Changes In Klotho Research Articles

Effect of recombinant human growth hormone on serum Klotho and fibroblast growth factor 23 in children with idiopathic short stature

To investigate the changes in the serum levels of Klotho, fibroblast growth factor 23 (FGF23), and insulin-like growth factor-1 (IGF-1) in children with idiopathic short stature (ISS) before and after recombinant human growth hormone (rhGH) treatment, as well as the correlation of Klotho and FGF23 with the growth hormone (GH)/IGF-1 growth axis in these children. A prospective study was conducted on 33 children who were diagnosed with ISS in the Department of Pediatrics, Hebei Provincial People's Hospital, from March 10, 2021 to December 1, 2022 (ISS group). Twenty-nine healthy children, matched for age and sex, who attended the Department of Child Healthcare during the same period, were enrolled as the healthy control group. The children in the ISS group were treated with rhGH, and the serum levels of Klotho, FGF23, and IGF-1 were measured before treatment and after 3, 6, and 9 months of treatment. A correlation analysis was conducted on these indexes. There were no significant differences in the serum levels of IGF-1, Klotho, and FGF23 between the ISS and healthy control groups (P>0.05). The serum levels of Klotho, FGF23, and IGF-1 increased significantly in the ISS group after 3, 6, and 9 months of rhGH treatment (P<0.05). In the ISS group, Klotho and FGF23 levels were positively correlated with the phosphate level before treatment (P<0.05). Before treatment and after 3, 6, and 9 months of rhGH treatment, the Klotho level was positively correlated with the IGF-1 level (P<0.05), the FGF23 level was positively correlated with the IGF-1 level (P<0.05), and the Klotho level was positively correlated with the FGF23 level (P<0.05), while Klotho and FGF23 levels were not correlated with the height standard deviation of point (P>0.05). The rhGH treatment can upregulate the levels of Klotho, FGF23, and IGF-1 and realize the catch-up growth in children with ISS. Klotho and FGF23 may not directly promote the linear growth of children with ISS, but may have indirect effects through the pathways such as IGF-1 and phosphate metabolism. The consistent changes in Klotho, FGF23 and IGF-1 levels show that there is a synergistic relationship among them in regulating the linear growth of ISS children.

Short-term changes in klotho and FGF23 in heart failure with reduced ejection fraction-a substudy of the DAPA-VO2 study.

The klotho and fibroblast growth factor 23 (FGF-23) pathway is implicated in cardiovascular pathophysiology. This substudy aimed to assess the changes in klotho and FGF-23 levels 1-month after dapagliflozin in patients with stable heart failure and reduced ejection fraction (HFrEF). The study included 29 patients (32.2% of the total), with 14 assigned to the placebo group and 15 to the dapagliflozin, as part of the double-blind, randomized clinical trial [DAPA-VO2 (NCT04197635)]. Blood samples were collected at baseline and after 30 days, and Klotho and FGF-23 levels were measured using ELISA Kits. Between-treatment changes (raw data) were analyzed by using the Mann-Whitney test and expressed as median (p25%-p75%). Linear regression models were utilized to analyze changes in the logarithm (log) of klotho and FGF-23. The median age was 68.3 years (60.8-72.1), with 79.3% male and 81.5% classified as NYHA II. The baseline medians of left ventricular ejection fraction, glomerular filtration rate, NT-proBNP, klotho, and FGF-23 were 35.8% (30.5-37.8), 67.4 ml/min/1.73 m2 (50.7-82.8), 1,285 pg/ml (898-2,305), 623.4 pg/ml (533.5-736.6), and 72.6 RU/ml (62.6-96.1), respectively. The baseline mean peak oxygen uptake was 13.1 ± 4.0 ml/kg/min. Compared to placebo, patients on dapagliflozin showed a significant median increase of klotho [Δ+29.5, (12.9-37.2); p = 0.009] and a non-significant decrease of FGF-23 [Δ-4.6, (-1.7 to -5.4); p = 0.051]. A significant increase in log-klotho (p = 0.011) and a decrease in log-FGF-23 (p = 0.040) were found in the inferential analysis. In conclusion, in patients with stable HFrEF, dapagliflozin led to a short-term increase in klotho and a decrease in FGF-23.

Klotho, FOXO1 and cytokines associations in patients with coronary artery disease

IntroductionAtherosclerosis is one of the main reasons for adult mortality in advanced populations and countries with high stress levels. Klotho family are single-pass trans-membrane proteins that involve in the genesis and progression of various diseases, including acardiovascular disease, apoptosis and stress oxidative imbalance.Present study, investigates the pattern of changes in Klotho and FOXO1 gene expressions and levels in atherosclerosis. MethodsPresent case control study consisted of 79 patients with atherosclerosis and 78 healthy controls. PBMC (peripheral mono-nuclear blood cells) expression levels of Klotho and FOXO1 were assayed, using qPCR method. Serum concentration of Klotho and FOXO1 were measured by ELISA method. ResultsA significant reduction was found in PBMC genes expression levels of Klotho (P < 0.01) of patients as comparison with controls. PBMC Gene expression of FOXO1 in patients was increased significantly (P < 0.01) when compared with controls. Pearson analysis showed a positive correlation between PBMC Klotho gene expression and Klotho levels of patients (P < 0.01). The correlation between serum concentrations of Klotho and FOXO1 of patients was also positive significantly (P < 0.01). AUC of ROC for gene expression and serum concentration of Klotho in patients were 0.701 and 0.737 respectively. ConclusionInvestigating the PBMC gene expression and serum concentration of Klotho in patients with atherosclerosis is suggested could be a convenient novel biomarker for predicting, prognosis, monitoring the disease progression and designing a suitable drug for patients with atherosclerosis.

Improvement of Cardiac Function in Rats With Myocardial Infarction by Low-Intensity to Moderate-Intensity Endurance Exercise Is Associated With Normalization of Klotho and SIRT1.

Exercise training (Ex) has beneficial effects on cardiovascular diseases by increasing Klotho and SIRT1. This study aimed to investigate whether the beneficial impact of Ex on myocardial infarction (MI) is mediated through Klotho and SIRT1. Fifty-six Wistar rats were divided into 4 main groups of Sham, MI, Ex, and MI + Ex. MI was induced by the closure of the left anterior descending. Animals were trained by endurance exercise for 4 weeks. In the end, hemodynamic and heart contractility indices were assessed. The levels of Klotho and SIRT1 in the serum and heart were measured by enzyme-linked immunosorbent assay and Western blot, respectively. The ADAM17 level in the heart and kidneys was assessed by enzyme-linked immunosorbent assay. The infarct size and fibrosis area were assessed by triphenyltetrazolium chloride and Masson trichrome staining, respectively. Ex recovered the reduction of dp/dt max and dp/dt min and decreased myocardial infarct size and fibrotic area in the MI group. Ex normalized the increase in heart rate, systolic blood pressure, left ventricular systolic pressure, and left ventricular end diastolic pressure in the MI group. Ex also normalized the reduction of the levels of Klotho and SIRT1 in serum and heart in the MI group. The changes of Klotho and SIRT1 in serum were positively correlated. Ex also restored ADAM17 levels in the MI group. Ex improved cardiac function in the MI group and is associated with reduction of the infarct size and normalization of Klotho and SIRT1 levels. Regarding unidirectional changes in Klotho and SIRT1, these proteins may play a role in beneficial effects of Ex on MI recovery.

Circulating Klotho Response To A Behavioral Weight Loss Intervention In Adults With Overweight Or Obesity

Klotho, a biomarker of aging, is associated with a slower aging process. Klotho concentration is lower among adults with obesity compared to normal-weight adults, and exercise may independently increase levels of Klotho. Whether Klotho is altered by weight loss and whether there is an added effect of exercise are not understood. PURPOSE: This study examined changes in Klotho concentration in response to a behavioral weight loss intervention among adults with overweight or obesity. METHODS: A subset of 152 adults (age: 45.4+8.0 years; BMI: 32.1+3.7 kg/m2) who participated in a 12-month weight loss intervention were classified as an intervention “responder” (achieved >10% weight loss at both 6- and 12 months) or “non-responder” (achieved <5% weight loss at both 6- and 12 months). Intervention conditions included: 1) diet only (1200-1800 kcal/day), 2) diet plus 150 min/wk of moderate-to-vigorous intensity physical activity (MVPA) per week, 3) or diet plus 250 min/wk of unsupervised MVPA per week. Measures of height, weight, body composition, cardiorespiratory fitness, and Klotho were completed at baseline, 6-, and 12 months. Klotho was analyzed using solid-phase sandwich ELISA kits. RESULTS: There were significant (p<0.0001) changes in weight (-12.5±9.1 kg), percent body fat (-7.1±5.5%), lean body mass (-1.7±2.0 kg), and cardiorespiratory fitness (+3.3±4.1 ml/kg/min) from baseline to 12-months. Klotho significantly (p=0.009) changed across the 12 months (baseline: 933±381 pg/mL; 6 months: 985±450 pg/mL; 12 months: 940±423 pg/mL), with no difference by intervention group or weight loss response. Participants who performed physical activity had non-significantly greater changes in Klotho. Klotho was consistently associated with lean body mass at baseline (r=-0.19), 6 (r=-0.23), and 12 months (r=-0.19) (p<0.05). Klotho was not predictive of change in weight, body composition, or fitness. CONCLUSION: Klotho significantly, but modestly, increases with weight loss; however, the increase in Klotho was not sustained throughout the intervention. There may be an influence of physical activity on change in Klotho with weight loss, but this warrants further investigation. Further investigation to examine how weight loss and physical activity may alter biomarkers of aging in adults with obesity may be warranted.

Serum Klotho in Living Kidney Donors and Kidney Transplant Recipients: A Meta-Analysis.

α-Klotho is a known anti-aging protein that exerts diverse physiological effects, including phosphate homeostasis. Klotho expression occurs predominantly in the kidney and is significantly decreased in patients with chronic kidney disease. However, changes in serum klotho levels and impacts of klotho on outcomes among kidney transplant (KTx) recipients and kidney donors remain unclear. A literature search was conducted using MEDLINE, EMBASE, and Cochrane Database from inception through October 2019 to identify studies evaluating serum klotho levels and impacts of klotho on outcomes among KTx recipients and kidney donors. Study results were pooled and analyzed utilizing a random-effects model. Ten cohort studies with a total of 431 KTx recipients and 5 cohort studies with a total of 108 living kidney donors and were identified. After KTx, recipients had a significant increase in serum klotho levels (at 4 to 13 months post-KTx) with a mean difference (MD) of 243.11 pg/mL (three studies; 95% CI 67.41 to 418.81 pg/mL). Although KTx recipients had a lower serum klotho level with a MD of = −234.50 pg/mL (five studies; 95% CI −444.84 to −24.16 pg/mL) compared to healthy unmatched volunteers, one study demonstrated comparable klotho levels between KTx recipients and eGFR-matched controls. Among kidney donors, there was a significant decrease in serum klotho levels post-nephrectomy (day 3 to day 5) with a mean difference (MD) of −232.24 pg/mL (three studies; 95% CI –299.41 to −165.07 pg/mL). At one year following kidney donation, serum klotho levels remained lower than baseline before nephrectomy with a MD of = −110.80 pg/mL (two studies; 95% CI 166.35 to 55.24 pg/mL). Compared to healthy volunteers, living kidney donors had lower serum klotho levels with a MD of = −92.41 pg/mL (two studies; 95% CI −180.53 to −4.29 pg/mL). There is a significant reduction in serum klotho levels after living kidney donation and an increase in serum klotho levels after KTx. Future prospective studies are needed to assess the impact of changes in klotho on clinical outcomes in KTx recipients and living kidney donors.

Changes in Biomarker Profile and Left Ventricular Hypertrophy Regression: Results from the Frequent Hemodialysis Network Trials

Background: Regression of left ventricular hypertrophy (LVH) is feasible with more frequent hemodialysis (HD). We aimed to ascertain pathways associated with regression of left ventricular mass (LVM) in patients enrolled in the Frequent HD Network (FHN) trials. Methods: This was a post hoc observational cohort study. We hypothesized LVH regression with frequent HD was associated with a different cardiovascular biomarker profile. Regressors were defined as patients who achieved a reduction of more than 10% in LVM at 12 months. Progressors were defined as patients who had a minimum of 10% increase in LVM at 12 months. Results: Among 332 randomized patients, 243 had biomarker data available. Of these, 121 patients did not progress or regress, 77 were regressors, and 45 were progressors. Mean LVM change differed between regressors and progressors by –65.6 (–74.0 to –57.2) g, p < 0.001. Regressors had a median (interquartile range) increase in dialysis frequency (from 3.0 [3.0–3.0] to 4.9 [3–5.7] per week, p = 0.001) and reductions in pre-dialysis systolic (from 149.0 [136.0–162.0] to 136.0 [123.0–152.0] mm Hg, p < 0.001) and diastolic (from 83.0 [71.0–91.0] to 76.0 [68.0–84.0] mm Hg, p < 0.001) blood pressures. Klotho levels increased in regressors versus progressors (76.9 [10.5–143.3] pg/mL, p = 0.024). Tissue inhibitors of metalloproteinase (TIMP)-2 levels fell in regressors compared to progressors (–7,853 [–14,653 to –1,052] pg/mL, p = 0.024). TIMP-1 and log (brain natriuretic ­peptide [BNP]) levels also tended to fall in regressors. Changes in LVM correlated inversely with changes in klotho (r = –0.24, p = 0.014). ­Conclusions: Markers of collagen turnover and changes in klotho levels are potential novel pathways associated with regression of LVH in the dialysis population, which will require further prospective validation.

Biological effects of dosing aerobic exercise and neuromuscular electrical stimulation in rats

Aerobic exercise (AE) and non-aerobic neuromuscular electric stimulation (NMES) are common interventions used in physical therapy. We explored the dose-dependency (low, medium, high) of these interventions on biochemical factors, such as brain derived neurotrophic growth factor (BDNF), vascular endothelial growth factor-A (VEGF-A), insulin-like growth factor-1 (IGF-1) and Klotho, in the blood and brain of normal rats, as well as a treadmill-based maximum capacity test (MCT). A medium dose of AE produced the most improvement in MCT with dose-dependent changes in Klotho in the blood. A dose-dependent increase of BDNF was evident following completion of an NMES protocol, but there was no improvement in MCT performance. Gene expression in the hippocampus was increased after both AE and NMES, with IGF-1 being a signaling molecule that correlated with MCT performance in the AE conditions, but also highly correlated with VEGF-A and Klotho. Blood Klotho levels can serve as a biomarker of therapeutic dosing of AE, whereas IGF-1 is a key molecule coupled to gene expression of other molecules in the hippocampus. This approach provides a translatable paradigm to investigate the mode and mechanism of action of interventions employed in physical therapy that can improve our understanding of how these factors change under pathological conditions.

Alteration in serum klotho levels in anorexia nervosa patients

Klotho is a trans-membrane protein which can be shed to act as a hormone; its blood levels may be regulated by the GH/IGF-1 axis. Klotho deficient mice exhibit short lifespan and characteristics of aging and malnutrition, including decreased fat and muscle mass, osteopenia, and impaired fertility. As anorexia nervosa (AN) is characterized by malnutrition and GH resistance, we hypothesized klotho levels would be altered in AN, and aimed to assess klotho levels in undernourished AN patients and changes in klotho following weight rehabilitation. 19 adolescent female AN inpatients (aged 16.1±1.8 years) admitted to an inpatient service for eating disorders in a tertiary center were recruited. Blood samples were obtained on admission and after weight restoration (interval 4.0±2.3 months) and analyzed for klotho, IGF-1, calcium, phosphorus, and alkaline phosphatase. Klotho levels on admission were lower than expected for age, and correlated with lumbar spine BMD Z-score (r=-0.81, p<0.001) and alkaline phosphatase levels (r=0.66, p=0.003) but not with age, height-SDS, weight-SDS, BMI-SDS, or serum calcium, phosphorus and IGF-1 levels. Both IGF-1 and klotho levels increased significantly during hospitalization (IGF-1: 44±17nmol/l to 53±11nmol/l, p=0.008; klotho: 1061±421pg/ml to 1519±781pg/ml, p=0.008). Klotho levels are low in the acute stage of AN and increase with nutritional rehabilitation. Low klotho on admission may be secondary to low IGF-1 levels and may contribute to the clinical manifestations of AN. The role of klotho in the pathophysiology of AN and as a novel marker of disease severity should be further explored.

Klotho Deficiency Disrupts Hematopoietic Stem Cell Development and Erythropoiesis

Klotho deficiency is a characteristic feature of chronic kidney disease in which anemia and cardiovascular complications are prevalent. Disruption of the Klotho gene in mice results in hypervitaminosis D and a syndrome resembling accelerated aging that includes osteopenia and vascular calcifications. Given that the bone microenvironment and its cellular components considerably influence hematopoiesis, in the present study, we addressed the in vivo role of klotho in blood cell formation and differentiation. Herein, we report that genetic ablation of Klotho in mice results in a significant increase in erythropoiesis and a decrease in the hematopoietic stem cell pool size in the bone marrow, leading to impaired hematopoietic stem cell homing in vivo. Our data also suggest that high vitamin D levels are only partially responsible for these hematopoietic changes in Klotho(-/-) mice. Importantly, we found similar hematopoietic abnormalities in Klotho(-/-) fetal liver cells, suggesting that the effects of klotho in hematopoietic stem cell development are independent of the bone microenvironment. Finally, injection of klotho protein results in hematopoietic changes opposite to the ones observed in Klotho(-/-) mice. These observations unveil a novel role for the antiaging hormone klotho in the regulation of prenatal and postnatal hematopoiesis and provide new insights for the development of therapeutic strategies targeting klotho to treat hematopoietic disorders associated with aging.

Biochemical and Functional Characterization of the Klotho-VS Polymorphism Implicated in Aging and Disease Risk

Klotho (KL) is an age-regulating protein named after the Greek goddess who spins the thread of life. Mice deficient in KL are normal throughout development, but rapidly degenerate and display a variety of aging-associated abnormalities that eventually lead to decreased life expectancy. While multiple genetic association studies have identified KL polymorphisms linked with changes in disease risk, there is a paucity of concrete mechanistic data to explain how these amino acid substitutions alter KL protein function. The KLVS polymorphism is suggested to lead to changes in protein trafficking although the mechanism is unclear. Our studies have sought to further investigate the functional differences in the KLVS variant that result in increased risk of many age-related diseases. Our findings suggest that the F352V and C370S substitutions lead to alterations in processing as seen by differences in shedding and half-life. Their co-expression in KLVS results in a phenotype resembling wild-type, but despite this intragenic complementation there are still changes in homodimerization and interactions with FGFR1c. Taken together, these studies suggest that KLVS leads to altered homodimerization that indirectly leads to changes in processing and FGFR1c interactions. These findings help elucidate the functional differences that result from the VS polymorphism, which will help clarify how alterations in KL function can lead to human disease and affect cognition and lifespan.

Aging related glomerulosclerosis is associated with decreased in klotho expression and increased in superoxide production

ObjectiveAging is associated with glomerulosclerosis and a decline in renal function. Klotho is a recently-discovered anti-aging gene. The purpose of this study was to determine changes in klotho, endothelin (ET)...

Aging-related kidney damage is associated with a decrease in klotho expression and an increase in superoxide production

The purpose of this study was to determine changes in klotho, endothelin (ET) receptors, and superoxide production in kidneys of aged rats and whether these changes are exacerbated in aged rats with cognitive impairment. Twenty aged rats (male, 27 months) were divided into an Old Impaired group (n=9) and an Old Intact group (n=11) according to a cognitive function test. A group of 12-month-old rats (n=10) was used as a Young Intact group. Serum creatinine was increased significantly in the Old Impaired group, suggesting impaired renal function. Aged rats showed glomerulosclerosis and tubulointerstitialfibrosis. These pathological changes were markedly aggravated in the old cognitively impaired than in the old cognitively intact animals. Notably, aged rats demonstrated a significant decrease in klotho protein expression in renal cortex and medulla. Protein expression of IL-6, Nox2, ETa receptors and superoxide production were increased whereas mitochondrial SOD (MnSOD) and ETb receptors expression were decreased in kidneys of the aged rats. Interestingly, these changes were more pronounced in the old impaired than in the old intact rats. In conclusion, the aging-related kidney damage was exacerbated in aged rats with cognitive impairment. Klotho, ETB, and MnSOD were downregulated but ETa, IL-6, Nox2, and superoxide production were upregulated in the aging-related kidney damage. These changes were more pronounced in rats with cognitive impairment.

Aging‐Related Renal Damage Is Associated with Decreased Klotho Expression and Increased Superoxide Production

Klotho is a recently‐discovered anti‐aging gene. The purpose of this study was to determine changes in klotho, endothelin (ET) receptors, NADPH oxidases, and superoxide production in kidneys of aged rats. Twenty aged rats (male, 36 months) were divided into an impaired group (n=9) and an intact aging group (n=11) according to a cognitive function test. A group of 12 month‐old rats (n=10) was used as a young group. Plasma creatinine was significantly greater in the impaired group, suggesting impaired renal function. Aged rats showed a decrease in the number of glomeruli, an increase in collagen staining (fibrosis) around glomeruli and tubules, and an increase in periodic acid Schiff (PAS) staining (matrix remodeling) in and around glomeruli, indicating renal structural damage. These pathological changes were markedly aggravated in the impaired than in intact animals. Notably, aged rats demonstrated a significant decrease in klotho protein expression in renal cortex and medulla. Protein expression of interleukin‐6, Nox2 and ETA receptors and superoxide production were increased whereas MnSOD and ETB receptor expression were decreased in kidneys of aged rats. Interestingly, these changes were more pronounced in the impaired than in the intact rats. Conclusions: Aging‐related renal damage was associated with decreased klotho, increased inflammation, and increased superoxide production. Renal damage parallels with cognitive function impairment. Further studies are required to evaluate the role of klotho, ET receptors, and Nox2 and their relationship in aging‐related renal damage.