranin, and total α-synuclein. Although age-related differences in glial fibrillary acidic protein, triggering receptor expressed on myeloid cells, and chitinase-3-like protein 1 are evident for both KL-VS groups, the magnitude of the effect is markedly stronger for KL-VS non-carriers. Higher levels of neuroinflammation, neurodegeneration, and synaptic dysfunction in older adults are attenuated in KL-VS heterozygotes.

Knockout of the longevity gene Klotho perturbs aging and Alzheimer’s disease-linked brain microRNAs and tRNA fragments

Overexpression of the longevity gene Klotho prolongs lifespan, while its knockout shortens lifespan and impairs cognition via perturbation of myelination and synapse formation. However, comprehensive analysis of Klotho knockout effects on mammalian brain transcriptomics is lacking. Here, we report that Klotho knockout alters the levels of aging- and cognition related mRNAs, long non-coding RNAs, microRNAs and tRNA fragments. These include altered neuronal and glial regulators in murine models of aging and Alzheimer’s disease and in human Alzheimer’s disease post-mortem brains. We further demonstrate interaction of the knockout-elevated tRNA fragments with the spliceosome, possibly affecting RNA processing. Last, we present cell type-specific short RNA-seq datasets from FACS-sorted neurons and microglia of live human brain tissue demonstrating in-depth cell-type association of Klotho knockout-perturbed microRNAs. Together, our findings reveal multiple RNA transcripts in both neurons and glia from murine and human brain that are perturbed in Klotho deficiency and are aging- and neurodegeneration-related.

Role of serum α-Klotho level in patients with breast carcinoma.

e15031 Background: The Klotho gene regulates multiple intracellular signalling pathways involving FGF-23, Insulin, IGF1, TGF-β1, Wnt/β-catenin and mammalian targets of rapamycin. The Klotho gene is downregulated in cancer and has a tumour suppressor role. Only a few studies have been done assessing its role in various cancers. None has looked into its association with all the clinicopathological characteristics of Carcinoma breast along with Pathological complete response (PCR). In August 2022, an oral senolytic form of Klotho was identified making it a possible and targetable protein. Methods: This was a Prospective cross-sectional study. Patients with biopsy-proven carcinoma breast who were previously untreated and had no significant past history were included. 84 patients were studied. Serum αKlotho level was estimated before initiating any treatment and its association with clinicopathological characteristics and with PCR was analysed. Results: A total of 84 patients were studied. The mean age was 50.76 years. Amongst our patients 65% were Estrogen Receptor (ER)+, 41.6% HER2+ and 11.9% were TNBC. 11.9% were of T1 stage, 29.8% T2, 19% T3, and 39.3% were T4. 16.7% had N0, 48.8% N1, 14.3% N2 and 20.2% had N3 stage. 20.2% were metastatic (MBC) and 79.8% were non-metastatic. 33.3% had grade 3 tumours, 56% grade 2 and 10.7% had grade 1. 61.9% were treated with NACT. The mean serum αKlotho level was 1.81ng/ml ranging from 0-5.15ng/ml. The αKlotho level was 2.04ng/ml in ER+ and 1.37ng/ml in ER-negative (p 0.011). As the Nottingham grade of the tumour increased from 1 to 3, αKlotho level decreased, with a mean value of 3.54ng/ml in grade 1, 1.71ng/ml in grade 2, and 1.42ng/ml in grade 3 (p 0.001). As the T stage increased from 1 to 4, αKlotho level decreased from 2.6ng/ml to 1.61ng/ml. Patients with N0 had a higher αKlotho of 2.92ng/ml, N1 had 1.64ng/ml, N2 1.79ng/ml, and N3 had 1.31ng/ml (p 0.001). MBC had a lower level of 1.47ng/ml than non-metastatic(1.9ng/ml). αKlotho level negatively correlated with ki67 with a correlation coefficient of -0.2. Among the patients who received NACT, we analysed 36 patients for the correlation with PCR. αKlotho level in patients who attained PCR was 1.58ng/ml and in those who did not attain PCR was 1.64ng/ml which was not significant. Conclusions: Klotho gene is identified to have a tumour suppressor role and its product αKlotho seems to have a protective role in Carcinoma breast. We found that patients with a higher serum αKlotho level had a lower histological grade(p 0.001) and a Node-negative (p 0.001) disease. Non-metastatic patients and patients with lower Ki 67 had high αKlotho levels. However, we could not find any significant association between αKlotho level and PCR. This is the first study with a large sample size done to look at the association of serum αKlotho with clinicopathological characteristics of carcinoma breast and that has found a significant association of αKlotho levels with higher grade and Node-negative disease.

Hypermethylation of Klotho and Peroxisome Proliferator-Activated Receptor γ Concomitant with Overexpression of DNA Methyltransferase 1 in Adenomyosis.

Cellular senescence is known to be involved in tissue repair, but its role in adenomyosis remains unclear. This study was tasked to evaluate the expression of Klotho, a well-known aging-suppressing protein, as well as PPARγ and DNMT1 in adenomyotic lesions (AD) in comparison with that of control endometrium (CT). We performed immunohistochemistry analysis of markers of cellular senescence p16 and p21, along with Klotho, PPARγ and DNMT1 in CT and AD samples, followed by the quantification of gene expression of Klotho, PPARγ and DNMT1 in epithelial organoids derived from AD and CT samples and methylation-specific PCR to evaluate promoter methylation status. The effect of forced expression and knockdown of DNMT1 on Klotho and PPARγ expression in ectopic endometrial epithelial cells was evaluated. We found that both p16 and p21 immunoreactivity in AD was significantly higher while that of Klotho and PPARγ was significantly lower than CT samples, which was concomitant with elevated immunoexpression of DNMT1. The results were confirmed by transcriptional analysis using epithelial organoids derived from AD and CT samples. In addition, the promoter regions of both Klotho and PPARγ genes were hypermethylated in AD as compared with CT, and treatment with HDAC and DNMT inhibitors reactivated the expression of both Klotho and PPARγ. Forced expression of DNMT1 resulted in downregulation of both Klotho and PPARγ but its knockdown increased their expression. Thus, overexpression of DNMT1 seems to facilitate the promoter hypermethylation of both Klotho and PPARγ in AD, resulting in their reduced expression that is suggestive of the role of senescence in adenomyosis.

A study of the relationship between metilation level of Klotho gene and dietary habits

A study of the relationship between metilation level of Klotho gene and dietary habits

Association of KLOTHO gene variants with metabolic and renal function parameters in Mexican patients living with type 2 diabetes.

Type 2 diabetes (T2D) and high blood pressure are the main causes of chronic kidney disease (CKD) in adulthood. Both metabolic and oxidative stresses driven by hyperglycemia as well as genetic factors have been suggested as pathogenic causes of renal failure. Some single nucleotide variants (SNVs) on gene coding KLOTHO (KL) have been implicated in several clinical scenarios including hypertension, diabetes, and cardiovascular disease. The aim of this study was to analyze the association of rs1207568 (-395G > A), rs953614 (+ 1062T > G) and rs564481 (+ 1818C > T) SNVs with metabolic and renal function parameters in Mexican patients living with type 2 diabetes. A cross-sectional study was conducted in 637 Mexican patients with T2D, and/or hypertension without previous diagnosis of CKD. Anthropometric, metabolic, and renal function parameters were determined. Patients were genotyped for rs1207568, rs953614 and rs564481 SNVs and associations under a dominant genetic model were analyzed by logistic regression. For rs9536314, G-allele showed to be protective for hypo-HDL-C, albuminuria, and CKD. Carriers of minor allele of rs564481 had low odds for high glucose levels. No differences in genotype nor allele frequencies between the patients and the reference population were observed. In Mexican patients living with type 2 diabetes, KL variant rs9536314 was found associated with low odds of hypo-HDL cholesterol, albuminuria and presence of CKD. Meanwhile the consensus of soluble KLOTHO measurement is reached, genetic variants in the KL gene could be considered as genetic markers for CKD susceptibility in patients at high-risk of vascular complications.

Klotho-mediated activation of the anti-oxidant Nrf2/ARE signal pathway affects cell apoptosis, senescence and mobility in hypoxic human trophoblasts: involvement of Klotho in the pathogenesis of preeclampsia.

The anti-aging gene Klotho is implicated in the pathogenesis of preeclampsia (PE), which is a pregnancy disease characterized by hypertension and proteinuria. Oxidative stress is closely associated with the worse outcomes in PE, and Klotho can eliminate Reactive Oxygen Species (ROS), but it is still unclear whether Klotho regulates PE pathogenesis through modulating oxidative damages. Here, by analyzing the clinical data, we found that Klotho was aberrantly downregulated in PE umbilical cord serum and placental tissues, compared to their normal counterparts. In in vitro experiments, the human trophoblasts were subjected to hypoxic pressure to establish the PE models, and we confirmed that hypoxia also decreased the expression levels of Klotho in those trophoblasts. In addition, through performing functional experiments, we confirmed that hypoxia promoted oxidative damages, cell apoptosis and senescence, whereas suppressed cell invasion in human trophoblasts, which were all reversed overexpressing Klotho. The following mechanical experiments verified that Klotho increased the levels of nuclear Nrf2, total Nrf2, SOD2 and NQO1 to activate the anti-oxidant Nrf2/ARE signal pathway, and silencing of Nrf2 abrogated the protective effects of Klotho overexpression on hypoxic human trophoblasts. Consistently, in in vivo experiments, Klotho overexpression restrained oxidative damages and facilitated cell mitosis in PE rats' placental tissues. In conclusion, this study validated that Klotho activated the Nrf2/ARE signal pathway to eliminate hypoxia-induced oxidative damages, cell apoptosis and senescence to recover normal cellular functions in human trophoblasts, and our data supported that Klotho could be used as novel biomarker for PE diagnosis and treatment.

Overexpression of α-Klotho isoforms promotes distinct Effects on BDNF-Induced Alterations in Dendritic Morphology

α-Klotho (α-Kl) is a modulator of aging, neuroprotection, and cognition. Transcription of the Klotho gene produces two splice variants—a membrane protein (mKl), which can be cleaved and released into the extracellular milieu, and a truncated secreted form (sKl). Despite mounting evidence supporting a role for α-Kl in brain function, the specific roles of α-Kl isoforms in neuronal development remain elusive. Here, we examined α-Kl protein levels in rat brain and observed region-specific expression in the adult that differs between isoforms. In the developing hippocampus, levels of isoforms decrease after the third postnatal week, marking the end of the critical period for development. We overexpressed α-Kl isoforms in primary cultures of rat cortical neurons and evaluated effects on brain-derived neurotrophic factor (BDNF) signaling. Overexpression of either isoform attenuated BDNF-mediated signaling and reduced intracellular Ca2+ levels, with mKl promoting a greater effect. mKl or sKl overexpression in hippocampal neurons resulted in a partially overlapping reduction in secondary dendrite branching. Moreover, mKl overexpression increased primary dendrite number. BDNF treatment of neurons overexpressing sKl resulted in a dendrite branching phenotype similar to control neurons. In neurons overexpressing mKl, BDNF treatment restored branching of secondary and higher order dendrites close, but not distal, to the soma. Taken together, the data presented support the idea that sKl and mKl play distinct roles in neuronal development, and specifically, in dendrite morphogenesis.

Klotho exerts protection in chronic kidney disease associated with regulating inflammatory response and lipid metabolism

BackgroundThe anti-aging protein Klotho plays a protective role in kidney disease, but its potential as a biomarker for chronic kidney disease (CKD) is controversial. Additionally, the main pathways through which Klotho exerts its effects on CKD remain unclear. Therefore, we used bioinformatics and clinical data analysis to determine its role in CKD.ResultsWe analyzed the transcriptomic and clinical data from the Nephroseq v5 database and found that the Klotho gene was mainly expressed in the tubulointerstitium, and its expression was significantly positively correlated with estimated glomerular filtration rate (eGFR) and negatively correlated with blood urea nitrogen (BUN) in CKD. We further found that Klotho gene expression was mainly negatively associated with inflammatory response and positively associated with lipid metabolism in CKD tubulointerstitium by analyzing two large sample-size CKD tubulointerstitial transcriptome datasets. By analyzing 10-year clinical data from the National Health and Nutrition Examination Survey (NHANES) 2007–2016, we also found that Klotho negatively correlated with inflammatory biomarkers and triglyceride and positively correlated with eGFR in the CKD population. Mediation analysis showed that Klotho could improve renal function in the general population by modulating the inflammatory response and lipid metabolism, while in the CKD population, it primarily manifested by mediating the inflammatory response. Restricted cubic spline (RCS) analysis showed that the optimal concentration range for Klotho to exert its biological function was around 1000 pg/ml. Kaplan–Meier curves showed that lower cumulative hazards of all-cause mortality in participants with higher levels of Klotho. We also demonstrated that Klotho could reduce cellular inflammatory response and improve cellular lipid metabolism by establishing an in vitro model similar to CKD.ConclusionsOur results suggest that Klotho exerts protection in CKD, which may be mainly related to the regulation of inflammatory response and lipid metabolism, and it can serve as a potential biomarker for CKD.

Overexpression of Klotho gene using CRISPR/Cas9 induces apoptosis and inhibits cell motility in the human colorectal cancer cells.

Despite advances in early detection and treatment, colorectal cancer remains one of the leading causes of cancer-related deaths. The klotho (KL) gene plays a critical role in the development and progression of colorectal cancer. This study investigates the role of the KL gene in colorectal cancer by using the CRISPR/Cas9 system to overexpress and knock out (KO) the KL gene in human colorectal cancer cells (Caco-2). The effects of the changes were assessed by gene expression analysis, flow cytometry, scratch wound closure assays, colony formation assays, and immunofluorescence staining. Our results showed that overexpression of the KL gene increased apoptosis and decreased cell motility in cancer cells, whereas knockout of the KL gene had the opposite role. The present study elucidates the mechanisms underlying this role and highlights the potential of the CRISPR/Cas9 system as a gene editing tool in cancer research. Our data suggest that activation of the KL gene may serve as a novel therapeutic strategy and biomarker for studies in colorectal cancer.

Protein interaction networks characterizing the A549 cells Klotho transfected are associated with activated pro-apoptotic Bim and suppressed Wnt/β-catenin signaling pathway

Invasive assays and lung tumor-bearing mice models using a human lung adenocarcinoma cell line A549 cells transfected with the Klotho (KL) gene, A549/KL cells, have confirmed that KL suppresses invasive/metastatic potential. This study aimed to identify the co-expression protein networks and proteomic profiles associated with A549/KL cells to understand how Klotho protein expression affects molecular networks associated with lung carcinoma malignancy. A two-step application of a weighted network correlation analysis to the cells’ quantitative proteome datasets of a total of 6,994 proteins, identified by mass spectrometry-based proteomic analysis with data-independent acquisition (DIA), identified one network module as most significantly associated with the A549/KL trait. Upstream analyses, confirmed by western blot, implicated the pro-apoptotic Bim (Bcl-2-like protein 11) as a master regulator of molecular networks affected by Klotho. GeneMANIA interaction networks and quantitative proteome data implicated that Klotho interacts with two signaling axes: negatively with the Wnt/β-catenin axis, and positively by activating Bim. Our findings might contribute to the development of future therapeutic strategies.

Involvement of Single Nucleotide Variants in the Klotho Gene Among Obesity Individuals with and without Type 2 Diabetes Mellitus in the Saudi Population.

Aging is characterized by the gradual physiological changes and alterations that accumulate over time in the human body. The combination of obesity and ageing can lead to an increased risk of serious health issues or death. Single nucleotide variants (SNVs) in the Klotho gene were commonly studied, including that in type 2 diabetes mellitus (T2DM). The aim of this study is to examine the possible effect of SNVs in Klotho on the obese population in Saudi Arabia using middle-aged participants with and without T2DM. This study consists of 100 controls and 100 obesity patients, in which 50had T2DM and the remaining 50 were obese without T2DM. Genotyping was performed with PCR, and Sanger sequencing analysis was used to validate the molecular association. In this study, rs1207568 (p = 0.001-0.003) and rs9527025 (p = 0.001-0.00004) SNVs were associated with obesity cases. However, none of the genotypes or allele frequencies showed a positive association with the rs564481 SNV (p = 0.344-0.881). The multiple linear regression model showed that waist and hip were associated (p = 0.01-0.02). ANOVA analysis showed age (p = 0.04), hip (p = 0.002), SBP, and TC (p = 0.02) were associated. Finally, SNV (rs1207568 and rs95270250) and obesity (p < 0.001) associations were confirmed through gene multifactor dimensionality reduction analysis with gene-gene interaction, dendrogram, and graphical depletion method. This study concludes that rs1207568 and rs9527025 SNVs are associated with obesity in the Saudi population. Additional genetical statistics showed significant association between dependent and independent variables. SNVs in Klotho play a role in the Saudi population's susceptibility to obesity.

Evaluation of klotho expression on peripheral blood lymphocytes among hemodialysis patients and its possible contribution to their immuno-compromised status

Infection is the second most common cause of mortality among end-stage kidney disease (ESKD) patients. Uremic toxins are the main cause of impaired immune response among ESKD patients. Klotho gene, the anti-aging gene, encodes the transmembrane alpha klotho (αKL) protein which acts as an obligate coreceptor for fibroblast growth factor 23 (FGF23). Klotho protein may play a role in immune cell functions, particularly in anti-inflammatory response; however, its role is still incompletely understood. In the present study, we aimed to measure αKL protein expression on peripheral blood lymphocytes (PBLs) among hemodialysis (HD) patients, and we assumed that decreased αKL expression on PBLs may contribute to the impaired immunity among HD patients. This case-control study included 20 ESKD patients on regular hemodialysis for more than 3 months. Their ages ranged from 24 to 69 years. Patients with primary immunodeficiencies, those on systemic immunosuppressive drugs, those with ongoing infections or who had recently recovered from infections, and those with malignancies on active treatment were excluded. A control group of 20 normal subjects of comparable age and gender were also included. We compared αKL protein expression on PBLs by flow cytometry between both groups. Significant reductions in percentages of αKL protein expression on B lymphocytes (CD19), T lymphocytes (CD3), and natural killer cells (CD56) were observed among HD patients compared to controls. We also noticed a significant reduction in the percentages of natural killer cells among HD patients. The present study suggests that decreased αKL expression on PBLs may contribute to the immunocompromised status among HD patients, highlighting the importance of understanding the exact function of αKL protein on immune cells. This may offer a future diagnostic and therapeutic tool to improve the immune response among HD patients.

New insights into the role of Klotho in inflammation and fibrosis: molecular and cellular mechanisms.

As the body's defense mechanism against damage and infection, the inflammatory response is a pathological process that involves a range of inflammatory cells and cytokines. A healthy inflammatory response helps the body repair by eliminating dangerous irritants. However, tissue fibrosis can result from an overly intense or protracted inflammatory response. The anti-aging gene Klotho suppresses oxidation, delays aging, and fosters development of various organs. Numerous investigations conducted in the last few years have discovered that Klotho expression is changed in a variety of clinical diseases and is strongly linked to the course and outcome of a disease. Klotho functions as a co-receptor for FGF and as a humoral factor that mediates intracellular signaling pathways such as transforming growth factor β (TGF-β), toll-like receptors (TLRs), nuclear factor-kappaB (NF-κB), renin -angiotensin system (RAS), and mitogen-activated protein kinase (MAPK). It also interferes with the phenotype and function of inflammatory cells, such as monocytes, macrophages, T cells, and B cells. Additionally, it regulates the production of inflammatory factors. This article aims to examine Klotho's scientific advances in terms of tissue fibrosis and the inflammatory response in order to provide novel therapy concepts for fibrotic and inflammatory disorders.

Comparing Western and traditional Chinese medicine for male sexual dysfunction: can Klotho represent a silk road?

Traditional Chinese medicine (TCM) and Western Medicine both have shown efficacy in treating male sexual dysfunction (MSD). The aim of this perspective paper is to discuss a possible link between Western medicine and TCM in the MSD field as represented by the entity of Klotho. Klotho is a recently discovered protein, mainly expressed in the kidney, encoded by the anti-aging gene klotho. Not only is Klotho significantly correlated with the development and progression of kidney diseases and their complications, but increasing evidence indicates that it is also closely related to MSD. A comprehensive search within PubMed database was performed to retrieve available evidence on Klotho's roles, particularly in kidney and in MSD. Indeed, in the TCM theory, the concept of the "kidney" is entirely different from the Western medicine: it is closely related to metabolism and to the reproductive, nervous, endocrine systems, being more than just a urinary organ. According to the "Kidney storing essence (jīng) and governing reproduction" (KSEGR) theory, a cornerstone in TCM, the treatment of MSD mainly consists of restoring the kidney's function. Signs of decreasing kidney essence show a consistent similarity to deficiencies of Klotho, also for what regards the male sexual function. Based on the current evidence, Klotho may represent a potential biological indicator for sexual desire and sexual function and a kind of new scientific Silk Road between TCM and Western medicine for MSD; nevertheless, there is a need to conduct further high-quality research to prove this hypothesis.