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Nambidi S, Pallatt S, Banerjee A, Pathak S, Chan MKS. Klotho protein: a multifaceted regulator in aging and cancer dynamics. Mol Biol Rep 2025; 52:507. [PMID: 40423846 DOI: 10.1007/s11033-025-10575-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2025] [Accepted: 05/04/2025] [Indexed: 05/28/2025]
Abstract
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.
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Affiliation(s)
- Sibin Nambidi
- Department of Medical Biotechnology, Faculty of Allied Health Sciences, Chettinad Academy of Research and Education (CARE), Chettinad Hospital and Research Institute (CHRI), Chennai, Tamil Nadu, India
| | - Sneha Pallatt
- Department of Medical Biotechnology, Faculty of Allied Health Sciences, Chettinad Academy of Research and Education (CARE), Chettinad Hospital and Research Institute (CHRI), Chennai, Tamil Nadu, India
| | - Antara Banerjee
- Department of Medical Biotechnology, Faculty of Allied Health Sciences, Chettinad Academy of Research and Education (CARE), Chettinad Hospital and Research Institute (CHRI), Chennai, Tamil Nadu, India.
| | - Surajit Pathak
- Department of Medical Biotechnology, Faculty of Allied Health Sciences, Chettinad Academy of Research and Education (CARE), Chettinad Hospital and Research Institute (CHRI), Chennai, Tamil Nadu, India.
| | - Mike K S Chan
- European Wellness Biomedical Group, Klosterstrasse 205, 67480, Edenkoben, Germany
- Baden R&D Laboratories GmbH, Ferdinand-Lassalle-Strasse 40, 72770, Reutlingen, Germany
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Tang Y, Lei M, Dong W, Liu Z, Jiang W, Hao J, Hu Z. Association between serum α-Klotho levels and mortality in US adults with osteoporosis. BMC Public Health 2025; 25:1332. [PMID: 40205380 PMCID: PMC11984054 DOI: 10.1186/s12889-025-22540-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Accepted: 03/28/2025] [Indexed: 04/11/2025] Open
Abstract
BACKGROUND Klotho, a protein known for its significant involvement in the aging process and age-related diseases, has been demonstrated to be inextricably linked to osteoporosis. Nevertheless, the relationship between serum Klotho levels and mortality risk among individuals with osteoporosis has not been definitively established. Therefore, the purpose of the current research is to examine the potential relationship between serum Klotho levels and mortality risk in individuals aged 40 and above with osteoporosis. METHODS The current study included adults aged 40 years and older diagnosed with osteoporosis from the National Health and Nutrition Examination Survey. Osteoporosis diagnosis was based on a history of osteoporosis or bone mineral density. Moreover, Cox proportional hazards regression, Kaplan-Meier (KM) curves, and restricted cubic spline (RCS) curves were utilized to assess the relationship between Klotho levels and mortality risk. In addition, subgroup analysis was performed using stratification and interaction analysis for all covariates. RESULTS A total of 1004 participants (median age: 65 years) with a median follow-up of 9.33 years were included in the final analysis. This study found that serum Klotho levels established a U-shaped relationship with the risk of all-cause mortality in individuals with osteoporosis, with a nadir of Klotho levels was approximately 900 pg/mL, in which lower (< 850 pg/mL) or higher (> 950 pg/mL) Klotho levels were significantly associated with an increased risk of all-cause mortality. Moreover, the results of subgroup analysis indicated that the associations between Klotho levels and mortality risk were modified by several factors, especially a history of hypertension. Specifically, Klotho levels established an L-shaped relationship with the risk of all-cause mortality among participants with a history of hypertension, while a positive and linear relationship with the risk of all-cause mortality among those without a history of hypertension. CONCLUSIONS For individuals with osteoporosis, it is necessary to be alert to cases with high or low Klotho levels, which may potentially indicate an increased mortality risk.
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Affiliation(s)
- Yuchen Tang
- Department of Orthopedics, University-Town Hospital of Chongqing Medical University, Chongqing, China
- Department of Orthopedics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Miao Lei
- Department of Orthopedics, University-Town Hospital of Chongqing Medical University, Chongqing, China
- Department of Orthopedics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Wei Dong
- Department of Spinal Surgery, Chongqing Orthopedic Hospital of Traditional Chinese Medicine, Chongqing, China
| | - Zeyu Liu
- Department of Orthopedics, University-Town Hospital of Chongqing Medical University, Chongqing, China
- Department of Orthopedics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Wei Jiang
- Department of Orthopedics, Nanchuan Hospital of Chongqing Medical University, Chongqing, China
| | - Jie Hao
- Department of Orthopedics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
| | - Zhenming Hu
- Department of Orthopedics, University-Town Hospital of Chongqing Medical University, Chongqing, China.
- Department of Orthopedics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
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Hao JB, Wang SY, Chen T, Yuan B, Hao LR. Risk factors for radial artery calcification in patients with and without uremia. BMC Nephrol 2025; 26:18. [PMID: 39799338 PMCID: PMC11724451 DOI: 10.1186/s12882-024-03940-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2024] [Accepted: 12/31/2024] [Indexed: 01/15/2025] Open
Abstract
BACKGROUND Calcification of the radial artery is one of the main causes of anastomotic stenosis in autogenous arteriovenous fistulas in uremic patients. However, the pathogenesis of calcification is still unknown. This study attempted to screen and validate the risk factors for vascular calcification in patients with uremia. METHODS Serum of blood were collected and tissue samples from radial artery were obtained from 60 uremia patients with or without hemodialysis. General biochemical indicators and calcification-related molecules were collected and detected via ELISA or correlation analysis. In addition, pathological changes and calcification-related molecules in the radial artery were evaluated by HE or immunohistochemical staining. RESULTS There were differences in total calcium, calcium-phosphorus products, allograft inflammatory factor 1 (AIF-1), intact parathyroid hormone (iPTH), vitamin D (VD), fibroblast growth factor 23 (FGF23) and soluble klotho (sKlotho) in the blood of uremic patients with or without hemodialysis. Furthermore, these factors are related to calcification of the radial artery. The expression of AIF-1, PTHR1, VDR, FGF23 and sKlotho was also increased in the calcified radial artery. CONCLUSIONS The levels of AIF-1, PTH, VDR, FGF23 and sKlotho in serum were associated with calcification of the radial artery in patients with uremia. Furthermore, calcification of the radial artery was further aggravated by abnormalities in calcium and phosphorus in maintenance hemodialysis patients.
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Affiliation(s)
- Jian-Bing Hao
- Department of Nephrology, Southern University of Science and Technology Hospital, Shenzhen, China.
| | - Si-Yu Wang
- Department of Nephrology, Southern University of Science and Technology Hospital, Shenzhen, China
| | - Tong Chen
- Department of Nephrology, Southern University of Science and Technology Hospital, Shenzhen, China
| | - Bo Yuan
- Department of Clinical Laboratory, Southern University of Science and Technology Hospital, Shenzhen, China
| | - Li-Rong Hao
- Department of Nephrology, Southern University of Science and Technology Hospital, Shenzhen, China
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Amaro-Gahete FJ, Espuch-Oliver A, Cano-Nieto A, Alcantara JMA, García-Lario JV, De Haro T, Llamas-Elvira JM, Muñoz Torres M, Castillo MJ, Labayen I, Ruiz JR. Impact of 24-week supervised concurrent exercise on S-Klotho and vitamin D levels: A randomized controlled trial. J Sports Sci 2024; 42:2562-2571. [PMID: 39831661 DOI: 10.1080/02640414.2025.2453328] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Accepted: 01/07/2025] [Indexed: 01/22/2025]
Abstract
This study aimed to investigate the effects 24 weeks of supervised exercise training at different intensities on S-Klotho and 25-hydroxyvitamin D plasma levels in young adults. This report was based on a secondary analysis from the ACTIBATE single-center unblinded randomized controlled trial (ClinicalTrials.gov ID: NCT02365129). A total of 144 young adults (~34% men and ~66% women) aged between 18 and 25 years took part in the study. The participants were randomly assigned to 3 different groups: (i) concurrent exercise training program based on the international physical activity recommendations at vigorous intensity (Ex-Vigorous group), (ii) at moderate intensity (Ex-Moderate group), and (iii) control group (no exercise). S-Klotho and 25-hydroxyvitamin D plasma levels were determined before and after the 24-week intervention programme. A significant decrease of 25-hydroxyvitamin D plasma levels were identified across time in all groups (p < 0.001), whereas no significant differences across time were observed in S-Klotho plasma levels (p = 0.497). There was no time x group interaction neither in S-Klotho nor in 25-hydroxyvitamin D plasma levels (all p > 0.7). In summary, our results showed that 24 weeks of supervised concurrent exercise training does not induce significant changes on S-Klotho and 25-hydroxyvitamin D independently of the exercise intensity in young adults.
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Affiliation(s)
- F J Amaro-Gahete
- Department of Physiology, Faculty of Medicine, University of Granada, Granada, Spain
- Centro de Investigación Biomédica en Red Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III, Madrid, Spain
- Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA), Granada, Spain
| | - A Espuch-Oliver
- Unidad de Gestión Clínica de Laboratorios Clínicos, Hospital Clínico Universitario San Cecilio, Ibs.Granada, Complejo Hospitalario de Granada, Granada, Spain
| | - A Cano-Nieto
- Department of Physical Education and Sports, Faculty of Sport Sciences, Sport and Health University Research Institute (iMUDS), Granada, Spain
| | - J M A Alcantara
- Centro de Investigación Biomédica en Red Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III, Madrid, Spain
- Navarra Institute for Health Research, Pamplona, Spain
- Department of Education, Faculty of Education Sciences, University of Almería, Almería, Spain
| | - J V García-Lario
- Unidad de Gestión Clínica de Laboratorios Clínicos, Hospital Clínico Universitario San Cecilio, Ibs.Granada, Complejo Hospitalario de Granada, Granada, Spain
| | - T De Haro
- Unidad de Gestión Clínica de Laboratorios Clínicos, Hospital Clínico Universitario San Cecilio, Ibs.Granada, Complejo Hospitalario de Granada, Granada, Spain
| | - J M Llamas-Elvira
- Servicio de Medicina Nuclear, Hospital Universitario Virgen de las Nieves, Granada, Spain
| | - M Muñoz Torres
- Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA), Granada, Spain
- Department of Medicine, University of Granada, Granada, Spain
- CIBER on Frailty and Healthy Aging (CIBERFES), Instituto de Salud Carlos III, Madrid, Spain
- Endocrinology and Nutrition Unit, University Hospital Clínico San Cecilio, Granada, Spain
| | - M J Castillo
- Department of Physiology, Faculty of Medicine, University of Granada, Granada, Spain
- Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA), Granada, Spain
| | - I Labayen
- Centro de Investigación Biomédica en Red Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III, Madrid, Spain
- Department of Physical Education and Sports, Faculty of Sport Sciences, Sport and Health University Research Institute (iMUDS), Granada, Spain
- Department of Medicine, University of Granada, Granada, Spain
- Institute for Sustainability & Food Chain Innovation, Department of Health Sciences, Public University of Navarre, Pamplona, Spain
| | - J R Ruiz
- Centro de Investigación Biomédica en Red Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III, Madrid, Spain
- Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA), Granada, Spain
- Department of Physical Education and Sports, Faculty of Sport Sciences, Sport and Health University Research Institute (iMUDS), Granada, Spain
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Mohanty SK, Mohanty AK, Kumar MS, Suchiang K. Triiodothyronine enhances various forms of kidney-specific Klotho protein and suppresses the Wnt/β-catenin pathway: Insights from in-vitro, in-vivo and in-silico investigations. Cell Signal 2024; 120:111214. [PMID: 38729322 DOI: 10.1016/j.cellsig.2024.111214] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2024] [Revised: 04/21/2024] [Accepted: 05/06/2024] [Indexed: 05/12/2024]
Abstract
Age-related diseases are intricately linked to the molecular processes underlying aging, with the decline of the antiaging protein Klotho being a key factor. Investigating these processes is crucial for developing therapeutic strategies. The age-associated reduction in Klotho expression, coupled with a decline in the endocrine hormone triiodothyronine (T3), prompted a detailed exploration of their potential interplay. Our research, conducted through both in-vitro and in-vivo studies on BALB/c mice, unveiled a significant capacity of T3 to upregulate various forms of Klotho via ATF-3/p-c-Jun transcription factor. This effect was particularly noteworthy in aged individuals, where Klotho expression had waned compared to their younger counterparts. Importantly, T3 demonstrated a promising therapeutic impact in rejuvenating Klotho expression in this context. Further investigations elucidated the molecular mechanisms underlying T3's impact on aging-related pathways. In-vitro and in-vivo experiments established T3's ability to downregulate the Wnt/β-Catenin pathway by enhancing Klotho expression. In-silico analyses provided insights into Klotho's intricate role, showing its capacity to inhibit Wnt ligands such as Wnt3 and Wnt8a, consequently disrupting their interaction with the Wnt receptor. Additionally, T3 was found to downregulate kidney-specific GSK-3β expression through the augmentation of Klotho expression. The study also highlighted T3's role in maintaining calcium and phosphate homeostasis via Klotho. This comprehensive investigation not only sheds light on the intricate mechanisms governing aging processes but also presents promising avenues for therapeutic interventions targeting the Wnt/β-Catenin pathway implicated in various age-associated diseases.
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Affiliation(s)
- Saswat Kumar Mohanty
- Department of Biochemistry and Molecular Biology, Pondicherry University, Pondicherry 605 014, India.
| | | | | | - Kitlangki Suchiang
- Department of Biochemistry, North Eastern Hill University, Shillong, Meghalaya 793022, India.
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Hu M, Yang M, Tang H, Zhang C. The association between exposure to volatile organic chemicals and serum α-Klotho in USA middle to old aged population: A cross-sectional study from NHANES 2011-2016. THE SCIENCE OF THE TOTAL ENVIRONMENT 2024; 934:173083. [PMID: 38761942 DOI: 10.1016/j.scitotenv.2024.173083] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/16/2024] [Revised: 03/30/2024] [Accepted: 05/07/2024] [Indexed: 05/20/2024]
Abstract
BACKGROUND Volatile Organic Compounds (VOCs) constitute an omnipresent category of environmental contaminants. Numerous studies have identified associations between various VOCs and human diseases. The anti-aging protein α-Klotho has been shown to exert protective influences across a variety of disease origins and progressions. This study aims to explore the relationship between serum α-Klotho levels and exposure to VOCs in humans. METHODS This analysis utilized data from 1672 participants aged from 40 to 79 years in 2011-2016 NHANES. Exposure to VOCs was assessed through measurements of urinary VOC metabolites (mVOCs), with 16 mVOCs selected for analysis. Multivariate generalized linear models (GLM), restricted cubic splines (RCS), weighted quantile sum (WQS) regression models, and Bayesian kernel machine regression (BKMR) models were employed to examine the connection between serum α-Klotho and individual mVOCs and mVOCs mixtures, as well as to identify the primary monomeric mVOCs responsible for these associations. RESULTS Our research revealed that 8 mVOCs exhibited inverse associations with serum α-Klotho levels in GLM and RCS models. Particularly noteworthy, N-Acetyl-S-(2-cyanoethyl)-L-cysteine (CYMA), a metabolite of acrylonitrile, emerged as the most influential mVOC in both WQS and BKMR models. Furthermore, the mVOCs mixture was found to be negatively correlated with serum α-Klotho. The detrimental effects of mVOCs on serum α-Klotho were observed to significantly diminish in individuals with elevated serum vitamin D levels. CONCLUSION Our study highlights a significant inverse relationship between serum α-Klotho and the mixture of mVOCs, indicating that exposure to VOCs may impact the molecular pathways of aging and related diseases by influencing α-Klotho concentrations. Remarkably, the attenuation of this association by high serum vitamin D levels implies potential therapeutic strategies. Our study underscores the importance of minimizing VOCs exposure to mitigate the adverse effects on α-Klotho. Further research is warranted to elucidate the underlying mechanisms of these relationships.
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Affiliation(s)
- Mingcun Hu
- Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China
| | - Min Yang
- Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China
| | - Hui Tang
- Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China
| | - Chun Zhang
- Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China.
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Liu Y, Zhou C, Shen R, Wang A, Zhang T, Cao Z. Dietary folate intake and serum klotho levels in adults aged 40-79 years: a cross-sectional study from the national health and nutrition examination survey 2007-2016. Front Nutr 2024; 11:1420087. [PMID: 39040924 PMCID: PMC11260802 DOI: 10.3389/fnut.2024.1420087] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2024] [Accepted: 06/26/2024] [Indexed: 07/24/2024] Open
Abstract
Objective This study aims to explore the relationship between dietary folate intake and serum Klotho levels in adults from aged 40 to 79 years in the United States, seeking to elucidate the intricacies of their interaction. Methods Analyzing data from the National Health and Nutrition Examination Survey (NHANES) spanning 2007 to 2016. The survey research determined folate intake through a 24-h dietary recall and nutrient density modeling, and assessed Klotho levels using enzyme-linked immunosorbent assay (ELISA). The relationship between folate intake and Klotho levels was evaluated using weighted linear regression, and complemented by analysis via smoothed curve models for nuanced understanding. Results The study encompassed 10,278 participants, with an average age of 57.64 years, revealing a noteworthy positive correlation between dietary folate and serum Klotho levels. The regression coefficient stood at 0.11 (95% confidence interval, 0.05, 0.18) post-adjustment for various covariates. When dietary folate intake was categorized into quartiles, the second, third, and fourth quartiles exhibited statistically significant differences compared to the lowest quartile. This indicates that higher folate intake correlates with increased serum Klotho levels. These findings underscore the potential benefits of elevating folate intake to enhance serum Klotho levels. Stratified analysis indicated that this association was more pronounced among males aged 60 years or older and individuals with hypertension. Conclusion The findings suggest a significant correlation between increased dietary folate intake and elevated serum Klotho levels in adults aged 40-79 years. Hinting at the potential nutritional influences on the aging process and associated health conditions. This calls for further exploration into the mechanisms and broader implications of this association.
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Affiliation(s)
- Yang Liu
- Department of Medical Laboratory, Guihang 300 Hospital Affiliated to Zunyi Medical University, Guiyang, China
| | - Chunhuan Zhou
- Department of Medical Laboratory, Guihang 300 Hospital Affiliated to Zunyi Medical University, Guiyang, China
| | - Rongjun Shen
- Hospital Infection Control Department, Guihang 300 Hospital Affiliated to Zunyi Medical University, Guiyang, China
| | - Anxian Wang
- Department of Medical Laboratory, Guihang 300 Hospital Affiliated to Zunyi Medical University, Guiyang, China
| | - Tingting Zhang
- Department of Endocrinology, Guihang 300 Hospital Affiliated to Zunyi Medical University, Guiyang, China
| | - Zhengyuan Cao
- Department of Medical Laboratory, Guihang 300 Hospital Affiliated to Zunyi Medical University, Guiyang, China
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Liu S, Zhu Z, Yu K, Zhang W, Pu J, Lv Y, Tang Z, Liu F, Sun Y. U-shaped association between serum Klotho and all-cause mortality in US cardiovascular patients: a prospective cohort study. Front Endocrinol (Lausanne) 2024; 15:1405665. [PMID: 38948524 PMCID: PMC11212453 DOI: 10.3389/fendo.2024.1405665] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2024] [Accepted: 05/31/2024] [Indexed: 07/02/2024] Open
Abstract
Background Increased levels of serum Klotho have been associated with a reduced risk of several cardiovascular diseases (CVD). However, limited studies exist on the association between serum Klotho and mortality in patients with CVD. Methods We collected data from CVD patients in the National Health and Nutrition Examination Survey (NHANES) spanning 2007 to 2016. We linked NHANES data with the National Death Index to determine the survival status of participants. Univariate and multivariable Cox regression models were used to investigate the relationship between serum Klotho levels and mortality in CVD patients. The relationship between serum Klotho quartiles and mortality in CVD patients was visualized using Kaplan-Meier (KM) curves and restricted cubic spine. Finally, subgroup analyses were used to examine the association between serum Klotho and all-cause mortality in different populations. Results 1905 patients with CVD were finally enrolled in our study with a mean follow-up of 7.1 years. The average age of the participants was 63.4 years, with 58.40% being male. KM showed that lower Klotho levels were associated with lower survival rates. After adjusting for potential confounders, patients with higher serum Klotho levels had lower all-cause mortality (Q1: 1.00, Q2: 0.58 (0.42-0.80), Q3: 0.69 (0.47-1.01), and Q4:0.64 (0.45-0.92). However, the relationship between serum Klotho levels and cardiovascular mortality was not statistically significant. Dose-response analysis shows a U-shaped relationship between serum Klotho levels and all-cause mortality in patients with CVD (P nonlinear=0.002). Subgroup analysis indicated that participants with a history of hypertension had a higher risk of all-cause mortality in serum Klotho Q4 compared to Q1 (P trend <0.05). Conclusion The relationship between serum Klotho levels and all-cause mortality in CVD patients exhibits a U-shaped association. The underlying mechanisms of this association need further investigation.
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Affiliation(s)
- Shasha Liu
- Department of Cardiology, Shaanxi Provincial People’s Hospital, Xi’an, China
| | - Zhanfang Zhu
- Department of Internal Medicine, Xi’an Jiaotong University Hospital, Xi’an, China
| | - Kai Yu
- Department of Cardiology, Pucheng County Hospital, Weinan, China
| | - Wei Zhang
- Department of Cardiology, Shaanxi Provincial People’s Hospital, Xi’an, China
| | - Jie Pu
- Department of Cardiology, Shaanxi Provincial People’s Hospital, Xi’an, China
| | - Ying Lv
- Department of Cardiology, Shaanxi Provincial People’s Hospital, Xi’an, China
| | - Zhiguo Tang
- Department of Cardiology, Shaanxi Provincial People’s Hospital, Xi’an, China
| | - Fuqiang Liu
- Department of Cardiology, Shaanxi Provincial People’s Hospital, Xi’an, China
| | - Yongqiang Sun
- Department of Cardiology, Shaanxi Provincial People’s Hospital, Xi’an, China
- Department of Interventional Radiography, Shanxi Provincial People’s Hospital, Xi’an, China
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Zhang FF, Xu YQ, Xiong JH, Hu JX, Zhu GS, Cheng SM. Bibliometric study and review of Klotho research: global characteristics and trends from 2000 to 2023. Int Urol Nephrol 2024; 56:1045-1056. [PMID: 37728807 DOI: 10.1007/s11255-023-03792-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2023] [Accepted: 09/06/2023] [Indexed: 09/21/2023]
Abstract
BACKGROUND Although Klotho-related research has seen a significant upsurge, the field lacks comprehensive analytical representation and in-depth exploration of pertinent areas such as prevailing research trends and key focus areas. METHOD This review presents a bibliometric analysis of literature data gathered from the Web of Science Core Collection databases from January 1, 2000, to April 30, 2023. Parameters such as co-authorship, co-citation, co-occurrence, and the emergence of publications, countries, categories, references, and keywords were scrutinized predominantly using Citespace software. RESULTS Our investigation amassed a total of 3548 papers, with the United States leading in the quantity of publications (1175, accounting for 33.12%), followed by China (867, representing 24.44%), and Japan (439, accounting for 12.37%). While the United States is preeminent in the overall volume of publications, Scotland holds prominence in terms of centrality. Out of a total of 96 subject categories, urology and nephrology (573), and endocrinology and metabolism (542) were the two leading domains of Klotho-related publications. The 2011 paper titled "FGF23 induces left ventricular hypertrophy" by Faul C et al. holds the distinction of being the most frequently cited. The keywords "fibroblast growth factor 23," "phosphate homeostasis," and "functional variants" demonstrated the highest intensity, underscoring the potential of these research areas. CONCLUSION As the volume of literature grows, the role of Klotho in disease management and its applicability as a marker in disease progression warrant vigilant tracking and study.
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Affiliation(s)
- Fen-Fen Zhang
- Graduate School, Jiangxi University of Traditional Chinese Medicine, Jiangxi, China
| | - Yue-Qi Xu
- Graduate School, Jiangxi University of Traditional Chinese Medicine, Jiangxi, China
| | - Jiang-Hao Xiong
- Graduate School, Jiangxi University of Traditional Chinese Medicine, Jiangxi, China
| | - Jun-Xia Hu
- Graduate School, Jiangxi University of Traditional Chinese Medicine, Jiangxi, China
| | - Guo-Shuang Zhu
- College of Traditional Chinese Medicine, Jiangxi University of Traditional Chinese Medicine, No.1688 Meiling Avenue, Nanchang, 33004, Jiangxi Province, China.
| | - Shao-Min Cheng
- College of Traditional Chinese Medicine, Jiangxi University of Traditional Chinese Medicine, No.1688 Meiling Avenue, Nanchang, 33004, Jiangxi Province, China.
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Liu L, Jia J, Cheng X, Gao S, Yan T. The optimal cut-off values of Klotho for predicting all-cause and cardiovascular mortality among chronic kidney disease: results from NHANES. Sci Rep 2024; 14:4647. [PMID: 38409304 PMCID: PMC10897465 DOI: 10.1038/s41598-024-52701-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2023] [Accepted: 01/22/2024] [Indexed: 02/28/2024] Open
Abstract
To explore the optimal cut-off values of Klotho for predicting all-cause and cardiovascular mortality among chronic kidney disease (CKD) patients. Klotho was measured in 40-79-year-old individuals in the NHANES 2007-2016. A total of 2418 patients with stage 1-4 CKD were included. The optimal cut-off values of Klotho were utilized using receiver operator characteristic (ROC) curves and be verified on the effects of all-cause and cardiovascular mortality. Restricted cubic splines were used to examine the relationship between Klotho and all-cause and cardiovascular mortality with the optimal cutpoints as the reference. After a mean follow-up period of 87.9 months, 535 deaths occurred and 188 died of cardiovascular disease. Cubic splines showed that the risk of all-cause and cardiovascular mortality increased gradually for Klotho < 700 pg/ml. ROC curves revealed that the optimal cut-off values of Klotho for all-cause and cardiovascular mortality are 548.8 pg/ml and 660.9 pg/ml, respectively. Compared to patients with higher levels of Klotho, HRs (95% CIs) for all-cause and cardiovascular mortality were 1.52 (1.23, 1.87) and 1.58 (1.13, 2.22) among patients with lower levels of Klotho, respectively, in the multivariate model (P < .0001 and P = 0.008). Our findings revealed the optimal cut-off values of Klotho for all-cause and cardiovascular mortality in CKD.
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Affiliation(s)
- Lili Liu
- Department of Nephrology, General Hospital of Tianjin Medical University, No. 154, Anshan Road, Heping District, Tianjin, 300052, China
| | - Junya Jia
- Department of Nephrology, General Hospital of Tianjin Medical University, No. 154, Anshan Road, Heping District, Tianjin, 300052, China
| | - Xi Cheng
- Department of Nephrology, General Hospital of Tianjin Medical University, No. 154, Anshan Road, Heping District, Tianjin, 300052, China
| | - Shan Gao
- Department of Nephrology, General Hospital of Tianjin Medical University, No. 154, Anshan Road, Heping District, Tianjin, 300052, China
| | - Tiekun Yan
- Department of Nephrology, General Hospital of Tianjin Medical University, No. 154, Anshan Road, Heping District, Tianjin, 300052, China.
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Chen Z, Liu M, Xu X, He L, Wang P, Cai X, Huang R, Zhang S, Xu X, Lai Y, Huang Y, Li M, Lin Y, Xie P, Liao X, Zhuang X, Guo Y. Serum Klotho Modifies the Associations of 25-Hydroxy Vitamin D With All-Cause and Cardiovascular Mortality. J Clin Endocrinol Metab 2024; 109:581-591. [PMID: 37579499 DOI: 10.1210/clinem/dgad480] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2023] [Revised: 08/03/2023] [Accepted: 08/10/2023] [Indexed: 08/16/2023]
Abstract
BACKGROUND The association between 25-hydroxyvitamin D and mortality remains controversial. Klotho, a biomarker of vitamin D activation and metabolism, may play a key role in this association. However, it is unclear whether the association between vitamin D deficiency and mortality risk is modified by klotho levels. Therefore, this study investigated the joint association of serum 25-hydroxyvitamin D [25(OH)D] and klotho with mortality risk in American community-dwelling adults. METHODS A total of 9870 adults from the National Health and Nutrition Examination Survey (2007-2016) were included in our study. Mortality data were ascertained by linking participants to National Death Index records. Cox proportional hazards models were used to assess the association among serum 25(OH)D, serum klotho, and all-cause and cardiovascular disease (CVD) mortality. RESULTS We found a significant interaction between klotho and serum 25(OH)D in all-cause mortality (P = .028). With klotho > 848.4 pg/mL (risk threshold on mortality), no significant all-cause and CVD mortality risk was observed at any level of serum 25(OH)D. However, with klotho < 848.4 pg/mL, a significant all-cause and CVD mortality risk was observed with serum 25(OH)D < 50 nmol/L [hazards ratio (HR), 1.36; 95% confidence interval (CI), 1.10-1.69; HR, 1.78; 95% CI, 1.16-3.45) and serum 25(OH)D of continuous variable (HR, 0.98; 95% CI, .97-.99; HR, 0.98; 95% CI, .98-.99). In addition, vitamin D metabolism disruption accessed by the combination of decreasing serum 25(OH)D (<50 nmol/L) and klotho (<848.4 pg/mL) was associated with significant all-cause mortality (HR, 1.48; 95% CI, 1.11-1.96) and CVD mortality (HR, 2.36; 95% CI, 1.48-3.75). CONCLUSIONS Vitamin D-associated mortality risk is observed only with concurrently decreasing klotho, indicating that vitamin D metabolism dysfunction increases the risk of mortality. Klotho levels could help predict long-term mortality outcomes and thus may be useful concurrently for guiding vitamin D supplementation therapy decision-making in populations with vitamin D deficiency.
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Affiliation(s)
- Zhuohui Chen
- Department of Cardiology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510080, P.R. China
- NHC Key Laboratory of Assisted Circulation (Sun Yat-sen University), Guangzhou, Guangdong 510080, P. R. China
| | - Menghui Liu
- Department of Cardiology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510080, P.R. China
- NHC Key Laboratory of Assisted Circulation (Sun Yat-sen University), Guangzhou, Guangdong 510080, P. R. China
| | - Xingfeng Xu
- Department of Cardiology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510080, P.R. China
- NHC Key Laboratory of Assisted Circulation (Sun Yat-sen University), Guangzhou, Guangdong 510080, P. R. China
| | - Lixiang He
- Department of Cardiology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510080, P.R. China
- NHC Key Laboratory of Assisted Circulation (Sun Yat-sen University), Guangzhou, Guangdong 510080, P. R. China
| | - Peng Wang
- Department of Cardiology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510080, P.R. China
- NHC Key Laboratory of Assisted Circulation (Sun Yat-sen University), Guangzhou, Guangdong 510080, P. R. China
| | - Xiaojie Cai
- Department of Cardiology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510080, P.R. China
- NHC Key Laboratory of Assisted Circulation (Sun Yat-sen University), Guangzhou, Guangdong 510080, P. R. China
| | - Rihua Huang
- Department of Cardiology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510080, P.R. China
- NHC Key Laboratory of Assisted Circulation (Sun Yat-sen University), Guangzhou, Guangdong 510080, P. R. China
| | - Shaozhao Zhang
- Department of Cardiology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510080, P.R. China
- NHC Key Laboratory of Assisted Circulation (Sun Yat-sen University), Guangzhou, Guangdong 510080, P. R. China
| | - Xinghao Xu
- Department of Cardiology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510080, P.R. China
- NHC Key Laboratory of Assisted Circulation (Sun Yat-sen University), Guangzhou, Guangdong 510080, P. R. China
| | - Yuhui Lai
- Department of Cardiology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510080, P.R. China
- NHC Key Laboratory of Assisted Circulation (Sun Yat-sen University), Guangzhou, Guangdong 510080, P. R. China
| | - Yiquan Huang
- Department of Cardiology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510080, P.R. China
- NHC Key Laboratory of Assisted Circulation (Sun Yat-sen University), Guangzhou, Guangdong 510080, P. R. China
| | - Miaohong Li
- Department of Cardiology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510080, P.R. China
- NHC Key Laboratory of Assisted Circulation (Sun Yat-sen University), Guangzhou, Guangdong 510080, P. R. China
| | - Yifen Lin
- Department of Cardiology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510080, P.R. China
- NHC Key Laboratory of Assisted Circulation (Sun Yat-sen University), Guangzhou, Guangdong 510080, P. R. China
| | - Peihan Xie
- Department of Cardiology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510080, P.R. China
- NHC Key Laboratory of Assisted Circulation (Sun Yat-sen University), Guangzhou, Guangdong 510080, P. R. China
| | - Xinxue Liao
- Department of Cardiology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510080, P.R. China
- NHC Key Laboratory of Assisted Circulation (Sun Yat-sen University), Guangzhou, Guangdong 510080, P. R. China
| | - Xiaodong Zhuang
- Department of Cardiology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510080, P.R. China
- NHC Key Laboratory of Assisted Circulation (Sun Yat-sen University), Guangzhou, Guangdong 510080, P. R. China
| | - Yue Guo
- Department of Cardiology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510080, P.R. China
- NHC Key Laboratory of Assisted Circulation (Sun Yat-sen University), Guangzhou, Guangdong 510080, P. R. China
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Ranjbar N, Raeisi M, Barzegar M, Ghorbanihaghjo A, Shiva S, Sadeghvand S, Negargar S, Poursistany H, Raeisi S. The possible anti-seizure properties of Klotho. Brain Res 2023; 1820:148555. [PMID: 37634687 DOI: 10.1016/j.brainres.2023.148555] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2023] [Revised: 07/30/2023] [Accepted: 08/23/2023] [Indexed: 08/29/2023]
Abstract
Recurrent seizures in epilepsy may lead to progressive neuronal damage, which can diminish health-related quality of life. Evaluation and control of pathological processes in the brain is valuable. It seems imperative that new markers and approaches for seizure alleviation be discovered. Klotho (Kl), an antiaging protein, has protective effects in the brain against neurological disorders. It may also have antiseizure effects by improving creatine transfer to the brain, upregulating excitatory amino acid transporters, and inhibiting insulin/insulin-like growth factor-1 (IGF-1), Wingless (Wnt), transforming growth factor-beta (TGF-β), and retinoic-acid-inducible gene-I (RIG-I)/nuclear translocation of nuclear factor-κB (NF-κB) pathways. Stimulation and activation of the nuclear factor erythroid 2-related factor 2 (Nrf2) and apoptosis signal-regulating kinase 1 (ASK1)/p38 mitogen‑activated protein kinase (MAPK) signaling pathways could also be considered other possible antiseizure mechanisms of Kl. In the present review, the roles of Kl in the central nervous system as well as its possible anti-seizure properties are discussed for the first time.
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Affiliation(s)
- Nasrin Ranjbar
- Department of Clinical Biochemistry and Laboratory Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammadreza Raeisi
- Student Research Committee, Ahvaz Jondishapur University of Medical Sciences, Ahvaz, Iran
| | - Mohammad Barzegar
- Pediatric Health Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Amir Ghorbanihaghjo
- Biothechnology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Siamak Shiva
- Pediatric Health Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Shahram Sadeghvand
- Pediatric Health Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Sohrab Negargar
- Cardiovascular Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Haniyeh Poursistany
- Department of Clinical Biochemistry and Laboratory Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Sina Raeisi
- Pediatric Health Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Clinical Research Development Unit of Zahra Mardani Azari Children Educational and Treatment Center, Tabriz University of Medical Sciences, Tabriz, Iran.
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13
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Li H, Miao S, Zhang M, Zhang P, Li YB, Duan RS. U-shaped association between serum Klotho and accelerated aging among the middle-aged and elderly US population: a cross-sectional study. BMC Geriatr 2023; 23:780. [PMID: 38017397 PMCID: PMC10685632 DOI: 10.1186/s12877-023-04479-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2023] [Accepted: 11/10/2023] [Indexed: 11/30/2023] Open
Abstract
BACKGROUND Phenotypic age acceleration, which reflects the difference between phenotypic age and chronological age, is an assessment to measure accelerated aging. Klotho is a protein related to slower aging, but its association with accelerated aging remains unclear. METHODS Based on data from the 2007-2010 National Health and Nutrition Examination Survey, phenotypic age was calculated using chronological age and 9 aging-related biomarkers. A total of 4388 participants aged 40 to 79 years with measured serum Klotho and calculated phenotypic age were enrolled. The association between serum Klotho and phenotypic age acceleration was estimated using multivariable linear regression models. The possible nonlinear relationship was examined with smooth curve fitting. We also conducted a segmented regression model to examine the threshold effect. RESULTS The association between serum Klotho and phenotypic age acceleration followed a U-shaped curve (p for nonlinearity < 0.001), with the inflection point at 870.7 pg/ml. The phenotypic age acceleration significantly decreased with the increment of serum Klotho (per SD increment: β -1.77; 95% CI, -2.57 ~ -0.98) in participants with serum Klotho < 870.7 pg/ml, and increased with the increment of serum Klotho (per SD increment:β, 1.03; 95% CI: 0.53 ~ 1.54) in participants with serum Klotho ≥ 870.7 pg/ml. CONCLUSION There was a U-shaped association between serum Klotho and accelerated aging among the middle-aged and elderly US population.
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Affiliation(s)
- Heng Li
- Department of Neurology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, 250014, People's Republic of China
- Shandong Institute of Neuroimmunology, Jinan, 250014, People's Republic of China
| | - Shuai Miao
- Medical School of Chinese People's Liberation Army (PLA), Beijing, 100853, People's Republic of China
- Department of Neurology, the First Medical Center, Chinese PLA General Hospital, Beijing, 100853, People's Republic of China
| | - Min Zhang
- Department of Neurology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, 250014, People's Republic of China
- Shandong Institute of Neuroimmunology, Jinan, 250014, People's Republic of China
| | - Peng Zhang
- Department of Neurology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, 250014, People's Republic of China
- Shandong Institute of Neuroimmunology, Jinan, 250014, People's Republic of China
| | - Yan-Bin Li
- Department of Neurology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, 250014, People's Republic of China
- Shandong Institute of Neuroimmunology, Jinan, 250014, People's Republic of China
| | - Rui-Sheng Duan
- Department of Neurology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, 250014, People's Republic of China.
- Shandong Institute of Neuroimmunology, Jinan, 250014, People's Republic of China.
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14
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Chuang MH, Wang HW, Huang YT, Jiang MY. Association between soluble α-klotho and mortality risk in middle-aged and older adults. Front Endocrinol (Lausanne) 2023; 14:1246590. [PMID: 37693344 PMCID: PMC10484398 DOI: 10.3389/fendo.2023.1246590] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2023] [Accepted: 08/11/2023] [Indexed: 09/12/2023] Open
Abstract
Introduction Studies on association of α-klotho levels with mortality risk in general population are relatively scarce and inconclusive. Therefore, we conducted a population-based cohort study to investigate the relationship between soluble α-klotho and all-cause mortality in a nationally representative sample of middle-aged and older adults in the United States (U.S.). Methods The study population was 2007-2016 National Health and Nutrition Examination Survey (NHANES) participants, totaling 13,583 adults aged 40-79 years. Participants were divided into 7 groups by septile of α-klotho levels. We linked the NHANES data to the National Death Index to determine participants' survival status. End of follow-up was participants' death date or December 31, 2019. Results We observed that males, current smokers, older age, higher body mass index, and lower estimated glomerular filtration rate correlated to lower α-klotho levels, while hepatitis C virus infection correlated to higher α-klotho. The population mortality rate was 11.8 per 10,000 person-months (1,490 deaths); group 1 (the first septile) had higher mortality risk compared with group 2 through group 7. By weighted Cox regression with adjustment for potential confounders, we found that group 2 through group 6, but not group 7, were associated with 25% to 35% lower risk of all-cause mortality compared with group 1. When compared with group 4, we observed that both group 1 (HR: 1.46, 95% CI 1.13-1.88) and group 7 (HR: 1.38, 95% CI 1.09-1.74) were associated with higher mortality risk. Conclusion In summary, among middle-aged and older U.S. adults, we observed a non-linear association between soluble α-klotho and all-cause mortality, with individuals at the two extremes at increased risk of death.
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Affiliation(s)
- Min-Hsiang Chuang
- Renal Division, Department of Internal Medicine, Chi Mei Medical Center, Tainan, Taiwan
| | - Hung-Wei Wang
- Renal Division, Department of Internal Medicine, Chi Mei Hospital Chiali, Tainan, Taiwan
| | - Yun-Ting Huang
- Renal Division, Department of Internal Medicine, Chi Mei Hospital Chiali, Tainan, Taiwan
| | - Ming-Yan Jiang
- Renal Division, Department of Internal Medicine, Chi Mei Medical Center, Tainan, Taiwan
- Department of Pharmacy, Chia Nan University of Pharmacy & Science, Tainan, Taiwan
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15
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Giannese D, D'Alessandro C, Panichi V, Pellegrino N, Cupisti A. Nutritional Treatment as a Synergic Intervention to Pharmacological Therapy in CKD Patients. Nutrients 2023; 15:2715. [PMID: 37375619 DOI: 10.3390/nu15122715] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Revised: 06/03/2023] [Accepted: 06/06/2023] [Indexed: 06/29/2023] Open
Abstract
Nutritional and pharmacological therapies represent the basis for non-dialysis management of CKD patients. Both kinds of treatments have specific and unchangeable features and, in certain cases, they also have a synergic action. For instance, dietary sodium restriction enhances the anti-proteinuric and anti-hypertensive effects of RAAS inhibitors, low protein intake reduces insulin resistance and enhances responsiveness to epoetin therapy, and phosphate restriction cooperates with phosphate binders to reduce the net phosphate intake and its consequences on mineral metabolism. It can also be speculated that a reduction in either protein or salt intake can potentially amplify the anti-proteinuric and reno-protective effects of SGLT2 inhibitors. Therefore, the synergic use of nutritional therapy and medications optimizes CKD treatment. Quality of care management is improved and becomes more effective when compared to either treatment alone, with lower costs and fewer risks of unwanted side effects. This narrative review summarizes the established evidence of the synergistic action carried out by the combination of nutritional and pharmacological treatments, underlying how they are not alternative but complementary in CKD patient care.
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Affiliation(s)
- Domenico Giannese
- Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy
| | - Claudia D'Alessandro
- Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy
| | - Vincenzo Panichi
- Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy
| | - Nicola Pellegrino
- Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy
| | - Adamasco Cupisti
- Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy
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16
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Ostojic SM, Hillesund ER, Øverby NC, Vik FN, Medin AC. Individual nutrients and serum klotho levels in adults aged 40-79 years. Food Sci Nutr 2023; 11:3279-3286. [PMID: 37324910 PMCID: PMC10261765 DOI: 10.1002/fsn3.3310] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Accepted: 02/24/2023] [Indexed: 03/11/2023] Open
Abstract
Several dietary factors (including adherence to the Mediterranean diet or higher nut intake) seem to positively affect circulating antiaging Klotho protein levels; yet, a description of possible relationships between individual nutrients and Klotho activity has not been evaluated. We analyzed the association of dietary intake of individual macro- and micronutrients and nonnutritive food components with circulating Klotho levels in a sample of 40- to 79-year-old US adults. Data from the 2015-2016 National Health and Nutrition Examination Survey were analyzed. Nutrient/food component intakes were calculated in relation to total energy intake using the nutrient density method, and available pristine serum samples were analyzed for serum Klotho concentrations. The final study sample consisted of 2637 participants (mean age 59.0 ± 10.7 years; 52% women). Higher Klotho concentrations were found with higher intake of carbohydrates (p < .001), total sugars (p < .001), dietary fibers (p < .001), vitamin D (p = .05), total folates (p = .015), and copper (p = .018). The results of the regression analysis with a crude model showed significant associations among five nutrients/food components (carbohydrates, alcohol, total sugars, dietary fibers, and niacin) and soluble Klotho levels across the sample. After adjusting the models for age and gender, the nutrient/food component-Klotho association remained significant for carbohydrates, total sugars, and alcohol (p < .05). Dietary exposure to individual nutrients and nonnutritive food components appears to be associated with Klotho activity; however, additional research is needed to investigate the relationship between cause and effect in diet composition-Klotho interplay.
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Affiliation(s)
- Sergej M. Ostojic
- Department of Nutrition and Public HealthUniversity of AgderKristiansandNorway
| | | | - Nina C. Øverby
- Department of Nutrition and Public HealthUniversity of AgderKristiansandNorway
| | - Frøydis N. Vik
- Department of Nutrition and Public HealthUniversity of AgderKristiansandNorway
| | - Anine C. Medin
- Department of Nutrition and Public HealthUniversity of AgderKristiansandNorway
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17
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Aczel D, Torma F, Jokai M, McGreevy K, Boros A, Seki Y, Boldogh I, Horvath S, Radak Z. The Circulating Level of Klotho Is Not Dependent upon Physical Fitness and Age-Associated Methylation Increases at the Promoter Region of the Klotho Gene. Genes (Basel) 2023; 14:525. [PMID: 36833453 PMCID: PMC9957177 DOI: 10.3390/genes14020525] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Revised: 02/06/2023] [Accepted: 02/15/2023] [Indexed: 02/22/2023] Open
Abstract
(1) Background: Higher levels of physical fitness are believed to increase the physiological quality of life and impact the aging process with a wide range of adaptive mechanisms, including the regulation of the expression of the age-associated klotho (KL) gene and protein levels. (2) Methods: Here, we tested the relationship between the DNA methylation-based epigenetic biomarkers PhenoAge and GrimAge and methylation of the promoter region of the KL gene, the circulating level of KL, and the stage of physical fitness and grip force in two groups of volunteer subjects, trained (TRND) and sedentary (SED), aged between 37 and 85 years old. (3) Results: The circulating KL level is negatively associated with chronological age in the TRND group (r = -0.19; p = 0.0295) but not in the SED group (r = -0.065; p = 0.5925). The age-associated decrease in circulating KL is partly due to the increased methylation of the KL gene. In addition, higher plasma KL is significantly related to epigenetic age-deceleration in the TRND group, assessed by the biomarker of PhenoAge (r = -0.21; p = 0.0192). (4) Conclusions: The level of physical fitness, on the other hand, does not relate to circulating KL levels, nor to the rate of the methylation of the promoter region of the KL gene, only in males.
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Affiliation(s)
- Dora Aczel
- Research Institute of Sport Science, Hungarian University of Sport Science, 1123 Budapest, Hungary
| | - Ferenc Torma
- Research Institute of Sport Science, Hungarian University of Sport Science, 1123 Budapest, Hungary
- Sports Neuroscience Division, Advanced Research Initiative for Human High Performance (ARIHHP), Faculty of Health and Sport Sciences, University of Tsukuba, Tsukuba 305-8574, Japan
| | - Matyas Jokai
- Research Institute of Sport Science, Hungarian University of Sport Science, 1123 Budapest, Hungary
| | - Kristen McGreevy
- Department of Biostatistics, Fielding School of Public Health, University of California Los Angeles, Los Angeles, CA 90095, USA
| | - Anita Boros
- Research Institute of Sport Science, Hungarian University of Sport Science, 1123 Budapest, Hungary
| | - Yasuhiro Seki
- Faculty of Sport Sciences, Waseda University, Tokorozawa 2-579-15, Japan
| | - Istvan Boldogh
- Department of Microbiology and Immunology, University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA
| | - Steve Horvath
- Department of Biostatistics, Fielding School of Public Health, University of California Los Angeles, Los Angeles, CA 90095, USA
| | - Zsolt Radak
- Research Institute of Sport Science, Hungarian University of Sport Science, 1123 Budapest, Hungary
- Faculty of Sport Sciences, Waseda University, Tokorozawa 2-579-15, Japan
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18
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The Anti-Aging Hormone Klotho Promotes Retinal Pigment Epithelium Cell Viability and Metabolism by Activating the AMPK/PGC-1α Pathway. Antioxidants (Basel) 2023; 12:antiox12020385. [PMID: 36829944 PMCID: PMC9952846 DOI: 10.3390/antiox12020385] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Revised: 01/30/2023] [Accepted: 01/30/2023] [Indexed: 02/08/2023] Open
Abstract
Initially discovered by Makuto Kuro-o in 1997, Klotho is a putative aging-suppressor gene when overexpressed and accelerates aging when deleted in mice. Previously, we showed that α-Klotho regulates retinal pigment epithelium (RPE) functions and protects against oxidative stress. However, the mechanisms by which Klotho influences RPE and retinal homeostasis remain elusive. Here, by performing a series of in vitro and in vivo experiments, we demonstrate that Klotho regulates cell viability under oxidative stress, mitochondrial gene expression and activity by inducing the phosphorylation of AMPK and p38MAPK, which in turn phosphorylate and activate CREB and ATF2, respectively, triggering PGC-1α transcription. The inhibition of Klotho in human RPE cells using CRISPR-Cas9 gene editing confirmed that a lack of Klotho negatively affects RPE functions, including mitochondrial activity and cell viability. Proteomic analyses showed that myelin sheath and mitochondrial-related proteins are downregulated in the RPE/retina of Kl-/- compared to WT mice, further supporting our biochemical observations. We conclude that Klotho acts upstream of the AMPK/PGC-1α pathway and regulates RPE/retinal resistance to oxidative stress, mitochondrial function, and gene and protein expressions. Thus, KL decline during aging could negatively impact retinal health, inducing age-related retinal degeneration.
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Zhu J, Wei Y. Exposure to p-dichlorobenzene and serum α-Klotho levels among US participants in their middle and late adulthood. THE SCIENCE OF THE TOTAL ENVIRONMENT 2023; 858:159768. [PMID: 36309252 DOI: 10.1016/j.scitotenv.2022.159768] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/09/2022] [Revised: 10/21/2022] [Accepted: 10/23/2022] [Indexed: 06/16/2023]
Abstract
P-dichlorobenzene (p-DCB) is a volatile compound commonly used as pest repellent and air deodorant in the home and public buildings, leading to a widespread exposure in indoor environments. There has been an increasing concern about its metabolic and endocrine effects. In this study, we explored the relation between p-DCB exposure and serum levels of soluble α-Klotho, an anti-aging hormone, in US adults. A nationally representative subsample of 1485 adults 40-79 ages in the 2013-2016 National Health and Nutrition Examination Survey was analyzed for the association between p-DCB exposure, measured as urinary concentrations of 2,5-dichlorophenol (2,5-DCP), the major metabolite of p-DCB, and serum α-Klotho levels using multiple general linear models, adjusting for potential confounders. Age- and sex-specific analyses were further conducted. The weighted geometric mean of urinary 2,5-DCP was 2.43 μg/L and the weighted mean of serum α-Klotho was 831.97 pg/mL in the study participants during 2013-2016. After adjusting for potential confounders and urinary creatinine, urinary 2,5-DCP was significantly associated with decreased serum levels of α-Klotho (regression coefficient β = -9.88; p = 0.0133) in the total study population. When age- and sex-specific analyses being conducted, a significantly inverse association was found in older adults aged 60-79 years (β = -20.40; p = 0.0001) and in males (β = -13.81; p = 0.0097), but not in the middle ages (40-59 years) and in females. The strongest association was observed in older (60-79 years) male participants, with a 25.43 pg/mL reduction of α-Klotho levels per 1-unit increase of 2,5-DCP concentrations (p = 0.0008). This is the first study demonstrating a relation between p-DCB exposure, measured as 2,5-DCP, and decreased α-Klotho levels in older males. Additional studies would further explore these interactions and elucidate the pathogenesis of the potential effects of p-DCB exposure on aging.
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Affiliation(s)
- Jianmin Zhu
- Department of Mathematics and Computer Science, Fort Valley State University, Fort Valley, GA, USA
| | - Yudan Wei
- Department of Community Medicine, Mercer University School of Medicine, Macon, GA, USA.
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20
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Katsaounis PV, Hadjiyannis ES, Skaltsi T, Anargyrou VA, Alexopoulou AA, Dourakis SP, Koskinas JS. Bone disease in patients with cirrhosis of different etiology and severity; are Klotho protein and osteoprotegerin potential biomarkers? Scand J Gastroenterol 2023; 58:185-192. [PMID: 36028955 DOI: 10.1080/00365521.2022.2114813] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
BACKGROUND AND AIMS Cirrhosis is associated with increased risk for osteoporosis and osteopenia. This study aims to further investigate this relationship by examining if etiology and severity of cirrhosis are independent predictors of bone mineral density (BMD) loss. Furthermore we examined the serum levels of osteoprotegerin (OPG) and Klotho proteins that have been involved in bone metabolism. METHODS Seventy-four patients with cirrhosis of different etiology and 25 matched healthy controls were included in this study. Bone mineral densitometry at both lumbar spine and femoral neck was measured. Serum total OPG, Klotho protein and vitamin D levels were also determined. Comparisons were performed according to etiology and severity of cirrhosis. RESULTS Decreased bone density was observed in cirrhotic patients compared to healthy controls with T = -1.46 and T = -1.37 in lumbar spine and femoral bone respectively compared to T = -0.396 and T = -0.672 in the control group. In the cirrhotic group, osteopenia was observed in 46% in lumbar spine and 51% in femoral bone whereas osteoporosis was observed in 20% in lumbar spine and 9% in femoral bone. Decreased bone density was confirmed, regardless of cirrhosis etiology or stage of liver function. Patients were found to have higher levels of OPG than the control group (136 pg/ml vs. 67 pg/ml, p < 0.001), but lower levels of Klotho protein (1051 pg/ml vs. 1842 pg/ml, p < 0.001) regardless etiology and severity of cirrhosis. High OPG levels were found to be associated with low femoral bone density. CONCLUSIONS BMD is lower in cirrhotic patients regardless etiology and severity of liver disease with osteopenia and osteoporosis be present in 50% and 20%, respectively. Higher levels of OPG and lower levels of Klotho protein were observed in cirrhotic patients regardless etiology and severity in comparison to matched healthy group.
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Affiliation(s)
- Panagiotis V Katsaounis
- Second Department of Medicine, Medical School, National and Kapodistrian University of Athens, Hippokrateion General Hospital, Athens, Greece
| | - Emilia S Hadjiyannis
- Second Department of Medicine, Medical School, National and Kapodistrian University of Athens, Hippokrateion General Hospital, Athens, Greece
| | - Teressa Skaltsi
- Second Department of Medicine, Medical School, National and Kapodistrian University of Athens, Hippokrateion General Hospital, Athens, Greece
| | - Vassiliki A Anargyrou
- Second Department of Medicine, Medical School, National and Kapodistrian University of Athens, Hippokrateion General Hospital, Athens, Greece
| | - Alexandra A Alexopoulou
- Second Department of Medicine, Medical School, National and Kapodistrian University of Athens, Hippokrateion General Hospital, Athens, Greece
| | - Spyridon P Dourakis
- Second Department of Medicine, Medical School, National and Kapodistrian University of Athens, Hippokrateion General Hospital, Athens, Greece
| | - John S Koskinas
- Second Department of Medicine, Medical School, National and Kapodistrian University of Athens, Hippokrateion General Hospital, Athens, Greece
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21
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Alharbi KS, Afzal O, Altamimi ASA, Almalki WH, Kazmi I, Al-Abbasi FA, Alzarea SI, Makeen HA, Albratty M. A study of the molecular mechanism of quercetin and dasatinib combination as senolytic in alleviating age-related and kidney diseases. J Food Biochem 2022; 46:e14471. [PMID: 36268851 DOI: 10.1111/jfbc.14471] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2022] [Revised: 09/16/2022] [Accepted: 09/26/2022] [Indexed: 01/14/2023]
Abstract
Aging is a significant risk factor for the majority of prevalent human illnesses. The chance of having severe chronic conditions grows dramatically with advancing age. Indeed, more than 90% of people over 65 get at least one chronic disease, including diabetes, heart disease, malignancy, memory loss, and kidney disease, whereas more than 70% have two or more of these ailments. Mouse and human aging lead to increased senescent cells and decreased klotho concentrations. Mice lacking the protein α-klotho show faster aging, similar to human aging. α-Klotho upregulation extends life and slows or suppresses the onset of many age-related illnesses and kidney diseases. Like the consequences of α-klotho deficiency, senescent cell accumulation is linked to tissue dysfunction in various organs and multiple age-related kidney diseases. In addition, α-klotho and cell senescence are negatively and presumably mechanistically linked. Earlier research has demonstrated that klotho exerts its protective effects in age-related and kidney disease by interacting with Wnt ligands, serving as an endogenous antagonist of Wnt/β-catenin signaling. In addition, decreasing senescent cell burden with senolytics, a class of drugs that remove senescent cells selectively and extend the life span of mice. In this work, we are studying the molecular mechanism of the combination of quercetin and dasatinib as senolytic in easing age-related chronic renal illness by altering the level of klotho/Wnt/β-catenin. PRACTICAL APPLICATIONS: There is an inverse relationship between the onset and the development of age-related disorders and cellular senescence and Klotho. Earlier attempts to suppress transforming growth factor-beta 1 (TGF-β1) in kidney disease with anti-TGF-β1 antibodies were ineffective, and this should be kept in mind. Senolytic medications may benefit from targeting senescent cells, which enhances the protective factor α-klotho. In addition, our study provides a unique, translationally feasible route for creating orally active small compounds to enhance α-klotho, which may also be a valuable biomarker for age-related kidney disease. Additionally, other aspects of aging can be affected by senolytics, such as limiting age-related mitochondrial dysfunction, lowering inflammation and fibrosis, blunting reactive oxygen species (ROS) generation, decreasing deoxyribonucleic acid (DNA) damage, and reinforcing insulin sensitivity. Senolytic agents have been shown to increase adipose progenitor and cardiac progenitor cell activity in aging animals and animals with cellular senescence-related diseases, such as heart, brain, and kidney disease.
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Affiliation(s)
- Khalid Saad Alharbi
- Department of Pharmacology, College of Pharmacy, Jouf University, Sakaka, Saudi Arabia
| | - Obaid Afzal
- Department of Pharmaceutical Chemistry, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al Kharj, Saudi Arabia
| | | | - Waleed Hassan Almalki
- Department of Pharmacology, College of Pharmacy, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Imran Kazmi
- Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Fahad A Al-Abbasi
- Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Sami I Alzarea
- Department of Pharmacology, College of Pharmacy, Jouf University, Sakaka, Saudi Arabia
| | - Hafiz A Makeen
- Pharmacy Practice Research Unit, Clinical Pharmacy Department, College of Pharmacy, Jazan University, Jazan, Saudi Arabia
| | - Mohammed Albratty
- Department of Pharmaceutical Chemistry and Pharmacognosy, College of Pharmacy, Jazan University, Jazan, Saudi Arabia
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22
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Chen L, Yin X, Zhao Y, Chen H, Tan T, Yao P, Tang Y. Biological ageing and the risks of all-cause and cause-specific mortality among people with diabetes: a prospective cohort study. J Epidemiol Community Health 2022; 76:771-778. [PMID: 35738895 DOI: 10.1136/jech-2022-219142] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Accepted: 06/12/2022] [Indexed: 11/04/2022]
Abstract
BACKGROUND The aetiology of diabetes is complex with limited treatment strategies. Growing animal studies have shown that targeted antiageing can improve the outcomes of diabetes. However, population evidence is limited. This study aims to evaluate the associations of biological ageing with all-cause and cause-specific mortality among people with diabetes. METHODS A total of 5278 people with diabetes from the National Health and Nutrition Examination Survey 1999-2014 were included. Biological ageing was measured from different perspectives, including phenotypic age, biological age, telomere length and klotho concentration. Phenotypic/biological age acceleration was the residual resulting from a linear model when regressing phenotypic/biological age on chronological age. Cox proportional hazards models were used to examine the relationships between ageing and all-cause, cardiovascular disease (CVD), and cancer mortality. RESULTS Over median follow-up for 7.3 years, 1355 diabetics died. There was a positive and linear association of mortality with phenotypic age acceleration (HRall-cause 1.04; HRCVD 1.04; HRcancer 1.04, p<0.001) and biological age acceleration (HRall-cause 1.03; HRCVD 1.04; HRcancer 1.03, p<0.001). Telomere length was inversely associated with all-cause mortality (tertile (T)3 vs T1: HR 0.67, p<0.05). The concentration of klotho had a U-shaped relationship with mortality (T2 vs T1: HRall-cause 0.62; HRCVD 0.48; HRcancer 0.47, p<0.05). Further, stratified analysis by age and sex found that the associations of ageing-related markers with mortality were more significant in the aged and female subgroup. CONCLUSIONS Biological ageing was positively associated with mortality among people with diabetes, indicating therapies targeting antiageing could be encouraged to halt the progression of diabetes.
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Affiliation(s)
- Li Chen
- Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, Ministry of Education Key Laboratory of Environment and Health and MOE Key Lab of Environment and Health, Key Laboratory of Environment and Health (Wuhan), Ministry of Environmental Protection, State Key Laboratory of Environment Health (Incubation), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Xingzhu Yin
- Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, Ministry of Education Key Laboratory of Environment and Health and MOE Key Lab of Environment and Health, Key Laboratory of Environment and Health (Wuhan), Ministry of Environmental Protection, State Key Laboratory of Environment Health (Incubation), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Ying Zhao
- Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, Ministry of Education Key Laboratory of Environment and Health and MOE Key Lab of Environment and Health, Key Laboratory of Environment and Health (Wuhan), Ministry of Environmental Protection, State Key Laboratory of Environment Health (Incubation), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Huimin Chen
- Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, Ministry of Education Key Laboratory of Environment and Health and MOE Key Lab of Environment and Health, Key Laboratory of Environment and Health (Wuhan), Ministry of Environmental Protection, State Key Laboratory of Environment Health (Incubation), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Tianqi Tan
- Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, Ministry of Education Key Laboratory of Environment and Health and MOE Key Lab of Environment and Health, Key Laboratory of Environment and Health (Wuhan), Ministry of Environmental Protection, State Key Laboratory of Environment Health (Incubation), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Ping Yao
- Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, Ministry of Education Key Laboratory of Environment and Health and MOE Key Lab of Environment and Health, Key Laboratory of Environment and Health (Wuhan), Ministry of Environmental Protection, State Key Laboratory of Environment Health (Incubation), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Yuhan Tang
- Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, Ministry of Education Key Laboratory of Environment and Health and MOE Key Lab of Environment and Health, Key Laboratory of Environment and Health (Wuhan), Ministry of Environmental Protection, State Key Laboratory of Environment Health (Incubation), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
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23
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Bollen SE, Bass JJ, Fujita S, Wilkinson D, Hewison M, Atherton PJ. The Vitamin D/Vitamin D receptor (VDR) axis in muscle atrophy and sarcopenia. Cell Signal 2022; 96:110355. [PMID: 35595176 DOI: 10.1016/j.cellsig.2022.110355] [Citation(s) in RCA: 50] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2022] [Revised: 05/10/2022] [Accepted: 05/12/2022] [Indexed: 12/22/2022]
Abstract
Muscle atrophy and sarcopenia (the term given to the age-related decline in muscle mass and function), influence an individuals risk of falls, frailty, functional decline, and, ultimately, impaired quality of life. Vitamin D deficiency (low serum levels of 25-hydroxyvitamin D (25(OH)D3)) has been reported to impair muscle strength and increase risk of sarcopenia. The mechanisms that underpin the link between low 25(OH)D3 and sarcopenia are yet to be fully understood but several lines of evidence have highlighted the importance of both genomic and non-genomic effects of active vitamin D (1,25-dihydroxyvitamin D (1,25(OH)2D3)) and its nuclear vitamin D receptor (VDR), in skeletal muscle functioning. Studies in vitro have demonstrated a key role for the vitamin D/VDR axis in regulating biological processes central to sarcopenic muscle atrophy, such as proteolysis, mitochondrial function, cellular senescence, and adiposity. The aim of this review is to provide a mechanistic overview of the proposed mechanisms for the vitamin D/VDR axis in sarcopenic muscle atrophy.
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Affiliation(s)
- Shelby E Bollen
- MRC/ARUK Centre for Musculoskeletal Ageing Research and National Institute for Health Research (NIHR), Nottingham Biomedical Research Centre (BRC), School of Medicine, University of Nottingham, DE22 3DT, UK.
| | - Joseph J Bass
- MRC/ARUK Centre for Musculoskeletal Ageing Research and National Institute for Health Research (NIHR), Nottingham Biomedical Research Centre (BRC), School of Medicine, University of Nottingham, DE22 3DT, UK
| | - Satoshi Fujita
- Faculty of Sport and Health Science, Ritsumeikan University, Kusatsu, Shiga, Japan
| | - Daniel Wilkinson
- MRC/ARUK Centre for Musculoskeletal Ageing Research and National Institute for Health Research (NIHR), Nottingham Biomedical Research Centre (BRC), School of Medicine, University of Nottingham, DE22 3DT, UK
| | - Martin Hewison
- Metabolism and Systems Research, University of Birmingham, Birmingham, UK
| | - Philip J Atherton
- MRC/ARUK Centre for Musculoskeletal Ageing Research and National Institute for Health Research (NIHR), Nottingham Biomedical Research Centre (BRC), School of Medicine, University of Nottingham, DE22 3DT, UK.
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24
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Afsar B, Kanbay M, Afsar RE. Interconnections of fibroblast growth factor 23 and klotho with erythropoietin and hypoxia-inducible factor. Mol Cell Biochem 2022; 477:1973-1985. [PMID: 35381946 DOI: 10.1007/s11010-022-04422-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Accepted: 03/22/2022] [Indexed: 12/01/2022]
Abstract
Bone marrow (BM) hematopoiesis is tightly regulated process and bone components such as osteoblasts, extracellular matrix, and minerals influence hematopoiesis via regulation of hematopoietic stem cell function. Erythropoietin (EPO) secreted mostly by renal EPO producing (REP) cells which employ the hypoxia-inducible factor (HIF) pathway. When tissue hypoxia occurs, HIFs bind to hypoxia response element in the EPO promoter and induce EPO production. EPO binds to the EPO receptor on red cell progenitors in the BM and triggers expansion of red cell mass. Fibroblast growth factor-23 (FGF23) which is secreted mostly by osteoblasts and less by BM impacts hematopoiesis by influencing EPO production. Reciprocally, increases of EPO (acute or chronic) influence both FG23 production and cleavage resulting in variation of c fragment FGF23 (cFGF23) and intact FGF23 (iFGF23) ratios. As HIFs stimulate EPO production, they indirectly affect FGF23. Direct stimulation of FGF23 synthesis by binding of HIF on FGF23 promoter is also suggested. FGF23 cleavage by furin is another potential mechanism affecting FGF23 levels. Klotho is present in membrane-bound (transmembrane) and free (circulating) forms. Transmembrane klotho is the co-receptor of FGF23 and forms complexes with FGF23 receptors in the membrane surface and required for FGF23 actions. Recent evidence showed that klotho is also associated with EPO and HIF production suggesting a complex relationship between FGF23, klotho, EPO, and HIF. In this review, we have summarized the connections between FGF23, klotho, HIF, and EPO and their reflections to hematopoiesis.
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Affiliation(s)
- Baris Afsar
- Department of Nephrology, School of Medicine, Suleyman Demirel University, Isparta, Turkey.
| | - Mehmet Kanbay
- Department of Nephrology, School of Medicine, Koc University, Istanbul, Turkey
| | - Rengin Elsurer Afsar
- Department of Nephrology, School of Medicine, Suleyman Demirel University, Isparta, Turkey
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25
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Abstract
Klotho gene was originally recognized as a putative aging-suppressor and its prominent age-regulating effects are mostly attributed to the modulation of mineral homeostasis in the kidney. However, recent studies link alterations in hippocampal Klotho expression with cognitive impairment and neurodegenerative diseases. This suggests that hippocampal neurons require Klotho for health and proper functionality. Klotho protects against neuronal dysfunction and regulates several intracellular signaling pathways including oxidative stress response, inflammation, DNA damage, autophagy, endoplasmic reticulum stress response, and multiple types of cell death. Specifically, this chapter covers the current knowledge as to how Klotho protein affects the hippocampal neuronal cells, with special attention paid to underlying molecular mechanisms, and thus influences hippocampal development, hippocampal-dependent cognition, behavior, and motor skills as well as mediates neurodegenerative processes.
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Affiliation(s)
- Jennifer Mytych
- Department of Biotechnology, Institute of Biology and Biotechnology, Collegium Scientarium Naturalium, University of Rzeszow, Werynia, Poland.
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26
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Dittmer KE, Chernyavtseva A, Marshall JC, Cabrera D, Wolber FM, Kruger M. Expression of Renal Vitamin D and Phosphatonin-Related Genes in a Sheep Model of Osteoporosis. Animals (Basel) 2021; 12:ani12010067. [PMID: 35011173 PMCID: PMC8749731 DOI: 10.3390/ani12010067] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Accepted: 12/23/2021] [Indexed: 11/17/2022] Open
Abstract
Simple Summary Osteoporosis is a significant public health issue around the world, with post-menopausal osteoporosis due to estrogen deficiency resulting in approximately ¾ of cases. Treatment with glucocorticoids is another common cause of osteoporosis in humans. Sheep are a well-established model for osteoporosis in humans. In this study, aged sheep had their ovaries removed (ovariectomy) to simulate estrogen deficiency, and some sheep were also treated with glucocorticoids. The results showed that expression of the gene klotho in the kidney had the most marked difference in ovariectomized sheep treated with glucocorticoids for 2 months followed by a recovery period of 3 months. Klotho is known as the “anti-aging” hormone and is an important regulator of calcium and phosphorus metabolism. It may therefore be involved in the recovery of bone mineral density seen in ovariectomized sheep treated with glucocorticoids for 2 months followed by euthanasia at 5 months. As such, it could be an important treatment target for osteoporosis in humans. Abstract Osteoporosis is a significant public health issue around the world, with post-menopausal osteoporosis due to estrogen deficiency resulting in approximately ¾ of cases. In this study, 18 aged Merino ewes were ovariectomized, and 10 were controls. Three of the ovariectomized ewes were treated weekly with 400 mg of methylprednisolone for 5 months and three were treated weekly for 2 months, followed by a 3-month recovery period. At 2 months, five control animals and six ovariectomized animals were euthanized. At 5 months, all the remaining ewes were euthanized. Kidney samples were collected postmortem for qPCR analysis of NPT1, PTH1R, NPT2a, NPT2c, Klotho, FGFR1IIIc, VDR, CYP24A1, CYP27B1, TRPV5, TRPV6, CalD9k, CalD28k, PMCA and NCX1. Ovariectomized sheep had significantly greater VDR expression compared with other groups. Ovariectomized sheep treated with glucocorticoids for 2 months followed by euthanasia at 5 months showed significant differences in TRPV5, CYP24A1 and klotho gene expression compared to other groups. Differences in klotho expression were most marked after adjustment for repeated measures (p = 0.1). Klotho is known as the “anti-aging” hormone and is involved in calcium and phosphorus metabolism. Klotho may be involved in the recovery of bone mineral density in ovariectomized sheep treated with glucocorticoids for 2 months followed by euthanasia at 5 months. Further research on the role of klotho is recommended.
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Affiliation(s)
- Keren E. Dittmer
- School of Veterinary Science, Massey University, Palmerston North 4442, New Zealand;
- Correspondence:
| | | | - Jonathan C. Marshall
- School of Fundamental Sciences, Massey University, Palmerston North 4442, New Zealand;
| | - Diana Cabrera
- School of Food and Advanced Technology, Massey University, Palmerston North 4442, New Zealand; (D.C.); (F.M.W.)
| | - Frances M. Wolber
- School of Food and Advanced Technology, Massey University, Palmerston North 4442, New Zealand; (D.C.); (F.M.W.)
| | - Marlena Kruger
- School of Health Sciences, Massey University, Palmerston North 4442, New Zealand;
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27
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Fotheringham AK, Solon-Biet SM, Bielefeldt-Ohmann H, McCarthy DA, McMahon AC, Ruohonen K, Li I, Sullivan MA, Whiddett RO, Borg DJ, Cogger VC, Ballard WO, Turner N, Melvin RG, Raubenheimer D, Le Couteur DG, Simpson SJ, Forbes JM. Kidney disease risk factors do not explain impacts of low dietary protein on kidney function and structure. iScience 2021; 24:103308. [PMID: 34820603 PMCID: PMC8602032 DOI: 10.1016/j.isci.2021.103308] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Revised: 04/29/2021] [Accepted: 10/15/2021] [Indexed: 02/06/2023] Open
Abstract
The kidneys balance many byproducts of the metabolism of dietary components. Previous studies examining dietary effects on kidney health are generally of short duration and manipulate a single macronutrient. Here, kidney function and structure were examined in C57BL/6J mice randomized to consume one of a spectrum of macronutrient combinations (protein [5%–60%], carbohydrate [20%–75%], and fat [20%–75%]) from weaning to late-middle age (15 months). Individual and interactive impacts of macronutrients on kidney health were modeled. Dietary protein had the greatest influence on kidney function, where chronic low protein intake decreased glomerular filtration rates and kidney mass, whereas it increased kidney immune infiltration and structural injury. Kidney outcomes did not align with cardiometabolic risk factors including glucose intolerance, overweight/obesity, dyslipidemia, and hypertension in mice with chronic low protein consumption. This study highlights that protein intake over a lifespan is an important determinant of kidney function independent of cardiometabolic changes.
Chronic high macronutrient intake from any source increases kidney function (GFR) Low protein intake led to greater kidney tubular structural injury and inflammation Lower protein intake decreased kidney mass and glomerular filtration capacity Kidney outcomes did not align with longevity or cardiometabolic outcomes
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Affiliation(s)
- Amelia K Fotheringham
- Glycation and Diabetes Complications Group, Mater Research Institute-The University of Queensland, Translational Research Institute, 37 Kent Street, Woolloongabba, Brisbane 4072, QLD, Australia.,Faculty of Medicine, University of Queensland, Brisbane 4067, QLD, Australia
| | - Samantha M Solon-Biet
- Charles Perkins Centre, University of Sydney, Sydney 2006, NSW, Australia.,School of Medical Sciences, University of Sydney, Sydney 2006, NSW, Australia
| | - Helle Bielefeldt-Ohmann
- School of Veterinary Science, University of Queensland, Gatton Campus, Gatton 4343, QLD, Australia.,School of Chemistry & Molecular Biosciences, University of Queensland, Brisbane 4067, QLD, Australia
| | - Domenica A McCarthy
- Glycation and Diabetes Complications Group, Mater Research Institute-The University of Queensland, Translational Research Institute, 37 Kent Street, Woolloongabba, Brisbane 4072, QLD, Australia
| | - Aisling C McMahon
- Charles Perkins Centre, University of Sydney, Sydney 2006, NSW, Australia.,Centre for Education and Research on Aging, and Aging and Alzheimer's Institute, Concord Hospital, Sydney 2139, NSW, Australia.,ANZAC Research Institute, Concord Hospital, University of Sydney, Sydney 2139, NSW, Australia
| | - Kari Ruohonen
- Animal Nutrition and Health, Cargill, Sandnes, Norway
| | - Isaac Li
- Faculty of Medicine, University of Queensland, Brisbane 4067, QLD, Australia
| | - Mitchell A Sullivan
- Glycation and Diabetes Complications Group, Mater Research Institute-The University of Queensland, Translational Research Institute, 37 Kent Street, Woolloongabba, Brisbane 4072, QLD, Australia
| | - Rani O Whiddett
- Glycation and Diabetes Complications Group, Mater Research Institute-The University of Queensland, Translational Research Institute, 37 Kent Street, Woolloongabba, Brisbane 4072, QLD, Australia
| | - Danielle J Borg
- Glycation and Diabetes Complications Group, Mater Research Institute-The University of Queensland, Translational Research Institute, 37 Kent Street, Woolloongabba, Brisbane 4072, QLD, Australia.,Faculty of Medicine, University of Queensland, Brisbane 4067, QLD, Australia
| | - Victoria C Cogger
- Charles Perkins Centre, University of Sydney, Sydney 2006, NSW, Australia.,Centre for Education and Research on Aging, and Aging and Alzheimer's Institute, Concord Hospital, Sydney 2139, NSW, Australia.,ANZAC Research Institute, Concord Hospital, University of Sydney, Sydney 2139, NSW, Australia
| | - William O Ballard
- School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney 2052, NSW, Australia
| | - Nigel Turner
- Department of Pharmacology, School of Medical Sciences, Faculty of Medicine, University of New South Wales Sydney, NSW 2052, Australia
| | - Richard G Melvin
- Department of Biomedical Sciences, University of Minnesota Medical School, 1035 University Drive, Duluth 55812, MN, USA
| | - David Raubenheimer
- Charles Perkins Centre, University of Sydney, Sydney 2006, NSW, Australia.,School of Life and Environmental Sciences, University of Sydney, NSW, Australia
| | - David G Le Couteur
- Charles Perkins Centre, University of Sydney, Sydney 2006, NSW, Australia.,Centre for Education and Research on Aging, and Aging and Alzheimer's Institute, Concord Hospital, Sydney 2139, NSW, Australia.,ANZAC Research Institute, Concord Hospital, University of Sydney, Sydney 2139, NSW, Australia
| | - Stephen J Simpson
- Charles Perkins Centre, University of Sydney, Sydney 2006, NSW, Australia.,School of Life and Environmental Sciences, University of Sydney, NSW, Australia
| | - Josephine M Forbes
- Glycation and Diabetes Complications Group, Mater Research Institute-The University of Queensland, Translational Research Institute, 37 Kent Street, Woolloongabba, Brisbane 4072, QLD, Australia.,Faculty of Medicine, University of Queensland, Brisbane 4067, QLD, Australia.,Department of Medicine, University of Melbourne, Heidelberg, VIC 3084, Australia
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Abstract
Epigenetics examines heritable changes in DNA and its associated proteins except mutations in gene sequence. Epigenetic regulation plays fundamental roles in kidney cell biology through the action of DNA methylation, chromatin modification via epigenetic regulators and non-coding RNA species. Kidney diseases, including acute kidney injury, chronic kidney disease, diabetic kidney disease and renal fibrosis are multistep processes associated with numerous molecular alterations even in individual kidney cells. Epigenetic alterations, including anomalous DNA methylation, aberrant histone alterations and changes of microRNA expression all contribute to kidney pathogenesis. These changes alter the genome-wide epigenetic signatures and disrupt essential pathways that protect renal cells from uncontrolled growth, apoptosis and development of other renal associated syndromes. Molecular changes impact cellular function within kidney cells and its microenvironment to drive and maintain disease phenotype. In this chapter, we briefly summarize epigenetic mechanisms in four kidney diseases including acute kidney injury, chronic kidney disease, diabetic kidney disease and renal fibrosis. We primarily focus on current knowledge about the genome-wide profiling of DNA methylation and histone modification, and epigenetic regulation on specific gene(s) in the pathophysiology of these diseases and the translational potential of identifying new biomarkers and treatment for prevention and therapy. Incorporating epigenomic testing into clinical research is essential to elucidate novel epigenetic biomarkers and develop precision medicine using emerging therapies.
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29
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Galassi A, Ciceri P, Porata G, Iatrino R, Boni Brivio G, Fasulo E, Magagnoli L, Stucchi A, Frittoli M, Cara A, Cozzolino M. Current treatment options for secondary hyperparathyroidism in patients with stage 3 to 4 chronic kidney disease and vitamin D deficiency. Expert Opin Drug Saf 2021; 20:1333-1349. [PMID: 33993809 DOI: 10.1080/14740338.2021.1931117] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Introduction: Secondary hyperparathyroidism (SHPT) represents a complication of chronic kidney disease (CKD). Vitamin D system is altered since early CKD, and vitamin D deficiency is an established trigger of SHPT. Although untreated SHPT may degenerate into tertiary hyperparathyroidism with detrimental consequences in advanced CKD, best treatments for counteracting SHPT from stage 3 CKD are still debated. Enthusiasm on prescription of vitamin D receptor activators (VDRA) in non-dialysis renal patients, has been mitigated by the risk of low bone turnover and positive calcium-phosphate balance. Nutritional vitamin D is now suggested as first-line therapy to treat SHPT with low 25(OH)D insufficiency. However, no high-grade evidence supports the best choice between ergocalciferol, cholecalciferol, and calcifediol (in its immediate or extended-release formulation).Areas covered: The review discusses available data on safety and efficacy of nutritional vitamin D, VDRA and nutritional therapy in replenishing 25(OH)D deficiency and counteracting SHPT in non-dialysis CKD patients.Expert opinion: Best treatment for low 25(OH)D and SHPT remains unknown, due to incomplete understanding of the best homeostatic, as mutable, adaptation of mineral metabolism to CKD progression. Nutritional vitamin D and nutritional therapy appear safest interventions, whenever contextualized with single-patient characteristics. VDRA should be restricted to uncontrolled SHPT by first-line therapy.
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Affiliation(s)
- Andrea Galassi
- Renal and Dialysis Unit, ASST Santi Paolo E Carlo, Milan, Italy
| | - Paola Ciceri
- Renal Research Laboratory, Department of Nephrology, Dialysis and Renal Transplant, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico and Fondazione D'Amico per La Ricerca Sulle Malattie Renali, Milan, Italy
| | - Giulia Porata
- Renal and Dialysis Unit, ASST Santi Paolo E Carlo, Milan, Italy
| | | | - Giulia Boni Brivio
- Renal and Dialysis Unit, ASST Santi Paolo E Carlo, Milan, Italy.,Department of Health and Science, University of Milan, Milan, Italy
| | - Eliana Fasulo
- Renal and Dialysis Unit, ASST Santi Paolo E Carlo, Milan, Italy
| | - Lorenza Magagnoli
- Renal and Dialysis Unit, ASST Santi Paolo E Carlo, Milan, Italy.,Department of Health and Science, University of Milan, Milan, Italy
| | - Andrea Stucchi
- Renal and Dialysis Unit, ASST Santi Paolo E Carlo, Milan, Italy
| | - Michela Frittoli
- Renal and Dialysis Unit, ASST Santi Paolo E Carlo, Milan, Italy.,Department of Health and Science, University of Milan, Milan, Italy
| | - Anila Cara
- Renal and Dialysis Unit, ASST Santi Paolo E Carlo, Milan, Italy.,Department of Health and Science, University of Milan, Milan, Italy
| | - Mario Cozzolino
- Renal and Dialysis Unit, ASST Santi Paolo E Carlo, Milan, Italy.,Department of Health and Science, University of Milan, Milan, Italy
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30
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Carvalho LCDB, Velozo MP, Coelho VA, Custodio MR, Dalboni MA, Moysés RMA, Elias RM. Low Levels of Klotho are Associated with Intracranial Vascular Calcification in Patients with CKD. J Stroke Cerebrovasc Dis 2021; 30:105745. [PMID: 33903015 DOI: 10.1016/j.jstrokecerebrovasdis.2021.105745] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Accepted: 03/07/2021] [Indexed: 10/21/2022] Open
Affiliation(s)
| | - Mariana P Velozo
- Department of Medicine, Division of Nephrology, Hospital das Clinicas HCFMUSP, Universidade de Sao Paulo, Sao Paulo, SP, Brazil
| | - Venceslau A Coelho
- Department of Medicine, Division of Geriatric, Hospital das Clinicas HCFMUSP, Universidade de Sao Paulo, Sao Paulo, SP, Brazil
| | - Melani R Custodio
- Department of Medicine, Division of Nephrology, Hospital das Clinicas HCFMUSP, Universidade de Sao Paulo, Sao Paulo, SP, Brazil
| | | | - Rosa M A Moysés
- Department of Medicine, Division of Nephrology, Hospital das Clinicas HCFMUSP, Universidade de Sao Paulo, Sao Paulo, SP, Brazil
| | - Rosilene M Elias
- Department of Post-Graduation, Universidade Nove de Julho (UNINOVE), Sao Paulo, SP, Brazil; Department of Medicine, Division of Nephrology, Hospital das Clinicas HCFMUSP, Universidade de Sao Paulo, Sao Paulo, SP, Brazil.
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31
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Kositsawat J, Kuo CL, Barry LC, Melzer D, Bandinelli S, Ferrucci L, Wu R, Kuchel GA. Interaction Between Vitamin D and Interleukin 6 on Slow Gait Speed: 6-Year Follow-up Data of Older Adults From InCHIANTI. J Gerontol A Biol Sci Med Sci 2021; 75:1161-1166. [PMID: 31282535 DOI: 10.1093/gerona/glz165] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2018] [Indexed: 01/01/2023] Open
Abstract
BACKGROUND Whereas the independent effects of biomarkers, including 25-hydroxy vitamin D (25(OH)D), insulin-like growth factor 1, C-reactive protein, and interleukin 6 (IL-6), on gait speed in older adults have been evaluated, their joint effects on gait speed are not well understood. METHODS Study subjects aged at least 65 at baseline (N = 970) were enrolled in the population-based Invecchiare in Chianti (InCHIANTI) study from 1998 to 2000 and were followed up at 3 and 6 years. All above biomarkers and gait speed data were measured at each of the three time points. Using a generalized estimating equation approach, we determined if slow gait speed (<0.8 m/s) was associated with the biomarkers. Further investigation was conducted for interactions between high IL-6 (≥.87 pg/mL) and other biomarkers focusing on low 25(OH)D (<20 ng/mL). RESULTS After controlling for other biomarkers and potential confounders, IL-6 emerged as the only biomarker independently associated with gait speed. The association between high IL-6 and slow gait speed was enhanced by low 25(OH)D, with significant interaction between high IL-6 and low 25(OH)D (p = .038). The odds ratio of slow gait speed for low 25(OH)D and high IL-6 was 1.63 (95% confidence interval [CI]: 1.15, 2.32) compared with the reference groups with both biomarker levels at the other ends. CONCLUSION The association of low vitamin D with slow gait speed statistically interacts with high IL-6. Coexisting vitamin D insufficiency and inflammation may provide a better biomarker for identifying those at risk of developing impairments in gait speed than either factor alone.
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Affiliation(s)
| | - Chia-Ling Kuo
- Connecticut Institute for Clinical and Translational Science, Farmington
| | - Lisa C Barry
- Center on Aging, University of Connecticut Health Center, Farmington
| | - David Melzer
- Center on Aging, University of Connecticut Health Center, Farmington.,Epidemiology and Public Health, University of Exeter Medical School, Devon, UK
| | | | | | - Rong Wu
- Connecticut Institute for Clinical and Translational Science, Farmington
| | - George A Kuchel
- Center on Aging, University of Connecticut Health Center, Farmington
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32
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Panza F, La Montagna M, Lampignano L, Zupo R, Bortone I, Castellana F, Sardone R, Borraccino L, Dibello V, Resta E, Altamura M, Daniele A, Lozupone M. Vitamin D in the development and progression of alzheimer's disease: implications for clinical management. Expert Rev Neurother 2021; 21:287-301. [PMID: 33406925 DOI: 10.1080/14737175.2021.1873768] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
INTRODUCTION Although the pathophysiological bases of Alzheimer's disease (AD) remain incompletely understood and disease-modifying therapies are not available, intervention on modifiable risk factors is warranted. Research on nutrition and dietary components is challenging and controversies still persist about the role of micro- and macronutrients and health outcomes in dementia. Importantly, results of preclinical investigations have shown that vitamin D triggers different neural pathways that may be protective against these neurodegenerative mechanisms, including the deposition of amyloid plaques, inflammatory processes, neurofibrillary degeneration, glutamatergic excitotoxicity, excessive intraneuronal calcium influx, and oxidative stress, although its relationship with AD still needs to be fully understood. AREAS COVERED The authors analyzed the recent evidence about the effects of vitamin D insufficiency on AD and the role of supplementation. EXPERT OPINION Both insufficient (25-49.9 ng/ml) and deficient levels (<25 ng/ml) of vitamin D may contribute to an increased susceptibility to AD. However, further well-designed prospective studies are needed for a better understanding of the involvement of low vitamin D concentrations in the AD natural history. Randomized clinical trials will also be necessary to address the issue of causality and determine whether vitamin D supplementation may be effective for the prevention or treatment of AD.
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Affiliation(s)
- Francesco Panza
- Frailty Phenotypes Research Unit, "Salus in Apulia Study", National Institute of Gastroenterology "Saverio De Bellis", Research Hospital, Bari, Italy
| | - Maddalena La Montagna
- Psychiatric Unit, Department of Clinical and Experimental Medicine, University of Foggia, Foggia, Italy
| | - Luisa Lampignano
- Frailty Phenotypes Research Unit, "Salus in Apulia Study", National Institute of Gastroenterology "Saverio De Bellis", Research Hospital, Bari, Italy
| | - Roberta Zupo
- Frailty Phenotypes Research Unit, "Salus in Apulia Study", National Institute of Gastroenterology "Saverio De Bellis", Research Hospital, Bari, Italy
| | - Ilaria Bortone
- Frailty Phenotypes Research Unit, "Salus in Apulia Study", National Institute of Gastroenterology "Saverio De Bellis", Research Hospital, Bari, Italy
| | - Fabio Castellana
- Frailty Phenotypes Research Unit, "Salus in Apulia Study", National Institute of Gastroenterology "Saverio De Bellis", Research Hospital, Bari, Italy
| | - Rodolfo Sardone
- Frailty Phenotypes Research Unit, "Salus in Apulia Study", National Institute of Gastroenterology "Saverio De Bellis", Research Hospital, Bari, Italy
| | - Luisa Borraccino
- Psychiatric Unit, Department of Clinical and Experimental Medicine, University of Foggia, Foggia, Italy
| | - Vittorio Dibello
- Frailty Phenotypes Research Unit, "Salus in Apulia Study", National Institute of Gastroenterology "Saverio De Bellis", Research Hospital, Bari, Italy.,Department of Orofacial Pain & Dysfunction, Academic Centre of Dentistry Amsterdam (ACTA), University of Amsterdam & Vrije Universiteit Amsterdam, The Netherlands
| | - Emanuela Resta
- Department of Cardiac, Thoracic, and Vascular Science, Institute of Respiratory Disease, University of Bari Aldo Moro, Bari, Italy.,Translational Medicine & Management of Health Systems, University of Foggia, Foggia, Italy
| | - Mario Altamura
- Psychiatric Unit, Department of Clinical and Experimental Medicine, University of Foggia, Foggia, Italy
| | - Antonio Daniele
- Institute of Neurology, Catholic University of Sacred Heart, Rome, Italy.,Institute of Neurology, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
| | - Madia Lozupone
- Neurodegenerative Disease Unit, Department of Basic Medicine, Neuroscience, and Sense Organs, University of Bari Aldo Moro, Bari, Italy
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33
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Erkus E, Buyukterzı Z, Karakose S, Kurku H, Kurtgoz PO, Topal M, Guney I. The relationship of soluble klotho level with uremic cardiomyopathy and ecocardiographic parameters in hemodialysis patients. Semin Dial 2020; 34:157-162. [PMID: 33252840 DOI: 10.1111/sdi.12942] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
There are studies reporting that soluble kltho (sKlotho) deficiency plays a role in cardiovascular disease in addition to traditional risk factors such as diabetes, hypertension, anemia, smoking, and excessive volume burden. Our aim in this study was to investigate the relationship of sKlotho with uremic cardiomyopathy and echocardiographic parameters in patients receiving hemodialysis treatment. According to the median value, the sKlotho value was divided into two groups as ≥1.24 and <1.24 ng/ml. Ventricular wall thicknesses, ejection fractions, left atrium, M mode aorta systole, and diastole diameter measurements were taken. The left ventricular mass (LVM) was calculated using the Devereux formula. There were significant differences between the two groups in terms of age, number of patients with diabetes mellitus, comorbidity, dialysis time, sKlotho, phosphorus, parathormone, and albumin parameters. No significant difference was found between the two groups that were separated according to the median sKlotho value, when the echocardiographic parameters of interventricular septum thickness, left ventricular posterior wall thickness, left atrial diameter, left ventricular ejection fraction, and LVM index were compared. In conclusion, sKlotho is not a marker for showing and predicting uremic cardiomyopathy in hemodialysis patients.
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Affiliation(s)
- Edip Erkus
- Nephrology Department, University of Health Sciences, Konya Research and Training Hospital, Konya, Turkey
| | - Zafer Buyukterzı
- Cardiology Department, University of Health Sciences, Konya Research and Training Hospital, Konya, Turkey
| | - Suleyman Karakose
- Nephrology Department, University of Health Sciences, Konya Research and Training Hospital, Konya, Turkey
| | - Huseyın Kurku
- Bıochemıstry Department, University of Health Sciences, Konya Research and Training Hospital, Konya, Turkey
| | - Pervın O Kurtgoz
- Nephrology Department, University of Health Sciences, Konya Research and Training Hospital, Konya, Turkey
| | - Mustafa Topal
- Nephrology Department, University of Health Sciences, Konya Research and Training Hospital, Konya, Turkey
| | - Ibrahim Guney
- Nephrology Department, University of Health Sciences, Konya Research and Training Hospital, Konya, Turkey
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34
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Schrumpf JA, van der Does AM, Hiemstra PS. Impact of the Local Inflammatory Environment on Mucosal Vitamin D Metabolism and Signaling in Chronic Inflammatory Lung Diseases. Front Immunol 2020; 11:1433. [PMID: 32754156 PMCID: PMC7366846 DOI: 10.3389/fimmu.2020.01433] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2020] [Accepted: 06/03/2020] [Indexed: 02/06/2023] Open
Abstract
Vitamin D plays an active role in the modulation of innate and adaptive immune responses as well as in the protection against respiratory pathogens. Evidence for this immunomodulatory and protective role is derived from observational studies showing an association between vitamin D deficiency, chronic airway diseases and respiratory infections, and is supported by a range of experimental studies using cell culture and animal models. Furthermore, recent intervention studies have now shown that vitamin D supplementation reduces exacerbation rates in vitamin D-deficient patients with chronic obstructive pulmonary disease (COPD) or asthma and decreases the incidence of acute respiratory tract infections. The active vitamin D metabolite, 1,25-dihydroxy-vitamin D (1,25(OH)2D), is known to contribute to the integrity of the mucosal barrier, promote killing of pathogens (via the induction of antimicrobial peptides), and to modulate inflammation and immune responses. These mechanisms may partly explain its protective role against infections and exacerbations in COPD and asthma patients. The respiratory mucosa is an important site of local 1,25(OH)2D synthesis, degradation and signaling, a process that can be affected by exposure to inflammatory mediators. As a consequence, mucosal inflammation and other disease-associated factors, as observed in e.g., COPD and asthma, may modulate the protective actions of 1,25(OH)2D. Here, we discuss the potential consequences of various disease-associated processes such as inflammation and exposure to pathogens and inhaled toxicants on vitamin D metabolism and local responses to 1,25(OH)2D in both immune- and epithelial cells. We furthermore discuss potential consequences of disturbed local levels of 25(OH)D and 1,25(OH)2D for chronic lung diseases. Additional insight into the relationship between disease-associated mechanisms and local effects of 1,25(OH)2D is expected to contribute to the design of future strategies aimed at improving local levels of 1,25(OH)2D and signaling in chronic inflammatory lung diseases.
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Affiliation(s)
- Jasmijn A Schrumpf
- Department of Pulmonology, Leiden University Medical Center, Leiden, Netherlands
| | - Anne M van der Does
- Department of Pulmonology, Leiden University Medical Center, Leiden, Netherlands
| | - Pieter S Hiemstra
- Department of Pulmonology, Leiden University Medical Center, Leiden, Netherlands
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35
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Mehrabadi S, Sadr SS. Administration of Vitamin D3 and E supplements reduces neuronal loss and oxidative stress in a model of rats with Alzheimer’s disease. Neurol Res 2020; 42:862-868. [DOI: 10.1080/01616412.2020.1787624] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Affiliation(s)
- Shima Mehrabadi
- Department of Physiology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Seyed Shahabeddin Sadr
- Department of Physiology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
- Electrophysiology Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran
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36
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The association between Single Nucleotide Polymorphisms of Klotho Gene and Mortality in Elderly Men: The MrOS Sweden Study. Sci Rep 2020; 10:10243. [PMID: 32581247 PMCID: PMC7314825 DOI: 10.1038/s41598-020-66517-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2019] [Accepted: 02/24/2020] [Indexed: 12/12/2022] Open
Abstract
The Klotho (KL) gene is involved in phosphate homeostasis. Polymorphisms in this gene have been reported to be associated with the risk of cardiovascular disease. Here we used computational tools to predict the damage-associated single nucleotide polymorphisms (SNPs) in the human KL gene. We further investigated the association of SNPs in the KL gene and mortality in the Swedish multicenter prospective Osteoporotic Fractures in Men (MrOS) cohort. This study included 2921 men (aged 69-81 years) with mean 4.49 ± 1.03 years follow-up. 18 SNPs in the KL gene were genotyped using Sequenom. These SNPs were identified by in silico tools for the coding and noncoding genome to predict the damaging SNPs. After quality analyses, SNPs were analyzed for mortality risk using two steps approach on logistic regression model screening and then Cox regression model confirmation. Two non-synonymous SNPs rs9536314 and rs9527025 were found to be potentially damaging SNPs that affect KL protein stability and expression. However, these two SNPs were not statistically significantly associated with all-cause mortality (crude Hazard ratio [HR] 1.72, 95% confidence interval [CI] 0.96-3.07 in rs9536314; crude HR 1.82, 95% CI 0.998-3.33 in rs9527025) or cardiovascular mortality (crude HR 1.52, 95% CI 0.56-4.14 in rs9536314; crude HR 1.54, 95% CI 0.55-4.33 in rs9527025) in additive model using Cox regression analysis. In conclusion, these two potentially damaging SNPs (rs9536314 and rs9527025) in the KL gene were not associated with all-cause mortality or cardiovascular mortality in MrOs cohort. Larger scales studies and meta-analysis are needed to confirm the correlation between polymorphisms of the KL gene and mortality.
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37
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Farahmand F, Nourshahi M, Soleimani M, Rajabi H, Power KE. The effect of 6 weeks of high intensity interval training on myelin biomarkers and demyelination in experimental autoimmune encephalomyelitis model. J Neuroimmunol 2020; 346:577306. [PMID: 32629305 DOI: 10.1016/j.jneuroim.2020.577306] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2020] [Revised: 06/05/2020] [Accepted: 06/22/2020] [Indexed: 11/26/2022]
Abstract
Exercise has been shown to increase myelin biomarkers such as klotho and PLP and improve clinical and pathological symptoms using the experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis (MS). In the present study, we evaluated whether 6 weeks of high-intensity interval training (HIIT) prior to induction of EAE increase klotho and/or PLP and attenuate the severity of symptoms and/or disease progression in EAE model. Our data demonstrate that HIIT increased klotho and PLP and decreased disability. These proteins are associated with maintaining myelination and further research is required to examine potential clinical relevance.
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Affiliation(s)
- Fattaneh Farahmand
- Department of Biological Sciences in Sport and Health, Faculty of Sports Sciences and Health, Shahid Beheshti University, Tehran, Iran.
| | - Maryam Nourshahi
- Department of Biological Sciences in Sport and Health, Faculty of Sports Sciences and Health, Shahid Beheshti University, Tehran, Iran.
| | - Maryam Soleimani
- Department of Medical Basic Sciences, University of Social Welfare and Rehabilitation Sciences Tehran, Iran.
| | - Hamid Rajabi
- Department of Exercise Physiology, Sport Science Faculty, Kharazmi University, Tehran, Iran.
| | - Kevin E Power
- School of Human Kinetics and Recreation, Memorial University of Newfoundland, St. John's, NL, Canada.
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38
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Electrochemical genosensor for Klotho detection based on aliphatic and aromatic thiols self-assembled monolayers. Talanta 2020; 212:120735. [DOI: 10.1016/j.talanta.2020.120735] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2019] [Revised: 01/07/2020] [Accepted: 01/10/2020] [Indexed: 11/22/2022]
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39
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Salech F, Varela-Nallar L, Arredondo SB, Bustamante DB, Andaur GA, Cisneros R, Ponce DP, Ayala P, Inestrosa NC, Valdés JL, I Behrens M, Couve A. Local Klotho Enhances Neuronal Progenitor Proliferation in the Adult Hippocampus. J Gerontol A Biol Sci Med Sci 2020; 74:1043-1051. [PMID: 29300914 DOI: 10.1093/gerona/glx248] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2017] [Accepted: 12/28/2017] [Indexed: 12/21/2022] Open
Abstract
Klotho is an aging-related protein associated with hippocampal cognitive performance in mammals. Klotho regulates progenitor cell proliferation in non-neuronal tissues, but its role in adult hippocampal neurogenesis (AHN) has not been explored. Klotho expression in the adult mouse hippocampus was examined by immunofluorescence and polymerase chain reaction. AHN was evaluated in the hippocampus of klotho knock-out mice (KO), klotho KO/vitamin D-receptor mutant mice, and in a model of local klotho hippocampal knockdown. The recombinant Klotho effect on proliferation was measured in mouse-derived hippocampal neural progenitor cells. Hippocampal-dependent memory was assessed by a dry-land version of the Morris water maze. Klotho was expressed in the granular cell layer of the adult Dentate Gyrus. AHN was increased in klotho KO mice, but not in klotho KO/vitamin D-receptor mutant mice. Inversely, local downregulation of hippocampal Klotho diminished AHN. Recombinant Klotho increased the proliferation rate of neural progenitors. Downregulation of hippocampal Klotho correlated with a decreased performance in hippocampal-dependent memory. These results suggest that Klotho directly participates in regulating AHN. Our observations indicate that Klotho promotes proliferation, AHN and hippocampal-dependent cognition. Increased neurogenesis in klotho KO mice may be secondary to the activation of other pathways altered in the model, such as vitamin D.
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Affiliation(s)
- Felipe Salech
- Department of Neuroscience, Faculty of Medicine, Universidad de Chile, Santiago, Chile.,Biomedical Neuroscience Institute (BNI), Santiago, Chile.,Unidad de Geriatría, Hospital Clínico Universidad de Chile, Santiago.,Centro de Investigación Clínica Avanzada (CICA), Hospital Clínico Universidad de Chile, Santiago
| | - Lorena Varela-Nallar
- Centro de Investigaciones Biomédicas (CIB), Facultad de Ciencias Biológicas y Facultad de Medicina, Universidad Andrés Bello, Santiago, Chile
| | - Sebastián B Arredondo
- Centro de Investigaciones Biomédicas (CIB), Facultad de Ciencias Biológicas y Facultad de Medicina, Universidad Andrés Bello, Santiago, Chile
| | - Daniel B Bustamante
- Centro de Investigaciones Biomédicas (CIB), Facultad de Ciencias Biológicas y Facultad de Medicina, Universidad Andrés Bello, Santiago, Chile
| | - Gabriela A Andaur
- Centro de Investigaciones Biomédicas (CIB), Facultad de Ciencias Biológicas y Facultad de Medicina, Universidad Andrés Bello, Santiago, Chile
| | - Rodrigo Cisneros
- Department of Neuroscience, Faculty of Medicine, Universidad de Chile, Santiago, Chile
| | - Daniela P Ponce
- Centro de Investigación Clínica Avanzada (CICA), Hospital Clínico Universidad de Chile, Santiago
| | - Patricia Ayala
- Centro de Investigación Clínica Avanzada (CICA), Hospital Clínico Universidad de Chile, Santiago
| | - Nibaldo C Inestrosa
- Centro de Envejecimiento y Regeneración (CARE), Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, P. Universidad Católica de Chile, Santiago.,Center for Healthy Brain Ageing, School of Psychiatry, Faculty of Medicine, University of New South Wales, Sydney, Australia.,Centro de Excelencia en Biomedicina de Magallanes (CEBIMA), Universidad de Magallanes, Punta Arenas, Chile
| | - José L Valdés
- Department of Neuroscience, Faculty of Medicine, Universidad de Chile, Santiago, Chile.,Biomedical Neuroscience Institute (BNI), Santiago, Chile
| | - María I Behrens
- Centro de Investigación Clínica Avanzada (CICA), Hospital Clínico Universidad de Chile, Santiago.,Departamento de Neurología y Neurocirugía, Hospital Clínico Universidad de Chile, Santiago.,Clínica Alemana de Santiago, Chile
| | - Andrés Couve
- Department of Neuroscience, Faculty of Medicine, Universidad de Chile, Santiago, Chile.,Biomedical Neuroscience Institute (BNI), Santiago, Chile
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40
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Antiaging Factor Klotho Retards the Progress of Intervertebral Disc Degeneration through the Toll-Like Receptor 4-NF- κB Pathway. Int J Cell Biol 2020; 2020:8319516. [PMID: 32256598 PMCID: PMC7106913 DOI: 10.1155/2020/8319516] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2019] [Revised: 01/09/2020] [Accepted: 01/31/2020] [Indexed: 12/18/2022] Open
Abstract
Antiaging protein Klotho exhibits impressive properties of anti-inflammation, however is declined early after intervertebral disc injury, making Klotho restoration an attractive strategy of treating intervertebral disc inflammatory disorders. Here, we have found that Klotho is enriched in nucleus pulposus (NP) cells and Klotho overexpression attenuates H2O2-induced acute inflammation essentially via suppressing Toll-like receptor 4 (TLR4). The proinflammatory NF-κB signaling and cytokine expressions paralleled with Klotho repression and TLR4 elevation in both NP cells (H2O2 treatment) and rat intervertebral disc (needle puncture treatment). Overexpression of TLR4 downregulated expression of Klotho, whereas interfering TLR4 expression diminished the inhibitory effects of H2O2 on Klotho in NP cells. Consistently, Klotho knockdown by RNA interferences largely diminished the anti-inflammatory and intervertebral disc protective effects in an Intervertebral Disc Degeneration (IDD) model. Thus, our study indicates that TLR4-NF-κB signaling and Klotho form a negative-feedback loop in NP cells. Also, we demonstrate that the expression of Klotho is regulated by the balance between upregulation and downregulation of TLR4-NF-κB signaling.
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Celarain N, Tomas-Roig J. Aberrant DNA methylation profile exacerbates inflammation and neurodegeneration in multiple sclerosis patients. J Neuroinflammation 2020; 17:21. [PMID: 31937331 PMCID: PMC6961290 DOI: 10.1186/s12974-019-1667-1] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2019] [Accepted: 11/27/2019] [Indexed: 12/12/2022] Open
Abstract
Multiple sclerosis (MS) is an autoimmune and demyelinating disease of the central nervous system characterised by incoordination, sensory loss, weakness, changes in bladder capacity and bowel function, fatigue and cognitive impairment, creating a significant socioeconomic burden. The pathogenesis of MS involves both genetic susceptibility and exposure to distinct environmental risk factors. The gene x environment interaction is regulated by epigenetic mechanisms. Epigenetics refers to a complex system that modifies gene expression without altering the DNA sequence. The most studied epigenetic mechanism is DNA methylation. This epigenetic mark participates in distinct MS pathophysiological processes, including blood-brain barrier breakdown, inflammatory response, demyelination, remyelination failure and neurodegeneration. In this study, we also accurately summarised a list of environmental factors involved in the MS pathogenesis and its clinical course. A literature search was conducted using MEDLINE through PubMED and Scopus. In conclusion, an exhaustive study of DNA methylation might contribute towards new pharmacological interventions in MS by use of epigenetic drugs.
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Affiliation(s)
- Naiara Celarain
- Girona Neuroimmunology and Multiple Sclerosis Unit (UNIEM), Dr. Josep Trueta University Hospital and Girona Biomedical Research Institute (IDIBGI), Girona, Spain.
| | - Jordi Tomas-Roig
- Girona Neuroimmunology and Multiple Sclerosis Unit (UNIEM), Dr. Josep Trueta University Hospital and Girona Biomedical Research Institute (IDIBGI), Girona, Spain.
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Management of Secondary Hyperparathyroidism in Chronic Kidney Disease: A Focus on the Elderly. Drugs Aging 2019; 36:885-895. [DOI: 10.1007/s40266-019-00696-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
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Abolghasemi M, Yousefi T, Maniati M, Qujeq D. The interplay of Klotho with signaling pathway and microRNAs in cancers. J Cell Biochem 2019; 120:14306-14317. [DOI: 10.1002/jcb.29022] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2018] [Revised: 04/16/2019] [Accepted: 04/18/2019] [Indexed: 12/15/2022]
Affiliation(s)
- Maryam Abolghasemi
- Cellular and Molecular Biology Research Center, Health Research Institute Babol University of Medical Sciences Babol Iran
- Department of Clinical Biochemistry, School of Medicine Babol University of Medical Sciences Babol Iran
- Student Research Committee Babol University of Medical Sciences Babol Iran
| | - Tooba Yousefi
- Cellular and Molecular Biology Research Center, Health Research Institute Babol University of Medical Sciences Babol Iran
- Department of Clinical Biochemistry, School of Medicine Babol University of Medical Sciences Babol Iran
- Student Research Committee Babol University of Medical Sciences Babol Iran
| | - Mahmood Maniati
- Assistant Professor of the English Department Ahvaz Jundishapur University of Medical Sciences Ahvaz Iran
| | - Durdi Qujeq
- Cellular and Molecular Biology Research Center, Health Research Institute Babol University of Medical Sciences Babol Iran
- Department of Clinical Biochemistry, School of Medicine Babol University of Medical Sciences Babol Iran
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LCE: an open web portal to explore gene expression and clinical associations in lung cancer. Oncogene 2018; 38:2551-2564. [PMID: 30532070 PMCID: PMC6477796 DOI: 10.1038/s41388-018-0588-2] [Citation(s) in RCA: 77] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2018] [Revised: 09/04/2018] [Accepted: 09/05/2018] [Indexed: 02/06/2023]
Abstract
We constructed a lung cancer-specific database housing expression data and clinical data from over 6700 patients in 56 studies. Expression data from 23 genome-wide platforms were carefully processed and quality controlled, whereas clinical data were standardized and rigorously curated. Empowered by this lung cancer database, we created an open access web resource—the Lung Cancer Explorer (LCE), which enables researchers and clinicians to explore these data and perform analyses. Users can perform meta-analyses on LCE to gain a quick overview of the results on tumor vs non-malignant tissue (normal) differential gene expression and expression-survival association. Individual dataset-based survival analysis, comparative analysis, and correlation analysis are also provided with flexible options to allow for customized analyses from the user.
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Xing Y, Smith MJ, Goetz CA, McElmurry RT, Parker SL, Min D, Hollander GA, Weinberg KI, Tolar J, Stefanski HE, Blazar BR. Thymic Epithelial Cell Support of Thymopoiesis Does Not Require Klotho. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2018; 201:3320-3328. [PMID: 30373854 PMCID: PMC6275142 DOI: 10.4049/jimmunol.1800670] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/11/2018] [Accepted: 09/28/2018] [Indexed: 12/25/2022]
Abstract
Age-related thymic involution is characterized by a decrease in thymic epithelial cell (TEC) number and function parallel to a disruption in their spatial organization, resulting in defective thymocyte development and proliferation as well as peripheral T cell dysfunction. Deficiency of Klotho, an antiaging gene and modifier of fibroblast growth factor signaling, causes premature aging. To investigate the role of Klotho in accelerated age-dependent thymic involution, we conducted a comprehensive analysis of thymopoiesis and peripheral T cell homeostasis using Klotho-deficient (Kl/Kl) mice. At 8 wk of age, Kl/Kl mice displayed a severe reduction in the number of thymocytes (10-100-fold reduction), especially CD4 and CD8 double-positive cells, and a reduction of both cortical and medullary TECs. To address a cell-autonomous role for Klotho in TEC biology, we implanted neonatal thymi from Klotho-deficient and -sufficient mice into athymic hosts. Kl/Kl thymus grafts supported thymopoiesis equivalently to Klotho-sufficient thymus transplants, indicating that Klotho is not intrinsically essential for TEC support of thymopoiesis. Moreover, lethally irradiated hosts given Kl/Kl or wild-type bone marrow had normal thymocyte development and comparably reconstituted T cells, indicating that Klotho is not inherently essential for peripheral T cell reconstitution. Because Kl/Kl mice have higher levels of serum phosphorus, calcium, and vitamin D, we evaluated thymus function in Kl/Kl mice fed with a vitamin D-deprived diet. We observed that a vitamin D-deprived diet abrogated thymic involution and T cell lymphopenia in 8-wk-old Kl/Kl mice. Taken together, our data suggest that Klotho deficiency causes thymic involution via systemic effects that include high active vitamin D levels.
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Affiliation(s)
- Yan Xing
- Division of Blood and Marrow Transplantation, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455
| | - Michelle J Smith
- Division of Blood and Marrow Transplantation, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455
- Center for Immunology, University of Minnesota Medical School, Minneapolis, MN 55455
| | - Christine A Goetz
- Division of Blood and Marrow Transplantation, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455
- Center for Immunology, University of Minnesota Medical School, Minneapolis, MN 55455
| | - Ron T McElmurry
- Division of Blood and Marrow Transplantation, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455
| | - Sarah L Parker
- Division of Blood and Marrow Transplantation, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455
| | - Dullei Min
- Division of Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, Stanford Medicine, Stanford University, Palo Alto, CA 94304
| | - Georg A Hollander
- Department of Biomedicine, University of Basel, 4056 Basel, Switzerland; and
- Department of Paediatrics, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Headington, Oxford OX3 9DS, United Kingdom
| | - Kenneth I Weinberg
- Division of Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, Stanford Medicine, Stanford University, Palo Alto, CA 94304
| | - Jakub Tolar
- Division of Blood and Marrow Transplantation, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455
| | - Heather E Stefanski
- Division of Blood and Marrow Transplantation, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455
| | - Bruce R Blazar
- Division of Blood and Marrow Transplantation, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455;
- Center for Immunology, University of Minnesota Medical School, Minneapolis, MN 55455
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Boisvert NC, Holterman CE, Gutsol A, Coulombe J, Pan W, Alexander RT, Gray DA, Kennedy CR. Ubiquitin COOH-terminal hydrolase L1 deletion is associated with urinary α-klotho deficiency and perturbed phosphate homeostasis. Am J Physiol Renal Physiol 2018; 315:F353-F363. [DOI: 10.1152/ajprenal.00411.2017] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Loss of ubiquitin COOH-terminal hydrolase L1 (UCHL1), a deubiquitinating enzyme required for neuronal function, led to hyperphosphatemia accompanied by phosphaturia in mice, while calcium homeostasis remained intact. We therefore investigated the mechanisms underlying the phosphate imbalance in Uchl1−/− mice. Interestingly, phosphaturia was not a result of lower renal brush border membrane sodium-phosphate cotransporter expression as sodium-phosphate cotransporter 2a and 2c expression levels was similar to wild-type levels. Plasma parathyroid hormone and fibroblast growth factor 23 levels were not different; however, fibroblast growth factor 23 mRNA levels were significantly increased in femur homogenates from Uchl1−/− mice. Full-length and soluble α-klotho levels were comparable in kidneys from wild-type and Uchl1−/− mice; however, soluble α-klotho was reduced in Uchl1−/− mice urine. Consistent with unchanged components of 1,25(OH)2D3 metabolism (i.e., CYP27B1 and CYP24A1), sodium-phosphate cotransporter 2b protein levels were not different in ileum brush borders from Uchl1−/− mice, suggesting that the intestine is not the source of hyperphosphatemia. Nonetheless, when Uchl1−/− mice were fed a low-phosphate diet, plasma phosphate, urinary phosphate, and fractional excretion of phosphate were significantly attenuated and comparable to levels of low-phosphate diet-fed wild-type mice. Our findings demonstrate that Uchl1-deleted mice exhibit perturbed phosphate homeostasis, likely consequent to decreased urinary soluble α-klotho, which can be rescued with a low-phosphate diet. Uchl1−/− mice may provide a useful mouse model to study mild perturbations in phosphate homeostasis.
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Affiliation(s)
- Naomi C. Boisvert
- Kidney Research Centre, The Ottawa Hospital, Ottawa, Ontario, Canada
- Ottawa Hospital Research Institute, The Ottawa Hospital, Ottawa, Ontario, Canada
- Faculty of Medicine, Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - Chet E. Holterman
- Kidney Research Centre, The Ottawa Hospital, Ottawa, Ontario, Canada
- Ottawa Hospital Research Institute, The Ottawa Hospital, Ottawa, Ontario, Canada
| | - Alexey Gutsol
- Kidney Research Centre, The Ottawa Hospital, Ottawa, Ontario, Canada
- Ottawa Hospital Research Institute, The Ottawa Hospital, Ottawa, Ontario, Canada
| | - Josée Coulombe
- Ottawa Hospital Research Institute, The Ottawa Hospital, Ottawa, Ontario, Canada
| | - Wanling Pan
- Department of Physiology, University of Alberta, Edmonton, Alberta, Canada
| | - R. Todd Alexander
- Department of Physiology, University of Alberta, Edmonton, Alberta, Canada
- Membrane Protein Disease Research Group, University of Alberta, Edmonton, Alberta, Canada
- Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada
| | - Douglas A. Gray
- Ottawa Hospital Research Institute, The Ottawa Hospital, Ottawa, Ontario, Canada
- Faculty of Medicine, Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada
| | - Chris R. Kennedy
- Kidney Research Centre, The Ottawa Hospital, Ottawa, Ontario, Canada
- Ottawa Hospital Research Institute, The Ottawa Hospital, Ottawa, Ontario, Canada
- Faculty of Medicine, Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada
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Mytych J, Romerowicz-Misielak M, Koziorowski M. Klotho protects human monocytes from LPS-induced immune impairment associated with immunosenescent-like phenotype. Mol Cell Endocrinol 2018; 470:1-13. [PMID: 28478304 DOI: 10.1016/j.mce.2017.05.003] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2016] [Revised: 04/30/2017] [Accepted: 05/02/2017] [Indexed: 12/01/2022]
Abstract
In this study, we provide a new evidence on immunosenescent-like phenotype induction in low density monocytes due to the long-term treatment with lipopolysaccharide (LPS). We show that LPS caused oxidative and nitrosative stress through zinc downregulation and calcium accumulation. In turn, increased amounts of ROS/RNS and pro-inflammatory cytokines TNFα, IL-1β, IL-6 led to the irreversible DNA damage, persistent DDR activation, proliferation inhibition, reduction in cell growth and immune impairment. Furthermore, we provide evidence that klotho reduced levels of ROS/RNS and pro-inflammatory cytokines as well as upregulated secretion of anti-inflammatory IL-10 in LPS-treated monocytes, thus the observed DNA damage was less severe, promptly and properly fixed and cells quickly resumed normal proliferation and maintained their immune functionality. Therefore, klotho protein could be considered as a protective factor against immunosenescent-like phenotype in monocytes an issue relevant to many immune disorders.
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Affiliation(s)
- Jennifer Mytych
- Institute of Applied Biotechnology and Basic Sciences, University of Rzeszow, Werynia 502, 36-100 Kolbuszowa, Poland; Centre of Applied Biotechnology and Basic Sciences, University of Rzeszow, Werynia 502, 36-100 Kolbuszowa, Poland.
| | - Maria Romerowicz-Misielak
- Institute of Applied Biotechnology and Basic Sciences, University of Rzeszow, Werynia 502, 36-100 Kolbuszowa, Poland; Centre of Applied Biotechnology and Basic Sciences, University of Rzeszow, Werynia 502, 36-100 Kolbuszowa, Poland
| | - Marek Koziorowski
- Institute of Applied Biotechnology and Basic Sciences, University of Rzeszow, Werynia 502, 36-100 Kolbuszowa, Poland; Centre of Applied Biotechnology and Basic Sciences, University of Rzeszow, Werynia 502, 36-100 Kolbuszowa, Poland
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Rudenko TE, Bobkova IN, Kamyshova ES, Gorelova IA. [Role of the mechanisms of replicative cellular senescence in structural and functional changes of the vascular wall in chronic kidney disease]. TERAPEVT ARKH 2017; 89:102-109. [PMID: 28745697 DOI: 10.17116/terarkh2017896102-109] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
This review considers the mechanisms and risk factors for the development of replicative cellular senescence of the vascular wall in patients with CKD and discusses therapeutic approaches to slowing the accelerated vascular aging.
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Affiliation(s)
- T E Rudenko
- I.M. Sechenov First Moscow State Medical University, Ministry of Health of Russia, Moscow, Russia
| | - I N Bobkova
- I.M. Sechenov First Moscow State Medical University, Ministry of Health of Russia, Moscow, Russia
| | - E S Kamyshova
- I.M. Sechenov First Moscow State Medical University, Ministry of Health of Russia, Moscow, Russia
| | - I A Gorelova
- I.M. Sechenov First Moscow State Medical University, Ministry of Health of Russia, Moscow, Russia
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Abstract
The vertebrate endoskeleton is not a mere frame for muscle attachment to facilitate locomotion, but is a massive organ integrated with many physiologic functions including mineral and energy metabolism. Mineral balance is maintained by tightly controlled ion fluxes that are external (intestine and kidney) and internal (between bone and other organs), and are regulated and coordinated by many endocrine signals between these organs. The endocrine fibroblast growth factors (FGFs) and Klotho gene families are complex systems that co-evolved with the endoskeleton. In particular, FGF23 and αKlotho which are primarily derived from bone and kidney respectively, are critical in maintaining mineral metabolism where each of these proteins serving highly diverse roles; abound with many unanswered questions regarding their upstream regulation and downstream functions. Genetic lesions of components of this network produce discreet disturbances in many facets of mineral metabolism. One acquired condition with colossal elevations of FGF23 and suppression of αKlotho is chronic kidney disease where multiple organ dysfunction contributes to the morbidity and mortality. However, the single most important group of derangements that encompasses the largest breadth of complications is mineral metabolism disorders. Mineral metabolic disorders in CKD impact negatively and significantly on the progression of renal disease as well as extra-renal complications. Knowledge of the origin, nature, and impact of phosphate, FGF23, and αKlotho derangements is pivotal to understanding the pathophysiology and treatment of CKD.
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Affiliation(s)
- Makoto Kuro-O
- Center for Molecular Medicine, Jichi Medical University, Tochigi, Japan; Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA; Charles and Jane Pak Center of Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, TX, USA.
| | - Orson W Moe
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA; Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX, USA; Charles and Jane Pak Center of Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, TX, USA.
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50
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Kunert SK, Hartmann H, Haffner D, Leifheit-Nestler M. Klotho and fibroblast growth factor 23 in cerebrospinal fluid in children. J Bone Miner Metab 2017; 35:215-226. [PMID: 27017221 DOI: 10.1007/s00774-016-0746-y] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2015] [Accepted: 02/15/2016] [Indexed: 12/13/2022]
Abstract
The fibroblast growth factor (FGF) 23/Klotho axis is a principal regulator of phosphate hemostasis and vitamin D metabolism, but limited data is available on its role in the central nervous system. Here, we investigate soluble α-Klotho (sKlotho) and C-terminal as well as intact FGF23 in cerebrospinal fluid (CSF) and plasma and their relationship to mineral metabolism parameters in humans. In 39 children aged 0.3-16.8 years undergoing lumbar puncture for the exclusion of inflammatory neurological disease, sKlotho and FGF23 were investigated by Western blot analysis, followed by ELISA quantification in CSF and plasma. The percentage of intrathecal synthesis of both proteins was calculated by measuring both the expected and observed CSF/plasma ratios of sKlotho and FGF23. The secreted (KL1) and cleaved (KL1+KL2) isoforms of sKlotho, and FGF23 were clearly detected in CSF in all subjects, although protein levels were lower compared to those of plasma samples (each p < 0.01). The intrathecal percentage of CSF sKlotho and FGF23 synthesis amounted to 98 and 99 %, respectively. CSF sKlotho levels were higher in boys than in girls (p < 0.01), and correlated positively with plasma C-terminal FGF23 concentrations (p < 0.05) and standardized height (p < 0.01). Importantly, there were no significant correlations between plasma and CSF levels of sKlotho or FGF23. Plasma sKlotho as well as C-terminal and intact FGF23, respectively, were associated with parameters of mineral metabolism These results provide evidence that cleaved and secreted sKlotho and FGF23 are present in CSF, mainly derived from brain and affected by sex, height, and mineral metabolism parameters in children. Nevertheless, the absence of significant associations between plasma and CSF levels of Klotho and FGF23, respectively, suggest that the regulation of Klotho and FGF23 may be different between organs secreting these hormones into blood and CSF.
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Affiliation(s)
- Svenja Kristin Kunert
- Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany
| | - Hans Hartmann
- Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany
| | - Dieter Haffner
- Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany
| | - Maren Leifheit-Nestler
- Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany.
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