Klotho (biology)
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 and bone loss.[2] Transgenic mice that overexpress Klotho live longer than wild-type mice.[3]
Function
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 aging. Its discovery was documented in 1997 by Kuro-o et al.[4] The name of the gene comes from Klotho or Clotho, one of the Moirae, or Fates, in Greek mythology.
The Klotho protein is a novel β-glucuronidase (EC number 3.2.1.31) capable of hydrolyzing steroid β-glucuronides. Genetic variants in KLOTHO have been associated with human aging,[5] and Klotho protein has been shown to be a circulating factor detectable in serum that declines with age.[6]
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.[7] However, the actual use of overexpressing Klotho for extending life-span without side-effects is still a matter of speculation and remains to be justified by further experimentation.
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).[8][9][10][11]
References
- ^ Matsumura Y, Aizawa H, Shiraki-Iida T, Nagai R, Kuro-o M, Nabeshima Y (January 1998). "Identification of the human klotho gene and its two transcripts encoding membrane and secreted klotho protein". Biochem. Biophys. Res. Commun. 242 (3): 626–30. doi:10.1006/bbrc.1997.8019. PMID 9464267.
- ^ "Entrez Gene: klotho". http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=9365.
- ^ Kurosu, H.; Yamamoto, M.; Clark, J. D.; Pastor, J. V.; Nandi, A.; Gurnani, P.; McGuinness, O. P.; Chikuda, H. et al. (2005). "Suppression of Aging in Mice by the Hormone Klotho". Science 309 (5742): 1829–1833. Bibcode 2005Sci...309.1829K. doi:10.1126/science.1112766. PMC 2536606. PMID 16123266. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2536606. edit
- ^ 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 (November 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.
- ^ Arking DE, Krebsova A, Macek M Sr, Macek M Jr, Arking A, Mian IS, Fried L, Hamosh A, Dey S, McIntosh I, Dietz HC (January 2002). "Association of human aging with a functional variant of klotho". Proc. Natl. Acad. Sci. U.S.A. 99 (2): 856–61. Bibcode 2002PNAS...99..856A. doi:10.1073/pnas.022484299. PMC 117395. PMID 11792841. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=117395.
- ^ Xiao NM, Zhang YM, Zheng Q, Gu J (May 2004). "Klotho is a serum factor related to human aging". Chin. Med. J. 117 (5): 742–7. PMID 15161545. http://www.cmj.org/Periodical/LinkIn.asp?journal=Chinese%20Medical%20Journal&linkintype=pubmed&year=2004&vol=117&issue=5&beginpage=742.
- ^ 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 (September 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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2536606.
- ^ Kuro-O, M. (2009). "Klotho and aging". Biochimica et biophysica acta 1790 (10): 1049–1058. doi:10.1016/j.bbagen.2009.02.005. PMC 2743784. PMID 19230844. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2743784. edit
- ^ Medici, D.; Razzaque, M. S.; Deluca, S.; Rector, T. L.; Hou, B.; Kang, K.; Goetz, R.; Mohammadi, M. et al. (2008). "FGF-23-Klotho signaling stimulates proliferation and prevents vitamin D-induced apoptosis". The Journal of Cell Biology 182: 459. doi:10.1083/jcb.200803024. PMID 18678710. edit
- ^ Tsujikawa H, Kurotaki Y, Fujimori T, Fukuda K, Nabeshima Y (December 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 (12): 2393–403. doi:10.1210/me.2003-0048. PMID 14528024.
- ^ 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 (June 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.
Further reading
- Shimoyama Y, Taki K, Mitsuda Y, et al. (2009). "KLOTHO gene polymorphisms G-395A and C1818T are associated with low-density lipoprotein cholesterol and uric acid in Japanese hemodialysis patients.". Am. J. Nephrol. 30 (4): 383–8. doi:10.1159/000235686. PMID 19690404.
- Choi BH, Kim CG, Lim Y, et al. (2010). "Transcriptional activation of the human Klotho gene by epidermal growth factor in HEK293 cells; role of Egr-1.". Gene 450 (1-2): 121–7. doi:10.1016/j.gene.2009.11.004. PMID 19913601.
- Fukumoto S (2009). "[Chronic kidney disease (CKD) and bone. Regulation of calcium and phosphate metabolism by FGF23/Klotho]". Clin Calcium 19 (4): 523–8. PMID 19329831.
- Nabeshima Y (2000). "Challenge of overcoming aging-related disorders.". J. Dermatol. Sci. 24 Suppl 1: S15–21. doi:10.1016/S0923-1811(00)00136-5. PMID 11137391.
- Razzaque MS (2009). "FGF23-mediated regulation of systemic phosphate homeostasis: is Klotho an essential player?". Am. J. Physiol. Renal Physiol. 296 (3): F470–6. doi:10.1152/ajprenal.90538.2008. PMC 2660189. PMID 19019915. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2660189.
- Menon R, Pearce B, Velez DR, et al. (2009). "Racial disparity in pathophysiologic pathways of preterm birth based on genetic variants.". Reprod. Biol. Endocrinol. 7: 62. doi:10.1186/1477-7827-7-62. PMC 2714850. PMID 19527514. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2714850.
- Prié D, Ureña Torres P, Friedlander G (2009). "[Fibroblast Growth Factor 23-Klotho: a new axis of phosphate balance control]". Med Sci (Paris) 25 (5): 489–95. doi:10.1051/medsci/2009255489. PMID 19480830.
- Torres PU, Prié D, Beck L, et al. (2009). "Klotho gene, phosphocalcic metabolism, and survival in dialysis.". J Ren Nutr 19 (1): 50–6. doi:10.1053/j.jrn.2008.10.018. PMID 19121771.
- Halaschek-Wiener J, Amirabbasi-Beik M, Monfared N, et al. (2009). Mary Bridger, Joanna. ed. "Genetic variation in healthy oldest-old.". PLoS ONE 4 (8): e6641. Bibcode 2009PLoSO...4.6641H. doi:10.1371/journal.pone.0006641. PMC 2722017. PMID 19680556. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2722017.
- Shimoyama Y, Nishio K, Hamajima N, Niwa T (2009). "KLOTHO gene polymorphisms G-395A and C1818T are associated with lipid and glucose metabolism, bone mineral density and systolic blood pressure in Japanese healthy subjects.". Clin. Chim. Acta 406 (1-2): 134–8. doi:10.1016/j.cca.2009.06.011. PMID 19539617.
- Wang HL, Xu Q, Wang Z, et al. (2010). "A potential regulatory single nucleotide polymorphism in the promoter of the Klotho gene may be associated with essential hypertension in the Chinese Han population.". Clin. Chim. Acta 411 (5-6): 386–90. doi:10.1016/j.cca.2009.12.004. PMID 20005218.
- Yerges LM, Klei L, Cauley JA, et al. (2009). "High-density association study of 383 candidate genes for volumetric BMD at the femoral neck and lumbar spine among older men.". J. Bone Miner. Res. 24 (12): 2039–49. doi:10.1359/jbmr.090524. PMC 2791518. PMID 19453261. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2791518.
- Torres PU, Prié D, Molina-Blétry V, et al. (2007). "Klotho: an antiaging protein involved in mineral and vitamin D metabolism.". Kidney Int. 71 (8): 730–7. doi:10.1038/sj.ki.5002163. PMID 17332731.
- Kurosu H, Kuro-o M (2008). "The Klotho gene family and the endocrine fibroblast growth factors.". Curr. Opin. Nephrol. Hypertens. 17 (4): 368–72. doi:10.1097/MNH.0b013e3282ffd994. PMID 18660672.
- Kuro-o M (2009). "Klotho and aging.". Biochim. Biophys. Acta 1790 (10): 1049–58. doi:10.1016/j.bbagen.2009.02.005. PMC 2743784. PMID 19230844. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2743784.
- Wolf I, Laitman Y, Rubinek T, et al. (2010). "Functional variant of KLOTHO: a breast cancer risk modifier among BRCA1 mutation carriers of Ashkenazi origin.". Oncogene 29 (1): 26–33. doi:10.1038/onc.2009.301. PMID 19802015.
- Invidia L, Salvioli S, Altilia S, et al. (2010). "The frequency of Klotho KL-VS polymorphism in a large Italian population, from young subjects to centenarians, suggests the presence of specific time windows for its effect.". Biogerontology 11 (1): 67–73. doi:10.1007/s10522-009-9229-z. PMID 19421891.
- Nabeshima Y (2008). "[Discovery of alpha-Klotho and FGF23 unveiled new insight into calcium and phosphate homeostasis]". Clin Calcium 18 (7): 923–34. PMID 18591743.
- Chen SN, Cilingiroglu M, Todd J, et al. (2009). "Candidate genetic analysis of plasma high-density lipoprotein-cholesterol and severity of coronary atherosclerosis.". BMC Med. Genet. 10: 111. doi:10.1186/1471-2350-10-111. PMC 2775733. PMID 19878569. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2775733.
- Zhang R, Zheng F (2008). "PPAR-gamma and aging: one link through klotho?". Kidney Int. 74 (6): 702–4. doi:10.1038/ki.2008.382. PMID 18756295.
External links
This article incorporates text from the United States National Library of Medicine, which is in the public domain.