Changes in expression of klotho affect physiological processes, diseases, and cancer.

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Kuro-o M. Klotho and aging. Biochim Biophys Acta. 2009;1790:1049–1058.

Cha SK, Ortega B, Kurosu H, Rosenblatt KP, Kuro OM, Huang CL. 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. 2008;105:9805–9810.

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Kuro-o M, Matsumura Y, Aizawa H, Kawaguchi H, Suga T, Utsugi T, et al. Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature. 1997;390:45–51.

Liu Y, Zhang Q. Periodontitis aggravated pancreatic beta-cell dysfunction in diabetic mice through interleukin-12 regulation on Klotho. J Diabetes Investig. 2016;7:303–311.

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Chen CD, Sloane JA, Li H, Aytan N, Giannaris EL, Zeldich E, et al. The antiaging protein klotho enhances oligodendrocyte maturation and myelination of the CNS. J Neurosci. 2013;33:1927–1939.

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Wang Y, Kuro-o M, Sun Z. Klotho gene delivery suppresses Nox2 expression and attenuates oxidative stress in rat aortic smooth muscle cells via the cAMP-PKA pathway. Aging Cell. 2012;11:410–417.

de Oliveira RM. Klotho RNAi induces premature senescence of human cells via a p53/p21 dependent pathway. FEBS Lett. 2006;580:5753–5758.

Kokkinaki M, Abu-Asab M, Gunawardena N, Ahern G, Javidnia M, Young J, et al. Klotho regulates retinal pigment epithelial functions and protects against oxidative stress. J Neurosci. 2013;33:16346–1659.

Markiewicz M, Panneerselvam K, Marks N. Role of Klotho in migration and proliferation of human dermal microvascular endothelial cells. Microvasc Res. 2016;107:76–82.

Liu CY, Zhang ZH, Yang HF, Xu H, Cheng FF, Xu JZ. Effect of vitamin D3 on maturation and antigen-presenting function of dendritic cells treated with Mycobacterium tuberculosis. Asian Pac J Trop Med. 2016;9:54–57.

Shumilina E, Nurbaeva MK, Yang W, Schmid E, Szteyn K, Russo A, et al. Altered regulation of cytosolic Ca(2)(+) concentration in dendritic cells from klotho hypomorphic mice. Am J Physiol Cell Physiol. 2013;305:C70–77.

Leibrock CB, Voelkl J, Kuro OM, Lang F, Lang UE. 1,25(OH)2D3 dependent overt hyperactivity phenotype in klotho-hypomorphic mice. Sci Rep. 2016;6:24879.

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Borst O, Munzer P, Schmid E, Schmidt EM, Russo A, Walker B, et al. 1,25(OH)2 vitamin D3-dependent inhibition of platelet Ca2+signaling and thrombus formation in klotho-deficient mice. FASEB J. 2014;28:2108–2119.

Zhang B, Yan J, Umbach AT, Fakhri H, Fajol A, Schmidt S, et al. NFkappaB-sensitive Orai1 expression in the regulation of FGF23 release. J Mol Med (Berl) 2016;94:557–566.

Luik RM, Wang B, Prakriya M, Wu MM, Lewis RS. Oligomerization of STIM1 couples ER calcium depletion to CRAC channel activation. Nature. 2008;454:538–542.

Schoeber JP, Hoenderop JG, Bindels RJ. Concerted action of associated proteins in the regulation of TRPV5 and TRPV6. Biochem Soc Trans. 2007;35:115–119.

Topala CN, Bindels RJ, Hoenderop JG. Regulation of the epithelial calcium channel TRPV5 by extracellular factors. Curr Opin Nephrol Hypertens. 2007;16:319–324.

Lee J, Jeong DJ, Kim J, Lee S, Park JH, Chang B, et al. The anti-aging gene KLOTHO is a novel target for epigenetic silencing in human cervical carcinoma. Mol Cancer. 2010;9:109.

Shu G, Xie B, Ren F, Liu DC, Zhou J, Li Q, et al. Restoration of klotho expression induces apoptosis and autophagy in hepatocellular carcinoma cells. Cell Oncol (Dordr) 2013;36:121–129.

Sun CY, Chang SC, Wu MS. Suppression of Klotho expression by protein-bound uremic toxins is associated with increased DNA methyltransferase expression and DNA hypermethylation. Kidney Int. 2012;81:640–650.

Yamazaki Y, Imura A, Urakawa I, Shimada T, Murakami J, Aono Y, et al. Establishment of sandwich ELISA for soluble alpha-Klotho measurement: Age-dependent change of soluble alpha-Klotho levels in healthy subjects. Biochem Biophys Res Commun. 2010;398:513–518.

Yamagishi T, Saito Y, Nakamura T, Takeda S, Kanai H, Sumino H, et al. Troglitazone improves endothelial function and augments renal klotho mRNA expression in Otsuka Long-Evans Tokushima Fatty (OLETF) rats with multiple atherogenic risk factors. Hypertens Res. 2001;24:705–709.

Hsu SC, Huang SM, Lin SH, Ka SM, Chen A, Shih MF, et al. Testosterone increases renal anti-aging klotho gene expression via the androgen receptor-mediated pathway. Biochem J. 2014;464:221–229.

Oz OK, Hajibeigi A, Howard K, Cummins CL, van Abel M, Bindels RJ, et al. Aromatase deficiency causes altered expression of molecules critical for calcium reabsorption in the kidneys of female mice *. J Bone Miner Res. 2007;22:1893–1902.

Xuan NT, Trang PT, Van Phong N, Toan NL, Trung DM, Bac ND, et al. Klotho sensitive regulation of dendritic cell functions by vitamin E. Biol Res. 2016;49:45.

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Kawamura Y, Matsuo H, Chiba T, Nagamori S, Nakayama A, Inoue H, et al. Pathogenic GLUT9 mutations causing renal hypouricemia type 2 (RHUC2) Nucleosides Nucleotides Nucleic Acids. 2011;30:1105–1111.

Vadakke Madathil S, Coe LM, Casu C, Sitara D. Klotho deficiency disrupts hematopoietic stem cell development and erythropoiesis. Am J Pathol. 2014;184:827–841.

Dinour D, Bahn A, Ganon L, Ron R, Geifman-Holtzman O, Knecht A, et al. URAT1 mutations cause renal hypouricemia type 1 in Iraqi Jews. Nephrol Dial Transplant. 2011;26:2175–2181.

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Koh N, Fujimori T, Nishiguchi S, Tamori A, Shiomi S, Nakatani T, et al. Severely reduced production of klotho in human chronic renal failure kidney. Biochem Biophys Res Commun. 2001;280:1015–1020.

Semba RD, Cappola AR, Sun K, Bandinelli S, Dalal M, Crasto C, et al. Plasma klotho and cardiovascular disease in adults. J Am Geriatr Soc. 2011;59:1596–1601.

Karalliedde J, Maltese G, Hill B, Viberti G, Gnudi L. Effect of renin-angiotensin system blockade on soluble Klotho in patients with type 2 diabetes, systolic hypertension, and albuminuria. Clin J Am Soc Nephrol. 2013;8:1899–1905.

Schmid C, Neidert MC, Tschopp O, Sze L, Bernays RL. Growth hormone and Klotho. J Endocrinol. 2013;219:R37–57.

Wang L, Wang X, Jie P, Lu H, Zhang S, Lin X, et al. Klotho is silenced through promoter hypermethylation in gastric cancer. Am J Cancer Res. 2011;1:111–119.

Rubinek T, Shulman M, Israeli S, Bose S, Avraham A, Zundelevich A, et al. Epigenetic silencing of the tumor suppressor klotho in human breast cancer. Breast Cancer Res Treat. 2012;133:649–657.

Pan J, Zhong J, Gan LH, Chen SJ, Jin HC, Wang X, et al. Klotho, an anti-senescence related gene, is frequently inactivated through promoter hypermethylation in colorectal cancer. Tumour Biol. 2011;32:729–735.

Wolf I, Levanon-Cohen S, Bose S, Ligumsky H, Sredni B, Kanety H, et al. Klotho: a tumor suppressor and a modulator of the IGF-1 and FGF pathways in human breast cancer. Oncogene. 2008;27:7094–7105.

MacDonald BT, Tamai K, He X. Wnt/beta-catenin signaling: components, mechanisms, and diseases. Dev Cell. 2009;17:9–26.

Shimoyama Y, Taki K, Mitsuda Y, Tsuruta Y, Hamajima N, Niwa T. KLOTHO gene polymorphisms G-395A and C1818T are associated with low-density lipoprotein cholesterol and uric acid in Japanese hemodialysis patients. Am J Nephrol. 2009;30:383–388.

Pollak MN, Schernhammer ES, Hankinson SE. Insulin-like growth factors and neoplasia. Nat Rev Cancer. 2004;4:505–518.

Lojkin I, Rubinek T, Orsulic S, Schwarzmann O, Karlan BY, Bose S, et al. Reduced expression and growth inhibitory activity of the aging suppressor klotho in epithelial ovarian cancer. Cancer Lett. 2015;362:149–157.

Lorenzi O, Veyrat-Durebex C, Wollheim CB, Villemin P, Rohner-Jeanrenaud F, Zanchi A, et al. Evidence against a direct role of klotho in insulin resistance. Pflugers Arch. 2010;459:465–473.

Giles RH, van Es JH, Clevers H. Caught up in a Wnt storm: Wnt signaling in cancer. Biochim Biophys Acta. 2003;1653:1–24.

Chen B, Wang X, Zhao W, Wu J. Klotho inhibits growth and promotes apoptosis in human lung cancer cell line A549. J Exp Clin Cancer Res. 2010;29:99.

Wolf I, Laitman Y, Rubinek T, Abramovitz L, Novikov I, Beeri R, et al. Functional variant of KLOTHO: a breast cancer risk modifier among BRCA1 mutation carriers of Ashkenazi origin. Oncogene. 2010;29:26–33.

Arking DE, Krebsova A, Macek M, Sr, Macek M, Jr, Arking A, Mian IS, et al. Association of human aging with a functional variant of klotho. Proc Natl Acad Sci U S A. 2002;99:856–861.

Arking DE, Atzmon G, Arking A, Barzilai N, Dietz HC. Association between a functional variant of the KLOTHO gene and high-density lipoprotein cholesterol, blood pressure, stroke, and longevity. Circ Res. 2005;96:412–418.

Rhee EJ, Oh KW, Yun EJ, Jung CH, Lee WY, Kim SW, et al. Relationship between polymorphisms G395A in promoter and C1818T in exon 4 of the KLOTHO gene with glucose metabolism and cardiovascular risk factors in Korean women. J Endocrinol Invest. 2006;29:613–618.

Liu C, Cui W, Wang L, Yan L, Ruan X, Liu Y, et al. Klotho gene polymorphisms are related to colorectal cancer susceptibility. Int J Clin Exp Pathol. 2015;8:7446–7449.

Wang HL, Xu Q, Wang Z, Zhang YH, Si LY, Li XJ, et al. 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. 2010;411:386–390.

Rhee EJ, Oh KW, Lee WY, Kim SY, Jung CH, Kim BJ, et al. The differential effects of age on the association of KLOTHO gene polymorphisms with coronary artery disease. Metabolism. 2006;55:1344–1351.

Nolan VG, Baldwin C, Ma Q, Wyszynski DF, Amirault Y, Farrell JJ, et al. Association of single nucleotide polymorphisms in klotho with priapism in sickle cell anaemia. Br J Haematol. 2005;128:266–272.

Lustosa Souza CR, Azevedo Shimmoto MM, Vicari P, Mecabo G, Arruda MM, Figueiredo MS. Klotho gene polymorphisms and their association with sickle cell disease phenotypes. Rev Bras Hematol Hemoter. 2015;37:275–276.

Friedman DJ, Afkarian M, Tamez H, Bhan I, Isakova T, Wolf M, et al. Klotho variants and chronic hemodialysis mortality. J Bone Miner Res. 2009;24:1847–1855.