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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 3.2.1.31) capable of hydrolyzing steroidβ-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]
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]
References
↑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. PMID9464267.
↑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. PMID9363890.
↑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. PMID14528024.
↑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. PMID17569864.
Further reading
Shimoyama Y, Taki K, Mitsuda Y, Tsuruta Y, Hamajima N, Niwa T (2009). "KLOTHO gene polymorphisms G-395A and C1818T are associated with low-density lipoprotein cholesterol and uric acid in Japanese hemodialysis patients". American Journal of Nephrology. 30 (4): 383–8. doi:10.1159/000235686. PMID19690404.
Choi BH, Kim CG, Lim Y, Lee YH, Shin SY (Jan 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. PMID19913601.
Fukumoto S (Apr 2009). "[Chronic kidney disease (CKD) and bone. Regulation of calcium and phosphate metabolism by FGF23/Klotho]". Clinical Calcium. 19 (4): 523–8. PMID19329831.
Nabeshima Y (Dec 2000). "Challenge of overcoming aging-related disorders". Journal of Dermatological Science. 24 Suppl 1: S15–21. doi:10.1016/S0923-1811(00)00136-5. PMID11137391.
Shimoyama Y, Nishio K, Hamajima N, Niwa T (Aug 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". Clinica Chimica Acta; International Journal of Clinical Chemistry. 406 (1–2): 134–8. doi:10.1016/j.cca.2009.06.011. PMID19539617.
Wang HL, Xu Q, Wang Z, Zhang YH, Si LY, Li XJ, Yang QH, Xiao H (Mar 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". Clinica Chimica Acta; International Journal of Clinical Chemistry. 411 (5–6): 386–90. doi:10.1016/j.cca.2009.12.004. PMID20005218.
Torres PU, Prié D, Molina-Blétry V, Beck L, Silve C, Friedlander G (Apr 2007). "Klotho: an antiaging protein involved in mineral and vitamin D metabolism". Kidney International. 71 (8): 730–7. doi:10.1038/sj.ki.5002163. PMID17332731.
Kurosu H, Kuro-o M (Jul 2008). "The Klotho gene family and the endocrine fibroblast growth factors". Current Opinion in Nephrology and Hypertension. 17 (4): 368–72. doi:10.1097/MNH.0b013e3282ffd994. PMID18660672.
Wolf I, Laitman Y, Rubinek T, Abramovitz L, Novikov I, Beeri R, Kuro-O M, Koeffler HP, Catane R, Freedman LS, Levy-Lahad E, Karlan BY, Friedman E, Kaufman B (Jan 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. PMID19802015.
Invidia L, Salvioli S, Altilia S, Pierini M, Panourgia MP, Monti D, De Rango F, Passarino G, Franceschi C (Feb 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. PMID19421891.
Nabeshima Y (Jul 2008). "[Discovery of alpha-Klotho and FGF23 unveiled new insight into calcium and phosphate homeostasis]". Clinical Calcium. 18 (7): 923–34. PMID18591743.
Zhang R, Zheng F (Sep 2008). "PPAR-gamma and aging: one link through klotho?". Kidney International. 74 (6): 702–4. doi:10.1038/ki.2008.382. PMID18756295.