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Can we exploit the Klotho gene for Ageing therapy?

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Antonio Carusillo
Antonio Carusillo Dec 06, 2020

[1]Buchanan Sarah, Combet Emilie, Stenvinkel Peter, Shiels Paul G. Klotho, Aging, and the Failing Kidney, Frontiers in Endocrinology vol. 11, 2020 560 DOI=10.3389/fendo.2020.00560

[2]Kuro-o, M., Matsumura, Y., Aizawa, H. et al. Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature 390, 45–51 (1997). https://doi.org/10.1038/36285

[3]Ryozo Nagai, Makoto Kuro-o, Yo-ichi Nabeshima, Structure of the mouse klotho gene and its two transcripts encoding membrane and secreted protein1The nucleotide sequence data reported in this paper will appear in the DDBJ, EMBL and GenBank nucleotide sequence databases with the accession numbers AB010088, AB010089, AB010090 and AB010091.1, FEBS Letters, Volume 424, Issues 1–2, 1998, Pages 6-10, ISSN 0014-5793, https://doi.org/10.1016/S0014-5793(98)00127-6.

[4]Yuechi Xu, Zhongjie Sun, Molecular Basis of Klotho: From Gene to Function in Aging, Endocrine Reviews, Volume 36, Issue 2, 1 April 2015, Pages 174–193, https://doi.org/10.1210/er.2013-1079

[5]van Loon EP, Pulskens WP, van der Hagen EA, Lavrijsen M, Vervloet MG, van Goor H, Bindels RJ, Hoenderop JG. Shedding of klotho by ADAMs in the kidney. Am J Physiol Renal Physiol. 2015 Aug 15;309(4):F359-68. doi: 10.1152/ajprenal.00240.2014. Epub 2015 Jul 8. PMID: 26155844.

[6]Lim K, Groen A, Molostvov G, et al. α-Klotho Expression in Human Tissues. J Clin Endocrinol Metab. 2015;100(10):E1308-E1318. doi:10.1210/jc.2015-1800

[7]Chen G, Liu Y, Goetz R, Fu L, Jayaraman S, Hu MC, Moe OW, Liang G, Li X, Mohammadi M. α-Klotho is a non-enzymatic molecular scaffold for FGF23 hormone signalling. Nature. 2018 Jan 25;553(7689):461-466. doi: 10.1038/nature25451. Epub 2018 Jan 17. PMID: 29342138; PMCID: PMC6007875.

[8]o-ichi Nabeshima, Klotho deficient mouse: an in vivo model for human aging, Drug Discovery Today: Disease Models, Volume 1, Issue 3, 2004, Pages 223-227, ISSN 1740-6757, https://doi.org/10.1016/j.ddmod.2004.11.023.

[9]Abolghasemi M, Yousefi T, Maniati M, Qujeq D. The interplay of Klotho with signaling pathway and microRNAs in cancers. J Cell Biochem. 2019 Sep;120(9):14306-14317. doi: 10.1002/jcb.29022. Epub 2019 May 24. PMID: 31127658.

[10]Shimamura Y, Hamada K, Inoue K, Ogata K, Ishihara M, Kagawa T, Inoue M, Fujimoto S, Ikebe M, Yuasa K, Yamanaka S, Sugiura T, Terada Y. Serum levels of soluble secreted α-Klotho are decreased in the early stages of chronic kidney disease, making it a probable novel biomarker for early diagnosis. Clin Exp Nephrol. 2012 Oct;16(5):722-9. doi: 10.1007/s10157-012-0621-7. Epub 2012 Mar 29. PMID: 22457086.

[11]Mazzotta C, Manetti M, Rosa I, et al. Proangiogenic effects of soluble α-Klotho on systemic sclerosis dermal microvascular endothelial cells. Arthritis Res Ther. 2017;19(1):27. Published 2017 Feb 10. doi:10.1186/s13075-017-1233-0

[12]Hu MC, Shi M, Zhang J, et al. Klotho deficiency causes vascular calcification in chronic kidney disease. J Am Soc Nephrol. 2011;22(1):124-136. doi:10.1681/ASN.2009121311

[13]A single combination gene therapy treats multiple age-related diseases Noah Davidsohn, Matthew Pezone, Andyna Vernet, Amanda Graveline, Daniel Oliver, Shimyn Slomovic, Sukanya Punthambaker, Xiaoming Sun, Ronglih Liao, Joseph V. Bonventre, George M. Church

[14]Prud'homme GJ, Glinka Y, Kurt M, Liu W, Wang Q. The anti-aging protein Klotho is induced by GABA therapy and exerts protective and stimulatory effects on pancreatic beta cells. Biochem Biophys Res Commun. 2017 Dec 2;493(4):1542-1547. doi: 10.1016/j.bbrc.2017.10.029. Epub 2017 Oct 6. PMID: 28993191.

[15]Zhou, X., Fang, X., Jiang, Y. et al. Klotho, an anti-aging gene, acts as a tumor suppressor and inhibitor of IGF-1R signaling in diffuse large B cell lymphoma. J Hematol Oncol 10, 37 (2017). https://doi.org/10.1186/s13045-017-0391-5

[16]Tang, X., Wang, Y., Fan, Z. et al. Klotho: a tumor suppressor and modulator of the Wnt/β-catenin pathway in human hepatocellular carcinoma. Lab Invest 96, 197–205 (2016). https://doi.org/10.1038/labinvest.2015.86

Creative contributions

Use tools to find compounds that increase the expression of the Klotho gene.

Jamila Dec 11, 2020

[1]Haridas, Valsala, et al. "The anticancer plant triterpenoid, avicin D, regulates glucocorticoid receptor signaling: implications for cellular metabolism." PLoS One 6.11 (2011): e28037.

[2]Stancu, Andreea L. "AMPK activation can delay aging." Discoveries 3.4 (2015).

[3]Johnson, Simon C., Peter S. Rabinovitch, and Matt Kaeberlein. "mTOR is a key modulator of ageing and age-related disease." Nature 493.7432 (2013): 338-345.

[4]Barbosa, María Carolina, Rubén Adrián Grosso, and Claudio Marcelo Fader. "Hallmarks of aging: an autophagic perspective." Frontiers in endocrinology 9 (2019): 790.

[5]Kozeretska, Irina A., et al. "Epigenetic regulation of longevity in insects." Advances in Insect Physiology. Vol. 53. Academic Press, 2017. 87-114.

[6]Fields, Gregg B. "The rebirth of matrix metalloproteinase inhibitors: moving beyond the dogma." Cells 8.9 (2019): 984.

[7]Thorn, Caroline F., et al. "Doxorubicin pathways: pharmacodynamics and adverse effects." Pharmacogenetics and genomics 21.7 (2011): 440.

[8]Li, Zheng, et al. "Exploring the antitumor mechanism of high-dose cytarabine through the metabolic perturbations of ribonucleotide and deoxyribonucleotide in human promyelocytic leukemia HL-60 cells." Molecules 22.3 (2017): 499.

Considerations for therapeutic use of klotho

Shubhankar Kulkarni
Shubhankar Kulkarni Dec 15, 2020

[1]Kurosu H, Yamamoto M, Clark JD, Pastor J V, Nandi A, Gurnani P, et al. Suppression of Aging in Mice by the Hormone Klotho. Science (80- ) [Internet]. 2005 Sep 16;309(5742):1829–33. Available from: https://www.sciencemag.org/lookup/doi/10.1126/science.1112766

[2]Mori K, Yahata K, Mukoyama M, Suganami T, Makino H, Nagae T, et al. Disruption of klotho Gene Causes an Abnormal Energy Homeostasis in Mice. Biochem Biophys Res Commun [Internet]. 2000 Nov;278(3):665–70. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0006291X00938646

[3]Mengel-From J, Soerensen M, Nygaard M, McGue M, Christensen K, Christiansen L. Genetic Variants in KLOTHO Associate With Cognitive Function in the Oldest Old Group. Journals Gerontol Ser A Biol Sci Med Sci [Internet]. 2016 Sep;71(9):1151–9. Available from: https://academic.oup.com/biomedgerontology/article-lookup/doi/10.1093/gerona/glv163

[4]Brownstein CA, Adler F, Nelson-Williams C, Iijima J, Li P, Imura A, et al. A translocation causing increased -Klotho level results in hypophosphatemic rickets and hyperparathyroidism. Proc Natl Acad Sci [Internet]. 2008 Mar 4;105(9):3455–60. Available from: http://www.pnas.org/cgi/doi/10.1073/pnas.0712361105

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