Klotho (biology)

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Klotho is an enzyme that in humans is encoded by the KL gene.[1]

This gene encodes a type-I membrane protein that is related to β-glucuronidases. Reduced production of this protein has been observed in patients with chronic renal failure (CRF), and this may be one of the factors underlying the degenerative processes (e.g., arteriosclerosis, osteoporosis, and skin atrophy) seen in CRF. Also, mutations within this protein have been associated with ageing, bone loss and alcohol consumption.[2][3] Transgenic mice that overexpress Klotho live longer than wild-type mice.[4]


Klotho is a transmembrane protein that, in addition to other effects, provides some control over the sensitivity of the organism to insulin and appears to be involved in ageing. Its discovery was documented in 1997 by Kuro-o et al.[5] The name of the gene comes from Klotho or Clotho, one of the Moirai, or Fates, in Greek mythology.

The Klotho protein is a novel β-glucuronidase (EC number capable of hydrolyzing steroid β-glucuronides. Genetic variants in KLOTHO have been associated with human aging,[6][7] and Klotho protein has been shown to be a circulating factor detectable in serum that declines with age.[8]

The binding of certain fibroblast growth factors (FGF's) viz., FGF19, FGF20, and FGF23, to their fibroblast growth factor receptors, is promoted via their interactions as co-receptors with β-Klotho.[9][10]

Klotho-deficient mice manifest a syndrome resembling accelerated human aging and display extensive and accelerated arteriosclerosis. Additionally, they exhibit impaired endothelium dependent vasodilation and impaired angiogenesis, suggesting that Klotho protein may protect the cardiovascular system through endothelium-derived NO production.

Although the vast majority of research has been based on lack of Klotho, it was demonstrated that an overexpression of Klotho in mice might extend their average life span between 19% and 31% compared to normal mice.[4] In addition, variations in the Klotho gene (SNP Rs9536314) are associated with both life extension and increased cognition in human populations.[11]

The mechanism of action of klotho is not fully understood, but it changes cellular calcium homeostasis, by both increasing the expression and activity of TRPV5 and decreasing that of TRPC6.[12] Additionally, klotho increases membrane expression of the inward rectifier channel ROMK.[12] Klotho-deficient mice show increased production of vitamin D, and altered mineral-ion homeostasis is suggested to be a cause of premature aging‑like phenotypes, because the lowering of vitamin D activity by dietary restriction reverses the premature aging‑like phenotypes and prolongs survival in these mutants. These results suggest that aging‑like phenotypes were due to klotho-associated vitamin D metabolic abnormalities (hypervitaminosis).[13][14][15][16]


  1. Matsumura Y, Aizawa H, Shiraki-Iida T, Nagai R, Kuro-o M, Nabeshima Y (Jan 1998). "Identification of the human klotho gene and its two transcripts encoding membrane and secreted klotho protein". Biochemical and Biophysical Research Communications. 242 (3): 626–30. doi:10.1006/bbrc.1997.8019. PMID 9464267.
  2. "Entrez Gene: klotho".
  3. Schumann G, Liu C, O'Reilly P, Gao H, Song P, Xu B, et al. (2016). "KLB is associated with alcohol drinking, and its gene product β-Klotho is necessary for FGF21 regulation of alcohol preference". Proceedings of the National Academy of Sciences of the United States of America. 113 (50): 14372–14377. doi:10.1073/pnas.1611243113. PMC 5167198. PMID 27911795.
  4. 4.0 4.1 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 (Sep 2005). "Suppression of aging in mice by the hormone Klotho". Science. 309 (5742): 1829–33. Bibcode:2005Sci...309.1829K. doi:10.1126/science.1112766. PMC 2536606. PMID 16123266.
  5. 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 YI (Nov 1997). "Mutation of the mouse klotho gene leads to a syndrome resembling ageing". Nature. 390 (6655): 45–51. Bibcode:1997Natur.390...45K. doi:10.1038/36285. PMID 9363890.
  6. Arking DE, Krebsova A, Macek M, Macek M, Arking A, Mian IS, Fried L, Hamosh A, Dey S, McIntosh I, Dietz HC (Jan 2002). "Association of human aging with a functional variant of klotho". Proceedings of the National Academy of Sciences of the United States of America. 99 (2): 856–61. Bibcode:2002PNAS...99..856A. doi:10.1073/pnas.022484299. PMC 117395. PMID 11792841.
  7. Rodriguez T (2015). "Identifying significant biological markers in Klotho gene variants across wide ranging taxonomy". Journal of Molecular Biology Research. 5 (1): 11. doi:10.5539/jmbr.v5n1p11.
  8. Xiao NM, Zhang YM, Zheng Q, Gu J (May 2004). "Klotho is a serum factor related to human aging". Chinese Medical Journal. 117 (5): 742–7. PMID 15161545.[permanent dead link]
  9. Helsten T, Schwaederle M, Kurzrock R (2015). "Fibroblast growth factor receptor signaling in hereditary and neoplastic disease: biologic and clinical implications". Cancer Metastasis Reviews. 34 (3): 479–96. doi:10.1007/s10555-015-9579-8. PMC 4573649. PMID 26224133.
  10. Talukdar S, Owen BM, Song P, Hernandez G, Zhang Y, Zhou Y, Scott WT, Paratala B, Turner T, Smith A, Bernardo B, Müller CP, Tang H, Mangelsdorf DJ, Goodwin B, Kliewer SA (February 2016). "FGF21 Regulates Sweet and Alcohol Preference". Cell Metabolism. 23 (2): 344–9. doi:10.1016/j.cmet.2015.12.008. PMC 4749404. PMID 26724861.
  11. Dena B. Dubal et al., Life Extension Factor Klotho Enhances Cognition, Cell Reports, 2014, DOI: 10.1016/j.celrep.2014.03.076 (open access)
  12. 12.0 12.1 Huang CL (May 2010). "Regulation of ion channels by secreted Klotho: mechanisms and implications". Kidney International. 77 (10): 855–60. doi:10.1038/ki.2010.73. PMID 20375979.
  13. Kuro-o M (Oct 2009). "Klotho and aging". Biochimica et Biophysica Acta. 1790 (10): 1049–58. doi:10.1016/j.bbagen.2009.02.005. PMC 2743784. PMID 19230844.
  14. Medici D, Razzaque MS, Deluca S, Rector TL, Hou B, Kang K, Goetz R, Mohammadi M, Kuro-O M, Olsen BR, Lanske B (Aug 2008). "FGF-23-Klotho signaling stimulates proliferation and prevents vitamin D-induced apoptosis". The Journal of Cell Biology. 182 (3): 459–65. doi:10.1083/jcb.200803024. PMC 2500132. PMID 18678710.
  15. Tsujikawa H, Kurotaki Y, Fujimori T, Fukuda K, Nabeshima Y (Dec 2003). "Klotho, a gene related to a syndrome resembling human premature aging, functions in a negative regulatory circuit of vitamin D endocrine system". Molecular Endocrinology. 17 (12): 2393–403. doi:10.1210/me.2003-0048. PMID 14528024.
  16. Imura A, Tsuji Y, Murata M, Maeda R, Kubota K, Iwano A, Obuse C, Togashi K, Tominaga M, Kita N, Tomiyama K, Iijima J, Nabeshima Y, Fujioka M, Asato R, Tanaka S, Kojima K, Ito J, Nozaki K, Hashimoto N, Ito T, Nishio T, Uchiyama T, Fujimori T, Nabeshima Y (Jun 2007). "alpha-Klotho as a regulator of calcium homeostasis". Science. 316 (5831): 1615–8. Bibcode:2007Sci...316.1615I. doi:10.1126/science.1135901. PMID 17569864.

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This article incorporates text from the United States National Library of Medicine, which is in the public domain.