Pflügers Archiv - European Journal of Physiology

, Volume 459, Issue 2, pp 333–343 | Cite as


Integrative Physiology


The klotho gene was identified as an “aging-suppressor” gene in mice that accelerates aging when disrupted and extends life span when overexpressed. It encodes a single-pass transmembrane protein and is expressed primarily in renal tubules. The extracellular domain of Klotho protein is secreted into blood and urine by ectodomain shedding. The two forms of Klotho protein, membrane Klotho and secreted Klotho, exert distinct functions. Membrane Klotho forms a complex with fibroblast growth factor (FGF) receptors and functions as an obligate co-receptor for FGF23, a bone-derived hormone that induces phosphate excretion into urine. Mice lacking Klotho or FGF23 not only exhibit phosphate retention but also display a premature-aging syndrome, revealing an unexpected link between phosphate metabolism and aging. Secreted Klotho functions as a humoral factor that regulates activity of multiple glycoproteins on the cell surface, including ion channels and growth factor receptors such as insulin/insulin-like growth factor-1 receptors. Potential contribution of these multiple activities of Klotho protein to aging processes is discussed.


Klotho FGF23 Phosphate Vitamin D βKlotho 


  1. 1.
    Anamizu Y, Kawaguchi H, Seichi A, Yamaguchi S, Kawakami E, Kanda N, Matsubara S, Kuro-o M, Nabeshima Y, Nakamura K, Oyanagi K (2005) Klotho insufficiency causes decrease of ribosomal RNA gene transcription activity, cytoplasmic RNA and rough ER in the spinal anterior horn cells. Acta Neuropathol (Berl) 109:457–466Google Scholar
  2. 2.
    Asadi F, Rostami A, Asadian P, Pourkabir M (2007) Serum biochemistry and hematology values and hemoglobin electrophoresis in Persian squirrels (Sciurus anomalus). Vet Clin Pathol 36:188–191PubMedGoogle Scholar
  3. 3.
    Badman MK, Pissios P, Kennedy AR, Koukos G, Flier JS, Maratos-Flier E (2007) Hepatic fibroblast growth factor 21 is regulated by PPARalpha and is a key mediator of hepatic lipid metabolism in ketotic states. Cell Metab 5:426–437PubMedGoogle Scholar
  4. 4.
    Bartke A, Brown-Borg H (2004) Life extension in the dwarf mouse. Curr Top Dev Biol 63:189–225PubMedGoogle Scholar
  5. 5.
    Ben-Dov IZ, Galitzer H, Lavi-Moshayoff V, Goetz R, Kuro-o M, Mohammadi M, Sirkis R, Naveh-Many T, Silver J (2007) The parathyroid is a target organ for FGF23 in rats. J Clin Invest 117:4003–4008PubMedGoogle Scholar
  6. 6.
    Bluher M, Kahn BB, Kahn CR (2003) Extended longevity in mice lacking the insulin receptor in adipose tissue. Science 299:572–574PubMedGoogle Scholar
  7. 7.
    Bose S, French S, Evans FJ, Joubert F, Balaban RS (2003) Metabolic network control of oxidative phosphorylation: multiple roles of inorganic phosphate. J Biol Chem 278:39155–39165PubMedGoogle Scholar
  8. 8.
    Brown-Borg HM, Borg KE, Meliska CJ, Bartke A (1996) Dwarf mice and the ageing process [letter]. Nature 384:33PubMedGoogle Scholar
  9. 9.
    Cao SX, Dhahbi JM, Mote PL, Spindler SR (2001) Genomic profiling of short- and long-term caloric restriction effects in the liver of aging mice. Proc Natl Acad Sci U S A 98:10630–10635PubMedGoogle Scholar
  10. 10.
    Cha SK, Hu MC, Kurosu H, Kuro-o M, Moe O, Huang CL (2009) Regulation of ROMK1 channel and renal K+ excretion by Klotho. Mol Pharmacol 76:38–46PubMedGoogle Scholar
  11. 11.
    Cha SK, Ortega B, Kurosu H, Rosenblatt KP, Kuro-o M, Huang CL (2008) 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 105:9805–9810PubMedGoogle Scholar
  12. 12.
    Chang Q, Hoefs S, van der Kemp AW, Topala CN, Bindels RJ, Hoenderop JG (2005) The beta-glucuronidase klotho hydrolyzes and activates the TRPV5 channel. Science 310:490–493PubMedGoogle Scholar
  13. 13.
    Chen CD, Podvin S, Gillespie E, Leeman SE, Abraham CR (2007) Insulin stimulates the cleavage and release of the extracellular domain of Klotho by ADAM10 and ADAM17. Proc Natl Acad Sci U S A 104:19796–19801PubMedGoogle Scholar
  14. 14.
    Clancy DJ, Gems D, Harshman LG, Oldham S, Stocker H, Hafen E, Leevers SJ, Partridge L (2001) Extension of life-span by loss of CHICO, a Drosophila insulin receptor substrate protein. Science 292:104–106PubMedGoogle Scholar
  15. 15.
    Di Marco GS, Hausberg M, Hillebrand U, Rustemeyer P, Wittkowski W, Lang D, Pavenstadt H (2008) Increased inorganic phosphate induces human endothelial cell apoptosis in vitro. Am J Physiol Renal Physiol 294:F1381–F1387PubMedGoogle Scholar
  16. 16.
    Dusso AS, Brown AJ, Slatopolsky E (2005) Vitamin D. Am J Physiol Renal Physiol 289:F8–28PubMedGoogle Scholar
  17. 17.
    Feldhamer GA, Thompson BC, Chapman JA (2003) Wild mammals of North America: biology, management, and conservation. JHU, BaltimoreGoogle Scholar
  18. 18.
    Field KJ, Sibold AL, Suckow MA (1998) The laboratory hamster & gerbil. CRC, Boca RatonGoogle Scholar
  19. 19.
    Flurkey K, Papaconstantinou J, Harrison DE (2002) The Snell dwarf mutation Pit1(dw) can increase life span in mice. Mech Ageing Dev 123:121–130PubMedGoogle Scholar
  20. 20.
    Goetz R, Beenken A, Ibrahimi OA, Kalinina J, Olsen SK, Eliseenkova AV, Xu C, Neubert T, Zhang F, Linhardt RJ, Yu X, White KE, Inagaki T, Kliewer SA, Yamamoto M, Kurosu H, Ogawa Y, Kuro-o M, Lanske B, Razzaque MS, Mohammadi M (2007) Molecular Insights into the Klotho-Dependent, Endocrine Mode of Action of FGF19 Subfamily Members. Mol Cell Biol 27:3417–3428PubMedGoogle Scholar
  21. 21.
    Goodman WG, Goldin J, Kuizon BD, Yoon C, Gales B, Sider D, Wang Y, Chung J, Emerick A, Greaser L, Elashoff RM, Salusky IB (2000) Coronary-artery calcification in young adults with end-stage renal disease who are undergoing dialysis. N Engl J Med 342:1478–1483PubMedGoogle Scholar
  22. 22.
    Gorbunova V, Bozzella MJ, Seluanov A (2008) Rodents for comparative aging studies: from mice to beavers. Age (Dordr) 30:111–119Google Scholar
  23. 23.
    Haap M, Heller E, Thamer C, Tschritter O, Stefan N, Fritsche A (2006) Association of serum phosphate levels with glucose tolerance, insulin sensitivity and insulin secretion in non-diabetic subjects. Eur J Clin Nutr 60:734–739PubMedGoogle Scholar
  24. 24.
    Heard DJ, Ruiz MM, Harr KE (2006) Comparison of serum and plasma for determination of blood biochemical values in Malaysian flying foxes (Pteropus vampyrus). J Zoo Wildl Med 37:245–248PubMedGoogle Scholar
  25. 25.
    Hesse M, Frohlich LF, Zeitz U, Lanske B, Erben RG (2007) Ablation of vitamin D signaling rescues bone, mineral, and glucose homeostasis in Fgf-23 deficient mice. Matrix Biol 26:75–84PubMedGoogle Scholar
  26. 26.
    Hoenderop JG, Nilius B, Bindels RJ (2005) Calcium absorption across epithelia. Physiol Rev 85:373–422PubMedGoogle Scholar
  27. 27.
    Holliday R (1995) Understanding of ageing. Cambridge University Press, CambridgeGoogle Scholar
  28. 28.
    Holzenberger M, Dupont J, Ducos B, Leneuve P, Geloen A, Even PC, Cervera P, Le Bouc Y (2003) IGF-1 receptor regulates lifespan and resistance to oxidative stress in mice. Nature 421:182–187PubMedGoogle Scholar
  29. 29.
    Imura A, Iwano A, Tohyama O, Tsuji Y, Nozaki K, Hashimoto N, Fujimori T, Nabeshima Y (2004) Secreted Klotho protein in sera and CSF: implication for post-translational cleavage in release of Klotho protein from cell membrane. FEBS Lett 565:143–147PubMedGoogle Scholar
  30. 30.
    Inagaki T, Choi M, Moschetta A, Peng L, Cummins CL, McDonald JG, Luo G, Jones SA, Goodwin B, Richardson JA, Gerard RD, Repa JJ, Mangelsdorf DJ, Kliewer SA (2005) Fibroblast growth factor 15 functions as an enterohepatic signal to regulate bile acid homeostasis. Cell Metab 2:217–225PubMedGoogle Scholar
  31. 31.
    Inagaki T, Dutchak P, Zhao G, Ding X, Gautron L, Parameswara V, Li Y, Goetz R, Mohammadi M, Esser V, Elmquist JK, Gerard RD, Burgess SC, Hammer RE, Mangelsdorf DJ, Kliewer SA (2007) Endocrine regulation of the fasting response by PPARalpha-mediated induction of fibroblast growth factor 21. Cell Metab 5:415–425PubMedGoogle Scholar
  32. 32.
    Inagaki T, Lin VY, Goetz R, Mohammadi M, Mangelsdorf DJ, Kliewer SA (2008) Inhibition of growth hormone signaling by the fasting-induced hormone FGF21. Cell Metab 8:77–83PubMedGoogle Scholar
  33. 33.
    Ishii M, Yamaguchi Y, Yamamoto H, Hanaoka Y, Ouchi Y (2008) Airspace enlargement with airway cell apoptosis in klotho mice: a model of aging lung. J Gerontol A Biol Sci Med Sci 63:1289–1298PubMedGoogle Scholar
  34. 34.
    Ito S, Fujimori T, Furuya A, Satoh J, Nabeshima Y, Nabeshima Y (2005) Impaired negative feedback suppression of bile acid synthesis in mice lacking betaKlotho. J Clin Invest 115:2202–2208PubMedGoogle Scholar
  35. 35.
    Ito S, Kinoshita S, Shiraishi N, Nakagawa S, Sekine S, Fujimori T, Nabeshima Y (2000) Molecular cloning and expression analyses of mouse betaklotho, which encodes a novel Klotho family protein. Mech Dev 98:115–119PubMedGoogle Scholar
  36. 36.
    Itoh N, Ornitz DM (2004) Evolution of the Fgf and Fgfr gene families. Trends Genet 20:563–569PubMedGoogle Scholar
  37. 37.
    Kamemori M, Ohyama Y, Kurabayashi M, Takahashi K, Nagai R, Furuya N (2002) Expression of Klotho protein in the inner ear. Hear Res 171:103–110PubMedGoogle Scholar
  38. 38.
    Kawaguchi H, Manabe N, Miyaura C, Chikuda H, Nakamura K, Kuro-o M (1999) Independent impairment of osteoblast and osteoclast differentiation in klotho mouse exhibiting low-turnover osteopenia. J Clin Invest 104:229–237PubMedGoogle Scholar
  39. 39.
    Kayo T, Allison DB, Weindruch R, Prolla TA (2001) Influences of aging and caloric restriction on the transcriptional profile of skeletal muscle from rhesus monkeys. Proc Natl Acad Sci U S A 98:5093–5098PubMedGoogle Scholar
  40. 40.
    Kenyon C (2005) The plasticity of aging: insights from long-lived mutants. Cell 120:449–460PubMedGoogle Scholar
  41. 41.
    Kenyon C, Chang J, Gensch E, Rudner A, Tabtiang R (1993) A C. elegans mutant that lives twice as long as wild type. Nature 366:461–464PubMedGoogle Scholar
  42. 42.
    Kirstetter P, Anderson K, Porse BT, Jacobsen SE, Nerlov C (2006) Activation of the canonical Wnt pathway leads to loss of hematopoietic stem cell repopulation and multilineage differentiation block. Nat Immunol 7:1048–1056PubMedGoogle Scholar
  43. 43.
    Koh N, Fujimori T, Nishiguchi S, Tamori A, Shiomi S, Nakatani T, Sugimura K, Kishimoto T, Kinoshita S, Kuroki T, Nabeshima Y (2001) Severely reduced production of klotho in human chronic renal failure kidney. Biochem Biophys Res Commun 280:1015–1020PubMedGoogle Scholar
  44. 44.
    Kuro-o M (2006) Klotho as a regulator of fibroblast growth factor signaling and phosphate/calcium metabolism. Curr Opin Nephrol Hypertens 15:437–441PubMedGoogle Scholar
  45. 45.
    Kuro-o M (2008) Endocrine FGFs and Klothos: emerging concepts. Trends Endocrinol Metab 19:239–245PubMedGoogle Scholar
  46. 46.
    Kuro-o M (2008) Klotho as a regulator of oxidative stress and senescence. Biol Chem 389:233–241PubMedGoogle Scholar
  47. 47.
    Kuro-o M, Hanaoka K, Hiroi Y, Noguchi T, Fujimori Y, Takewaki S, Hayasaka M, Katoh H, Miyagishi A, Nagai R, Nabeshima Y (1995) Salt-sensitive hypertension in transgenic mice overexpressing Na(+)-proton exchanger. Circ Res 76:148–153PubMedGoogle Scholar
  48. 48.
    Kuro-o M, Matsumura Y, Aizawa H, Kawaguchi H, Suga T, Utsugi T, Ohyama Y, Kurabayashi M, Kaname T, Kume E, Iwasaki H, Iida A, Shiraki-Iida T, Nishikawa S, Nagai R, Nabeshima Y (1997) Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature 390:45–51PubMedGoogle Scholar
  49. 49.
    Kurosu H, Choi M, Ogawa Y, Dickson AS, Goetz R, Eliseenkova AV, Mohammadi M, Rosenblatt KP, Kliewer SA, Kuro-o M (2007) Tissue-specific expression of betaKlotho and fibroblast growth factor (FGF) receptor isoforms determines metabolic activity of FGF19 and FGF21. J Biol Chem 282:26687–26695PubMedGoogle Scholar
  50. 50.
    Kurosu H, Kuro-o M (2008) The Klotho gene family and the endocrine fibroblast growth factors. Curr Opin Nephrol Hypertens 17:368–372PubMedGoogle Scholar
  51. 51.
    Kurosu H, Kuro-o M (2009) Endocrine fibroblast growth factors as regulators of metabolic homeostasis. Biofactors 35:52–60PubMedGoogle Scholar
  52. 52.
    Kurosu H, Kuro-o M (2009) The Klotho gene family as a regulator of endocrine fibroblast growth factors. Mol Cell Endocrinol 299:72–78PubMedGoogle Scholar
  53. 53.
    Kurosu H, Ogawa Y, Miyoshi M, Yamamoto M, Nandi A, Rosenblatt KP, Baum MG, Schiavi S, Hu MC, Moe OW, Kuro-o M (2006) Regulation of fibroblast growth factor-23 signaling by klotho. J Biol Chem 281:6120–6123PubMedGoogle Scholar
  54. 54.
    Kurosu H, Yamamoto M, Clark JD, Pastor JV, Nandi A, Gurnani P, McGuinness OP, Chikuda H, Yamaguchi M, Kawaguchi H, Shimomura I, Takayama Y, Herz J, Kahn CR, Rosenblatt KP, Kuro-o M (2005) Suppression of aging in mice by the hormone Klotho. Science 309:1829–1833PubMedGoogle Scholar
  55. 55.
    Lee CK, Klopp RG, Weindruch R, Prolla TA (1999) Gene expression profile of aging and its retardation by caloric restriction. Science 285:1390–1393PubMedGoogle Scholar
  56. 56.
    Liu H, Fergusson MM, Castilho RM, Liu J, Cao L, Chen J, Malide D, Rovira II, Schimel D, Kuo CJ, Gutkind JS, Hwang PM, Finkel T (2007) Augmented Wnt signaling in a mammalian model of accelerated aging. Science 317:803–806PubMedGoogle Scholar
  57. 57.
    Liu S, Quarles LD (2007) How fibroblast growth factor 23 works. J Am Soc Nephrol 18:1637–1647PubMedGoogle Scholar
  58. 58.
    Liu S, Tang W, Zhou J, Stubbs JR, Luo Q, Pi M, Quarles LD (2006) Fibroblast growth factor 23 is a counter-regulatory phosphaturic hormone for vitamin D. J Am Soc Nephrol 17:1305–1315PubMedGoogle Scholar
  59. 59.
    Matsumura Y, Aizawa H, Shiraki-Iida T, Nagai R, Kuro-o M, Nabeshima Y (1998) Identification of the human klotho gene and its two transcripts encoding membrane and secreted klotho protein. Biochem Biophys Res Commun 242:626–630PubMedGoogle Scholar
  60. 60.
    Meyer KB, Levey AS (1998) 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 9:S31–42PubMedGoogle Scholar
  61. 61.
    Mian IS (1998) Sequence, structural, functional, and phylogenetic analyses of three glycosidase families. Blood Cells Mol Dis 24:83–100PubMedGoogle Scholar
  62. 62.
    Min D, Panoskaltsis-Mortari A, Kuro-o M, Hollander GA, Blazar BR, Weinberg KI (2007) Sustained thymopoiesis and improvement in functional immunity induced by exogenous KGF administration in murine models of aging. Blood 109:2529–2537PubMedGoogle Scholar
  63. 63.
    Moreau B, Vie JC, Cotellon P, De Thoisy I, Motard A, Raccurt CP (2003) Hematologic and serum biochemistry values in two species of free-ranging porcupines (Coendou prehensilis, Coendou melanurus) in French Guiana. J Zoo Wildl Med 34:159–162PubMedGoogle Scholar
  64. 64.
    Morishita K, Shirai A, Kubota M, Katakura Y, Nabeshima Y, Takeshige K, Kamiya T (2001) The progression of aging in klotho mutant mice can be modified by dietary phosphorus and zinc. J Nutr 131:3182–3188PubMedGoogle Scholar
  65. 65.
    Morris JZ, Tissenbaum HA, Ruvkun G (1996) A phosphatidylinositol-3-OH kinase family member regulating longevity and diapause in Caenorhabditis elegans. Nature 382:536–539PubMedGoogle Scholar
  66. 66.
    Munson L, Koehler JW, Wilkinson JE, Miller RE (1998) Vesicular and ulcerative dermatopathy resembling superficial necrolytic dermatitis in captive black rhinoceroses (Diceros bicornis). Vet Pathol 35:31–42PubMedCrossRefGoogle Scholar
  67. 67.
    Nagai T, Yamada K, Kim HC, Kim YS, Noda Y, Imura A, Nabeshima Y, Nabeshima T (2003) Cognition impairment in the genetic model of aging klotho gene mutant mice: a role of oxidative stress. Faseb J 17:50–52PubMedGoogle Scholar
  68. 68.
    Ogawa Y, Kurosu H, Yamamoto M, Nandi A, Rosenblatt KP, Goetz R, Eliseenkova AV, Mohammadi M, Kuro-o M (2007) betaKlotho is required for metabolic activity of fibroblast growth factor 21. Proc Natl Acad Sci U S A 104:7432–7437PubMedGoogle Scholar
  69. 69.
    Ohnishi M, Nakatani T, Lanske B, Razzaque MS (2009) Reversal of mineral ion homeostasis and soft-tissue calcification of klotho knockout mice by deletion of vitamin D 1alpha-hydroxylase. Kidney Int 75:1166–1172PubMedGoogle Scholar
  70. 70.
    Papa S, Skulachev VP (1997) Reactive oxygen species, mitochondria, apoptosis and aging. Mol Cell Biochem 174:305–319PubMedGoogle Scholar
  71. 71.
    Passeri G, Vescovini R, Sansoni P, Galli C, Franceschi C, Passeri M (2008) Calcium metabolism and vitamin D in the extreme longevity. Exp Gerontol 43:79–87PubMedGoogle Scholar
  72. 72.
    Paula FJ, Plens AE, Foss MC (1998) Effects of hypophosphatemia on glucose tolerance and insulin secretion. Horm Metab Res 30:281–284PubMedGoogle Scholar
  73. 73.
    Perwad F, Azam N, Zhang MY, Yamashita T, Tenenhouse HS, Portale AA (2005) Dietary and serum phosphorus regulate fibroblast growth factor 23 expression and 1, 25-dihydroxyvitamin D metabolism in mice. Endocrinology 146:5358–5364PubMedGoogle Scholar
  74. 74.
    Pugh DG (2002) Sheep & goat medicine. Elsevier, AmsterdamGoogle Scholar
  75. 75.
    Quarles LD (2008) Endocrine functions of bone in mineral metabolism regulation. J Clin Invest 118:3820–3828PubMedGoogle Scholar
  76. 76.
    Ramsay EC (2003) Ursidae and Hyanidae. In: Fowler ME, Miller RE (eds) Zoo and wild animal medicine. Saunders, St Louis, pp 523–538Google Scholar
  77. 77.
    Razzaque MS, Sitara D, Taguchi T, St-Arnaud R, Lanske B (2006) Premature aging-like phenotype in fibroblast growth factor 23 null mice is a vitamin D-mediated process. FASEB J 20:720–722PubMedGoogle Scholar
  78. 78.
    Saeed A, Khan IA, Hussein MM (2009) Change in biochemical profile of pregnant camels (Camelus dromedarius) at term. Comp Clin Pathol 18:139–143Google Scholar
  79. 79.
    Saito H, Maeda A, Ohtomo S, Hirata M, Kusano K, Kato S, Ogata E, Segawa H, Miyamoto K, Fukushima N (2005) Circulating FGF-23 is regulated by 1alpha, 25-dihydroxyvitamin D3 and phosphorus in vivo. J Biol Chem 280:2543–2549PubMedGoogle Scholar
  80. 80.
    Sarnak MJ, Levey AS, Schoolwerth AC, Coresh J, Culleton B, Hamm LL, McCullough PA, Kasiske BL, Kelepouris E, Klag MJ, Parfrey P, Pfeffer M, Raij L, Spinosa DJ, Wilson PW (2003) 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 108:2154–2169PubMedGoogle Scholar
  81. 81.
    Sato A, Hirai T, Imura A, Kita N, Iwano A, Muro S, Nabeshima Y, Suki B, Mishima M (2007) Morphological mechanism of the development of pulmonary emphysema in klotho mice. Proc Natl Acad Sci U S A 104:2361–2365PubMedGoogle Scholar
  82. 82.
    Scheller M, Huelsken J, Rosenbauer F, Taketo MM, Birchmeier W, Tenen DG, Leutz A (2006) Hematopoietic stem cell and multilineage defects generated by constitutive beta-catenin activation. Nat Immunol 7:1037–1047PubMedGoogle Scholar
  83. 83.
    Segawa H, Kawakami E, Kaneko I, Kuwahata M, Ito M, Kusano K, Saito H, Fukushima N, Miyamoto K (2003) Effect of hydrolysis-resistant FGF23–R179Q on dietary phosphate regulation of the renal type-II Na/Pi transporter. Pflugers Arch 446:585–592PubMedGoogle Scholar
  84. 84.
    Segawa H, Yamanaka S, Ohno Y, Onitsuka A, Shiozawa K, Aranami F, Furutani J, Tomoe Y, Ito M, Kuwahata M, Imura A, Nabeshima Y, Miyamoto K (2007) Correlation between hyperphosphatemia and type II Na-Pi cotransporter activity in klotho mice. Am J Physiol Renal Physiol 292:F769–779PubMedGoogle Scholar
  85. 85.
    Selman C, Lingard S, Choudhury AI, Batterham RL, Claret M, Clements M, Ramadani F, Okkenhaug K, Schuster E, Blanc E, Piper MD, Al-Qassab H, Speakman JR, Carmignac D, Robinson IC, Thornton JM, Gems D, Partridge L, Withers DJ (2008) Evidence for lifespan extension and delayed age-related biomarkers in insulin receptor substrate 1 null mice. FASEB J 22:807–818PubMedGoogle Scholar
  86. 86.
    Shimada T, Hasegawa H, Yamazaki Y, Muto T, Hino R, Takeuchi Y, Fujita T, Nakahara K, Fukumoto S, Yamashita T (2004) FGF-23 is a potent regulator of vitamin D metabolism and phosphate homeostasis. J Bone Miner Res 19:429–435 Epub 2003 Dec 2029PubMedGoogle Scholar
  87. 87.
    Shimada T, Kakitani M, Yamazaki Y, Hasegawa H, Takeuchi Y, Fujita T, Fukumoto S, Tomizuka K, Yamashita T (2004) Targeted ablation of Fgf23 demonstrates an essential physiological role of FGF23 in phosphate and vitamin D metabolism. J Clin Invest 113:561–568PubMedGoogle Scholar
  88. 88.
    Shimada T, Muto T, Urakawa I, Yoneya T, Yamazaki Y, Okawa K, Takeuchi Y, Fujita T, Fukumoto S, Yamashita T (2002) Mutant FGF-23 responsible for autosomal dominant hypophosphatemic rickets is resistant to proteolytic cleavage and causes hypophosphatemia in vivo. Endocrinology 143:3179–3182PubMedGoogle Scholar
  89. 89.
    Shimada T, Urakawa I, Yamazaki Y, Hasegawa H, Hino R, Yoneya T, Takeuchi Y, Fujita T, Fukumoto S, Yamashita T (2004) FGF-23 transgenic mice demonstrate hypophosphatemic rickets with reduced expression of sodium phosphate cotransporter type IIa. Biochem Biophys Res Commun 314:409–414PubMedGoogle Scholar
  90. 90.
    Shiraki-Iida T, Aizawa H, Matsumura Y, Sekine S, Iida A, Anazawa H, Nagai R, Kuro-o M, Nabeshima Y (1998) Structure of the mouse klotho gene and its two transcripts encoding membrane and secreted protein. FEBS Lett 424:6–10PubMedGoogle Scholar
  91. 91.
    Stubbs JR, Liu S, Tang W, Zhou J, Wang Y, Yao X, Quarles LD (2007) Role of hyperphosphatemia and 1, 25-dihydroxyvitamin D in vascular calcification and mortality in fibroblastic growth factor 23 null mice. J Am Soc Nephrol 18:2116–2124PubMedGoogle Scholar
  92. 92.
    Suga T, Kurabayashi M, Sando Y, Ohyama Y, Maeno T, Maeno Y, Aizawa H, Matsumura Y, Kuwaki T, Kuro-o M, Nabeshima Y, Nagai R (2000) Disruption of the klotho gene causes pulmonary emphysema in mice. Defect in maintenance of pulmonary integrity during postnatal life. Am J Respir Cell Mol Biol 22:26–33PubMedGoogle Scholar
  93. 93.
    Suh Y, Atzmon G, Cho MO, Hwang D, Liu B, Leahy DJ, Barzilai N, Cohen P (2008) Functionally significant insulin-like growth factor I receptor mutations in centenarians. Proc Natl Acad Sci U S A 105:3438–3442PubMedGoogle Scholar
  94. 94.
    Taguchi A, Wartschow LM, White MF (2007) Brain IRS2 signaling coordinates life span and nutrient homeostasis. Science 317:369–372PubMedGoogle Scholar
  95. 95.
    Takeda E, Yamamoto H, Nashiki K, Sato T, Arai H, Taketani Y (2004) Inorganic phosphate homeostasis and the role of dietary phosphorus. J Cell Mol Med 8:191–200PubMedGoogle Scholar
  96. 96.
    Tatar M, Kopelman A, Epstein D, Tu M-P, Yin C-M, Garofalo RS (2001) A mutant Drosophila insulin receptor homolog that extends life-span and impairs neuroendocrine function. Science 292:107–110PubMedGoogle Scholar
  97. 97.
    Thrall MA, Baker DC, Campbell TW, Lassen ED, DeNicola DB, Rebar A, Fettman MJ, Weiser G (2004) Veterinary hematology and clinical chemistry: text and clinical case presentations set. Wiley-Blackwell, HobokenGoogle Scholar
  98. 98.
    Tohyama O, Imura A, Iwano A, Freund JN, Henrissat B, Fujimori T, Nabeshima Y (2004) Klotho is a novel beta-glucuronidase capable of hydrolyzing steroid beta-glucuronides. J Biol Chem 279:9777–9784PubMedGoogle Scholar
  99. 99.
    Tonelli M, Sacks F, Pfeffer M, Gao Z, Curhan G (2005) Relation between serum phosphate level and cardiovascular event rate in people with coronary disease. Circulation 112:2627–2633PubMedGoogle Scholar
  100. 100.
    Tsujikawa H, Kurotaki Y, Fujimori T, Fukuda K, Nabeshima Y (2003) Klotho, a gene related to a syndrome resembling human premature aging, functions in a negative regulatory circuit of vitamin D endocrine system. Mol Endocrinol 17:2393–2403PubMedGoogle Scholar
  101. 101.
    Tsuruoka S, Nishiki K, Ioka T, Ando H, Saito Y, Kurabayashi M, Nagai R, Fujimura A (2006) Defect in parathyroid-hormone-induced luminal calcium absorption in connecting tubules of Klotho mice. Nephrol Dial Transplant 21:2762–2767PubMedGoogle Scholar
  102. 102.
    Tuntasuvan D, Theeraphan A, Phoengpong N, Jitnupong W, Lungka G (2002) Comparison of serum chemistry values and serum mineral values between captive and free-ranging elephants in Thailand. In: Baker I, Kashio M (eds) Giants on Our Hands: Proceedings of the International Workshop on the Domesticated Asian Elephant. RAP, Bangkok, p 278Google Scholar
  103. 103.
    Urakawa I, Yamazaki Y, Shimada T, Iijima K, Hasegawa H, Okawa K, Fujita T, Fukumoto S, Yamashita T (2006) Klotho converts canonical FGF receptor into a specific receptor for FGF23. Nature 444:770–774PubMedGoogle Scholar
  104. 104.
    Utsugi T, Ohno T, Ohyama Y, Uchiyama T, Saito Y, Matsumura Y, Aizawa H, Itoh H, Kurabayashi M, Kawazu S, Tomono S, Oka Y, Suga T, Kuro-o M, Nabeshima Y, Nagai R (2000) Decreased insulin production and increased insulin sensitivity in the klotho mutant mouse, a novel animal model for human aging. Metabolism 49:1118–1123PubMedGoogle Scholar
  105. 105.
    Virkki LV, Biber J, Murer H, Forster IC (2007) Phosphate transporters: a tale of two solute carrier families. Am J Physiol Renal Physiol 293:F643–654PubMedGoogle Scholar
  106. 106.
    Wetter TJ, Gazdag AC, Dean DJ, Cartee GD (1999) Effect of calorie restriction on in vivo glucose metabolism by individual tissues in rats. Am J Physiol 276:E728–738PubMedGoogle Scholar
  107. 107.
    White KE, Evans WE, O'Rlordan JLH, Speer MC, Econs MJ, Lorenz-Deplereux B, Grabowski M, Meitinger T, Storm TM (2000) Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF23. Nat Genet 26:345–348Google Scholar
  108. 108.
    Wolf I, Levanon-Cohen S, Bose S, Ligumsky H, Sredni B, Kanety H, Kuro-o M, Karlan B, Kaufman B, Koeffler HP, Rubinek T (2008) Klotho: a tumor suppressor and a modulator of the IGF-1 and FGF pathways in human breast cancer. Oncogene 27:7094–7105PubMedGoogle Scholar
  109. 109.
    Xie W, Li Y, Mechin MC, Van De Werve G (1999) Up-regulation of liver glucose-6-phosphatase in rats fed with a P(i)-deficient diet. Biochem J 343(Pt 2):393–396PubMedGoogle Scholar
  110. 110.
    Xie W, Tran TL, Finegood DT, van de Werve G (2000) Dietary P(i) deprivation in rats affects liver cAMP, glycogen, key steps of gluconeogenesis and glucose production. Biochem J 352(Pt 1):227–232PubMedGoogle Scholar
  111. 111.
    Yahav S, Buffenstein R, Pettifor JM (1993) Calcium and inorganic phosphorus metabolism in naked mole rats Heterocephalus glaber is only indirectly affected by cholecalciferol. Gen Comp Endocrinol 89:161–166PubMedGoogle Scholar
  112. 112.
    Yu X, Ibrahimi OA, Goetz R, Zhang F, Davis SI, Garringer HJ, Linhardt RJ, Ornitz DM, Mohammadi M, White KE (2005) Analysis of the biochemical mechanisms for the endocrine actions of fibroblast growth factor-23. Endocrinology 146:4647–4656PubMedGoogle Scholar
  113. 113.
    Yu X, Sabbagh Y, Davis SI, Demay MB, White KE (2005) Genetic dissection of phosphate- and vitamin D-mediated regulation of circulating Fgf23 concentrations. Bone 36:971–977PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  1. 1.Department of PathologyThe University of Texas Southwestern Medical Center at DallasDallasUSA

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