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Sheng Y, Wei H, Lu S, Hong W. Alternative splicing of vascular calcification: Insights, opportunities, and challenges. Cell Signal 2025; 127:111626. [PMID: 39875046 DOI: 10.1016/j.cellsig.2025.111626] [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: 11/30/2024] [Revised: 01/11/2025] [Accepted: 01/23/2025] [Indexed: 01/30/2025]
Abstract
Vascular calcification(VC) significantly increases the risk of cardiovascular events, leading to thickening of the myocardium and arteries, coronary heart disease, heart failure, and potentially triggering myocardial infarction and sudden cardiac death. Although VC is a reversible process, there are currently no methods or medications in clinical practice that can completely reverse or cure it. The current treatment strategies primarily focus on slowing the progression of VC and exploring new diagnostic and therapeutic approaches, making the identification of early diagnostic markers for VC particularly important. Alternative splicing(AS)has extensive potential in clinical applications as a biomarker, including in disease diagnosis and therapeutic targeting. This article provides an overview of the roles played by different isoforms of biomarkers in VC, with the aim of offering insights for early diagnosis and disease monitoring of VC.
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Affiliation(s)
- Yingkun Sheng
- Xingzhi College, Zhejiang Normal University, Jinhua 321100, China
| | - Hewen Wei
- Jinhua Key laboratory of Quality Evaluation and Standard Research of Traditional Chinese Medicine, Jinhua Food and Drug Inspection Research Institute, Jinhua 321000, China
| | - Shengmin Lu
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Zhejiang Key Laboratory of Intelligent Food Logistic and Processing, Institute of Food Science, Zhejiang Academy of Agricultural Sciences, Hangzhou 310021, China
| | - Weiling Hong
- Jinhua Advanced Research Institute, Jinhua 321019, China.
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2
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Rivoira MA, Peralta López ME, Areco V, Díaz de Barboza G, Dionisi MP, Tolosa de Talamoni N. Emerging concepts on the FGF23 regulation and activity. Mol Cell Biochem 2025; 480:75-89. [PMID: 38581553 DOI: 10.1007/s11010-024-04982-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Accepted: 02/28/2024] [Indexed: 04/08/2024]
Abstract
Fibroblast growth factor 23 (FGF23) discovery has provided new insights into the regulation of Pi and Ca homeostasis. It is secreted by osteoblasts and osteocytes, and acts mainly in the kidney, parathyroid, heart, and bone. The aim of this review is to highlight the current knowledge on the factors modulating the synthesis of FGF23, the canonical and non-canonical signaling pathways of the hormone, the role of FGF23 in different pathophysiological conditions, and the anti-FGF23 therapy. This is a narrative review based on the search of PubMed database in the range of years 2000-2023 using the keywords local and systemic regulators of FGF23 synthesis, FGF23 receptors, canonical and non-canonical pathways, pathophysiological conditions and FGF23, and anti-FGF23 therapy, focusing the data on the molecular mechanisms. The regulation of FGF23 synthesis is complex and multifactorial. It is regulated by local factors and systemic regulators mainly involved in bone mineralization. The excessive FGF23 production is associated with different congenital diseases and with diseases occurring with a secondary high FGF23 production such as in chronic disease kidney and tumor-induced osteomalacia (TIO). The anti-FGF23 therapy appears to be useful to treat chromosome X-linked hypophosphatemia and TIO, but there are doubts about the handle of excessive FGF23 production in CKD. FGF23 biochemistry and pathophysiology are generating a plethora of knowledge to reduce FGF23 bioactivity at many levels that might be useful for future therapeutics of diseases associated with high-serum FGF23 levels.
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Affiliation(s)
- María Angélica Rivoira
- Laboratorio "Dr. Fernando Cañas", Cátedra de Bioquímica y Biología Molecular, Facultad de Ciencias Médicas, INICSA (CONICET-Universidad Nacional de Córdoba), Pabellón Argentina, 2do, Piso, Ciudad Universitaria, 5000, Córdoba, Argentina
| | - María Elena Peralta López
- Laboratorio "Dr. Fernando Cañas", Cátedra de Bioquímica y Biología Molecular, Facultad de Ciencias Médicas, INICSA (CONICET-Universidad Nacional de Córdoba), Pabellón Argentina, 2do, Piso, Ciudad Universitaria, 5000, Córdoba, Argentina
| | - Vanessa Areco
- Laboratorio "Dr. Fernando Cañas", Cátedra de Bioquímica y Biología Molecular, Facultad de Ciencias Médicas, INICSA (CONICET-Universidad Nacional de Córdoba), Pabellón Argentina, 2do, Piso, Ciudad Universitaria, 5000, Córdoba, Argentina
- Instituto Multidisciplinario de Investigación y Transferencia Agroalimentaria y Biotecnológica (IMITAB, CONICET-UNVM), Córdoba, Argentina
| | - Gabriela Díaz de Barboza
- Laboratorio "Dr. Fernando Cañas", Cátedra de Bioquímica y Biología Molecular, Facultad de Ciencias Médicas, INICSA (CONICET-Universidad Nacional de Córdoba), Pabellón Argentina, 2do, Piso, Ciudad Universitaria, 5000, Córdoba, Argentina
| | - María Paula Dionisi
- Cátedra de Clínica Médica II - UHMI Nº 2, Hospital San Roque, Facultad de Ciencias Médicas, Universidad Nacional de Córdoba, Córdoba, Argentina
| | - Nori Tolosa de Talamoni
- Laboratorio "Dr. Fernando Cañas", Cátedra de Bioquímica y Biología Molecular, Facultad de Ciencias Médicas, INICSA (CONICET-Universidad Nacional de Córdoba), Pabellón Argentina, 2do, Piso, Ciudad Universitaria, 5000, Córdoba, Argentina.
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Wilson R, Mukherjee-Roy N, Gattineni J. The role of fibroblast growth factor 23 in regulation of phosphate balance. Pediatr Nephrol 2024; 39:3439-3451. [PMID: 38874635 DOI: 10.1007/s00467-024-06395-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2024] [Revised: 04/22/2024] [Accepted: 04/22/2024] [Indexed: 06/15/2024]
Abstract
Phosphate is essential for numerous biological processes, and serum levels are tightly regulated to accomplish these functions. The regulation of serum phosphate in a narrow physiological range is a well-orchestrated process and involves the gastrointestinal (GI) tract, bone, kidneys, and several hormones, namely, parathyroid hormone, fibroblast growth factor 23 (FGF23), and 1,25-dihydroxyvitamin D (1,25 Vitamin D). Although primarily synthesized in the bone, FGF23, an endocrine FGF, acts on the kidney to regulate phosphate and Vitamin D homeostasis by causing phosphaturia and reduced levels of 1,25 Vitamin D. Recent studies have highlighted the complex regulation of FGF23 including transcriptional and post-translational modification and kidney-bone cross talk. Understanding FGF23 biology has led to the identification of novel therapeutic agents to treat diseases that disrupt phosphate metabolism secondary to FGF23. The focus of this review is to provide an overview of phosphate homeostasis, FGF23 biology, and the role of FGF23 in phosphate balance.
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Affiliation(s)
| | - Neije Mukherjee-Roy
- Division of Pediatric Nephrology, Department of Pediatrics, The University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX, USA
| | - Jyothsna Gattineni
- Division of Pediatric Nephrology, Department of Pediatrics, The University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX, USA.
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Cararo-Lopes MM, Sadovnik R, Fu A, Suresh S, Gandu S, Firestein BL. Overexpression of α-Klotho isoforms promotes distinct Effects on BDNF-Induced Alterations in Dendritic Morphology. Mol Neurobiol 2024; 61:9155-9170. [PMID: 38589756 PMCID: PMC11496329 DOI: 10.1007/s12035-024-04171-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2023] [Accepted: 04/03/2024] [Indexed: 04/10/2024]
Abstract
α-Klotho (α-Kl) is a modulator of aging, neuroprotection, and cognition. Transcription of the Klotho gene produces two splice variants-a membrane protein (mKl), which can be cleaved and released into the extracellular milieu, and a truncated secreted form (sKl). Despite mounting evidence supporting a role for α-Kl in brain function, the specific roles of α-Kl isoforms in neuronal development remain elusive. Here, we examined α-Kl protein levels in rat brain and observed region-specific expression in the adult that differs between isoforms. In the developing hippocampus, levels of isoforms decrease after the third postnatal week, marking the end of the critical period for development. We overexpressed α-Kl isoforms in primary cultures of rat cortical neurons and evaluated effects on brain-derived neurotrophic factor (BDNF) signaling. Overexpression of either isoform attenuated BDNF-mediated signaling and reduced intracellular Ca2+ levels, with mKl promoting a greater effect. mKl or sKl overexpression in hippocampal neurons resulted in a partially overlapping reduction in secondary dendrite branching. Moreover, mKl overexpression increased primary dendrite number. BDNF treatment of neurons overexpressing sKl resulted in a dendrite branching phenotype similar to control neurons. In neurons overexpressing mKl, BDNF treatment restored branching of secondary and higher order dendrites close, but not distal, to the soma. Taken together, the data presented support the idea that sKl and mKl play distinct roles in neuronal development, and specifically, in dendrite morphogenesis.
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Affiliation(s)
- Marina Minto Cararo-Lopes
- Department of Cell Biology and Neuroscience, Rutgers, The State University of New Jersey, Piscataway, NJ, USA
- Cell and Developmental Biology Graduate Program, Rutgers, The State University of New Jersey, Piscataway, NJ, USA
| | - Ratchell Sadovnik
- Department of Cell Biology and Neuroscience, Rutgers, The State University of New Jersey, Piscataway, NJ, USA
| | - Allen Fu
- Department of Cell Biology and Neuroscience, Rutgers, The State University of New Jersey, Piscataway, NJ, USA
| | - Shradha Suresh
- Department of Cell Biology and Neuroscience, Rutgers, The State University of New Jersey, Piscataway, NJ, USA
- Neuroscience Graduate Program, Rutgers, The State University of New Jersey, Piscataway, NJ, USA
| | - Srinivasa Gandu
- Department of Cell Biology and Neuroscience, Rutgers, The State University of New Jersey, Piscataway, NJ, USA
- Cell and Developmental Biology Graduate Program, Rutgers, The State University of New Jersey, Piscataway, NJ, USA
| | - Bonnie L Firestein
- Department of Cell Biology and Neuroscience, Rutgers, The State University of New Jersey, Piscataway, NJ, USA.
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Chen X, Wei Y, Li Z, Zhou C, Fan Y. Distinct role of Klotho in long bone and craniofacial bone: skeletal development, repair and regeneration. PeerJ 2024; 12:e18269. [PMID: 39465174 PMCID: PMC11505971 DOI: 10.7717/peerj.18269] [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: 07/25/2024] [Accepted: 09/17/2024] [Indexed: 10/29/2024] Open
Abstract
Bone defects are highly prevalent diseases caused by trauma, tumors, inflammation, congenital malformations and endocrine abnormalities. Ideally effective and side effect free approach to dealing with bone defects remains a clinical conundrum. Klotho is an important protein, which plays an essential role in regulating aging and mineral ion homeostasis. More recently, research revealed the function of Klotho in regulating skeleton development and regeneration. Klotho has been identified in mesenchymal stem cells, osteoblasts, osteocytes and osteoclasts in different skeleton regions. The specific function and regulatory mechanisms of Klotho in long bone and craniofacial bone vary due to their different embryonic development, ossification and cell types, which remain unclear and without conclusion. Moreover, studies have confirmed that Klotho is a multifunctional protein that can inhibit inflammation, resist cancer and regulate the endocrine system, which may further accentuate the potential of Klotho to be the ideal molecule in inducing bone restoration clinically. Besides, as an endogenous protein, Klotho has a promising potential for clinical therapy without side effects. In the current review, we summarized the specific function of Klotho in long bone and craniofacial skeleton from phenotype to cellular alternation and signaling pathway. Moreover, we illustrated the possible future clinical application for Klotho. Further research on Klotho might help to solve the existing clinical difficulties in bone healing and increase the life quality of patients with bone injury and the elderly.
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Affiliation(s)
- Xinyu Chen
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Yali Wei
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases & Department of Operative Dentistry and Endodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Zucen Li
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases & Department of Operative Dentistry and Endodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Chenchen Zhou
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases & Department of Pediatric Dentistry, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Yi Fan
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases & Department of Operative Dentistry and Endodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China
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Rostamzadeh F, Joukar S, Yeganeh-Hajahmadi M. The role of Klotho and sirtuins in sleep-related cardiovascular diseases: a review study. NPJ AGING 2024; 10:43. [PMID: 39358364 PMCID: PMC11447243 DOI: 10.1038/s41514-024-00165-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/25/2024] [Accepted: 08/07/2024] [Indexed: 10/04/2024]
Abstract
The prevalence of sleep disorders has been reported from 1.6% to 56.0%, worldwide. Sleep deprivation causes cardiovascular diseases (CVDs) including atherosclerosis, vascular aging, hypertension, heart dysfunction, reduced heart rate variability, and cardiac arrhythmia. Reduced tissue oxygen causes various CVDs by activating pro-inflammatory factors and increasing oxidative stress. Sleep disorders are more important and prevalent in older people and cause more severe cardiovascular complications. On the other hand, the reduction of Klotho level, an age-dependent protein whose expression decreases with age, is associated with age-related diseases. Sirtuins, class III histone deacetylases, also are among the essential factors in postponing cellular aging and increasing the lifespan of organisms, and they do this by regulating different pathways in the cell. Sirtuins and Klotho play an important role in the pathophysiology of CVDS and both have anti-oxidative stress and anti-inflammatory activity. Studies have shown that the levels of Klotho and sirtuins are altered in sleep disorders. In this article, alterations of Klotho and sirtuins in sleep disorders and in the development of sleep-related CVDs were reviewed and the possible signaling pathways were discussed. The inclusion criteria were studies with keywords of different types of sleep disorders and CVDs, klotho, SIRT1-7, and sirtuins in PubMed, Scopus, Embase، Science Direct، Web of Sciences and Google Scholar by the end of 2023. The studies revealed there is a bidirectional relationship between sleep disorders and the serum and tissue levels of Klotho and sirtuins and sleep related-CVDs.
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Affiliation(s)
- Farzaneh Rostamzadeh
- Student Research Committee, Kerman University of Medical Sciences, Kerman, Iran
- Department of Physiology and Pharmacology, Afzalipour Faculty of Medicine, Kerman University of Medical Sciences, Kerman, Iran
| | - Siyavash Joukar
- Department of Physiology and Pharmacology, Afzalipour Faculty of Medicine, Kerman University of Medical Sciences, Kerman, Iran.
- Cardiovascular Research Center, Kerman University of Medical Sciences, Kerman, Iran.
| | - Mahboobeh Yeganeh-Hajahmadi
- Physiology Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran
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Grigore TV, Zuidscherwoude M, Olauson H, Hoenderop JG. Lessons from Klotho mouse models to understand mineral homeostasis. Acta Physiol (Oxf) 2024; 240:e14220. [PMID: 39176993 DOI: 10.1111/apha.14220] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2024] [Revised: 07/30/2024] [Accepted: 08/14/2024] [Indexed: 08/24/2024]
Abstract
AIM Klotho, a key component of the endocrine fibroblast growth factor receptor-fibroblast growth factor axis, is a multi-functional protein that impacts renal electrolyte handling. The physiological significance of Klotho will be highlighted in the regulation of calcium, phosphate, and potassium metabolism. METHODS In this review, we compare several murine models with different renal targeted deletions of Klotho and the insights into the molecular and physiological function that these models offer. RESULTS In vivo, Klotho deficiency is associated with severely impaired mineral metabolism, with consequences on growth, longevity and disease development. Additionally, we explore the perspectives of Klotho in renal pathology and vascular events, as well as potential Klotho treatment options. CONCLUSION This comprehensive review emphasizes the use of Klotho to shed light on deciphering the renal molecular in vivo mechanisms in electrolyte handling, as well as novel therapeutic interventions.
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Affiliation(s)
- Teodora V Grigore
- Department of Medical BioSciences, Radboud Research Institute for Medical Innovation, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Malou Zuidscherwoude
- Department of Medical BioSciences, Radboud Research Institute for Medical Innovation, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Hannes Olauson
- Division of Pathology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Joost G Hoenderop
- Department of Medical BioSciences, Radboud Research Institute for Medical Innovation, Radboud University Medical Center, Nijmegen, The Netherlands
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Wang K, Liu J. Positive association of the anti-aging protein α-Klotho with insulin resistance and its inverse L-shaped relationship with glycaemic control in the middle-aged and elderly population. Endocrine 2024; 86:143-155. [PMID: 38761344 DOI: 10.1007/s12020-024-03874-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2023] [Accepted: 05/09/2024] [Indexed: 05/20/2024]
Abstract
PURPOSE α-Klotho has been linked to insulin resistance (IR) in basic research. However, experimental evidence is inconsistent, and there is a lack of data from human research. This study seeks to elucidate the association of α-Klotho with IR in a nationwide, multiracial population. METHODS A total of 5289 participants aged 40-79 years were included in the National Health and Nutrition Examination Survey (NHANES) spanning 2007-2016. Serum α-Klotho was measured using enzyme-linked immunosorbent assays (ELISA), and IR was evaluated by the homeostatic model assessment of insulin resistance (HOMA-IR). Weighted multivariate logistic and linear regression analysis, subgroup analysis stratified by demographic characteristics, medical condition or obesity status, and sensitivity analysis using propensity score matching (PSM) were performed. Restricted cubic splines (RCS) were performed to explore the nonlinear relationship. RESULTS In the fully adjusted logistic regression model, a significant positive association was observed between log-transformed α-Klotho and IR (OR = 3.63, 95% CI: 1.56, 8.45), particularly in males or nonobese individuals (Pinteraction < 0.05). In the linear regression model, log10(α-Klotho) was associated with fasting blood glucose (FBG, β = 1.25, 95% CI: 0.74, 1.76) and glycosylated hemoglobin (HbA1c, β = 0.49, 95% CI: 0.20, 0.77). RCS revealed an inverse L-shaped dose-response relationship of α-Klotho with FBG and HbA1c (Pnonlinear <0.05). Beyond the inflection point of log10(α-Klotho) at 2.79, β coefficients sharply rose for these glycaemic control indicators. CONCLUSION The study provides clinical evidence supporting a positive association between α-Klotho and IR. Moreover, the inverse L-shaped relationship suggests that α-Klotho should reach a certain level to predict glycaemic changes effectively.
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Affiliation(s)
- Kai Wang
- Medical School, Southeast University, Nanjing, China
| | - Jianing Liu
- Medical Faculty, Ulm University, Ulm, Germany.
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Wang F, Colonnello E, Zhang H, Sansone A, Wang C, Dolci S, Guo J, Jannini EA. Comparing Western and traditional Chinese medicine for male sexual dysfunction: can Klotho represent a silk road? Andrology 2024; 12:1215-1223. [PMID: 38155398 DOI: 10.1111/andr.13580] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2023] [Revised: 10/30/2023] [Accepted: 11/28/2023] [Indexed: 12/30/2023]
Abstract
Traditional Chinese medicine (TCM) and Western Medicine both have shown efficacy in treating male sexual dysfunction (MSD). The aim of this perspective paper is to discuss a possible link between Western medicine and TCM in the MSD field as represented by the entity of Klotho. Klotho is a recently discovered protein, mainly expressed in the kidney, encoded by the anti-aging gene klotho. Not only is Klotho significantly correlated with the development and progression of kidney diseases and their complications, but increasing evidence indicates that it is also closely related to MSD. A comprehensive search within PubMed database was performed to retrieve available evidence on Klotho's roles, particularly in kidney and in MSD. Indeed, in the TCM theory, the concept of the "kidney" is entirely different from the Western medicine: it is closely related to metabolism and to the reproductive, nervous, endocrine systems, being more than just a urinary organ. According to the "Kidney storing essence (jīng) and governing reproduction" (KSEGR) theory, a cornerstone in TCM, the treatment of MSD mainly consists of restoring the kidney's function. Signs of decreasing kidney essence show a consistent similarity to deficiencies of Klotho, also for what regards the male sexual function. Based on the current evidence, Klotho may represent a potential biological indicator for sexual desire and sexual function and a kind of new scientific Silk Road between TCM and Western medicine for MSD; nevertheless, there is a need to conduct further high-quality research to prove this hypothesis.
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Affiliation(s)
- Fu Wang
- Department of Andrology, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing, China
| | - Elena Colonnello
- Chair of Endocrinology and Medical Sexology (ENDOSEX), Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Hui Zhang
- Chair of Endocrinology and Medical Sexology (ENDOSEX), Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Andrea Sansone
- Chair of Endocrinology and Medical Sexology (ENDOSEX), Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Chunlin Wang
- Chair of Endocrinology and Medical Sexology (ENDOSEX), Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Susanna Dolci
- Chair of Anatomy, Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy
| | - Jun Guo
- Department of Andrology, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing, China
| | - Emmanuele A Jannini
- Chair of Endocrinology and Medical Sexology (ENDOSEX), Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
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Kanbay M, Brinza C, Ozbek L, Guldan M, Sisman U, Copur S, Covic A, Scripcariu DV, Burlacu A, Covic A. The association between klotho and kidney and cardiovascular outcomes: a comprehensive systematic review and meta-analysis. Clin Kidney J 2024; 17:sfae255. [PMID: 39281418 PMCID: PMC11398896 DOI: 10.1093/ckj/sfae255] [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: 08/01/2024] [Indexed: 09/18/2024] Open
Abstract
Background Chronic kidney disease (CKD) and end-stage renal disease (ESKD) are significant global health challenges associated with progressive kidney dysfunction and numerous complications, including cardiovascular disease and mortality. This study aims to explore the potential association between plasma klotho levels and various prognostic outcomes in CKD and ESKD, including all-cause mortality, cardiovascular events, metabolic syndrome development and adverse renal events necessitating renal replacement therapies. Methods A literature search was conducted through 3 June 2024 using the electronic databases Cochrane Library, Ovid MEDLINE, CINAHL, Web of Science, SCOPUS and PubMed. This systematic review adheres to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Results Fourteen studies were included. For all-cause mortality, comparing CKD patients with low versus high klotho levels showed a significant association {odds ratio [OR] 1.81 [95% confidence interval (CI) 1.34-2.44], P = .0001}, with substantial heterogeneity (I 2 = 69%). Excluding one study reduced heterogeneity (I 2 = 43%) while maintaining significance [OR 1.97 (95% CI 1.45-2.66), P < .0001]. Cardiovascular mortality was higher in patients with low klotho levels [OR 2.11 (95% CI 1.61-2.76), P < .00001], with low heterogeneity (I 2 = 25%). Excluding one study eliminated heterogeneity (I 2 = 0%) while maintaining significance [OR 2.39 (95% CI 1.83-3.12), P < .00001]. Composite cardiovascular events did not differ significantly between low and high klotho groups [OR 1.51 (95% CI 0.82-2.77), P = .18], but with high heterogeneity (I 2 = 72%). Patients with low klotho levels had a higher risk of adverse renal events [OR 2.36 (95% CI 1.37-4.08), P = .002], with moderate heterogeneity (I 2 = 61%). Sensitivity analysis reduced heterogeneity (I 2 = 0%) while maintaining significance [OR 3.08 (95% CI 1.96-4.85), P < .00001]. Specifically, for ESKD or kidney replacement therapy risk, low klotho levels were associated with an increased risk [OR 2.30 (95% CI 1.26-4.21), P = .007]. Similarly, CKD progression risk was higher in patients with lower klotho levels [OR 2.48 (95% CI 1.45-4.23), P = .0009]. Conclusion Lower serum klotho levels serve as a significant predictor of adverse outcomes, including increased risks of all-cause mortality, cardiovascular mortality and progression to end-stage kidney disease among CKD patients.
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Affiliation(s)
- Mehmet Kanbay
- Department of Medicine, Division of Nephrology, Koç University School of Medicine, Istanbul, Turkey
| | - Crischentian Brinza
- Faculty of Medicine, University of Medicine and Pharmacy "Grigore T Popa", Iasi, Romania
- Institute of Cardiovascular Diseases "Prof. Dr George I.M. Georgescu", Iasi, Romania
| | - Lasin Ozbek
- Department of Medicine, Koç University School of Medicine, Istanbul, Turkey
| | - Mustafa Guldan
- Department of Medicine, Koç University School of Medicine, Istanbul, Turkey
| | - Uluman Sisman
- Department of Medicine, Koç University School of Medicine, Istanbul, Turkey
| | - Sidar Copur
- Department of Internal Medicine, Koç University School of Medicine, Istanbul, Turkey
| | - Andreea Covic
- Faculty of Medicine, University of Medicine and Pharmacy "Grigore T Popa", Iasi, Romania
| | | | - Alexandru Burlacu
- Faculty of Medicine, University of Medicine and Pharmacy "Grigore T Popa", Iasi, Romania
- Institute of Cardiovascular Diseases "Prof. Dr George I.M. Georgescu", Iasi, Romania
| | - Adrian Covic
- Faculty of Medicine, University of Medicine and Pharmacy "Grigore T Popa", Iasi, Romania
- Nephrology Clinic, Dialysis, and Renal Transplant Center "C.I. Parhon" University Hospital, Iasi, Romania
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Park MJ, Lee J, Bagon BB, Matienzo ME, Lee CM, Kim K, Kim DI. Therapeutic potential of AAV-FL-Klotho in obesity: Impact on weight loss and lipid metabolism in mice. Biochim Biophys Acta Mol Basis Dis 2024; 1870:167055. [PMID: 38325589 DOI: 10.1016/j.bbadis.2024.167055] [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: 10/19/2023] [Revised: 01/04/2024] [Accepted: 02/02/2024] [Indexed: 02/09/2024]
Abstract
Klotho, an anti-aging protein, has gained attention for its protective effects against various diseases, including metabolic disorders, through recombinant Klotho administration. However, the potential of Klotho as a target for gene therapy requires further exploration, as it remains relatively understudied in the context of metabolic disorders. In this study, we demonstrate that AAV-full length(FL)-Klotho administration induces weight loss in mice and provides protection against high-fat diet (HFD)-induced obesity and hepatic steatosis, concurrently reducing the weights of white adipose tissue and liver. AAV-FL-Klotho administration also enhanced thermogenic gene expression in brown adipose tissue (BAT) and improved the morphology of interscapular BAT. The weight loss effect of AAV-FL-Klotho was found to be, at least in part, mediated by UCP1-dependent thermogenesis in brown adipocytes, potentially influenced by hepatokines secreted from AAV-FL-Klotho-transduced hepatocytes. These findings suggest that AAV-FL-Klotho is an attractive candidate for gene therapy to combat obesity. Nevertheless, unbiased experiments have also revealed disturbances in lipid metabolism due to AAV-FL-Klotho, as evidenced by the emergence of lipomas and increased expression of hepatic lipogenic proteins.
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Affiliation(s)
- Min-Jung Park
- Department of Veterinary Physiology, College of Veterinary Medicine, Chonnam National University, Gwangju 61186, Republic of Korea
| | - Junhyeong Lee
- Department of Veterinary Physiology, College of Veterinary Medicine, Chonnam National University, Gwangju 61186, Republic of Korea; College of Veterinary Medicine and BK21 FOUR Program, Chonnam National University, Gwangju 61186, Republic of Korea
| | - Bernadette B Bagon
- Department of Veterinary Physiology, College of Veterinary Medicine, Chonnam National University, Gwangju 61186, Republic of Korea
| | - Merc Emil Matienzo
- Department of Veterinary Physiology, College of Veterinary Medicine, Chonnam National University, Gwangju 61186, Republic of Korea; College of Veterinary Medicine and BK21 FOUR Program, Chonnam National University, Gwangju 61186, Republic of Korea
| | - Chang-Min Lee
- College of Veterinary Medicine and BK21 FOUR Program, Chonnam National University, Gwangju 61186, Republic of Korea; Department of Veterinary Internal Medicine, College of Veterinary Medicine, Chonnam National University, Gwangju 61186, Republic of Korea
| | - Keon Kim
- College of Veterinary Medicine and BK21 FOUR Program, Chonnam National University, Gwangju 61186, Republic of Korea; Department of Veterinary Internal Medicine, College of Veterinary Medicine, Chonnam National University, Gwangju 61186, Republic of Korea.
| | - Dong-Il Kim
- Department of Veterinary Physiology, College of Veterinary Medicine, Chonnam National University, Gwangju 61186, Republic of Korea; College of Veterinary Medicine and BK21 FOUR Program, Chonnam National University, Gwangju 61186, Republic of Korea.
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12
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Fan Z, Wei X, Zhu X, Yang K, Tian L, Du Y, Yang L. Correlation between soluble klotho and chronic kidney disease-mineral and bone disorder in chronic kidney disease: a meta-analysis. Sci Rep 2024; 14:4477. [PMID: 38396063 PMCID: PMC10891172 DOI: 10.1038/s41598-024-54812-4] [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: 09/18/2023] [Accepted: 02/16/2024] [Indexed: 02/25/2024] Open
Abstract
We conducted a systematic search across medical databases, including PubMed, Web of Science, EMBASE, and Cochrane Library, up to March 2023. A total of 1944 subjects or individuals from 17 studies were included in our final analysis. The correlation coefficient (r) between sKlotho and calcium was [0.14, (0.02, 0.26)], and a moderate heterogeneity was observed (I2 = 66%, P < 0.05). The correlation coefficient (r) between Klotho and serum phosphate was [- 0.21, (- 0.37, - 0.04)], with apparent heterogeneity (I2 = 84%, P < 0.05). The correlation coefficient (r) between sKlotho and parathyroid hormone and vascular calcification was [- 0.23,(- 0.29, - 0.17); - 0.15, (- 0.23, - 0.08)], with no significant heterogeneity among the studies. (I2 = 40%, P < 0.05; I2 = 30%, P < 0.05). A significant correlation exists between low sKlotho levels and an increased risk of CKD-MBD in patients with CKD. According to the findings, sKlotho may play a role in alleviating CKD-MBD by lowering phosphorus and parathyroid hormone levels, regulating calcium levels, and suppressing vascular calcification. As analysis showed that sKlotho has an important impact on the pathogenesis and progression of CKD-MBD in CKD patients. Nonetheless, further comprehensive and high-quality studies are needed to validate our conclusions.
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Affiliation(s)
- Zhongyu Fan
- Department of Nephrology, The First Hospital of Jilin University, Changchun, China
| | - Xuejiao Wei
- Department of Nephrology, The First Hospital of Jilin University, Changchun, China
| | - Xiaoyu Zhu
- Department of Nephrology, The First Hospital of Jilin University, Changchun, China
| | - Kun Yang
- Department of Nephrology, The First Hospital of Jilin University, Changchun, China
| | - Ling Tian
- Department of Nephrology, The First Hospital of Jilin University, Changchun, China
| | - Yujun Du
- Department of Nephrology, The First Hospital of Jilin University, Changchun, China.
| | - Liming Yang
- Department of Nephrology, The First Hospital of Jilin University, Changchun, China.
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13
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Zangerolamo L, Carvalho M, Velloso LA, Barbosa HCL. Endocrine FGFs and their signaling in the brain: Relevance for energy homeostasis. Eur J Pharmacol 2024; 963:176248. [PMID: 38056616 DOI: 10.1016/j.ejphar.2023.176248] [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: 10/06/2023] [Revised: 11/10/2023] [Accepted: 11/30/2023] [Indexed: 12/08/2023]
Abstract
Since their discovery in 2000, there has been a continuous expansion of studies investigating the physiology, biochemistry, and pharmacology of endocrine fibroblast growth factors (FGFs). FGF19, FGF21, and FGF23 comprise a subfamily with attributes that distinguish them from typical FGFs, as they can act as hormones and are, therefore, referred to as endocrine FGFs. As they participate in a broad cross-organ endocrine signaling axis, endocrine FGFs are crucial lipidic, glycemic, and energetic metabolism regulators during energy availability fluctuations. They function as powerful metabolic signals in physiological responses induced by metabolic diseases, like type 2 diabetes and obesity. Pharmacologically, FGF19 and FGF21 cause body weight loss and ameliorate glucose homeostasis and energy expenditure in rodents and humans. In contrast, FGF23 expression in mice and humans has been linked with insulin resistance and obesity. Here, we discuss emerging concepts in endocrine FGF signaling in the brain and critically assess their putative role as therapeutic targets for treating metabolic disorders.
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Affiliation(s)
- Lucas Zangerolamo
- Obesity and Comorbidities Research Center, University of Campinas, UNICAMP, Campinas, Sao Paulo, Brazil
| | - Marina Carvalho
- Obesity and Comorbidities Research Center, University of Campinas, UNICAMP, Campinas, Sao Paulo, Brazil
| | - Licio A Velloso
- Laboratory of Cell Signaling, Obesity and Comorbidities Research Center, University of Campinas, UNICAMP, Campinas, Sao Paulo, Brazil
| | - Helena C L Barbosa
- Obesity and Comorbidities Research Center, University of Campinas, UNICAMP, Campinas, Sao Paulo, Brazil.
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14
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Ochi E, Barrington A, Wehling‐Henricks M, Avila M, Kuro‐o M, Tidball JG. Klotho regulates the myogenic response of muscle to mechanical loading and exercise. Exp Physiol 2023; 108:1531-1547. [PMID: 37864311 PMCID: PMC10841225 DOI: 10.1113/ep091263] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2023] [Accepted: 08/16/2023] [Indexed: 10/22/2023]
Abstract
NEW FINDINGS What is the central question of this study? Does the hormone Klotho affect the myogenic response of muscle cells to mechanical loading or exercise? What is the main finding and its importance? Klotho prevents direct, mechanical activation of genes that regulate muscle differentiation, including genes that encode the myogenic regulatory factor myogenin and proteins in the canonical Wnt signalling pathway. Similarly, elevated levels of klotho expression in vivo prevent the exercise-induced increase in myogenin-expressing cells and reduce exercise-induced activation of the Wnt pathway. These findings demonstrate a new mechanism through which the responses of muscle to the mechanical environment are regulated. ABSTRACT Muscle growth is influenced by changes in the mechanical environment that affect the expression of genes that regulate myogenesis. We tested whether the hormone Klotho could influence the response of muscle to mechanical loading. Applying mechanical loads to myoblasts in vitro increased RNA encoding transcription factors that are expressed in activated myoblasts (Myod) and in myogenic cells that have initiated terminal differentiation (Myog). However, application of Klotho to myoblasts prevented the loading-induced activation of Myog without affecting loading-induced activation of Myod. This indicates that elevated Klotho inhibits mechanically-induced differentiation of myogenic cells. Elevated Klotho also reduced the transcription of genes encoding proteins involved in the canonical Wnt pathway or their target genes (Wnt9a, Wnt10a, Ccnd1). Because the canonical Wnt pathway promotes differentiation of myogenic cells, these findings indicate that Klotho inhibits the differentiation of myogenic cells experiencing mechanical loading. We then tested whether these effects of Klotho occurred in muscles of mice experiencing high-intensity interval training (HIIT) by comparing wild-type mice and klotho transgenic mice. The expression of a klotho transgene combined with HIIT synergized to tremendously elevate numbers of Pax7+ satellite cells and activated MyoD+ cells. However, transgene expression prevented the increase in myogenin+ cells caused by HIIT in wild-type mice. Furthermore, transgene expression diminished the HIIT-induced activation of the canonical Wnt pathway in Pax7+ satellite cells. Collectively, these findings show that Klotho inhibits loading- or exercise-induced activation of muscle differentiation and indicate a new mechanism through which the responses of muscle to the mechanical environment are regulated.
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Affiliation(s)
- Eisuke Ochi
- Faculty of Bioscience and Applied ChemistryHosei UniversityTokyoJapan
- Department of Integrative Biology and PhysiologyUniversity of CaliforniaLos AngelesCAUSA
| | - Alice Barrington
- Department of Integrative Biology and PhysiologyUniversity of CaliforniaLos AngelesCAUSA
| | | | - Marcus Avila
- Department of Integrative Biology and PhysiologyUniversity of CaliforniaLos AngelesCAUSA
| | - Makoto Kuro‐o
- Division of Anti‐Aging MedicineCenter for Molecular MedicineJichi Medical UniversityTochigiJapan
| | - James G. Tidball
- Department of Integrative Biology and PhysiologyUniversity of CaliforniaLos AngelesCAUSA
- Molecular, Cellular & Integrative Physiology ProgramUniversity of CaliforniaLos AngelesCAUSA
- Department of BioengineeringUniversity of CaliforniaLos AngelesCAUSA
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLAUniversity of CaliforniaLos AngelesCAUSA
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15
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Liu Y, Chen M. Emerging role of α-Klotho in energy metabolism and cardiometabolic diseases. Diabetes Metab Syndr 2023; 17:102854. [PMID: 37722166 DOI: 10.1016/j.dsx.2023.102854] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Revised: 08/16/2023] [Accepted: 09/08/2023] [Indexed: 09/20/2023]
Abstract
BACKGROUND AND AIM Klotho was first identified as a gene associated with aging and longevity in 1997. α-Klotho is an anti-aging protein and its role in energy metabolism, various cardiovascular diseases (CVDs), and metabolic disorders is increasingly being recognized. In this review, we aimed to outline the potential protective role and therapeutic prospects of α-Klotho in energy metabolism and cardiometabolic diseases (CMDs). METHODS We comprehensively reviewed the relevant literature in PubMed using the keywords 'Klotho', 'metabolism', 'cardiovascular', 'diabetes', 'obesity', 'metabolic syndrome', and 'nonalcoholic fatty liver disease'. RESULTS α-Klotho can be divided into membrane-bound Klotho, secreted Klotho, and the most studied circulating soluble Klotho that can act as a hormone. Klotho gene polymorphisms have been implicated in energy metabolism and CMDs. α-Klotho can inhibit insulin/insulin growth factor-1 signaling and its overexpression can lead to a 'healthy insulin resistance' and may exert beneficial effects on the regulation of glycolipid metabolism and central energy homeostasis. α-Klotho, mainly serum Klotho, has been revealed to be protective against CVDs, diabetes and its complications, obesity, and nonalcoholic fatty liver disease. Human recombinant Klotho protein/Klotho gene delivery, multiple drugs, or natural products, and exercise can increase α-Klotho expression. CONCLUSION Overall, α-Klotho has demonstrated its potential as a promising target for modulating energy metabolism and CMDs, and further research is needed to explore its utilization in clinical practice in the future.
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Affiliation(s)
- Yuanbin Liu
- Department of Gastroenterology, Renmin Hospital of Wuhan University, No. 99 Zhang Zhidong Road, Wuhan, Hubei, 430000, PR China
| | - Mingkai Chen
- Department of Gastroenterology, Renmin Hospital of Wuhan University, No. 99 Zhang Zhidong Road, Wuhan, Hubei, 430000, PR China.
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16
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Jin HS, Jung D. The KL genetic polymorphisms Associated with type 2 diabetes Mellitus. Indian J Clin Biochem 2023; 38:385-392. [PMID: 37234182 PMCID: PMC10205947 DOI: 10.1007/s12291-022-01057-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Accepted: 06/06/2022] [Indexed: 10/15/2022]
Abstract
Growing number of research studies have shown that an anti-ageing gene Klotho (KL) is closely associated with Type 2 Diabetes Mellitus (T2DM). In this study, the association is genetically analyzed with single nucleotide polymorphism (SNP) of KL found in T2DM case of an Asian cohort. KL SNP information was obtained from a big database of the Korean Association Resource (KARE) from which 20 KL SNPs were available. Statistical analyses were conducted based on the 3 genetic models, such as additive, dominant, and recessive. Of the 20 KL SNPs, 12 SNPs were found to be significantly associated with T2DM in both of additive and dominant models. Odds ratios of the KL SNPs indicate increased susceptibility to T2DM in additive and dominant models. Significant association of KL with T2DM was further analyzed using imputed KL SNPs from HapMap reference data of the Eastern population. The statistically significant KL SNPs including the imputed SNPs distributed evenly over the KL gene area. The results in this study suggest klotho is a major player in the development of T2DM and the KL SNPs found in the case could be a risk marker of T2DM in the cohort.
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Affiliation(s)
- Hyun-Seok Jin
- Department of Biomedical Laboratory Science, College of Life and Health Sciences, Hoseo University, 31499 Asan, Chungnam Republic of Korea
| | - Dongju Jung
- Department of Biomedical Laboratory Science, College of Life and Health Sciences, Hoseo University, 31499 Asan, Chungnam Republic of Korea
- Klotho Sciences Corporation, Healthcare Innovation Park, Seoul National University Bundang Hospital Complex, Seongnam, Gyenggi Republic of Korea
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17
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Miklós Z, Horváth I. The Role of Oxidative Stress and Antioxidants in Cardiovascular Comorbidities in COPD. Antioxidants (Basel) 2023; 12:1196. [PMID: 37371927 DOI: 10.3390/antiox12061196] [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: 04/30/2023] [Revised: 05/28/2023] [Accepted: 05/30/2023] [Indexed: 06/29/2023] Open
Abstract
Oxidative stress driven by several environmental and local airway factors associated with chronic obstructive bronchiolitis, a hallmark feature of COPD, plays a crucial role in disease pathomechanisms. Unbalance between oxidants and antioxidant defense mechanisms amplifies the local inflammatory processes, worsens cardiovascular health, and contributes to COPD-related cardiovascular dysfunctions and mortality. The current review summarizes recent developments in our understanding of different mechanisms contributing to oxidative stress and its countermeasures, with special attention to those that link local and systemic processes. Major regulatory mechanisms orchestrating these pathways are also introduced, with some suggestions for further research in the field.
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Affiliation(s)
- Zsuzsanna Miklós
- National Korányi Institute for Pulmonology, Korányi F. Street 1, H-1121 Budapest, Hungary
| | - Ildikó Horváth
- National Korányi Institute for Pulmonology, Korányi F. Street 1, H-1121 Budapest, Hungary
- Department of Pulmonology, University of Debrecen, Nagyerdei krt 98, H-4032 Debrecen, Hungary
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18
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Feng R, Wu S, Li R, Huang K, Zeng T, Zhou Z, Zhong X, Songyang Z, Liu F. mTORC1-induced bone marrow-derived mesenchymal stem cell exhaustion contributes to the bone abnormalities in klotho-deficient mice of premature aging. Stem Cells Dev 2023. [PMID: 36924305 DOI: 10.1089/scd.2022.0243] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/18/2023] Open
Abstract
Stem cell exhaustion is a hallmark of aging. Klotho-deficient mice (kl/kl mice) is a murine model that mimics human aging with significant bone abnormalities. The aim of this study is using kl/kl mice to investigate the functional change of bone marrow-derived mesenchymal stem cells (BMSCs) and explore the underlying mechanism. We found klotho-deficiency leads to bone abnormalities. In addition, kl/kl BMSCs manifested hyper-active proliferation but functional declined both in vivo and in vitro. mTORC1 activity was higher in freshly isolated kl/kl BMSCs and autophagy in kl/kl BMSCs were significantly decreased, possibly through mTORC1 activation. Conditional medium containing soluble Klotho protein (sKL) rescued hyper-proliferation of kl/kl BMSCs by inhibiting mTORC1 activity and restoring autophagy. Finally, intraperitoneally injection of mTORC1 inhibitor rapamycin restored BMSC quiescence, ameliorated bone phenotype and increased lifespan of kl/kl mice in vivo. This research highlights a therapeutic strategy to maintain the homeostasis of adult stem cell pool for healthy bone aging.
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Affiliation(s)
- Ran Feng
- Sun Yat-Sen University, 26469, MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, Guangzhou Key Laboratory of Healthy Aging Research, School of Life Sciences, Institute of Healthy Aging Research, Guangzhou, Guangdong, China;
| | - Su Wu
- Sun Yat-Sen University, 26469, Guangzhou, China, 510275.,Sun Yat-Sen Memorial Hospital, 56713, Guangzhou, China, 510120;
| | - Ruofei Li
- Sun Yat-Sen University, 26469, MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, Guangzhou Key Laboratory of Healthy Aging Research, School of Life Sciences, Institute of Healthy Aging Research, Guangzhou, Guangdong, China;
| | - Kunling Huang
- Sun Yat-Sen University, 26469, MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, Guangzhou Key Laboratory of Healthy Aging Research, School of Life Sciences, Institute of Healthy Aging Research, Guangzhou, Guangdong, China;
| | - Ting Zeng
- Sun Yat-Sen Memorial Hospital, 56713, Guangzhou, China;
| | - Zhifen Zhou
- Sun Yat-Sen Memorial Hospital, 56713, Guangzhou, Guangdong, China;
| | - Xiaoqin Zhong
- Sun Yat-Sen University, 26469, MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, Guangzhou Key Laboratory of Healthy Aging Research, School of Life Sciences, Institute of Healthy Aging Research, Guangzhou, Guangdong, China;
| | - Zhou Songyang
- Sun Yat-Sen University, 26469, MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, Guangzhou Key Laboratory of Healthy Aging Research, School of Life Sciences, Institute of Healthy Aging Research, Guangzhou, Guangdong, China.,Sun Yat-Sen Memorial Hospital, 56713, Guangzhou, Guangdong, China;
| | - Feng Liu
- Sun Yat-Sen University, 26469, MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, Guangzhou Key Laboratory of Healthy Aging Research, School of Life Sciences, Institute of Healthy Aging Research, Guangzhou, Guangdong, China;
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19
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Roig-Soriano J, Sánchez-de-Diego C, Esandi-Jauregui J, Verdés S, Abraham CR, Bosch A, Ventura F, Chillón M. Differential toxicity profile of secreted and processed α-Klotho expression over mineral metabolism and bone microstructure. Sci Rep 2023; 13:4211. [PMID: 36918615 PMCID: PMC10014869 DOI: 10.1038/s41598-023-31117-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2022] [Accepted: 03/07/2023] [Indexed: 03/15/2023] Open
Abstract
The aging-protective gene α-Klotho (KL) produces two main transcripts. The full-length mRNA generates a transmembrane protein that after proteolytic ectodomain shedding can be detected in serum as processed Klotho (p-KL), and a shorter transcript which codes for a putatively secreted protein (s-KL). Both isoforms exhibit potent pleiotropic beneficial properties, although previous reports showed negative side effects on mineral homeostasis after increasing p-KL concentration exogenously. Here, we expressed independently both isoforms using gene transfer vectors, to assess s-KL effects on mineral metabolism. While mice treated with p-KL presented altered expression of several kidney ion channels, as well as altered levels of Pi and Ca2+ in blood, s-KL treated mice had levels comparable to Null-treated control mice. Besides, bone gene expression of Fgf23 showed a fourfold increase after p-KL treatment, effects not observed with the s-KL isoform. Similarly, bone microstructure parameters of p-KL-treated mice were significantly worse than in control animals, while this was not observed for s-KL, which showed an unexpected increase in trabecular thickness and cortical mineral density. As a conclusion, s-KL (but not p-KL) is a safe therapeutic strategy to exploit KL anti-aging protective effects, presenting no apparent negative effects over mineral metabolism and bone microstructure.
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Affiliation(s)
- Joan Roig-Soriano
- Department of Biochemistry and Molecular Biology, Institut de Neurociènces (INc), Universitat Autònoma Barcelona, Bellaterra, Spain
| | - Cristina Sánchez-de-Diego
- Departament de Ciències Fisiològiques, Facultat de Medicina i Ciències de la Salut, IDIBELL, Universitat de Barcelona, L'Hospitalet de Llobregat, Spain
| | - Jon Esandi-Jauregui
- Department of Biochemistry and Molecular Biology, Institut de Neurociènces (INc), Universitat Autònoma Barcelona, Bellaterra, Spain
| | - Sergi Verdés
- Department of Biochemistry and Molecular Biology, Institut de Neurociènces (INc), Universitat Autònoma Barcelona, Bellaterra, Spain
| | - Carmela R Abraham
- Departments of Biochemistry and Pharmacology & Experimental Therapeutics, Boston University School of Medicine, Boston, MA, USA
| | - Assumpció Bosch
- Department of Biochemistry and Molecular Biology, Institut de Neurociènces (INc), Universitat Autònoma Barcelona, Bellaterra, Spain
- Vall d'Hebron Institut de Recerca (VHIR), Barcelona, Spain
- Centro de Investigación Biomédica en Red Sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain
| | - Francesc Ventura
- Departament de Ciències Fisiològiques, Facultat de Medicina i Ciències de la Salut, IDIBELL, Universitat de Barcelona, L'Hospitalet de Llobregat, Spain
| | - Miguel Chillón
- Department of Biochemistry and Molecular Biology, Institut de Neurociènces (INc), Universitat Autònoma Barcelona, Bellaterra, Spain.
- Vall d'Hebron Institut de Recerca (VHIR), Barcelona, Spain.
- Unitat Producció de Vectors (UPV), Universitat Autònoma Barcelona, Bellaterra, Spain.
- Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain.
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20
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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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21
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Klotho Regulated by Estrogen Plays a Key Role in Sex Differences in Stress Resilience in Rats. Int J Mol Sci 2023; 24:ijms24021206. [PMID: 36674721 PMCID: PMC9862442 DOI: 10.3390/ijms24021206] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Revised: 12/21/2022] [Accepted: 12/22/2022] [Indexed: 01/11/2023] Open
Abstract
Klotho (KL) is a glycosyl hydrolase and aging-suppressor gene. Stress is a risk factor for depression and anxiety, which are highly comorbid with each other. The aim of this study is to determine whether KL is regulated by estrogen and plays an important role in sex differences in stress resilience. Our results showed that KL is regulated by estrogen in rat hippocampal neurons in vivo and in vitro and is essential for the estrogen-mediated increase in the number of presynaptic vesicular glutamate transporter 1 (Vglut1)-positive clusters on the dendrites of hippocampal neurons. The role of KL in sex differences in stress response was examined in rats using 3-week chronic unpredictable mild stress (CUMS). CUMS produced a deficit in spatial learning and memory, anhedonic-like behaviors, and anxiety-like behaviors in male but not female rats, which was accompanied by a reduction in KL protein levels in the hippocampus of male but not female rats. This demonstrated the resilience of female rats to CUMS. Interestingly, the knockdown of KL protein levels in the rat hippocampus of both sexes caused a decrease in stress resilience in both sexes, especially in female rats. These results suggest that the regulation of KL by estrogen plays an important role in estrogen-mediated synapse formation and that KL plays a critical role in the sex differences in cognitive deficit, anhedonic-like behaviors, and anxiety-like behaviors induced by chronic stress in rats, highlighting an important role of KL in sex differences in stress resilience.
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Birdi A, Tomo S, Yadav D, Sharma P, Nebhinani N, Mitra P, Banerjee M, Purohit P. Role of Klotho Protein in Neuropsychiatric Disorders: A Narrative Review. Indian J Clin Biochem 2023; 38:13-21. [PMID: 36684492 PMCID: PMC9852376 DOI: 10.1007/s12291-022-01078-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Accepted: 07/20/2022] [Indexed: 01/25/2023]
Abstract
Neuropsychiatric disorders are comprised of diseases having both the neurological and psychiatric manifestations. The increasing burden of the disease on the population worldwide makes it necessary to adopt measures to decrease the prevalence. The Klotho is a single pass transmembrane protein that decreases with age, has been associated with various pathological diseases, like reduced bone mineral density, cardiac problems and cognitive impairment. However, multiple studies have explored its role in different neuropsychiatric disorders. A comprehensive search was undertaken in the Pubmed database for articles with the keywords "Klotho" and "neuropsychiatric disorders". The available literature, based on the above search strategy, has been compiled in this brief narrative review to describe the emerging role of Klotho in various neuropsychiatric disorders. The Klotho levels were decreased in various neuropsychiatric disorders except for bipolar disorder. A suppressed Klotho protein levels induced oxidative stress and incited pro-inflammatory conditions significantly contributing to the pathophysiology of neuropsychiatric disorder. The increasing evidence of altered Klotho protein levels in cognition-decrement-related disorders warrants its consideration as a biomarker in various neuropsychiatric diseases. However, further evidence is required to understand its role as a therapeutic target.
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Affiliation(s)
- Amandeep Birdi
- Department of Biochemistry, All India Institute of Medical Sciences, Jodhpur, Rajasthan India
| | - Sojit Tomo
- Department of Biochemistry, All India Institute of Medical Sciences, Jodhpur, Rajasthan India
| | - Dharmveer Yadav
- Department of Biochemistry, All India Institute of Medical Sciences, Jodhpur, Rajasthan India
| | - Praveen Sharma
- Department of Biochemistry, All India Institute of Medical Sciences, Jodhpur, Rajasthan India
| | - Naresh Nebhinani
- Department of Psychiatry, All India Institute of Medical Sciences, Jodhpur, Rajasthan India
| | - Prasenjit Mitra
- Department of Biochemistry, Post Graduate Institute of Medical Sciences, Chandigarh, Punjab India
| | - Mithu Banerjee
- Department of Biochemistry, All India Institute of Medical Sciences, Jodhpur, Rajasthan India
| | - Purvi Purohit
- Department of Biochemistry, All India Institute of Medical Sciences, Jodhpur, Rajasthan India
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Abraham CR, Li A. Aging-suppressor Klotho: Prospects in diagnostics and therapeutics. Ageing Res Rev 2022; 82:101766. [PMID: 36283617 DOI: 10.1016/j.arr.2022.101766] [Citation(s) in RCA: 56] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2022] [Revised: 10/16/2022] [Accepted: 10/17/2022] [Indexed: 01/31/2023]
Abstract
INTRODUCTION The protein Klotho (KL) was first discovered in KL-deficient mice, which developed a syndrome similar to premature aging in humans. Since then, KL has been implicated in multiple molecular signaling pathways and diseases. KL has been shown to have anti-aging, healthspan and lifespan extending, cognitive enhancing, anti-oxidative, anti-inflammatory, and anti-tumor properties. KL levels decrease with age and in many diseases. Therefore, it has been of great interest to develop a KL-boosting or restoring drug, or to supplement endogenous Klotho with exogenous Klotho genetic material or recombinant Klotho protein, and to use KL levels in the body as a marker for the efficacy of such drugs and as a biomarker for the diagnosis and management of diseases. OBJECTIVE The goal of this study was to provide a comprehensive review of KL levels across age groups in individuals who are healthy or have certain health conditions, using four sources: blood, cerebrospinal fluid, urine, and whole biopsy/necropsy tissue. By doing so, baseline KL levels can be identified across the lifespan, in the absence or presence of disease. In turn, these findings can be used to guide the development of future KL-based therapeutics and biomarkers, which will heavily rely on an individual's baseline KL range to be efficacious. METHODS A total of 65 studies were collected primarily using the PubMed database. Research articles that were published up to April 2022 were included. Statistical analysis was conducted using RStudio. RESULTS Mean and median blood KL levels in healthy individuals, mean blood KL levels in individuals with renal conditions, and mean blood KL levels in individuals with metabolic or endocrine conditions were shown to decrease with age. Similarly, CSF KL levels in patients with AD also declined compared with age-matched controls. CONCLUSIONS The present study confirms the trend that KL levels in blood decrease with age in humans, among those who are healthy, and even further among those with renal and endocrine/metabolic illnesses. Further, by drawing this trend from multiple published works, we were able to provide a general idea of baseline KL ranges, specifically in blood in these populations. These data add to the current knowledge on normal KL levels in the body and how they change with time and in disease, and can potentially support efforts to create KL-based treatments and screening tools to better manage aging, renal, and metabolic/endocrine diseases.
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Affiliation(s)
- Carmela R Abraham
- Department of Biochemistry, Boston University School of Medicine, USA; Department of Pharmacology & Experimental Therapeutics, Boston University School of Medicine, USA.
| | - Anne Li
- Division of Graduate Medical Sciences, Boston University School of Medicine, Boston, MA, USA.
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Zhang Z, Qiu S, Huang X, Jin K, Zhou X, Lin T, Zou X, Yang Q, Yang L, Wei Q. Association between testosterone and serum soluble α-klotho in U.S. males: a cross-sectional study. BMC Geriatr 2022; 22:570. [PMID: 35820842 PMCID: PMC9275159 DOI: 10.1186/s12877-022-03265-3] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2021] [Accepted: 07/04/2022] [Indexed: 02/08/2023] Open
Abstract
Purpose Testosterone plays a crucial role in males, and the deficiency of testosterone leads to multiple adverse health conditions. Klotho is a recently discovered protein encoded by antiaging gene klotho. Both the levels of testosterone and klotho change with aging, so the relationship between them is worth exploring. The purpose of this study was to investigate whether total testosterone is associated with serum klotho levels in U.S. males aged 40–79 years. Methods Included in this study were 3750 male participants from the 2011 to 2016 National Health and Nutrition Examination Survey, aged 40–79 years with included information on klotho and sex hormones. The sex steroid hormone levels and klotho concentrations were assayed in laboratories using the recommended methods according to Nutrition Examination Survey guidelines. The association between sex hormones and klotho was calculated using multivariate linear regression models after adjustment for several possible confounding variables. Results Among the 3750 participants, the total testosterone concentration was 399.048 ± 184.780 ng/dL, and the testosterone deficiency prevalence was 1160 (30.942%). The geometric mean of serum klotho levels was 791.000 pg/mL. In the adjusted models, klotho increased 0.165 pg/mL for every 1 ng/dL increase of total testosterone (p = 0.004). In addition, estradiol (β 2.232; 95% CI 0.588–3.876; p = 0.032) and sex hormone-binding globulin (β 2.013; 95% CI 1.173–2.583; p = 0.002) were also positively associated with klotho concentrations. Conclusion This study reported a significant association between klotho and sex hormones in the U.S. male population. The levels of klotho in men increased with total testosterone, estradiol and sex hormone-binding globulin levels, which may have implications for future research and clinical practice. Supplementary Information The online version contains supplementary material available at 10.1186/s12877-022-03265-3.
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Affiliation(s)
- Zilong Zhang
- Department of Urology and Institute of Urology and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 37, Guoxue Alley, Chengdu, 610041, Sichuan, China
| | - Shi Qiu
- Department of Urology and Institute of Urology and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 37, Guoxue Alley, Chengdu, 610041, Sichuan, China
| | - Xinyi Huang
- West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China
| | - Kun Jin
- Department of Urology and Institute of Urology and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 37, Guoxue Alley, Chengdu, 610041, Sichuan, China
| | - Xianghong Zhou
- Department of Urology and Institute of Urology and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 37, Guoxue Alley, Chengdu, 610041, Sichuan, China
| | - Tianhai Lin
- Department of Urology and Institute of Urology and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 37, Guoxue Alley, Chengdu, 610041, Sichuan, China
| | - Xiaoli Zou
- West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China
| | - Qiuxiang Yang
- Department of Urology and Institute of Urology and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 37, Guoxue Alley, Chengdu, 610041, Sichuan, China
| | - Lu Yang
- Department of Urology and Institute of Urology and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 37, Guoxue Alley, Chengdu, 610041, Sichuan, China.
| | - Qiang Wei
- Department of Urology and Institute of Urology and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 37, Guoxue Alley, Chengdu, 610041, Sichuan, China.
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Prognostic Value of Serum Soluble Klotho and Fibroblast Growth Factor-23 in Multiple Myeloma Patients. Indian J Hematol Blood Transfus 2022; 38:454-463. [DOI: 10.1007/s12288-021-01470-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2020] [Accepted: 07/05/2021] [Indexed: 10/20/2022] Open
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Guthrie G, Vonderohe C, Burrin D. Fibroblast growth factor 15/19 expression, regulation, and function: An overview. Mol Cell Endocrinol 2022; 548:111617. [PMID: 35301051 PMCID: PMC9038700 DOI: 10.1016/j.mce.2022.111617] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Accepted: 01/18/2022] [Indexed: 12/12/2022]
Abstract
Since the discovery of fibroblast growth factor (FGF)-19 over 20 years ago, our understanding of the peptide and its role in human biology has moved forward significantly. A member of a superfamily of paracrine growth factors regulating embryonic development, FGF19 is unique in that it is a dietary-responsive endocrine hormone linked with bile acid homeostasis, glucose and lipid metabolism, energy expenditure, and protein synthesis during the fed to fasted state. FGF19 achieves this through targeting multiple tissues and signaling pathways within those tissues. The diverse functional capabilities of FGF19 is due to the unique structural characteristics of the protein and its receptor binding in various cell types. This review will cover the current literature on the protein FGF19, its target receptors, and the biological pathways they target through unique signaling cascades.
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Affiliation(s)
- Greg Guthrie
- USDA-ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, United States
| | - Caitlin Vonderohe
- USDA-ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, United States
| | - Douglas Burrin
- USDA-ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, United States.
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Gupta M, Orozco G, Rao M, Gedaly R, Malluche HH, Neyra JA. The Role of Alterations in Alpha-Klotho and FGF-23 in Kidney Transplantation and Kidney Donation. Front Med (Lausanne) 2022; 9:803016. [PMID: 35602513 PMCID: PMC9121872 DOI: 10.3389/fmed.2022.803016] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Accepted: 02/03/2022] [Indexed: 12/12/2022] Open
Abstract
Cardiovascular disease and mineral bone disorders are major contributors to morbidity and mortality among patients with chronic kidney disease and often persist after renal transplantation. Ongoing hormonal imbalances after kidney transplant (KT) are associated with loss of graft function and poor outcomes. Fibroblast growth factor 23 (FGF-23) and its co-receptor, α-Klotho, are key factors in the underlying mechanisms that integrate accelerated atherosclerosis, vascular calcification, mineral disorders, and osteodystrophy. On the other hand, kidney donation is also associated with endocrine and metabolic adaptations that include transient increases in circulating FGF-23 and decreases in α-Klotho levels. However, the long-term impact of these alterations and their clinical relevance have not yet been determined. This manuscript aims to review and summarize current data on the role of FGF-23 and α-Klotho in the endocrine response to KT and living kidney donation, and importantly, underscore specific areas of research that may enhance diagnostics and therapeutics in the growing population of KT recipients and kidney donors.
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Affiliation(s)
- Meera Gupta
- Department of Surgery - Transplant Division, University of Kentucky, College of Medicine, Lexington, KY, United States
- Department of Surgery, University of Kentucky, Lexington, KY, United States
- *Correspondence: Meera Gupta
| | - Gabriel Orozco
- Department of Surgery - Transplant Division, University of Kentucky, College of Medicine, Lexington, KY, United States
- Department of Surgery, University of Kentucky, Lexington, KY, United States
| | - Madhumati Rao
- Department of Internal Medicine - Nephrology, Bone and Mineral Metabolism Division, University of Kentucky, College of Medicine, Lexington, KY, United States
| | - Roberto Gedaly
- Department of Surgery - Transplant Division, University of Kentucky, College of Medicine, Lexington, KY, United States
- Department of Surgery, University of Kentucky, Lexington, KY, United States
| | - Hartmut H. Malluche
- Department of Internal Medicine - Nephrology, Bone and Mineral Metabolism Division, University of Kentucky, College of Medicine, Lexington, KY, United States
| | - Javier A. Neyra
- Department of Internal Medicine - Nephrology, Bone and Mineral Metabolism Division, University of Kentucky, College of Medicine, Lexington, KY, United States
- Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States
- Javier A. Neyra
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Recombinant Klotho Protein Ameliorates Myocardial Ischemia/Reperfusion Injury by Attenuating Sterile Inflammation. Biomedicines 2022; 10:biomedicines10040894. [PMID: 35453645 PMCID: PMC9032004 DOI: 10.3390/biomedicines10040894] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2022] [Revised: 03/31/2022] [Accepted: 04/08/2022] [Indexed: 02/01/2023] Open
Abstract
Currently, no effective therapy and potential target have been elucidated for preventing myocardial ischemia and reperfusion injury (I/R). We hypothesized that the administration of recombinant klotho (rKL) protein could attenuate the sterile inflammation in peri-infarct regions by inhibiting the extracellular release of high mobility group box-1 (HMGB1). This hypothesis was examined using a rat coronary artery ligation model. Rats were divided into sham, sham+ rKL, I/R, and I/R+ rKL groups (n = 5/group). Administration of rKL protein reduced infarct volume and attenuated extracellular release of HMGB1 from peri-infarct tissue after myocardial I/R injury. The administration of rKL protein inhibited the expression of pro-inflammatory cytokines in the peri-infarct regions and significantly attenuated apoptosis and production of intracellular reactive oxygen species by myocardial I/R injury. Klotho treatment significantly reduced the increase in the levels of circulating HMGB1 in blood at 4 h after myocardial ischemia. rKL regulated the levels of inflammation-related proteins. This is the first study to suggest that exogenous administration of rKL exerts myocardial protection effects after I/R injury and provides new mechanistic insights into rKL that can provide the theoretical basis for clinical application of new adjunctive modality for critical care of acute myocardial infarction.
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Roig‐Soriano J, Griñán‐Ferré C, Espinosa‐Parrilla JF, Abraham CR, Bosch A, Pallàs M, Chillón M. AAV-mediated expression of secreted and transmembrane αKlotho isoforms rescues relevant aging hallmarks in senescent SAMP8 mice. Aging Cell 2022; 21:e13581. [PMID: 35274439 PMCID: PMC9009104 DOI: 10.1111/acel.13581] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Revised: 02/09/2022] [Accepted: 02/20/2022] [Indexed: 11/26/2022] Open
Abstract
Senescence represents a stage in life associated with elevated incidence of morbidity and increased risk of mortality due to the accumulation of molecular alterations and tissue dysfunction, promoting a decrease in the organism's protective systems. Thus, aging presents molecular and biological hallmarks, which include chronic inflammation, epigenetic alterations, neuronal dysfunction, and worsening of physical status. In this context, we explored the AAV9-mediated expression of the two main isoforms of the aging-protective factor Klotho (KL) as a strategy to prevent these general age-related features using the senescence-accelerated mouse prone 8 (SAMP8) model. Both secreted and transmembrane KL isoforms improved cognitive performance, physical state parameters, and different molecular variables associated with aging. Epigenetic landscape was recovered for the analyzed global markers DNA methylation (5-mC), hydroxymethylation (5-hmC), and restoration occurred in the acetylation levels of H3 and H4. Gene expression of pro- and anti-inflammatory mediators in central nervous system such as TNF-α and IL-10, respectively, had improved levels, which were comparable to the senescence-accelerated-mouse resistant 1 (SAMR1) healthy control. Additionally, this improvement in neuroinflammation was supported by changes in the histological markers Iba1, GFAP, and SA β-gal. Furthermore, bone tissue structural variables, especially altered during senescence, recovered in SAMP8 mice to SAMR1 control values after treatment with both KL isoforms. This work presents evidence of the beneficial pleiotropic role of Klotho as an anti-aging therapy as well as new specific functions of the KL isoforms for the epigenetic regulation and aged bone structure alteration in an aging mouse model.
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Affiliation(s)
- J. Roig‐Soriano
- Institut de Neurociènces (INc) Department of Biochemistry and Molecular Biology Universitat Autònoma Barcelona Bellaterra Spain
| | - C. Griñán‐Ferré
- Pharmacology Section Department of Pharmacology, Toxicology, and Therapeutic Chemistry Faculty of Pharmacy and Food Sciences Institut de Neurosciències‐Universitat de Barcelona (NeuroUB) Barcelona Spain
| | - J. F. Espinosa‐Parrilla
- Institut de Neurociènces (INc) Department of Biochemistry and Molecular Biology Universitat Autònoma Barcelona Bellaterra Spain
| | - C. R. Abraham
- Department of Pharmacology and Experimental Therapeutics Boston University School of Medicine Boston Massachusetts USA
| | - A. Bosch
- Institut de Neurociènces (INc) Department of Biochemistry and Molecular Biology Universitat Autònoma Barcelona Bellaterra Spain
- Vall d'Hebron Institut de Recerca (VHIR) Barcelona Spain
- Unitat producció de Vectors (UPV) Universitat Autònoma Barcelona Bellaterra Spain
- Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED) Instituto de Salud Carlos III Madrid Spain
| | - M. Pallàs
- Pharmacology Section Department of Pharmacology, Toxicology, and Therapeutic Chemistry Faculty of Pharmacy and Food Sciences Institut de Neurosciències‐Universitat de Barcelona (NeuroUB) Barcelona Spain
| | - Miguel Chillón
- Institut de Neurociènces (INc) Department of Biochemistry and Molecular Biology Universitat Autònoma Barcelona Bellaterra Spain
- Vall d'Hebron Institut de Recerca (VHIR) Barcelona Spain
- Unitat producció de Vectors (UPV) Universitat Autònoma Barcelona Bellaterra Spain
- Institució Catalana de Recerca i Estudis Avançats (ICREA) Passeig Lluis Companys Barcelona Spain
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Regulation of Aging and Longevity by Ion Channels and Transporters. Cells 2022; 11:cells11071180. [PMID: 35406743 PMCID: PMC8997527 DOI: 10.3390/cells11071180] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Revised: 03/22/2022] [Accepted: 03/29/2022] [Indexed: 12/10/2022] Open
Abstract
Despite significant advances in our understanding of the mechanisms that underlie age-related physiological decline, our ability to translate these insights into actionable strategies to extend human healthspan has been limited. One of the major reasons for the existence of this barrier is that with a few important exceptions, many of the proteins that mediate aging have proven to be undruggable. The argument put forth here is that the amenability of ion channels and transporters to pharmacological manipulation could be leveraged to develop novel therapeutic strategies to combat aging. This review delves into the established roles for ion channels and transporters in the regulation of aging and longevity via their influence on membrane excitability, Ca2+ homeostasis, mitochondrial and endolysosomal function, and the transduction of sensory stimuli. The goal is to provide the reader with an understanding of emergent themes, and prompt further investigation into how the activities of ion channels and transporters sculpt the trajectories of cellular and organismal aging.
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Hamdy M, Shaheen I, Seif El Din H, Ali B, Abdel Dayem O. Klotho Level as a Marker of Low Bone Mineral Density in Egyptian Sickle Cell Disease Patients. J Pediatr Hematol Oncol 2022; 44:e40-e45. [PMID: 34054039 DOI: 10.1097/mph.0000000000002231] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2020] [Accepted: 05/06/2021] [Indexed: 11/26/2022]
Abstract
Bone involvement of sickle cell disease (SCD) patients varies from acute clinical manifestations of painful vaso-occlusive crises or osteomyelitis to more chronic affection of bone mineral density (BMD) and debilitating osteonecrosis and osteoporosis. Secreted klotho protein is involved in calcium (Ca) reabsorption in the kidney. This study aimed to measure serum klotho levels in children with SCD to determine the possibility of using it as a marker of low BMD in children with SCD in correlation with a dual-energy radiograph absorptiometry scan. This study included 60 sickle disease patients and 30 age-matched and sex-matched control participants without SCD. A highly statistically significant difference was found between patients with normal BMD and those with low BMD, with serum Ca and klotho levels being lower in the latter group. Klotho serum level correlated positively with both serum Ca and BMD. Serum klotho level showed 94.9% sensitivity and 95.2% specificity in the detection of low BMD. Both serum Ca and klotho serum levels may be useful markers for detection of low BMD related to SCD with high sensitivity and specificity; however, klotho may be a better indicator as it is less affected by the nutritional and endocrinal status of patients or by intake of Ca supplements.
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Lin Y, Sun Z. Klotho deficiency-induced arterial calcification involves osteoblastic transition of VSMCs and activation of BMP signaling. J Cell Physiol 2022; 237:720-729. [PMID: 34368951 PMCID: PMC8810603 DOI: 10.1002/jcp.30541] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Revised: 07/07/2021] [Accepted: 07/24/2021] [Indexed: 01/03/2023]
Abstract
Klotho is an aging-suppressor gene. The purpose of this study was to investigate whether Klotho deficiency affects arterial structure. We found that Klotho-deficient (kl/kl) mice developed severe arterial calcification and elastin fragmentation. Klotho-deficient mice demonstrated higher levels of bone morphogenetic proteins (BMP2, BMP4) and runt-related transcription factor 2 (RUNX2) in aortas, indicating that Klotho deficiency upregulates expression of BMP2 and RUNX2 (a key transcription factor in osteoblasts). To exclude the potential involvement of hyperphosphatemia in arterial calcification, Klotho-deficient mice were given a low phosphate diet (0.2%). The low phosphate diet normalized blood phosphate levels and abolished calcification in the lungs and kidneys, but it did not prevent calcification in the aortas in Klotho-deficient mice. Thus, Klotho deficiency per se might play a causal role in the pathogenesis of arterial calcification, which is independent of hyperphosphatemia. In cultured mouse aortic smooth muscle cells (ASMCs), Klotho-deficient serum-induced transition of ASMCs to osteoblasts. Klotho-deficient serum promoted BMP2/vitamin D3-induced protein expression of PIT2 and RUNX2, phosphorylation of SMAD1/5/8 and SMAD2/3, and extracellular matrix calcification. Interestingly, treatments with recombinant Klotho protein abolished BMP2/vitamin D3-induced osteoblastic transition and morphogenesis and calcification. Therefore, Klotho is a critical regulator in the maintenance of normal arterial homeostasis. Klotho deficiency-induced arterial calcification is an active process that involves the osteoblastic transition of SMCs and activation of the BMP2-RUNX2 signaling.
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Affiliation(s)
- Yi Lin
- Department of Physiology, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK73104, USA
| | - Zhongjie Sun
- Department of Physiology, College of Medicine, University of Tennessee Health Sciences Center, Memphis, TN 73136, USA,Address Correspondence to: Zhongjie Sun, MD, PhD, FAHA, Professor and Chair, Department of Physiology, University of Tennessee HSC, C302B Coleman Bldg., 956 Court Ave., Memphis, TN 38163-2116, USA, Tel. 901-448-2679,
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Kundu P, Zimmerman B, Quinn JF, Kaye J, Mattek N, Westaway SK, Raber J. Serum Levels of α-Klotho Are Correlated with Cerebrospinal Fluid Levels and Predict Measures of Cognitive Function. J Alzheimers Dis 2022; 86:1471-1481. [PMID: 35213382 PMCID: PMC9108571 DOI: 10.3233/jad-215719] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/18/2022] [Indexed: 02/05/2023]
Abstract
BACKGROUND α-klotho might play a role in neurodegenerative diseases. OBJECTIVE To determine levels of α-klotho and apoE in serum and cerebrospinal fluid (CSF) samples and their relationship with the Mini-Mental State Examination (MMSE) and Clinical Dementia Rating (CDR). METHODS All subjects were between age 39 to 83+ (n = 94). CDR and MMSE were administered to all participants. CSF was collected in the early afternoon by lumbar puncture. RESULTS Serum and CSF levels of α-klotho are positively correlated and both predict scores on the MMSE and CDR, regardless of sex or apoE4 status. CONCLUSION Our results demonstrate that α-klotho may be an important biomarker of cognitive health and neurodegeneration, and that relatively non-invasive sampling of α-klotho from serum is likely highly reflective of CSF levels.
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Affiliation(s)
- Payel Kundu
- Department of Behavioral Neuroscience, Oregon Health and Science University, Portland, OR, USA
| | - Benjamin Zimmerman
- Department of Behavioral Neuroscience, Oregon Health and Science University, Portland, OR, USA
- Advanced Imaging Research Center, Oregon Health and Science University, Portland, OR, USA
- Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, IL, USA
| | - Joseph F. Quinn
- Department of Neurology, Oregon Health and Science University, Portland, OR, USA
- Department of Neurology, Veterans Affairs Medical Center, Portland, OR, USA
| | - Jeffrey Kaye
- Department of Neurology, Oregon Health and Science University, Portland, OR, USA
| | - Nora Mattek
- Department of Neurology, Oregon Health and Science University, Portland, OR, USA
| | - Shawn K. Westaway
- Department of Neurology, Oregon Health and Science University, Portland, OR, USA
| | - Jacob Raber
- Department of Behavioral Neuroscience, Oregon Health and Science University, Portland, OR, USA
- Department of Neurology, Oregon Health and Science University, Portland, OR, USA
- Departments of Psychiatry and Radiation Medicine, Division of Neuroscience, ONPRC, Oregon Health and Science University, Portland, OR, USA
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Gayan‐Ramirez G, Janssens W. Vitamin D Actions: The Lung Is a Major Target for Vitamin D, FGF23, and Klotho. JBMR Plus 2021; 5:e10569. [PMID: 34950829 PMCID: PMC8674778 DOI: 10.1002/jbm4.10569] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Revised: 09/29/2021] [Accepted: 10/09/2021] [Indexed: 11/16/2022] Open
Abstract
Vitamin D is well known for its role as a calcium regulator and in maintenance of phosphate homeostasis in musculoskeletal health, and fibroblast growth factor 23 (FGF23) and its coreceptor α-klotho are known for their roles as regulators of serum phosphate levels. However, apart from these classical actions, recent data point out a relevant role of vitamin D and FGF23/klotho in lung health. The expression of the vitamin D receptor by different cell types in the lung and the fact that those cells respond to vitamin D or can locally produce vitamin D indicate that the lung represents a target for vitamin D actions. Similarly, the presence of the four FGF receptor isoforms in the lung and the ability of FGF23 to stimulate pulmonary cells support the concept that the lung is a target for FGF23 actions, whereas the contribution of klotho is still undetermined. This review will give an overview on how vitamin D or FGF23/klotho may act on the lung and interfere positively or negatively with lung health. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
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Affiliation(s)
- Ghislaine Gayan‐Ramirez
- Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), Department CHROMETAKU LeuvenLeuvenBelgium
| | - Wim Janssens
- Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), Department CHROMETAKU LeuvenLeuvenBelgium
- Clinical Department of Respiratory DiseasesUZ LeuvenLeuvenBelgium
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Zhou H, Pu S, Zhou H, Guo Y. Klotho as Potential Autophagy Regulator and Therapeutic Target. Front Pharmacol 2021; 12:755366. [PMID: 34737707 PMCID: PMC8560683 DOI: 10.3389/fphar.2021.755366] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2021] [Accepted: 10/07/2021] [Indexed: 12/22/2022] Open
Abstract
The protein Klotho can significantly delay aging, so it has attracted widespread attention. Abnormal downregulation of Klotho has been detected in several aging-related diseases, such as Alzheimer’s disease, kidney injury, cancer, chronic obstructive pulmonary disease (COPD), vascular disease, muscular dystrophy and diabetes. Conversely, many exogenous and endogenous factors, several drugs, lifestyle changes and genetic manipulations were reported to exert therapeutic effects through increasing Klotho expression. In recent years, Klotho has been identified as a potential autophagy regulator. How Klotho may contribute to reversing the effects of aging and disease became clearer when it was linked to autophagy, the process in which eukaryotic cells clear away dysfunctional proteins and damaged organelles: the abovementioned diseases involve abnormal autophagy. Interestingly, growing evidence indicates that Klotho plays a dual role as inducer or inhibitor of autophagy in different physiological or pathological conditions through its influence on IGF-1/PI3K/Akt/mTOR signaling pathway, Beclin 1 expression and activity, as well as aldosterone level, which can help restore autophagy to beneficial levels. The present review examines the role of Klotho in regulating autophagy in Alzheimer’s disease, kidney injury, cancer, COPD, vascular disease, muscular dystrophy and diabetes. Targeting Klotho may provide a new perspective for preventing and treating aging-related diseases.
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Affiliation(s)
- Hongjing Zhou
- Department of Pharmacy, Chengdu Fifth People's Hospital, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Shiyun Pu
- Department of Pharmacy, Chengdu Fifth People's Hospital, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Houfeng Zhou
- Department of Pharmacy, Chengdu Fifth People's Hospital, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yuanxin Guo
- Department of Pharmacy, Chengdu Fifth People's Hospital, Chengdu University of Traditional Chinese Medicine, Chengdu, China
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Landry T, Shookster D, Huang H. Circulating α-klotho regulates metabolism via distinct central and peripheral mechanisms. Metabolism 2021; 121:154819. [PMID: 34153302 PMCID: PMC8277751 DOI: 10.1016/j.metabol.2021.154819] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Revised: 06/08/2021] [Accepted: 06/16/2021] [Indexed: 12/24/2022]
Abstract
Emerging evidence implicates the circulating α-klotho protein as a prominent regulator of energy balance and substrate metabolism, with diverse, tissue-specific functions. Despite its well-documented ubiquitous role inhibiting insulin signaling, α-klotho elicits potent antidiabetic and anti-obesogenic effects. α-Klotho facilitates insulin release and promotes β cell health in the pancreas, stimulates lipid oxidation in liver and adipose tissue, attenuates hepatic gluconeogenesis, and increases whole-body energy expenditure. The mechanisms underlying α-klotho's peripheral functions are multifaceted, including hydrolyzing transient receptor potential channels, stimulating integrin β1➔focal adhesion kinase signaling, and activating PPARα via inhibition of insulin-like growth factor receptor 1. Moreover, until recently, potential metabolic roles of α-klotho in the central nervous system remained unexplored; however, a novel α-klotho➔fibroblast growth factor receptor➔PI3kinase signaling axis in the arcuate nucleus of the hypothalamus has been identified as a critical regulator of energy balance and glucose metabolism. Overall, the role of circulating α-klotho in the regulation of metabolism is a new focus of research, but accumulating evidence identifies this protein as an encouraging therapeutic target for Type 1 and 2 Diabetes and obesity. This review analyzes the new literature investigating α-klotho-mediated regulation of metabolism and proposes impactful future directions to progress our understanding of this complex metabolic protein.
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Affiliation(s)
- Taylor Landry
- East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, NC, USA; Department of Kinesiology, East Carolina University, Greenville, NC, USA; Human Performance Laboratory, College of Human Performance and Health, East Carolina University, Greenville, NC, USA
| | - Daniel Shookster
- East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, NC, USA; Department of Kinesiology, East Carolina University, Greenville, NC, USA; Human Performance Laboratory, College of Human Performance and Health, East Carolina University, Greenville, NC, USA
| | - Hu Huang
- East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, NC, USA; Department of Kinesiology, East Carolina University, Greenville, NC, USA; Human Performance Laboratory, College of Human Performance and Health, East Carolina University, Greenville, NC, USA; Department of Physiology, East Carolina University, Greenville, NC, USA.
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Morevati M, Mace ML, Egstrand S, Nordholm A, Doganli C, Strand J, Rukov JL, Torsetnes SB, Gorbunova V, Olgaard K, Lewin E. Extrarenal expression of α-klotho, the kidney related longevity gene, in Heterocephalus glaber, the long living Naked Mole Rat. Sci Rep 2021; 11:15375. [PMID: 34321565 PMCID: PMC8319335 DOI: 10.1038/s41598-021-94972-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Accepted: 07/16/2021] [Indexed: 11/19/2022] Open
Abstract
The Naked Mole Rat (NMR), Heterocephalus glaber, provides an interesting model for studying biomarkers of longevity due to its long lifespan of more than 30 years, almost ten times longer than that of mice and rats. α-Klotho (klotho) is an aging-suppressor gene, and overexpression of klotho is associated with extended lifespan in mice. Klotho is predominantly expressed in the kidney. The expression profile of klotho in the NMR has not previously been reported. The present investigation studied the expression of klotho in the kidney of NMR with that of Rattus Norvegicus (RN) and demonstrated that klotho was expressed in the kidney of NMR at the same level as found in RN. Besides, a significant expression of Kl mRNA was found in the liver of NMR, in contrast to RN, where no hepatic expression was detected. The Klotho expression was further confirmed at the protein level. Thus, the results of the present comparative study indicate a differential tissue expression of klotho between different species. Besides its important function in the kidney, Klotho might also be of significance in the liver of NMR. It is suggested that the hepatic extrarenal expression of klotho may function as a further longevity-related factor in supplement to the Klotho in the kidney.
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Affiliation(s)
- M Morevati
- Nephrological Department P 2131, Rigshospitalet, University of Copenhagen, 9 Blegdamsvej, 2100, Copenhagen, Denmark.
| | - M L Mace
- Nephrological Department P 2131, Rigshospitalet, University of Copenhagen, 9 Blegdamsvej, 2100, Copenhagen, Denmark
| | - S Egstrand
- Nephrological Department P 2131, Rigshospitalet, University of Copenhagen, 9 Blegdamsvej, 2100, Copenhagen, Denmark
- Nephrological Department B, Herlev Hospital, University of Copenhagen, Copenhagen, Denmark
| | - A Nordholm
- Nephrological Department P 2131, Rigshospitalet, University of Copenhagen, 9 Blegdamsvej, 2100, Copenhagen, Denmark
- Nephrological Department B, Herlev Hospital, University of Copenhagen, Copenhagen, Denmark
| | - C Doganli
- Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark
| | - J Strand
- Randers Regnskov, Randers, Denmark
| | - J L Rukov
- Nephrological Department P 2131, Rigshospitalet, University of Copenhagen, 9 Blegdamsvej, 2100, Copenhagen, Denmark
| | - S B Torsetnes
- Department of Neurology, Akershus University Hospital, Oslo, Norway
| | - V Gorbunova
- Department of Biology, University of Rochester, Rochester, NY, USA
| | - K Olgaard
- Nephrological Department P 2131, Rigshospitalet, University of Copenhagen, 9 Blegdamsvej, 2100, Copenhagen, Denmark
| | - E Lewin
- Nephrological Department P 2131, Rigshospitalet, University of Copenhagen, 9 Blegdamsvej, 2100, Copenhagen, Denmark
- Nephrological Department B, Herlev Hospital, University of Copenhagen, Copenhagen, Denmark
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Tyurenkov IN, Perfilova VN, Nesterova AA, Glinka Y. Klotho Protein and Cardio-Vascular System. BIOCHEMISTRY (MOSCOW) 2021; 86:132-145. [PMID: 33832412 DOI: 10.1134/s0006297921020024] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Klotho protein affects a number of metabolic pathways essential for pathogenesis of cardio-vascular diseases and their prevention. It inhibits lipid peroxidation and inflammation, as well as prevents endothelial injury and calcification of blood vessels. Klotho decreases rigidity of blood vessels and suppresses development of the heart fibrosis. Low level of its expression is associated with a number of diseases. Cardioprotective effect of klotho is based on its ability to interact with multiple receptors and ion channels. Being a pleiotropic protein, klotho could be a useful target for therapeutic intervention in the treatment of cardio-vascular diseases. In this review we present data on pharmaceuticals that stimulate klotho expression and suggest some promising research directions.
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Affiliation(s)
- Ivan N Tyurenkov
- Volgograd State Medical University, Ministry of Health of the Russian Federation, Volgograd, 400066, Russia
| | - Valentina N Perfilova
- Volgograd State Medical University, Ministry of Health of the Russian Federation, Volgograd, 400066, Russia.
| | - Alla A Nesterova
- Pyatigorsk Medical and Pharmaceutical Institute, Branch of the Volgograd State Medical University, Ministry of Health of the Russian Federation, Pyatigorsk, 357500, Russia
| | - Yelena Glinka
- Keenan Research Centre, St. Michael's Hospital, Toronto, ON M5B 1W8, Canada
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Li L, Pastor J, Zhang J, Davidson T, Hu MC, Moe OW. In search of alternatively spliced alpha-Klotho Kl1 protein in mouse brain. FASEB Bioadv 2021; 3:531-540. [PMID: 34258522 PMCID: PMC8255843 DOI: 10.1096/fba.2020-00066] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Revised: 02/04/2021] [Accepted: 02/05/2021] [Indexed: 01/01/2023] Open
Abstract
Alpha‐Klotho is a multi‐functional protein essential for maintenance of a myriad of cell functions. αKlotho is a single transmembrane protein with a large extracellular segment consisting of two domains (termed Kl1 and Kl2) which is shed into the extracellular fluid by proteolytic cleavage to furnish circulating soluble αKlotho. Based on cDNA sequence, an alternatively spliced mRNA is predicted to translate to a putative soluble αKlotho protein in mouse and human with only the Kl1 domain that represents a “spliced αKlotho Kl1” (spKl1) and is released from the cell without membrane targeting or cleavage. The existence of this protein remains in silico for two decades. We generated a novel antibody (anti‐spE15) against the 15 amino acid epitope (E15; VSPLTKPSVGLLLPH) which is not present in Kl1 or full‐length αKlotho and validated its specific reactivity against spKl1 in vitro. Using anti‐spE15 and two well‐established anti‐αKlotho monoclonal antibodies, we performed immunoblots, immunoprecipitation, and immunohistochemistry to investigate for expression of spKl1 in the mouse brain. We found anti‐spE15 labeling in mouse brain but were not able to see co‐labelling of Kl1 and spE15 epitopes on the same protein, which is the pre‐requisite for the existence of a spKl1 polypeptide, indicating that anti‐spE15 likely binds to another protein other than the putative spKl1. In isolated choroid plexus from mouse brain, we found strong staining with anti‐spE15, but did not find the spliced αKlotho transcript. We conclude that using reliable reagents and inclusion of proper controls, there is no evidence of the spKl1 protein in the mouse brain.
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Affiliation(s)
- Liping Li
- Charles and Jane Pak Center for Mineral Metabolism and Clinical Research Dallas TX USA
| | - Johanne Pastor
- Charles and Jane Pak Center for Mineral Metabolism and Clinical Research Dallas TX USA
| | - Jianning Zhang
- Division of Nephrology Department of Internal Medicine University of Texas Southwestern Medical Center Dallas TX USA
| | - Taylor Davidson
- Charles and Jane Pak Center for Mineral Metabolism and Clinical Research Dallas TX USA
| | - Ming-Chang Hu
- Charles and Jane Pak Center for Mineral Metabolism and Clinical Research Dallas TX USA
| | - Orson W Moe
- Charles and Jane Pak Center for Mineral Metabolism and Clinical Research Dallas TX USA.,Division of Nephrology 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
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40
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Griñán-Ferré C, Bellver-Sanchis A, Izquierdo V, Corpas R, Roig-Soriano J, Chillón M, Andres-Lacueva C, Somogyvári M, Sőti C, Sanfeliu C, Pallàs M. The pleiotropic neuroprotective effects of resveratrol in cognitive decline and Alzheimer's disease pathology: From antioxidant to epigenetic therapy. Ageing Res Rev 2021; 67:101271. [PMID: 33571701 DOI: 10.1016/j.arr.2021.101271] [Citation(s) in RCA: 121] [Impact Index Per Article: 30.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2020] [Revised: 02/03/2021] [Accepted: 02/03/2021] [Indexed: 12/12/2022]
Abstract
While the elderly segment of the population continues growing in importance, neurodegenerative diseases increase exponentially. Lifestyle factors such as nutrition, exercise, and education, among others, influence ageing progression, throughout life. Notably, the Central Nervous System (CNS) can benefit from nutritional strategies and dietary interventions that prevent signs of senescence, such as cognitive decline or neurodegenerative diseases such as Alzheimer's disease and Parkinson's Disease. The dietary polyphenol Resveratrol (RV) possesses antioxidant and cytoprotective effects, producing neuroprotection in several organisms. The oxidative stress (OS) occurs because of Reactive oxygen species (ROS) accumulation that has been proposed to explain the cause of the ageing. One of the most harmful effects of ROS in the cell is DNA damage. Nevertheless, there is also evidence demonstrating that OS can produce other molecular changes such as mitochondrial dysfunction, inflammation, apoptosis, and epigenetic modifications, among others. Interestingly, the dietary polyphenol RV is a potent antioxidant and possesses pleiotropic actions, exerting its activity through various molecular pathways. In addition, recent evidence has shown that RV mediates epigenetic changes involved in ageing and the function of the CNS that persists across generations. Furthermore, it has been demonstrated that RV interacts with gut microbiota, showing modifications in bacterial composition associated with beneficial effects. In this review, we give a comprehensive overview of the main mechanisms of action of RV in different experimental models, including clinical trials and discuss how the interconnection of these molecular events could explain the neuroprotective effects induced by RV.
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Affiliation(s)
- Christian Griñán-Ferré
- Pharmacology Section, Department of Pharmacology, Toxicology, and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, Institute of Neuroscience, University of Barcelona (NeuroUB), Av Joan XXIII 27-31, 08028, Barcelona, Spain.
| | - Aina Bellver-Sanchis
- Pharmacology Section, Department of Pharmacology, Toxicology, and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, Institute of Neuroscience, University of Barcelona (NeuroUB), Av Joan XXIII 27-31, 08028, Barcelona, Spain
| | - Vanessa Izquierdo
- Pharmacology Section, Department of Pharmacology, Toxicology, and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, Institute of Neuroscience, University of Barcelona (NeuroUB), Av Joan XXIII 27-31, 08028, Barcelona, Spain
| | - Rubén Corpas
- Institut d'Investigacions Biomèdiques de Barcelona (IIBB), CSIC, IDIBAPS and CIBERESP, Barcelona, Spain
| | - Joan Roig-Soriano
- Department of Biochemistry and Molecular Biology, Universitat Autònoma Barcelona, Institut de Neurociènces (INc), Universitat Autònoma Barcelona, Bellaterra, Spain
| | - Miguel Chillón
- Department of Biochemistry and Molecular Biology, Universitat Autònoma Barcelona, Institut de Neurociènces (INc), Universitat Autònoma Barcelona, Bellaterra, Spain; Vall d'Hebron Institut de Recerca (VHIR), Research Group on Gene Therapy at Nervous System, Passeig de la Vall d'Hebron, Barcelona, Spain; Unitat producció de Vectors (UPV), Universitat Autònoma Barcelona, Bellaterra, Spain; Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain
| | - Cristina Andres-Lacueva
- Biomarkers and Nutrimetabolomics Laboratory, Department of Nutrition, Food Sciences and Gastronomy, Xarta, INSA, Faculty of Pharmacy and Food Sciences, Campus Torribera, University of Barcelona, Spain; CIBER de Fragilidad y Envejecimiento Saludable (CIBERFES), Instituto de Salut Carlos III, Barcelona, Spain
| | - Milán Somogyvári
- Department of Medical Chemistry, Semmelweis University, Budapest, Hungary
| | - Csaba Sőti
- Department of Medical Chemistry, Semmelweis University, Budapest, Hungary
| | - Coral Sanfeliu
- Institut d'Investigacions Biomèdiques de Barcelona (IIBB), CSIC, IDIBAPS and CIBERESP, Barcelona, Spain
| | - Mercè Pallàs
- Pharmacology Section, Department of Pharmacology, Toxicology, and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, Institute of Neuroscience, University of Barcelona (NeuroUB), Av Joan XXIII 27-31, 08028, Barcelona, Spain
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Mohanty SK, Suchiang K. Triiodothyronine (T3) enhances lifespan and protects against oxidative stress via activation of Klotho in Caenorhabditis elegans. Biogerontology 2021; 22:397-413. [PMID: 33851304 DOI: 10.1007/s10522-021-09923-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2021] [Accepted: 04/07/2021] [Indexed: 10/21/2022]
Abstract
Age predisposes individuals to significant diseases, and the biological processes contributing to aging are currently under intense investigation. Klotho is an anti-aging protein with multifaceted roles and is an essential component of the endocrine fibroblast growth factor. In Caenorhabditis elegans (C. elegans), there are two prospective orthologs of α-Klotho, C50F7.10, and E02H9.5, identified. The two orthologs' products are homologous to the highly conserved KL1 domain of human and mouse Klotho protein. Considering the endocrine system's major involvement in an organism's homeostasis and that thyroid disorders increase with advancing age, the molecular mechanisms underlying its impact on different endocrine components during the aging process remain poorly characterized. In this study, we sought to determine the regulatory role of Triiodothyronine (T3) on homologs genes of klotho and its impact on different parameters of aging in the C. elegans model organism. We showed that T3 could increase the mRNA expressions of the klotho homologous genes in C. elegans. Moreover, T3 could also extend a worm lifespan and modulate oxidative stress resistance and aging biomarkers significantly and positively. Further investigations employing different mutant and transgenic strains reveal that these observed effects are mediated through the EGL-17/EGL-15 pathway via Klotho activation along with the involvement of transcription factor DAF-16. In conclusion, these findings have revealed an unexpected link between T3 and Klotho and how this link can modulate the aging process in C. elegans via activation of klotho. This study will help understand the crosstalk and regulations of different endocrine components and their consequences on the aging process in multiple species.
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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 and Molecular Biology, Pondicherry University, Pondicherry, 605 014, India.
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42
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Hu PP, Bao JF, Li A. Roles for fibroblast growth factor-23 and α-Klotho in acute kidney injury. Metabolism 2021; 116:154435. [PMID: 33220250 DOI: 10.1016/j.metabol.2020.154435] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Revised: 11/08/2020] [Accepted: 11/13/2020] [Indexed: 12/21/2022]
Abstract
Acute kidney injury is a global disease with high morbidity and mortality. Recent studies have revealed that the fibroblast growth factor-23-α-Klotho axis is closely related to chronic kidney disease, and has multiple biological functions beyond bone-mineral metabolism. However, although dysregulation of fibroblast growth factor-23-α-Klotho has been observed in acute kidney injury, the role of fibroblast growth factor-23-α-Klotho in the pathophysiology of acute kidney injury remains largely unknown. In this review, we describe recent findings regarding fibroblast growth factor-23-α-Klotho, which is mainly involved in inflammation, oxidative stress, and hemodynamic disorders. Further, based on these recent results, we put forth novel insights regarding the relationship between the fibroblast growth factor-23-α-Klotho axis and acute kidney injury, which may provide new therapeutic targets for treating acute kidney injury.
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Affiliation(s)
- Pan-Pan Hu
- State Key Laboratory of Organ Failure Research, National Clinical Research Center for Kidney Disease, Nanfang Hospital, Southern Medical University, 510515 Guangzhou, China; Guangdong Provincial Key Laboratory of Renal Failure Research, Guangzhou Regenerative Medicine and Health Guangdong Laboratory, 510005 Guangzhou, China
| | - Jing-Fu Bao
- State Key Laboratory of Organ Failure Research, National Clinical Research Center for Kidney Disease, Nanfang Hospital, Southern Medical University, 510515 Guangzhou, China; Guangdong Provincial Key Laboratory of Renal Failure Research, Guangzhou Regenerative Medicine and Health Guangdong Laboratory, 510005 Guangzhou, China
| | - Aiqing Li
- State Key Laboratory of Organ Failure Research, National Clinical Research Center for Kidney Disease, Nanfang Hospital, Southern Medical University, 510515 Guangzhou, China; Guangdong Provincial Key Laboratory of Renal Failure Research, Guangzhou Regenerative Medicine and Health Guangdong Laboratory, 510005 Guangzhou, China.
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43
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Russell DL, Oates JC, Markiewicz M. Association Between the Anti-Aging Gene Klotho and Selected Rheumatologic Autoimmune Diseases. Am J Med Sci 2021; 361:169-175. [PMID: 33349438 PMCID: PMC9741923 DOI: 10.1016/j.amjms.2020.10.021] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2020] [Revised: 08/25/2020] [Accepted: 10/22/2020] [Indexed: 12/14/2022]
Abstract
Klotho long recognized for its role in anti-aging, is potentially implicated in the pathogenesis of rheumatoid arthritis, systemic lupus erythematosus, and systemic sclerosis. Aging of the immune system coincides with the inability of the body to recognize self-antigens, which often leads to autoimmune responses. The role of Klotho in these autoimmune diseases should be of high interest; however, few articles have been published exploring the role of Klotho in the pathogenesis, organ involvement, or clinical manifestation of rheumatoid arthritis, systemic lupus erythematosus, and systemic sclerosis. Herein, we discuss information gathered from peer-reviewed publications to describe the emerging role of Kl in these select rheumatologic autoimmune diseases.
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Affiliation(s)
| | - Jim C Oates
- Ralph H. Johnson VA Medical Center, Charleston, South Carolina;,Division of Rheumatology and Immunology, Medical University of South Carolina, Charleston, South Carolina
| | - Margaret Markiewicz
- Division of Rheumatology and Immunology, Medical University of South Carolina, Charleston, South Carolina
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44
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Ewendt F, Feger M, Föller M. Role of Fibroblast Growth Factor 23 (FGF23) and αKlotho in Cancer. Front Cell Dev Biol 2021; 8:601006. [PMID: 33520985 PMCID: PMC7841205 DOI: 10.3389/fcell.2020.601006] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Accepted: 10/15/2020] [Indexed: 12/16/2022] Open
Abstract
Together with fibroblast growth factors (FGFs) 19 and 21, FGF23 is an endocrine member of the family of FGFs. Mainly secreted by bone cells, FGF23 acts as a hormone on the kidney, stimulating phosphate excretion and suppressing formation of 1,25(OH)2D3, active vitamin D. These effects are dependent on transmembrane protein αKlotho, which enhances the binding affinity of FGF23 for FGF receptors (FGFR). Locally produced FGF23 in other tissues including liver or heart exerts further paracrine effects without involvement of αKlotho. Soluble Klotho (sKL) is an endocrine factor that is cleaved off of transmembrane Klotho or generated by alternative splicing and regulates membrane channels, transporters, and intracellular signaling including insulin growth factor 1 (IGF-1) and Wnt pathways, signaling cascades highly relevant for tumor progression. In mice, lack of FGF23 or αKlotho results in derangement of phosphate metabolism and a syndrome of rapid aging with abnormalities affecting most organs and a very short life span. Conversely, overexpression of anti-aging factor αKlotho results in a profound elongation of life span. Accumulating evidence suggests a major role of αKlotho as a tumor suppressor, at least in part by inhibiting IGF-1 and Wnt/β-catenin signaling. Hence, in many malignancies, higher αKlotho expression or activity is associated with a more favorable outcome. Moreover, also FGF23 and phosphate have been revealed to be factors relevant in cancer. FGF23 is particularly significant for those forms of cancer primarily affecting bone (e.g., multiple myeloma) or characterized by bone metastasis. This review summarizes the current knowledge of the significance of FGF23 and αKlotho for tumor cell signaling, biology, and clinically relevant parameters in different forms of cancer.
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Affiliation(s)
- Franz Ewendt
- Department of Nutritional Physiology, Institute of Agricultural and Nutritional Sciences, Martin-Luther University Halle-Wittenberg, Halle, Germany
| | - Martina Feger
- Department of Physiology, University of Hohenheim, Stuttgart, Germany
| | - Michael Föller
- Department of Physiology, University of Hohenheim, Stuttgart, Germany
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45
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Dias GP, Murphy T, Stangl D, Ahmet S, Morisse B, Nix A, Aimone LJ, Aimone JB, Kuro-O M, Gage FH, Thuret S. Intermittent fasting enhances long-term memory consolidation, adult hippocampal neurogenesis, and expression of longevity gene Klotho. Mol Psychiatry 2021; 26:6365-6379. [PMID: 34031536 PMCID: PMC8760057 DOI: 10.1038/s41380-021-01102-4] [Citation(s) in RCA: 58] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Revised: 03/19/2021] [Accepted: 04/06/2021] [Indexed: 02/03/2023]
Abstract
Daily calorie restriction (CR) and intermittent fasting (IF) enhance longevity and cognition but the effects and mechanisms that differentiate these two paradigms are unknown. We examined whether IF in the form of every-other-day feeding enhances cognition and adult hippocampal neurogenesis (AHN) when compared to a matched 10% daily CR intake and ad libitum conditions. After 3 months under IF, female C57BL6 mice exhibited improved long-term memory retention. IF increased the number of BrdU-labeled cells and neuroblasts in the hippocampus, and microarray analysis revealed that the longevity gene Klotho (Kl) was upregulated in the hippocampus by IF only. Furthermore, we found that downregulating Kl in human hippocampal progenitor cells led to decreased neurogenesis, whereas Kl overexpression increased neurogenesis. Finally, histological analysis of Kl knockout mice brains revealed that Kl is required for AHN, particularly in the dorsal hippocampus. These data suggest that IF is superior to 10% CR in enhancing memory and identifies Kl as a novel candidate molecule that regulates the effects of IF on cognition likely via AHN enhancement.
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Affiliation(s)
- Gisele Pereira Dias
- grid.13097.3c0000 0001 2322 6764Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK
| | - Tytus Murphy
- grid.13097.3c0000 0001 2322 6764Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK
| | - Doris Stangl
- grid.13097.3c0000 0001 2322 6764Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK
| | - Selda Ahmet
- grid.13097.3c0000 0001 2322 6764Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK
| | - Benjamin Morisse
- grid.13097.3c0000 0001 2322 6764Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK
| | - Alina Nix
- grid.13097.3c0000 0001 2322 6764Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK
| | - Lindsey J. Aimone
- grid.250671.70000 0001 0662 7144Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, CA USA
| | - James B. Aimone
- grid.474520.00000000121519272Center for Computing Research, Sandia National Laboratories, Albuquerque, NM USA
| | - Makoto Kuro-O
- grid.410804.90000000123090000Division of Anti-Ageing Medicine, Center for Molecular Medicine, Jichi Medical University, Tochigi, Japan
| | - Fred H. Gage
- grid.250671.70000 0001 0662 7144Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, CA USA
| | - Sandrine Thuret
- Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK. .,Department of Neurology, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
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46
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Najafipour H, Rostamzadeh F, Yeganeh-Hajahmadi M, Joukar S. Improvement of Cardiac Function in Rats With Myocardial Infarction by Low-Intensity to Moderate-Intensity Endurance Exercise Is Associated With Normalization of Klotho and SIRT1. J Cardiovasc Pharmacol 2021; 77:79-86. [PMID: 33079829 DOI: 10.1097/fjc.0000000000000935] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Accepted: 10/01/2020] [Indexed: 01/09/2023]
Abstract
ABSTRACT Exercise training (Ex) has beneficial effects on cardiovascular diseases by increasing Klotho and SIRT1. This study aimed to investigate whether the beneficial impact of Ex on myocardial infarction (MI) is mediated through Klotho and SIRT1. Fifty-six Wistar rats were divided into 4 main groups of Sham, MI, Ex, and MI + Ex. MI was induced by the closure of the left anterior descending. Animals were trained by endurance exercise for 4 weeks. In the end, hemodynamic and heart contractility indices were assessed. The levels of Klotho and SIRT1 in the serum and heart were measured by enzyme-linked immunosorbent assay and Western blot, respectively. The ADAM17 level in the heart and kidneys was assessed by enzyme-linked immunosorbent assay. The infarct size and fibrosis area were assessed by triphenyltetrazolium chloride and Masson trichrome staining, respectively. Ex recovered the reduction of dp/dt max and dp/dt min and decreased myocardial infarct size and fibrotic area in the MI group. Ex normalized the increase in heart rate, systolic blood pressure, left ventricular systolic pressure, and left ventricular end diastolic pressure in the MI group. Ex also normalized the reduction of the levels of Klotho and SIRT1 in serum and heart in the MI group. The changes of Klotho and SIRT1 in serum were positively correlated. Ex also restored ADAM17 levels in the MI group. Ex improved cardiac function in the MI group and is associated with reduction of the infarct size and normalization of Klotho and SIRT1 levels. Regarding unidirectional changes in Klotho and SIRT1, these proteins may play a role in beneficial effects of Ex on MI recovery.
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Affiliation(s)
- Hamid Najafipour
- Cardiovascular Research Center, Institute of Basic and Clinical Physiology Sciences, Kerman University of Medical Sciences, Kerman, Iran
| | - Farzaneh Rostamzadeh
- Physiology Research Center, Institute of Basic and Clinical Physiology Sciences, Kerman University of Medical Sciences, Kerman, Iran
| | - Mahboobeh Yeganeh-Hajahmadi
- Endocrinology and Metabolism Research Center, Institute of Basic and Clinical Physiology Sciences, Kerman University of Medical Sciences, Kerman, Iran; and
| | - Siyavash Joukar
- Neuroscience Research Center, Institute of Basic and Clinical Physiology Sciences, Department of Physiology and Pharmacology, Afzalipour Faculty of Medicine, Kerman University of Medical Sciences, Kerman, Iran
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47
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Neyra JA, Hu MC, Moe OW. Klotho in Clinical Nephrology: Diagnostic and Therapeutic Implications. Clin J Am Soc Nephrol 2020; 16:162-176. [PMID: 32699047 PMCID: PMC7792642 DOI: 10.2215/cjn.02840320] [Citation(s) in RCA: 105] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
αKlotho (called Klotho here) is a membrane protein that serves as the coreceptor for the circulating hormone fibroblast growth factor 23 (FGF23). Klotho is also cleaved and released as a circulating substance originating primarily from the kidney and exerts a myriad of housekeeping functions in just about every organ. The vital role of Klotho is shown by the multiorgan failure with genetic deletion in rodents, with certain features reminiscent of human disease. The most common causes of systemic Klotho deficiency are AKI and CKD. Preclinical data on Klotho biology have advanced considerably and demonstrated its potential diagnostic and therapeutic value; however, multiple knowledge gaps exist in the regulation of Klotho expression, release, and metabolism; its target organs; and mechanisms of action. In the translational and clinical fronts, progress has been more modest. Nonetheless, Klotho has potential clinical applications in the diagnosis of AKI and CKD, in prognosis of progression and extrarenal complications, and finally, as replacement therapy for systemic Klotho deficiency. The overall effect of Klotho in clinical nephrology requires further technical advances and additional large prospective human studies.
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Affiliation(s)
- Javier A. Neyra
- Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, Dallas, Texas
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
- Division of Nephrology, Bone and Mineral Metabolism, Department of Internal Medicine, University of Kentucky, Lexington, Kentucky
| | - Ming Chang Hu
- Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, Dallas, Texas
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Orson W. Moe
- Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, Dallas, Texas
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
- Department of Physiology, University of Texas Southwestern Medical Center, Dallas, Texas
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48
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Xing L, Guo H, Meng S, Zhu B, Fang J, Huang J, Chen J, Wang Y, Wang L, Yao X, Wang H. Klotho ameliorates diabetic nephropathy by activating Nrf2 signaling pathway in podocytes. Biochem Biophys Res Commun 2020; 534:450-456. [PMID: 33256980 DOI: 10.1016/j.bbrc.2020.11.061] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2020] [Accepted: 11/14/2020] [Indexed: 12/20/2022]
Abstract
Oxidative stress plays a key role in the pathogenesis of diabetic nephropathy (DN). The anti-aging protein Klotho has been demonstrated to have antioxidant capacity. Nuclear factor-erythroid 2-related factor 2 (Nrf2) is a central transcription factor regulating antioxidant responses. The present study aimed to explore the effects of Klotho on DN and the underlying mechanisms related to Nrf2. Low glucose (LG) or high glucose (HG) medium-cultured podocytes and diabetic db/db mice were overexpressed with Klotho via adenoviral transfer to evaluate the effects of Klotho on Nrf2 signaling, oxidative stress, podocyte apoptosis, and renal function and histopathology. Klotho overexpression significantly induced the expression and activation of Nrf2 as well as its downstream targets SOD2 and NQO1 in podocytes. Moreover, Klotho overexpression inhibited HG-induced oxidative stress and apoptosis in podocytes. Co-treatment with Nrf2 inhibitor trigonelline prevented Klotho-induced expression of SOD2 and NQO1, and abolished Klotho-conferred antioxidant and anti-apoptotic effects. In db/db mice, Klotho overexpression also activated Nrf2 signaling, and suppressed diabetes-induced oxidative stress and podocyte apoptosis, which were accompanied by improved renal function and decreased glomerulosclerosis. Our data highlight a novel Nrf2-mediated antioxidant mechanism underlying the protective effects of Klotho in podocytes and indicate the therapeutic potential of targeting Klotho to activate Nrf2 in DN.
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Affiliation(s)
- Lina Xing
- Department of Nephrology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200062, China
| | - Hengjiang Guo
- Department of Anesthesiology, Shanghai Children's Hospital, Shanghai Jiao Tong University, Shanghai, 200062, China
| | - Sixuan Meng
- Department of Nephrology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200062, China
| | - Bingbing Zhu
- Department of Nephrology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200062, China
| | - Ji Fang
- Department of Nephrology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200062, China
| | - Jiebo Huang
- Department of Nephrology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200062, China
| | - Junliang Chen
- Department of Nephrology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200062, China
| | - Yunman Wang
- Department of Nephrology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200062, China
| | - Li Wang
- Department of Nephrology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200062, China
| | - Xingmei Yao
- Department of Nephrology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200062, China.
| | - Hao Wang
- Department of Nephrology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200062, China.
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Xie T, Ye W, Liu J, Zhou L, Song Y. The Emerging Key Role of Klotho in the Hypothalamus-Pituitary-Ovarian Axis. Reprod Sci 2020; 28:322-331. [PMID: 32783104 DOI: 10.1007/s43032-020-00277-5] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Accepted: 07/24/2020] [Indexed: 12/16/2022]
Abstract
The hypothalamus-pituitary-ovary axis is the most important system for regulating female reproductive endocrine function. Its dysfunction would lead to the abnormal secretion of gonadotropin-releasing hormone, follicle-stimulating hormone, or luteinizing hormone, and eventually result in the occurrence of reproductive disease, such as congenital hypogonadotropic hypogonadism, polycystic ovary syndrome, and premature ovarian failure. Recently, an anti-aging gene, Klotho, has gained broad attention in female reproductive diseases. Reports have shown that Klotho is closely correlated to the hypothalamus-pituitary-ovary axis and plays a key role in the development and progression of reproductive diseases. With this issue, we generally review the physiological and pathological role of Klotho in the hypothalamus-pituitary-ovary axis. We also review the underlying mechanisms of Klotho in promoting and preventing female reproductive diseases, which involve the dysfunction of the fibroblast growth factor-Klotho endocrine system, the abnormal signaling regulation of Wnt-β-catenin and insulin-like growth factor-1, the accumulation of oxidative stress, and the inhibition of autophagy, eventually affecting the genesis, development, ovulation, or atresia of follicles. The present review would provide new insights and potential therapeutic target strategies for clinical strategies.
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Affiliation(s)
- Tingting Xie
- Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Ave., Guangzhou, 510515, China
| | - Wenting Ye
- Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Ave., Guangzhou, 510515, China
- State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Ave., Guangzhou, 510515, China
| | - Jing Liu
- Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Ave., Guangzhou, 510515, China
| | - Lili Zhou
- State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Ave., Guangzhou, 510515, China.
- Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou, China.
| | - Yali Song
- Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Ave., Guangzhou, 510515, China.
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50
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Liu QF, Li SS, Yu LX, Feng JH, Xue LL, Lu GY. The prognostic value of soluble Klotho in patients with haemodialysis: a systematic review and meta-analysis. Ther Adv Chronic Dis 2020; 11:2040622320940176. [PMID: 35154625 PMCID: PMC8832317 DOI: 10.1177/2040622320940176] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2019] [Accepted: 06/03/2020] [Indexed: 01/09/2023] Open
Abstract
Aim: The correlation between soluble Klotho (sKlotho) levels and clinical outcomes
remains inconclusive for patients undergoing maintenance haemodialysis
(MHD). We aimed to evaluate the potential predictive significance of sKlotho
in this population by conducting a meta-analysis. Methods: PubMed, Embase, Web of Science and Cochrane Library were comprehensively
searched for studies concerning the association between sKlotho level and
clinical outcomes including cardiovascular (CV) events and all-cause
mortality. The pooled hazard ratios (HR) and 95% confidence intervals (CI)
were generated using either random or fixed effects models. Sensitivity and
subgroup analyses were used to explore heterogeneity sources. Results: Eight prospective studies with 992 MHD participants were included and reduced
sKlotho levels predicted more adverse outcomes in this meta-analysis. The
pooled HRs and 95% CIs related to CV events, mortality, or composite
outcomes were 1.73 (95% CI 1.08–2.76, p = 0.02), 2.34 (95%
CI 1.34–2.07, p = 0.003) or 1.75 (95% CI 1.19–2.57,
p = 0.005). Moderate heterogeneity was observed in the
composite adverse outcomes (I2 = 57%,
p = 0.05). Age and sKlotho level were the main sources
of heterogeneities in the subgroup analysis. Conclusion: Lower sKlotho levels were associated with more CV events and all-cause
mortality, suggesting that sKlotho may have predictive value in CKD patients
receiving haemodialysis.
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Affiliation(s)
- Qi-Feng Liu
- Department of Nephrology, The First Affiliated Hospital of Soochow University, Jiangsu, China
- Department of Nephrology, Affiliated Kunshan Hospital of Jiangsu University, Kunshan, Jiangsu, China
| | - Sha-Sha Li
- Clinical Research & Lab Centre, Affiliated Kunshan Hospital of Jiangsu University, Kunshan, Jiangsu, China
- Immunology Laboratory, Affiliated Kunshan Hospital of Jiangsu University, Kunshan, Jiangsu, China
| | - Li-Xia Yu
- Department of Nephrology, Affiliated Kunshan Hospital of Jiangsu University, Kunshan, Jiangsu, China
| | - Jian-Hua Feng
- Department of Nephrology, Affiliated Kunshan Hospital of Jiangsu University, Kunshan, Jiangsu, China
| | - Li-Li Xue
- Department of Nephrology, Affiliated Kunshan Hospital of Jiangsu University, Kunshan, Jiangsu, China
| | - Guo-Yuan Lu
- Department of Nephrology, The First Affiliated Hospital of Soochow University, 188 Shizi Road Suzhou, Jiangsu, 215006, China
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