Klotho (biology)
Klotho is an enzyme that in humans is encoded by the KL gene.[5] There are three subfamilies of klotho: α-klotho, β-klotho, and γ-klotho.[6] α-klotho activates FGF23, and β-klotho activates FGF19 and FGF21.[7] When the subfamily is not specified, the word "klotho" generally means the α-klotho subfamily.[8]
Klotho can exist in a membrane-bound form or a (hormonal) soluble, circulating form.[9] Proteases can convert the membrane-bound form into the circulating form.[10]
The KL 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 kidney failure (CKF), and this may be one of the factors underlying the degenerative processes (e.g., arteriosclerosis, osteoporosis, and skin atrophy) seen in CKF. Also, mutations within this protein have been associated with ageing, bone loss and alcohol consumption.[11][12] Transgenic mice that overexpress Klotho live longer than wild-type mice.[13]
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 ageing. Its discovery was documented in 1997 by Makoto Kuro-o et al.[14] 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 steroid β-glucuronides. Genetic variants in KLOTHO have been associated with human aging,[15][16] and Klotho protein has been shown to be a circulating factor detectable in serum that declines with age.[17]
The binding of certain fibroblast growth factors (FGF's, viz., FGF19 and FGF21) to their fibroblast growth factor receptors, is promoted via their interactions as co-receptors with β-Klotho.[18][19]
α-klotho changes cellular calcium homeostasis, by both increasing the expression and activity of TRPV5 (decreasing phosphate reabsorption in the kidney) and decreasing that of TRPC6 (decreasing phosphate absorption from the intestine).[20] α-klotho increases kidney calcium reabsorption by stabilizing TPRV5.[21]
Clinical significance
α-klotho can suppress oxidative stress and inflammation, thereby reducing endothelial dysfunction and atherosclerosis.[8] Blood plasma α-klotho is increased by aerobic exercise, thereby reducing endothelial dysfunction.[22]
β-klotho activation of FGF21 protein has a protective effect on heart muscle cells.[23] Obesity is characterized by FGF21 resistance, believed to be caused by the inhibition of β-klotho by the inflammatory cell signalling protein (cytokine) tumor necrosis factor alpha.[23]
Klotho is required for oligodendrocyte maturation, myelin integrity, and can protect neurons from toxic effects.[24] Mice deficient in klotho have a reduced number of synapses and cognitive deficits, whereas mice overexpressing klotho have enhanced learning and memory.[25]
It has been found that the decreased Klotho expression may be due to DNA hypermethylation, which may have been induced by the overexpression of DNMT3a.[26] Klotho may be a reliable gene for early detection of methylation changes in oral tissues, and can be used as a target for therapeutic modification in oral cancer during the early stages.
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.
Effects on aging
Mice lacking either fibroblast growth factor 23 or the α-klotho enzyme display premature aging due to hyperphosphatemia.[27] Many of these symptoms can be alleviated by feeding the mice a low phosphate diet.[7]
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.[13] In addition, variations in the Klotho gene (SNP Rs9536314) are associated with both life extension and increased cognition in human populations.[28]
Klotho increases membrane expression of the inward rectifier ATP-dependent potassium channel ROMK.[20] 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).[29][30][31][32]
Klotho is an antagonist of the Wnt signaling pathway, and chronic Wnt stimulation can lead to stem cell depletion and aging.[33]
References
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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. PMID 19690404.
- 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. PMID 19913601.
- 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. PMID 19329831.
- 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. PMID 11137391.
- Razzaque MS (Mar 2009). "FGF23-mediated regulation of systemic phosphate homeostasis: is Klotho an essential player?". American Journal of Physiology. Renal Physiology. 296 (3): F470-6. doi:10.1152/ajprenal.90538.2008. PMC 2660189. PMID 19019915.
- Menon R, Pearce B, Velez DR, Merialdi M, Williams SM, Fortunato SJ, Thorsen P (2009). "Racial disparity in pathophysiologic pathways of preterm birth based on genetic variants". Reproductive Biology and Endocrinology. 7: 62. doi:10.1186/1477-7827-7-62. PMC 2714850. PMID 19527514.
{{cite journal}}
: CS1 maint: unflagged free DOI (link) - Prié D, Ureña Torres P, Friedlander G (May 2009). "[Fibroblast Growth Factor 23-Klotho: a new axis of phosphate balance control]". Médecine/Sciences. 25 (5): 489–95. doi:10.1051/medsci/2009255489. PMID 19480830.
- Torres PU, Prié D, Beck L, De Brauwere D, Leroy C, Friedlander G (Jan 2009). "Klotho gene, phosphocalcic metabolism, and survival in dialysis". Journal of Renal Nutrition. 19 (1): 50–6. doi:10.1053/j.jrn.2008.10.018. PMID 19121771.
- Halaschek-Wiener J, Amirabbasi-Beik M, Monfared N, Pieczyk M, Sailer C, Kollar A, Thomas R, Agalaridis G, Yamada S, Oliveira L, Collins JA, Meneilly G, Marra MA, Madden KM, Le ND, Connors JM, Brooks-Wilson AR (2009). Mary Bridger J (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.
{{cite journal}}
: CS1 maint: unflagged free DOI (link) - 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. PMID 19539617.
- 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. PMID 20005218.
- Yerges LM, Klei L, Cauley JA, Roeder K, Kammerer CM, Moffett SP, Ensrud KE, Nestlerode CS, Marshall LM, Hoffman AR, Lewis C, Lang TF, Barrett-Connor E, Ferrell RE, Orwoll ES, Zmuda JM (Dec 2009). "High-density association study of 383 candidate genes for volumetric BMD at the femoral neck and lumbar spine among older men". Journal of Bone and Mineral Research. 24 (12): 2039–49. doi:10.1359/jbmr.090524. PMC 2791518. PMID 19453261.
- 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. PMID 17332731.
- 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. PMID 18660672.
- Kuro-o M (Oct 2009). "Klotho and aging". Biochimica et Biophysica Acta (BBA) - General Subjects. 1790 (10): 1049–58. doi:10.1016/j.bbagen.2009.02.005. PMC 2743784. PMID 19230844.
- 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. PMID 19802015.
- 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. PMID 19421891.
- Nabeshima Y (Jul 2008). "[Discovery of alpha-Klotho and FGF23 unveiled new insight into calcium and phosphate homeostasis]". Clinical Calcium. 18 (7): 923–34. PMID 18591743.
- Chen SN, Cilingiroglu M, Todd J, Lombardi R, Willerson JT, Gotto AM, Ballantyne CM, Marian AJ (2009). "Candidate genetic analysis of plasma high-density lipoprotein-cholesterol and severity of coronary atherosclerosis". BMC Medical Genetics. 10: 111. doi:10.1186/1471-2350-10-111. PMC 2775733. PMID 19878569.
{{cite journal}}
: CS1 maint: unflagged free DOI (link) - 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. PMID 18756295.
External links
This article incorporates text from the United States National Library of Medicine, which is in the public domain.