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Klotho and the Aging Process

  • Kuro-o, Makoto (Department of Pathology, The University of Texas Southwestern Medical Center)
  • 발행 : 2011.06.01

초록

The klotho gene was originally identified as a putative age-suppressing gene in mice that extends life span when overexpressed. It induces complex phenotypes resembling human premature aging syndromes when disrupted. The gene was named after a Greek goddess Klotho who spun the thread of life. Since then, various functional aspects of the klotho gene have been investigated, leading to the identification of multiple novel endocrine axes that regulate various metabolic processes and an unexpected link between mineral metabolism and aging. The purposes of this review were to overview recent progress on Klotho research and to discuss a novel aging mechanism.

키워드

참고문헌

  1. Kuro-o M, Matsumura Y, Aizawa H, et al. Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature 1997;390:45-51. https://doi.org/10.1038/36285
  2. Kurosu H, Yamamoto M, Clark JD, et al. Suppression of aging in mice by the hormone Klotho. Science 2005;309:1829-1833. https://doi.org/10.1126/science.1112766
  3. Chen CD, Podvin S, Gillespie E, Leeman SE, Abraham CR. Insulin stimulates the cleavage and release of the extracellular domain of Klotho by ADAM10 and ADAM17. Proc Natl Acad Sci U S A 2007;104:19796-19801. https://doi.org/10.1073/pnas.0709805104
  4. Imura A, Iwano A, Tohyama O, et al. Secreted Klotho protein in sera and CSF: implication for post-translational cleavage in release of Klotho protein from cell membrane. FEBS Lett 2004;565:143-147. https://doi.org/10.1016/j.febslet.2004.03.090
  5. Bloch L, Sineshchekova O, Reichenbach D, et al. Klotho is a substrate for alpha-, beta- and gamma-secretase. FEBS Lett 2009;583:3221-3224. https://doi.org/10.1016/j.febslet.2009.09.009
  6. Kurosu H, Ogawa Y, Miyoshi M, et al. Regulation of fibroblast growth factor-23 signaling by klotho. J Biol Chem 2006;281:6120-6123. https://doi.org/10.1074/jbc.C500457200
  7. Urakawa I, Yamazaki Y, Shimada T, et al. Klotho converts canonical FGF receptor into a specific receptor for FGF23. Nature 2006;444:770-774. https://doi.org/10.1038/nature05315
  8. Kuro-o M. Klotho as a regulator of fibroblast growth factor signaling and phosphate/calcium metabolism. Curr Opin Nephrol Hypertens 2006;15:437-441. https://doi.org/10.1097/01.mnh.0000232885.81142.83
  9. Hsieh CC, Kuro-o M, Rosenblatt KP, Brobey R, Papaconstantinou J. The ASK1-Signalosome regulates p38 MAPK activity in response to levels of endogenous oxidative stress in the Klotho mouse models of aging. Aging (Albany NY) 2010;2:597-611.
  10. Kuro-o M. Klotho and aging. Biochim Biophys Acta 2009;1790:1049-1058. https://doi.org/10.1016/j.bbagen.2009.02.005
  11. Kuro-o M. Klotho. Pflugers Arch 2010;459:333-343. https://doi.org/10.1007/s00424-009-0722-7
  12. Yamamoto M, Clark JD, Pastor JV, et al. Regulation of oxidative stress by the anti-aging hormone klotho. J Biol Chem 2005;280:38029-38034. https://doi.org/10.1074/jbc.M509039200
  13. Itoh N, Ornitz DM. Functional evolutionary history of the mouse Fgf gene family. Dev Dyn 2008;237:18-27. https://doi.org/10.1002/dvdy.21388
  14. ADHR Consortium. Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF23. Nat Genet 2000;26:345-348. https://doi.org/10.1038/81664
  15. White KE, Carn G, Lorenz-Depiereux B, Benet-Pages A, Strom TM, Econs MJ. Autosomal-dominant hypophosphatemic rickets (ADHR) mutations stabilize FGF-23. Kidney Int 2001;60:2079-2086. https://doi.org/10.1046/j.1523-1755.2001.00064.x
  16. Quarles LD. Endocrine functions of bone in mineral metabolism regulation. J Clin Invest 2008;118:3820-3828. https://doi.org/10.1172/JCI36479
  17. Shimada T, Kakitani M, Yamazaki Y, et al. Targeted ablation of Fgf23 demonstrates an essential physiological role of FGF23 in phosphate and vitamin D metabolism. J Clin Invest 2004;113:561-568.
  18. Razzaque MS, Sitara D, Taguchi T, St-Arnaud R, Lanske B. Premature aging-like phenotype in fibroblast growth factor 23 null mice is a vitamin D-mediated process. FASEB J 2006;20:720-722.
  19. Tsujikawa H, Kurotaki Y, Fujimori T, Fukuda K, Nabeshima Y. Klotho, a gene related to a syndrome resembling human premature aging, functions in a negative regulatory circuit of vitamin D endocrine system. Mol Endocrinol 2003;17:2393-2403. https://doi.org/10.1210/me.2003-0048
  20. Yoshida T, Fujimori T, Nabeshima Y. Mediation of unusually high concentrations of 1,25-dihydroxyvitamin D in homozygous klotho mutant mice by increased expression of renal 1alpha-hydroxylase gene. Endocrinology 2002;143:683-689. https://doi.org/10.1210/en.143.2.683
  21. Tomiyama K, Maeda R, Urakawa I, et al. Relevant use of Klotho in FGF19 subfamily signaling system in vivo. Proc Natl Acad Sci U S A 2010;107:1666-1671. https://doi.org/10.1073/pnas.0913986107
  22. Goetz R, Beenken A, Ibrahimi OA, et al. Molecular insights into the klotho-dependent, endocrine mode of action of fibroblast growth factor 19 subfamily members. Mol Cell Biol 2007;27:3417-3428. https://doi.org/10.1128/MCB.02249-06
  23. Berndt T, Kumar R. Novel mechanisms in the regulation of phosphorus homeostasis. Physiology (Bethesda) 2009;24:17-25. https://doi.org/10.1152/physiol.00034.2008
  24. Dusso AS, Brown AJ, Slatopolsky E. Vitamin D. Am J Physiol Renal Physiol 2005;289:F8-F28. https://doi.org/10.1152/ajprenal.00336.2004
  25. Berndt T, Kumar R. Phosphatonins and the regulation of phosphate homeostasis. Annu Rev Physiol 2007;69:341-359. https://doi.org/10.1146/annurev.physiol.69.040705.141729
  26. Ben-Dov IZ, Galitzer H, Lavi-Moshayoff V, et al. The parathyroid is a target organ for FGF23 in rats. J Clin Invest 2007;117:4003-4008.
  27. Shimada T, Hasegawa H, Yamazaki Y, et al. FGF-23 is a potent regulator of vitamin D metabolism and phosphate homeostasis. J Bone Miner Res 2004;19:429-435.
  28. Saji F, Shiizaki K, Shimada S, et al. Regulation of fibroblast growth factor 23 production in bone in uremic rats. Nephron Physiol 2009;111:p59-p66.
  29. Lavi-Moshayoff V, Wasserman G, Meir T, et al. PTH increases FGF23 gene expression and mediates the high-FGF23 levels of experimental kidney failure: a bone parathyroid feedback loop. Am J Physiol Renal Physiol 2010;299:F882-F889. https://doi.org/10.1152/ajprenal.00360.2010
  30. John GB, Cheng CY, Kuro-o M. Role of Klotho in aging, phiosphate metabolism, and CKD. Am J Kidney Dis 2011 Apr 14 [Epub]. DOI: 10. 1053/j.ajkd.2010.12.027.
  31. Kuro-O M. Phosphate and klotho. Kidney Int Suppl 2011; (121):S20-S23.
  32. Stubbs JR, Liu S, Tang W, et al. Role of hyperphosphatemia and 1,25-dihydroxyvitamin D in vascular calcification and mortality in fibroblastic growth factor 23 null mice. J Am Soc Nephrol 2007;18:2116-2124. https://doi.org/10.1681/ASN.2006121385
  33. Hesse M, Frohlich LF, Zeitz U, Lanske B, Erben RG. Ablation of vitamin D signaling rescues bone, mineral, and glucose homeostasis in Fgf-23 deficient mice. Matrix Biol 2007;26:75-84. https://doi.org/10.1016/j.matbio.2006.10.003
  34. Ohnishi M, Nakatani T, Lanske B, Razzaque MS. Reversal of mineral ion homeostasis and soft-tissue calcification of klotho knockout mice by deletion of vitamin D 1alpha-hydroxylase. Kidney Int 2009;75:1166-1172. https://doi.org/10.1038/ki.2009.24
  35. Morishita K, Shirai A, Kubota M, et al. The progression of aging in klotho mutant mice can be modified by dietary phosphorus and zinc. J Nutr 2001;131:3182-3188.
  36. Ohnishi M, Razzaque MS. Dietary and genetic evidence for phosphate toxicity accelerating mammalian aging. FASEB J 2010;24:3562-3571. https://doi.org/10.1096/fj.09-152488
  37. Stevens LA, Li S, Wang C, et al. Prevalence of CKD and comorbid illness in elderly patients in the United States: results from the Kidney Early Evaluation Program (KEEP). Am J Kidney Dis 2010;55(3 Suppl 2):S23-S33.
  38. Zoccali C, Kramer A, Jager KJ. Epidemiology of CKD in Europe: an uncertain scenario. Nephrol Dial Transplant 2010;25:1731-1733. https://doi.org/10.1093/ndt/gfq250
  39. Tonelli M, Sacks F, Pfeffer M, Gao Z, Curhan G; Cholesterol And Recurrent Events Trial Investigators. Relation between serum phosphate level and cardiovascular event rate in people with coronary disease. Circulation 2005;112:2627-2633. https://doi.org/10.1161/CIRCULATIONAHA.105.553198
  40. Ganesh SK, Stack AG, Levin NW, Hulbert-Shearon T, Port FK. Association of elevated serum PO(4), Ca x PO(4) product, and parathyroid hormone with cardiac mortality risk in chronic hemodialysis patients. J Am Soc Nephrol 2001;12:2131-2138.
  41. Gutierrez O, Isakova T, Rhee E, et al. Fibroblast growth factor-23 mitigates hyperphosphatemia but accentuates calcitriol deficiency in chronic kidney disease. J Am Soc Nephrol 2005;16:2205-2215. https://doi.org/10.1681/ASN.2005010052
  42. National Kidney Foundation. K/DOQI clinical practice guidelines for bone metabolism and disease in chronic kidney disease. Am J Kidney Dis 2003;42(4 Suppl 3):S1-S201.
  43. Gutierrez OM, Mannstadt M, Isakova T, et al. Fibroblast growth factor 23 and mortality among patients undergoing hemodialysis. N Engl J Med 2008;359:584-592. https://doi.org/10.1056/NEJMoa0706130
  44. Koh N, Fujimori T, Nishiguchi S, et al. Severely reduced production of klotho in human chronic renal failure kidney. Biochem Biophys Res Commun 2001;280:1015-1020. https://doi.org/10.1006/bbrc.2000.4226
  45. El-Abbadi M, Giachelli CM. Arteriosclerosis, calcium phosphate deposition and cardiovascular disease in uremia: current concepts at the bench. Curr Opin Nephrol Hypertens 2005;14:519-524. https://doi.org/10.1097/01.mnh.0000168335.29381.23
  46. Sarnak MJ, Levey AS, Schoolwerth AC, et al. Kidney disease as a risk factor for development of cardiovascular disease: a statement from the American Heart Association Councils on Kidney in Cardiovascular Disease, High Blood Pressure Research, Clinical Cardiology, and Epidemiology and Prevention. Circulation 2003;108:2154-2169. https://doi.org/10.1161/01.CIR.0000095676.90936.80
  47. Go AS, Chertow GM, Fan D, McCulloch CE, Hsu CY. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med 2004;351:1296-1305. https://doi.org/10.1056/NEJMoa041031
  48. Hu MC, Shi M, Zhang J, et al. Klotho deficiency causes vascular calcification in chronic kidney disease. J Am Soc Nephrol 2011;22:124-136. https://doi.org/10.1681/ASN.2009121311
  49. Hruska KA, Choi ET, Memon I, Davis TK, Mathew S. Cardiovascular risk in chronic kidney disease (CKD): the CKD-mineral bone disorder (CKD-MBD). Pediatr Nephrol 2010;25:769-778. https://doi.org/10.1007/s00467-009-1337-0
  50. Meyer KB, Levey AS. Controlling the epidemic of cardiovascular disease in chronic renal disease: report from the National Kidney Foundation Task Force on cardiovascular disease. J Am Soc Nephrol 1998;9(12 Suppl):S31-S42.
  51. Shuto E, Taketani Y, Tanaka R, et al. Dietary phosphorus acutely impairs endothelial function. J Am Soc Nephrol 2009;20:1504-1512. https://doi.org/10.1681/ASN.2008101106
  52. Tohyama O, Imura A, Iwano A, et al. Klotho is a novel beta-glucuronidase capable of hydrolyzing steroid beta-glucuronides. J Biol Chem 2004;279:9777-9784.
  53. Chang Q, Hoefs S, van der Kemp AW, Topala CN, Bindels RJ, Hoenderop JG. The beta-glucuronidase klotho hydrolyzes and activates the TRPV5 channel. Science 2005;310:490-493. https://doi.org/10.1126/science.1114245
  54. Cha SK, Ortega B, Kurosu H, Rosenblatt KP, Kuro-O M, Huang CL. Removal of sialic acid involving Klotho causes cell-surface retention of TRPV5 channel via binding to galectin-1. Proc Natl Acad Sci U S A 2008;105:9805-9810. https://doi.org/10.1073/pnas.0803223105
  55. Mensenkamp AR, Hoenderop JG, Bindels RJ. Recent advances in renal tubular calcium reabsorption. Curr Opin Nephrol Hypertens 2006;15:524-529. https://doi.org/10.1097/01.mnh.0000242179.38739.fb
  56. Cha SK, Hu MC, Kurosu H, Kuro-o M, Moe O, Huang CL. Regulation of renal outer medullary potassium channel and renal K(+) excretion by Klotho. Mol Pharmacol 2009;76:38-46. https://doi.org/10.1124/mol.109.055780
  57. Hu MC, Shi M, Zhang J, et al. Klotho: a novel phosphaturic substance acting as an autocrine enzyme in the renal proximal tubule. FASEB J 2010;24:3438-3450. https://doi.org/10.1096/fj.10-154765
  58. Liu H, Fergusson MM, Castilho RM, et al. Augmented Wnt signaling in a mammalian model of accelerated aging. Science 2007;317:803-806. https://doi.org/10.1126/science.1143578
  59. Doi S, Zou Y, Togao O, et al. Klotho inhibits transforming growth factor-b1 (TGF-${\beta}1$) signaling and suppresses renal fibrosis and cancer metastasis in mice. J Biol Chem 2011;286:8655-8665. https://doi.org/10.1074/jbc.M110.174037
  60. Kenyon C. The plasticity of aging: insights from long-lived mutants. Cell 2005;120:449-460. https://doi.org/10.1016/j.cell.2005.02.002
  61. Willis BC, Borok Z. TGF-beta-induced EMT: mechanisms and implications for fibrotic lung disease. Am J Physiol Lung Cell Mol Physiol 2007;293:L525-L534. https://doi.org/10.1152/ajplung.00163.2007
  62. Thiery JP, Acloque H, Huang RY, Nieto MA. Epithelial-mesenchymal transitions in development and disease. Cell 2009;139:871-890. https://doi.org/10.1016/j.cell.2009.11.007
  63. Ito S, Kinoshita S, Shiraishi N, et al. Molecular cloning and expression analyses of mouse betaklotho, which encodes a novel Klotho family protein. Mech Dev 2000;98:115-119. https://doi.org/10.1016/S0925-4773(00)00439-1
  64. Ito S, Fujimori T, Hayashizaki Y, Nabeshima Y. Identification of a novel mouse membrane-bound family 1 glycosidase-like protein, which carries an atypical active site structure. Biochim Biophys Acta 2002;1576:341-345. https://doi.org/10.1016/S0167-4781(02)00281-6
  65. Ogawa Y, Kurosu H, Yamamoto M, et al. bKlotho is required for metabolic activity of fibroblast growth factor 21. Proc Natl Acad Sci U S A 2007;104:7432-7437. https://doi.org/10.1073/pnas.0701600104
  66. Kurosu H, Choi M, Ogawa Y, et al. Tissue-specific expression of betaKlotho and fibroblast growth factor (FGF) receptor isoforms determines metabolic activity of FGF19 and FGF21. J Biol Chem 2007;282:26687-26695. https://doi.org/10.1074/jbc.M704165200
  67. Fon Tacer K, Bookout AL, Ding X, et al. Research resource: Comprehensive expression atlas of the fibroblast growth factor system in adult mouse. Mol Endocrinol 2010;24:2050-2064. https://doi.org/10.1210/me.2010-0142
  68. Ogawa W, Matozaki T, Kasuga M. Role of binding proteins to IRS-1 in insulin signalling. Mol Cell Biochem 1998;182:13-22. https://doi.org/10.1023/A:1006862807598
  69. Kuro-o M. Endocrine FGFs and Klothos: emerging concepts. Trends Endocrinol Metab 2008;19:239-245. https://doi.org/10.1016/j.tem.2008.06.002
  70. Inagaki T, Choi M, Moschetta A, et al. Fibroblast growth factor 15 functions as an enterohepatic signal to regulate bile acid homeostasis. Cell Metab 2005;2:217-225. https://doi.org/10.1016/j.cmet.2005.09.001
  71. Ito S, Fujimori T, Furuya A, Satoh J, Nabeshima Y, Nabeshima Y. Impaired negative feedback suppression of bile acid synthesis in mice lacking betaKlotho. J Clin Invest 2005;115:2202-2208. https://doi.org/10.1172/JCI23076
  72. Yu C, Wang F, Kan M, et al. Elevated cholesterol metabolism and bile acid synthesis in mice lacking membrane tyrosine kinase receptor FGFR4. J Biol Chem 2000;275:15482-15489. https://doi.org/10.1074/jbc.275.20.15482
  73. Inagaki T, Dutchak P, Zhao G, et al. Endocrine regulation of the fasting response by PPARalpha-mediated induction of fibroblast growth factor 21. Cell Metab 2007;5:415-425. https://doi.org/10.1016/j.cmet.2007.05.003
  74. Inagaki T, Lin VY, Goetz R, Mohammadi M, Mangelsdorf DJ, Kliewer SA. Inhibition of growth hormone signaling by the fasting-induced hormone FGF21. Cell Metab 2008;8:77-83. https://doi.org/10.1016/j.cmet.2008.05.006
  75. Kuro-o M. A potential link between phosphate and aging: lessons from Klotho-deficient mice. Mech Ageing Dev 2010;131:270-275. https://doi.org/10.1016/j.mad.2010.02.008

피인용 문헌

  1. Dehydration: a new modulator of klotho expression vol.301, pp.4, 2011, https://doi.org/10.1152/ajprenal.00412.2011
  2. Pathophysiology of the aging kidney and therapeutic interventions vol.35, pp.12, 2011, https://doi.org/10.1038/hr.2012.159
  3. Impact of serum calcium and phosphate on coronary atherosclerosis detected by cardiac computed tomography vol.33, pp.22, 2012, https://doi.org/10.1093/eurheartj/ehs152
  4. Age-Associated Molecular Changes in the Kidney in Aged Mice vol.2012, pp.None, 2011, https://doi.org/10.1155/2012/171383
  5. Aging biology: a new frontier for drug discovery vol.7, pp.3, 2011, https://doi.org/10.1517/17460441.2012.660144
  6. Small-molecule Klotho enhancers as novel treatment of neurodegeneration vol.4, pp.13, 2012, https://doi.org/10.4155/fmc.12.134
  7. The effects of oxygen tension and antiaging factor Klotho on Wnt signaling in nucleus pulposus cells vol.14, pp.3, 2011, https://doi.org/10.1186/ar3830
  8. Biochemical Markers of Aging for Longitudinal Studies in Humans vol.35, pp.1, 2011, https://doi.org/10.1093/epirev/mxs011
  9. Deranged epidermal differentiation in kl/kl mouse and the effects of βKlotho siRNA on the differentiation of HaCaT cells vol.22, pp.11, 2011, https://doi.org/10.1111/exd.12258
  10. Melatonin and the theories of aging: a critical appraisal of melatonin's role in antiaging mechanisms vol.55, pp.4, 2013, https://doi.org/10.1111/jpi.12090
  11. ‘Time and Time Again’: Oscillatory and Longitudinal Time Patterns in Dialysis Patients vol.35, pp.6, 2011, https://doi.org/10.1159/000340022
  12. Sepsis-Induced Hypercytokinemia and Lymphocyte Apoptosis in Aging-Accelerated Klotho Knockout Mice vol.39, pp.3, 2011, https://doi.org/10.1097/shk.0b013e3182845445
  13. Altered regulation of cytosolic Ca2+ concentration in dendritic cells from klotho hypomorphic mice vol.305, pp.1, 2011, https://doi.org/10.1152/ajpcell.00355.2012
  14. Two cases of nevus sebaceous accompanying secondary tumors with βKlotho expression vol.41, pp.2, 2011, https://doi.org/10.1111/1346-8138.12371
  15. Reduced Klotho is associated with the presence and severity of coronary artery disease vol.100, pp.1, 2014, https://doi.org/10.1136/heartjnl-2013-304746
  16. The renin-angiotensin system and aging in the kidney vol.29, pp.3, 2014, https://doi.org/10.3904/kjim.2014.29.3.291
  17. Vitamin D and chronic kidney disease vol.29, pp.4, 2014, https://doi.org/10.3904/kjim.2014.29.4.416
  18. FGF23 in Acute and Chronic Illness vol.2015, pp.None, 2011, https://doi.org/10.1155/2015/358086
  19. Klotho Prevents NFκB Translocation and Protects Endothelial Cell From Senescence Induced by Uremia vol.70, pp.10, 2011, https://doi.org/10.1093/gerona/glu170
  20. βKlotho expression is reduced in human non‐melanoma skin cancer vol.54, pp.10, 2015, https://doi.org/10.1111/ijd.12924
  21. Klotho: a tumor suppressor and modulator of the Wnt/β-catenin pathway in human hepatocellular carcinoma vol.96, pp.2, 2011, https://doi.org/10.1038/labinvest.2015.86
  22. Cognitive Changes in Chronic Kidney Disease and After Transplantation vol.100, pp.4, 2016, https://doi.org/10.1097/tp.0000000000000968
  23. Expression of klotho and β‐catenin in esophageal squamous cell carcinoma, and their clinicopathological and prognostic significance vol.29, pp.3, 2011, https://doi.org/10.1111/dote.12289
  24. Deficiency in the anti‐aging gene Klotho promotes aortic valve fibrosis through AMPK α‐mediated activation of RUNX 2 vol.15, pp.5, 2011, https://doi.org/10.1111/acel.12494
  25. Association of Serum Phosphate Levels and Anemia in Critically Ill Surgical Patients vol.41, pp.6, 2017, https://doi.org/10.1177/0148607115626415
  26. Klotho suppresses the inflammatory responses and ameliorates cardiac dysfunction in aging endotoxemic mice vol.8, pp.9, 2011, https://doi.org/10.18632/oncotarget.14933
  27. Induction of anti-aging gene klotho with a small chemical compound that demethylates CpG islands vol.8, pp.29, 2011, https://doi.org/10.18632/oncotarget.18608
  28. Neuroprotective Effect of Ligustilide through Induction of α-Secretase Processing of Both APP and Klotho in a Mouse Model of Alzheimer’s Disease vol.9, pp.None, 2011, https://doi.org/10.3389/fnagi.2017.00353
  29. Vitamin D deficiency is associated with increased risk of bacterial infections after kidney transplantation vol.32, pp.3, 2011, https://doi.org/10.3904/kjim.2015.214
  30. FGF23 Neutralizing Antibody Ameliorates Hypophosphatemia and Impaired FGF Receptor Signaling in Kidneys of HMWFGF2 Transgenic Mice vol.232, pp.3, 2011, https://doi.org/10.1002/jcp.25458
  31. The SAMP8 mouse for investigating memory and the role of insulin in the brain vol.94, pp.None, 2011, https://doi.org/10.1016/j.exger.2016.12.009
  32. Epigenetic suppression of the anti-aging gene KLOTHO in human prostate cancer cell lines vol.21, pp.4, 2011, https://doi.org/10.1080/19768354.2017.1336112
  33. Klotho ameliorates oxidized low density lipoprotein (ox-LDL)-induced oxidative stress via regulating LOX-1 and PI3K/Akt/eNOS pathways vol.16, pp.None, 2011, https://doi.org/10.1186/s12944-017-0447-0
  34. The Biological Role of Klotho Protein in the Development of Cardiovascular Diseases vol.2018, pp.None, 2011, https://doi.org/10.1155/2018/5171945
  35. Maintenance of Kidney Metabolic Homeostasis by PPAR Gamma vol.19, pp.7, 2011, https://doi.org/10.3390/ijms19072063
  36. α-Klotho protein in neurodegenerative and mental diseases vol.119, pp.1, 2011, https://doi.org/10.17116/jnevro201911901180
  37. Role of Klotho in Chronic Calcineurin Inhibitor Nephropathy vol.2019, pp.None, 2011, https://doi.org/10.1155/2019/1825018
  38. Adherence to the Mediterranean diet, dietary factors, and S-Klotho plasma levels in sedentary middle-aged adults vol.119, pp.None, 2019, https://doi.org/10.1016/j.exger.2019.01.019
  39. The relationship between serum FGF-23 concentration and insulin resistance, prediabetes and dyslipidemia in obese children and adolescents vol.32, pp.7, 2019, https://doi.org/10.1515/jpem-2018-0507
  40. The relationship between serum FGF-23 concentration and insulin resistance, prediabetes and dyslipidemia in obese children and adolescents vol.32, pp.7, 2019, https://doi.org/10.1515/jpem-2018-0507
  41. Re: “Decreased Levels of Anti-Aging Klotho in Obstructive Sleep Apnea” by Pákó et al. (Rejuvenation Res 2019 [Epub ahead of print]; DOI: 10.1089/rej.2019.2183) vol.22, pp.4, 2011, https://doi.org/10.1089/rej.2019.2244
  42. Association of basal metabolic rate and fuel oxidation in basal conditions and during exercise, with plasma S-klotho: the FIT-AGEING study vol.11, pp.15, 2019, https://doi.org/10.18632/aging.102100
  43. The interplay of Klotho with signaling pathway and microRNAs in cancers vol.120, pp.9, 2011, https://doi.org/10.1002/jcb.29022
  44. Klotho Deficiency Accelerates Stem Cells Aging by Impairing Telomerase Activity vol.74, pp.9, 2011, https://doi.org/10.1093/gerona/gly261
  45. The Klotho Variant rs36217263 Is Associated With Poor Response to Cardioselective Beta‐Blocker Therapy Among Filipinos vol.107, pp.1, 2011, https://doi.org/10.1002/cpt.1585
  46. Mechanistic target of rapamycin signaling in mouse models of accelerated aging vol.75, pp.1, 2020, https://doi.org/10.1093/gerona/glz059
  47. Cellular Senescence in Kidney Fibrosis: Pathologic Significance and Therapeutic Strategies vol.11, pp.None, 2011, https://doi.org/10.3389/fphar.2020.601325
  48. Association between serum levels of Klotho and inflammatory cytokines in cardiovascular disease: a case-control study vol.12, pp.2, 2011, https://doi.org/10.18632/aging.102734
  49. Z‐ligustilide: A review of its pharmacokinetics and pharmacology vol.34, pp.8, 2011, https://doi.org/10.1002/ptr.6662
  50. Klotho-HIV and Oxidative Stress: The Role of Klotho in Cardiovascular Disease Under HIV Infection-A Review vol.39, pp.9, 2011, https://doi.org/10.1089/dna.2020.5444
  51. Enhanced Klotho availability protects against cardiac dysfunction induced by uraemic cardiomyopathy by regulating Ca 2+ handling vol.177, pp.20, 2011, https://doi.org/10.1111/bph.15235
  52. Expression of Phosphatonin-Related Genes in Sheep, Dog and Horse Kidneys Using Quantitative Reverse Transcriptase PCR vol.10, pp.10, 2020, https://doi.org/10.3390/ani10101806
  53. The Ability of Nutrition to Mitigate Epigenetic Drift: A Novel Look at Regulating Gene Expression vol.67, pp.6, 2011, https://doi.org/10.3177/jnsv.67.359
  54. Constitutive Expression of TERT Enhances β-Klotho Expression and Improves Age-Related Deterioration in Early Bovine Embryos vol.22, pp.10, 2021, https://doi.org/10.3390/ijms22105327
  55. Tacrolimus Decreases Cognitive Function by Impairing Hippocampal Synaptic Balance: a Possible Role of Klotho vol.58, pp.11, 2011, https://doi.org/10.1007/s12035-021-02499-3
  56. Klotho inhibits neuronal senescence in human brain organoids vol.7, pp.1, 2011, https://doi.org/10.1038/s41514-021-00070-x