View source for Biology:Klotho

{{short description|Human enzyme}}
{{Infobox_gene}}

'''Klotho''' is an [[Biology:Enzyme|enzyme]] that in humans is encoded by the ''KL'' [[Biology:Gene|gene]].<ref name="pmid9464267">{{cite journal | vauthors = Matsumura Y, Aizawa H, Shiraki-Iida T, Nagai R, Kuro-o M, Nabeshima Y | title = Identification of the human klotho gene and its two transcripts encoding membrane and secreted klotho protein | journal = Biochemical and Biophysical Research Communications | volume = 242 | issue = 3 | pages = 626–630 | date = January 1998 | pmid = 9464267 | doi = 10.1006/bbrc.1997.8019 }}</ref> The three subfamilies of klotho are α-klotho, β-klotho, and γ-klotho.<ref name="pmid30927227">{{cite journal | vauthors = Dolegowska K, Marchelek-Mysliwiec M, Nowosiad-Magda M, Slawinski M, Dolegowska B | title = FGF19 subfamily members: FGF19 and FGF21 | journal = Journal of Physiology and Biochemistry | volume = 75 | issue = 2 | pages = 229–240 | date = June 2019 | pmid = 30927227 | pmc = 6611749 | doi = 10.1007/s13105-019-00675-7 }}</ref> α-klotho activates FGF23, and β-klotho activates [[Biology:FGF19|FGF19]] and [[Biology:FGF21|FGF21]].<ref name="pmid30455427" /> When the subfamily is not specified, the word "klotho" typically refers to the α-klotho subfamily, because α-klotho was discovered before the other members.<ref name="pmid31546756">{{cite journal | vauthors = Lim K, Halim A, Lu TS, Ashworth A, Chong I | title = Klotho: A Major Shareholder in Vascular Aging Enterprises | journal = International Journal of Molecular Sciences | volume = 20 | issue = 18 | pages = E4637 | date = September 2019 | pmid = 31546756 | pmc = 6770519 | doi = 10.3390/ijms20184637 | doi-access = free }}</ref><ref name="pmid30455427" />

α-klotho is highly [[Biology:Gene expression|expressed]] in the brain, liver and kidney.<ref name="pmid34194816">{{cite journal | vauthors = Hanson K, Fisher K, Hooper NM | title = Exploiting the neuroprotective effects of α-klotho to tackle ageing- and neurodegeneration-related cognitive dysfunction | journal = Neuronal Signaling | volume = 5 | issue = 2 | pages = NS20200101 | date = June 2021 | pmid = 34194816 | pmc = 8204227 | doi = 10.1042/NS20200101 }}</ref> β-klotho is predominantly expressed in the liver.<ref>{{cite journal | vauthors = Kurt B, Kurtz A | title = Plasticity of renal endocrine function | journal = American Journal of Physiology. Regulatory, Integrative and Comparative Physiology | volume = 308 | issue = 6 | pages = R455–R466 | date = March 2015 | pmid = 25608752 | doi = 10.1152/ajpregu.00568.2013 | s2cid = 37452911 }}</ref><ref name="pmid34194816" /> γ-klotho is expressed in the skin.<ref name="pmid34194816" />

Klotho can exist in a membrane-bound form or a (hormonal) soluble, circulating form.<ref name="pmid27125740">{{cite book | vauthors=Buendía P, Ramírez R, Aljama P, Carracedo J | title=Klotho | chapter=Klotho Prevents Translocation of NFκB | series=Vitamins & Hormones | volume=101 | pages=119–150 | year=2016 | doi = 10.1016/bs.vh.2016.02.005 | pmid=27125740 | isbn=9780128048191 }}</ref> [[Biology:Protease|Protease]]s can convert the membrane-bound form into the circulating form.<ref name="pmid30860544">{{cite journal | vauthors = Martín-González C, González-Reimers E, Quintero-Platt G, Martínez-Riera A, Santolaria-Fernández F | title = Soluble α-Klotho in Liver Cirrhosis and Alcoholism | journal = Alcohol and Alcoholism | volume = 54 | issue = 3 | pages = 204–208 | date = May 2019 | pmid = 30860544 | pmc = 6731336 | doi = 10.1093/alcalc/agz019 }}</ref>

The ''KL'' gene encodes a type-I single-pass transmembrane protein<ref name="pmid30455427" /> that is related to [[Biology:Beta-glucuronidase|β-glucuronidase]]s. Reduced production of this protein has been observed in patients with chronic [[Medicine:Kidney failure|kidney failure]] (CKF), and this may be one of the factors underlying degenerative processes (e.g., [[Medicine:Arteriosclerosis|arteriosclerosis]], [[Medicine:Osteoporosis|osteoporosis]], and skin atrophy) seen in CKF. Mutations within the family have been associated with ageing, bone loss and alcohol consumption.<ref name="entrez">{{cite web | title = Entrez Gene: klotho| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=9365}}</ref><ref name="SchumannLiu2016">{{cite journal | vauthors = Schumann G, Liu C, O'Reilly P, Gao H, Song P, Xu B, Ruggeri B, Amin N, Jia T, Preis S, Segura Lepe M, Akira S, Barbieri C, Baumeister S, Cauchi S, Clarke TK, Enroth S, Fischer K, Hällfors J, Harris SE, Hieber S, Hofer E, Hottenga JJ, Johansson Å, Joshi PK, Kaartinen N, Laitinen J, Lemaitre R, Loukola A, Luan J, Lyytikäinen LP, Mangino M, Manichaikul A, Mbarek H, Milaneschi Y, Moayyeri A, Mukamal K, Nelson C, Nettleton J, Partinen E, Rawal R, Robino A, Rose L, Sala C, Satoh T, Schmidt R, Schraut K, Scott R, Smith AV, Starr JM, Teumer A, Trompet S, Uitterlinden AG, Venturini C, Vergnaud AC, Verweij N, Vitart V, Vuckovic D, Wedenoja J, Yengo L, Yu B, Zhang W, Zhao JH, Boomsma DI, Chambers J, Chasman DI, Daniela T, de Geus E, Deary I, Eriksson JG, Esko T, Eulenburg V, Franco OH, Froguel P, Gieger C, Grabe HJ, Gudnason V, Gyllensten U, Harris TB, Hartikainen AL, Heath AC, Hocking L, Hofman A, Huth C, Jarvelin MR, Jukema JW, Kaprio J, Kooner JS, Kutalik Z, Lahti J, Langenberg C, Lehtimäki T, Liu Y, Madden PA, Martin N, Morrison A, Penninx B, Pirastu N, Psaty B, Raitakari O, Ridker P, Rose R, Rotter JI, Samani NJ, Schmidt H, Spector TD, Stott D, Strachan D, Tzoulaki I, van der Harst P, van Duijn CM, Marques-Vidal P, Vollenweider P, Wareham NJ, Whitfield JB, Wilson J, Wolffenbuttel B, Bakalkin G, Evangelou E, Liu Y, Rice KM, Desrivières S, Kliewer SA, Mangelsdorf DJ, Müller CP, Levy D, Elliott P | display-authors = 6 | title = KLB is associated with alcohol drinking, and its gene product β-Klotho is necessary for FGF21 regulation of alcohol preference | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 113 | issue = 50 | pages = 14372–14377 | date = December 2016 | pmid = 27911795 | pmc = 5167198 | doi = 10.1073/pnas.1611243113 | bibcode = 2016PNAS..11314372S | doi-access = free }}</ref> Transgenic mice that overexpress Klotho live longer than wild-type mice.<ref name="pmid16123266"/>

== Structure ==
The ''α-klotho'' gene is located on chromosome 13, and is translated into a single-pass [[Biology:Integral membrane protein|integral membrane protein]].<ref name="pmid34194816" /> The intracellular portion of the α-klotho protein is short (11 [[Chemistry:Amino acid|amino acid]]s), whereas the extracellular portion is long (980 amino acids).<ref name="pmid34194816" /> The transmembrane portion is also comparatively short (21 amino acids).<ref name="pmid34194816" /> The extracellular portion contains two repeat sequences, termed the KL1 (about 450 amino acids) and KL2 (about 430 amino acids) domains.<ref name="pmid34194816" /><ref name="pmid30455427" /> In the kidney and the choroid plexus of the brain, the transmembrane protein can be [[Biology:Proteolysis|proteolytically]] cleaved to produce a 130-[[Kilo-]][[Dalton (unit)|Dalton]], soluble form of α-klotho protein, released into the [[Biology:Circulatory system|circulation]] and [[Biology:Cerebrospinal fluid|cerebrospinal fluid]], respectively.<ref name="pmid34194816" /> In humans, the secreted form of klotho is more dominant than the membrane form.<ref name="pmid33185993" />

The β-Klotho gene is located on chromosome 4. The protein shares homology (43.1% identity and 60.1% similarity) with ''α-klotho''. <ref>{{cite web |title=Klotho Beta |url=https://www.genecards.org/cgi-bin/carddisp.pl?gene=KLB |access-date=12 September 2023}}</ref> 
It should not be confused with the alpha-cut and beta-cut of alpha-klotho, which releases KL1+KL2 and KL2 domain, respectively.

== Function ==
Klotho is a [[Biology:Transmembrane protein|transmembrane protein]] that, in addition to other effects, provides some control over the sensitivity of the organism to [[Biology:Insulin|insulin]] and appears to be involved in ageing. Its discovery was documented in 1997 by Makoto Kuro-o ''et al.''<ref name="pmid9363890">{{cite journal | vauthors = 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 | display-authors = 6 | title = Mutation of the mouse klotho gene leads to a syndrome resembling ageing | journal = Nature | volume = 390 | issue = 6655 | pages = 45–51 | date = November 1997 | pmid = 9363890 | doi = 10.1038/36285 | s2cid = 4428141 | bibcode = 1997Natur.390...45K }}</ref> The name of the gene comes from Klotho or Clotho, one of the [[Philosophy:Moirai|Moirai]], or Fates, in [[Religion:Greek mythology|Greek mythology]], who spins the thread of human life.<ref name="pmid30455427">{{cite journal | vauthors = Kuro-O M | title = The Klotho proteins in health and disease | journal = Nature Reviews. Nephrology | volume = 15 | issue = 1 | pages = 27–44 | date = January 2019 | pmid = 30455427 | doi = 10.1038/s41581-018-0078-3 | s2cid = 53872296 }}</ref>

The klotho protein is a novel [[Biology:Beta-glucosidase|β-glucuronidase]] ([[Biology:Enzyme Commission number|EC number]] 3.2.1.31) capable of hydrolyzing [[Biology:Steroid|steroid]] [[Chemistry:Glucuronide|β-glucuronides]]. Genetic variants in ''KLOTHO'' have been associated with human aging,<ref name="pmid11792841">{{cite journal | vauthors = Arking DE, Krebsova A, Macek M, Macek M, Arking A, Mian IS, Fried L, Hamosh A, Dey S, McIntosh I, Dietz HC | display-authors = 6 | title = Association of human aging with a functional variant of klotho | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 99 | issue = 2 | pages = 856–861 | date = January 2002 | pmid = 11792841 | pmc = 117395 | doi = 10.1073/pnas.022484299 | doi-access = free | bibcode = 2002PNAS...99..856A }}</ref> and klotho protein has been shown to be a circulating factor detectable in [[Biology:Blood plasma|serum]] that declines with age.<ref name="pmid15161545">{{cite journal | vauthors = Xiao NM, Zhang YM, Zheng Q, Gu J | title = Klotho is a serum factor related to human aging | journal = Chinese Medical Journal | volume = 117 | issue = 5 | pages = 742–747 | date = May 2004 | pmid = 15161545 | url = http://www.cmj.org/Periodical/LinkIn.asp?journal=Chinese%20Medical%20Journal&linkintype=pubmed&year=2004&vol=117&issue=5&beginpage=742 }}{{dead link|date=December 2017 |bot=InternetArchiveBot |fix-attempted=yes }}</ref>

The binding of the endocrine [[Biology:Fibroblast growth factor|fibroblast growth factor]]s (FGF's, viz., FGF19 and FGF21) to their fibroblast growth factor receptors, is promoted via their interactions as [[Biology:Co-receptor|co-receptor]]s with β-klotho.<ref name="pmid26224133">{{cite journal | vauthors = Helsten T, Schwaederle M, Kurzrock R | title = Fibroblast growth factor receptor signaling in hereditary and neoplastic disease: biologic and clinical implications | journal = Cancer and Metastasis Reviews | volume = 34 | issue = 3 | pages = 479–496 | date = September 2015 | pmid = 26224133 | pmc = 4573649 | doi = 10.1007/s10555-015-9579-8 }}</ref><ref name="FGF21 receptor expression in the brain">{{cite journal | vauthors = Talukdar S, Owen BM, Song P, Hernandez G, Zhang Y, Zhou Y, Scott WT, Paratala B, Turner T, Smith A, Bernardo B, Müller CP, Tang H, Mangelsdorf DJ, Goodwin B, Kliewer SA | display-authors = 6 | title = FGF21 Regulates Sweet and Alcohol Preference | journal = Cell Metabolism | volume = 23 | issue = 2 | pages = 344–349 | date = February 2016 | pmid = 26724861 | pmc = 4749404 | doi = 10.1016/j.cmet.2015.12.008 }}</ref><ref name="pmid33185993" /><ref name="pmid30455427" /> Loss of β-Klotho abolishes all effects of FGF21.<ref name="pmid33758421">{{cite journal | vauthors = Flippo KH, Potthoff MJ | title = Metabolic Messengers: FGF21 | journal = Nature Metabolism | volume = 3 | issue = 3 | pages = 309–317 | date = March 2021 | pmid = 33758421 | pmc = 8620721 | doi = 10.1038/s42255-021-00354-2 }}</ref>

α-klotho, which binds to the endocrine FGF FGF23 changes cellular calcium homeostasis, by both increasing the expression and activity of [[Biology:TRPV5|TRPV5]] (decreasing phosphate reabsorption in the kidney) and decreasing that of [[Biology:TRPC6|TRPC6]] (decreasing phosphate absorption from the intestine).<ref name="Huang et al 2010">{{cite journal | vauthors = Huang CL | title = Regulation of ion channels by secreted Klotho: mechanisms and implications | journal = Kidney International | volume = 77 | issue = 10 | pages = 855–860 | date = May 2010 | pmid = 20375979 | doi = 10.1038/ki.2010.73 | doi-access = free }}</ref> α-klotho increases kidney calcium reabsorption by stabilizing TPRV5.<ref name="pmid27913205">{{cite journal | vauthors = van Goor MK, Hoenderop JG, van der Wijst J | title = TRP channels in calcium homeostasis: from hormonal control to structure-function relationship of TRPV5 and TRPV6 | journal = Biochimica et Biophysica Acta (BBA) - Molecular Cell Research | volume = 1864 | issue = 6 | pages = 883–893 | date = June 2017 | pmid = 27913205 | doi = 10.1016/j.bbamcr.2016.11.027 | doi-access = free }}</ref> About 95% to 98% of Ca<sup>2+</sup> filtered from the blood by the kidney is normally reabsorbed by the kidney's renal tubule, which is mediated by TRPV5.<ref name="pmid25378396">{{cite journal | vauthors = Wolf MT, An SW, Nie M, Bal MS, Huang CL | title = Klotho up-regulates renal calcium channel transient receptor potential vanilloid 5 (TRPV5) by intra- and extracellular N-glycosylation-dependent mechanisms | journal = The Journal of Biological Chemistry | volume = 289 | issue = 52 | pages = 35849–35857 | date = December 2014 | pmid = 25378396 | pmc = 4276853 | doi = 10.1074/jbc.M114.616649 | doi-access = free }}</ref>

== Clinical significance ==
α-klotho can suppress [[Biology:Oxidative stress|oxidative stress]] and [[Medicine:Inflammation|inflammation]], thereby reducing [[Medicine:Endothelial dysfunction|endothelial dysfunction]] and [[Medicine:Atherosclerosis|atherosclerosis]].<ref name="pmid31546756"/> Blood plasma α-klotho is increased by [[Medicine:Aerobic exercise|aerobic exercise]], thereby reducing endothelial dysfunction.<ref name="pmid29081845">{{cite journal | vauthors = Saghiv MS, Sira DB, Goldhammer E, Sagiv M | title = The effects of aerobic and anaerobic exercises on circulating soluble-Klotho and IGF-I in young and elderly adults and in CAD patients | journal = Journal of Circulating Biomarkers | volume = 6 | pages = 1849454417733388 | year = 2017 | pmid = 29081845 | pmc = 5644364 | doi = 10.1177/1849454417733388 }}</ref>

β-klotho activation of [[Biology:FGF21|FGF21]] protein has a protective effect on [[Biology:Cardiac muscle cell|heart muscle cells]].<ref name="pmid30671457">{{cite journal | vauthors = Olejnik A, Franczak A, Krzywonos-Zawadzka A, Kałużna-Oleksy M, Bil-Lula I | title = The Biological Role of Klotho Protein in the Development of Cardiovascular Diseases | journal = BioMed Research International | volume = 2018 | pages = 5171945 | year = 2018 | pmid = 30671457 | pmc = 6323445 | doi = 10.1155/2018/5171945 | doi-access = free }}</ref> Obesity is characterized by FGF21 resistance, believed to be caused by the inhibition of β-klotho by the inflammatory cell signalling protein ([[Biology:Cytokine|cytokine]]) [[Biology:Tumor necrosis factor alpha|tumor necrosis factor alpha]],<ref name="pmid30671457" /> but there is evidence against this mechanism.<ref name="pmid33185993">{{cite journal | vauthors = Baranowska B, Kochanowski J | title = The metabolic, neuroprotective cardioprotective and antitumor effects of the Klotho protein | journal = Neuro Endocrinology Letters | volume = 41 | issue = 2 | pages = 69–75 | date = September 2020 | pmid = 33185993 }}</ref>

Klotho is required for oligodendrocyte maturation, [[Biology:Myelin|myelin]] integrity, and can protect neurons from toxic effects.<ref name="pmid30062646">{{cite journal | vauthors = Torbus-Paluszczak M, Bartman W, Adamczyk-Sowa M | title = Klotho protein in neurodegenerative disorders | journal = Neurological Sciences | volume = 39 | issue = 10 | pages = 1677–1682 | date = October 2018 | pmid = 30062646 | pmc = 6154120 | doi = 10.1007/s10072-018-3496-x }}</ref> Mice deficient in klotho have a reduced number of [[Biology:Synapse|synapse]]s and cognitive deficits, whereas mice overexpressing klotho have enhanced learning and memory.<ref name="pmid30151342">{{cite journal | vauthors = Vo HT, Laszczyk AM, King GD | title = Klotho, the Key to Healthy Brain Aging? | journal = Brain Plasticity | volume = 3 | issue = 2 | pages = 183–194 | date = August 2018 | pmid = 30151342 | pmc = 6091049 | doi = 10.3233/BPL-170057 }}</ref> Research with injections of klotho in primates demonstrates a positive effect on memory that lasts for as long as two weeks.<ref name = "Tozer_2023" />

Reduced klotho [[Biology:Gene expression|expression]] is seen in the lung [[Biology:Macrophage|macrophage]]s of [[Chemistry:Tobacco smoking|smokers]].<ref name="pmid34737707" /> An abnormal form of [[Biology:Autophagy|autophagy]] associated with reduced expression of klotho is linked to the pathogenesis of [[Medicine:Chronic obstructive pulmonary disease|chronic obstructive pulmonary disease]].<ref name="pmid34737707" /> (Although normal autophagy helps maintain muscle, excessive autophagy causes loss of muscle mass.<ref name="pmid34737707" />)

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.<ref>{{cite journal | vauthors = Adhikari BR, Uehara O, Matsuoka H, Takai R, Harada F, Utsunomiya M, Chujo T, Morikawa T, Shakya M, Yoshida K, Sato J, Arakawa T, Nishimura M, Nagayasu H, Chiba I, Abiko Y | display-authors = 6 | title = Immunohistochemical evaluation of Klotho and DNA methyltransferase 3a in oral squamous cell carcinomas | journal = Medical Molecular Morphology | volume = 50 | issue = 3 | pages = 155–160 | date = September 2017 | pmid = 28303350 | doi = 10.1007/s00795-017-0156-9 | s2cid = 22810635 }}</ref> 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 [[Medicine:Syndrome|syndrome]] resembling accelerated human ageing and display extensive and accelerated [[Medicine:Arteriosclerosis|arteriosclerosis]]. Additionally, they exhibit impaired [[Biology:Endothelium|endothelium]] dependent [[Medicine:Vasodilation|vasodilation]] and impaired [[Biology:Angiogenesis|angiogenesis]], suggesting that klotho protein may protect the cardiovascular system through endothelium-derived [[Chemistry:Nitric oxide|nitric oxide]] production.<ref name="pmid33185993" />

Klotho could play a protective role in [[Medicine:Alzheimer's disease|Alzheimer's disease]] patients.<ref name="pmid29978424">{{cite journal | vauthors = Paroni G, Panza F, De Cosmo S, Greco A, Seripa D, Mazzoccoli G | title = Klotho at the Edge of Alzheimer's Disease and Senile Depression | journal = Molecular Neurobiology | volume = 56 | issue = 3 | pages = 1908–1920 | date = March 2019 | pmid = 29978424 | doi = 10.1007/s12035-018-1200-z | s2cid = 49567009 }}</ref><ref name="pmid32999998">{{cite journal | vauthors = Lehrer S, Rheinstein PH | title = Alignment of Alzheimer's disease amyloid β-peptide and klotho | journal = World Academy of Sciences Journal | volume = 2 | issue = 6 | date = 2020 | page = 1 | pmid = 32999998 | pmc = 7521834 | doi = 10.3892/wasj.2020.68 | doi-access = free }}</ref>

Research with injections of α-klotho in primates suggests a positive effect on memory that could have implications for research with humans.<ref name = "Tozer_2023">{{cite journal | vauthors = Tozer L | url = https://www.nature.com/articles/d41586-023-02214-3?utm_source=Nature+Briefing&utm_campaign=303d9b9929-briefing-dy-20230704&utm_medium=email&utm_term=0_c9dfd39373-303d9b9929-44393109 | title = Anti-ageing protein injection boosts monkeys' memories | journal = Nature | date = 4 July 2023 | volume=619 | issue=7969 | page=234 | doi=10.1038/d41586-023-02214-3 | pmid=37402904 | bibcode=2023Natur.619..234T | s2cid=259334272 }}</ref> Interestingly the cognitive effects in rhesus monkeys were observed even with [[Medicine:Subcutaneous injection|subcutaneous injection]] despite previous results showing that klotho protein fails to cross the [[Biology:Blood–brain barrier|blood–brain barrier]].<ref>{{cite journal | vauthors = Castner SA, Gupta S, Wang D, Moreno AJ, Park C, Chen C, Poon Y, Groen A, Greenberg K, David N, Boone T, Baxter MG, Williams GV, Dubal DB | display-authors = 6 | title = Longevity factor klotho enhances cognition in aged nonhuman primates | journal = Nature Aging | date = July 2023 | volume = 3 | issue = 8 | pages = 931–937 | pmid = 37400721 | doi = 10.1038/s43587-023-00441-x | pmc = 10432271 | s2cid = 259322607 | doi-access = free }}</ref>

== Effects on aging ==
Reduced α-klotho or FGF23 can result in impaired [[Chemistry:Phosphate|phosphate]] excretion from the kidney, leading to [[Medicine:Hyperphosphatemia|hyperphosphatemia]].<ref name="pmid30455427" /> In mice, this leads to a [[Biology:Phenotype|phenotype]] characteristic of premature aging, which can be mitigated by feeding the mice a low phosphate diet.<ref name="pmid30455427" />

The plasma (soluble) form of α-klotho is most easily measured, and has been shown to decrease after 40 years of age in humans.<ref name="pmid34407459">{{cite journal | vauthors = Veronesi F, Borsari V, Cherubini A, Fini M | title = Association of Klotho with physical performance and frailty in middle-aged and older adults: A systematic review | journal = Experimental Gerontology | volume = 154 | pages = 111518 | date = October 2021 | pmid = 34407459 | doi = 10.1016/j.exger.2021.111518 | s2cid = 237011996 | doi-access = free }}</ref> Lower plasma levels of α-klotho in older adults is associated with increased frailty and [[Mortality rate|all-cause mortality]].<ref name="pmid34407459" /> Physical activity has been shown to increase plasma α-klotho.<ref name="pmid34407459" />

Mice lacking either fibroblast growth factor 23 or the α-klotho enzyme display premature aging due to [[Medicine:Hyperphosphatemia|hyperphosphatemia]].<ref name="Huang et al 2010"/> Many of these symptoms can be alleviated by feeding the mice a low phosphate diet.<ref name="pmid30455427"/>

Although the majority of research has explored klotho's absence, it was demonstrated that klotho over-expression in mice extended their average life span between 19% and 31% compared to normal mice.<ref name="pmid16123266">{{cite journal | vauthors = 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 | display-authors = 6 | title = Suppression of aging in mice by the hormone Klotho | journal = Science | volume = 309 | issue = 5742 | pages = 1829–1833 | date = September 2005 | pmid = 16123266 | pmc = 2536606 | doi = 10.1126/science.1112766 | bibcode = 2005Sci...309.1829K }}</ref> In addition, variations in the Klotho gene (SNP Rs9536314) are associated with both life extension and increased cognition in human populations and mice, but only if the gene expression was [[Biology:Zygosity#Heterozygous|heterozygous]], not [[Biology:Zygosity#Homozygous|homozygous]].<ref name="pmid24813892">{{cite journal | vauthors = Dubal DB, Yokoyama JS, Zhu L, Broestl L, Worden K, Wang D, Sturm VE, Kim D, Klein E, Yu GQ, Ho K, Eilertson KE, Yu L, Kuro-o M, De Jager PL, Coppola G, Small GW, Bennett DA, Kramer JH, Abraham CR, Miller BL, Mucke L | display-authors = 6 | title = Life extension factor klotho enhances cognition | journal = Cell Reports | volume = 7 | issue = 4 | pages = 1065–1076 | date = May 2014 | pmid = 24813892 | pmc = 4176932 | doi = 10.1016/j.celrep.2014.03.076 | }}</ref><ref name="pmid34194816" /> The cognitive benefits of α-klotho are primarily seen late in life.<ref name="pmid34194816" />

Klotho increases membrane expression of the inward rectifier [[Chemistry:Adenosine triphosphate|ATP]]-dependent [[Biology:Potassium channel|potassium channel]] [[Biology:ROMK|ROMK]].<ref name="Huang et al 2010" /> Klotho-deficient mice show increased production of vitamin D, and altered mineral-ion homeostasis is suggested to cause premature aging‑like phenotypes, because reduced vitamin D activity from 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).<ref>{{cite journal | vauthors = Kuro-o M | title = Klotho and aging | journal = Biochimica et Biophysica Acta (BBA) - General Subjects | volume = 1790 | issue = 10 | pages = 1049–1058 | date = October 2009 | pmid = 19230844 | pmc = 2743784 | doi = 10.1016/j.bbagen.2009.02.005 }}</ref><ref>{{cite journal | vauthors = Medici D, Razzaque MS, Deluca S, Rector TL, Hou B, Kang K, Goetz R, Mohammadi M, Kuro-O M, Olsen BR, Lanske B | display-authors = 6 | title = FGF-23-Klotho signaling stimulates proliferation and prevents vitamin D-induced apoptosis | journal = The Journal of Cell Biology | volume = 182 | issue = 3 | pages = 459–465 | date = August 2008 | pmid = 18678710 | pmc = 2500132 | doi = 10.1083/jcb.200803024 }}</ref><ref name="pmid14528024">{{cite journal | vauthors = Tsujikawa H, Kurotaki Y, Fujimori T, Fukuda K, Nabeshima Y | title = Klotho, a gene related to a syndrome resembling human premature aging, functions in a negative regulatory circuit of vitamin D endocrine system | journal = Molecular Endocrinology | volume = 17 | issue = 12 | pages = 2393–2403 | date = December 2003 | pmid = 14528024 | doi = 10.1210/me.2003-0048 | doi-access = free | hdl = 2433/145275 | hdl-access = free }}</ref><ref name="pmid17569864">{{cite journal | vauthors = 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 | display-authors = 6 | title = alpha-Klotho as a regulator of calcium homeostasis | journal = Science | volume = 316 | issue = 5831 | pages = 1615–1618 | date = June 2007 | pmid = 17569864 | doi = 10.1126/science.1135901 | s2cid = 40529168 | bibcode = 2007Sci...316.1615I }}</ref>

Klotho is an antagonist of the [[Biology:Wnt signaling pathway|Wnt signaling pathway]], and chronic Wnt stimulation can lead to [[Biology:Stem cell|stem cell]] depletion and aging.<ref name="pmid17690294">{{cite journal | vauthors = Liu H, Fergusson MM, Castilho RM, Liu J, Cao L, Chen J, Malide D, Rovira II, Schimel D, Kuo CJ, Gutkind JS, Hwang PM, Finkel T | display-authors = 6 | title = Augmented Wnt signaling in a mammalian model of accelerated aging | journal = Science | volume = 317 | issue = 5839 | pages = 803–806 | date = August 2007 | pmid = 17690294 | doi = 10.1038/ki.2010.73 | doi-access = free }}</ref> Klotho inhibition of Wnt signaling can inhibit [[Medicine:Cancer|cancer]].<ref name="pmid34737707">{{cite journal | vauthors = Zhou H, Pu S, Zhou H, Guo Y | title = Klotho as Potential Autophagy Regulator and Therapeutic Target | journal = Frontiers in Pharmacology | volume = 12 | pages = 755366 | year = 2021 | pmid = 34737707 | pmc = 8560683 | doi = 10.3389/fphar.2021.755366 | doi-access = free }}</ref> The anti-aging effects of klotho are also a consequence of increased resistance to [[Medicine:Inflammation|inflammation]] and [[Biology:Oxidative stress|oxidative stress]].<ref name="pmid33185993" />

[[Biology:Extracellular vesicle|Extracellular vesicle]]s (EV) in young mice carried more copies of klotho-producing mRNA than those from old mice. Transfusing young EVs into older mice helped rebuild their muscles.<ref>{{Cite web| vauthors = Irving M |date=2021-12-10|title="Young blood" particles that help old mice fight aging identified |url= https://newatlas.com/medical/anti-aging-young-blood-particles/ |access-date=2021-12-11|website=New Atlas|language=en-US}}</ref>

The presence of [[Biology:Cellular senescence|senescent cells]] decreases α-klotho levels. [[Biology:Senolytic|Senolytic]] drugs reduce the level of these cells, allowing α-klotho levels to increase.<ref>{{Cite web | vauthors = Irving M |date=2022-03-16 |title=Senolytic drugs boost protein that protects against effects of aging |url=https://newatlas.com/medical/senolytics-drugs-protein-age-related-disease/ |access-date=2022-03-16 |website=New Atlas |language=en-US}}</ref>

== References ==
{{Reflist|33em}}
 
== Further reading ==
{{refbegin|33em}}
* {{cite journal | vauthors = Shimoyama Y, Taki K, Mitsuda Y, Tsuruta Y, Hamajima N, Niwa T | title = KLOTHO gene polymorphisms G-395A and C1818T are associated with low-density lipoprotein cholesterol and uric acid in Japanese hemodialysis patients | journal = American Journal of Nephrology | volume = 30 | issue = 4 | pages = 383–388 | year = 2009 | pmid = 19690404 | doi = 10.1159/000235686 | s2cid = 38277163 }}
* {{cite journal | vauthors = Choi BH, Kim CG, Lim Y, Lee YH, Shin SY | title = Transcriptional activation of the human Klotho gene by epidermal growth factor in HEK293 cells; role of Egr-1 | journal = Gene | volume = 450 | issue = 1–2 | pages = 121–127 | date = January 2010 | pmid = 19913601 | doi = 10.1016/j.gene.2009.11.004 }}
* {{cite journal | vauthors = Fukumoto S | title = [Chronic kidney disease (CKD) and bone. Regulation of calcium and phosphate metabolism by FGF23/Klotho] | journal = Clinical Calcium | volume = 19 | issue = 4 | pages = 523–528 | date = April 2009 | pmid = 19329831 }}
* {{cite journal | vauthors = Nabeshima Y | title = Challenge of overcoming aging-related disorders | journal = Journal of Dermatological Science | volume = 24 | pages = S15–S21 | date = December 2000 | issue = Suppl 1 | pmid = 11137391 | doi = 10.1016/S0923-1811(00)00136-5 }}
* {{cite journal | vauthors = Razzaque MS | title = FGF23-mediated regulation of systemic phosphate homeostasis: is Klotho an essential player? | journal = American Journal of Physiology. Renal Physiology | volume = 296 | issue = 3 | pages = F470–F476 | date = March 2009 | pmid = 19019915 | pmc = 2660189 | doi = 10.1152/ajprenal.90538.2008 }}
* {{cite journal | vauthors = Menon R, Pearce B, Velez DR, Merialdi M, Williams SM, Fortunato SJ, Thorsen P | title = Racial disparity in pathophysiologic pathways of preterm birth based on genetic variants | journal = Reproductive Biology and Endocrinology | volume = 7 | pages = 62 | date = June 2009 | pmid = 19527514 | pmc = 2714850 | doi = 10.1186/1477-7827-7-62 | doi-access = free }}
* {{cite journal | vauthors = Prié D, Ureña Torres P, Friedlander G | title = [Fibroblast Growth Factor 23-Klotho: a new axis of phosphate balance control] | journal = Médecine/Sciences | volume = 25 | issue = 5 | pages = 489–495 | date = May 2009 | pmid = 19480830 | doi = 10.1051/medsci/2009255489 | doi-access = free }}
* {{cite journal | vauthors = Torres PU, Prié D, Beck L, De Brauwere D, Leroy C, Friedlander G | title = Klotho gene, phosphocalcic metabolism, and survival in dialysis | journal = Journal of Renal Nutrition | volume = 19 | issue = 1 | pages = 50–56 | date = January 2009 | pmid = 19121771 | doi = 10.1053/j.jrn.2008.10.018 }}
* {{cite journal | vauthors = 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 | display-authors = 6 | title = Genetic variation in healthy oldest-old | journal = PLOS ONE | volume = 4 | issue = 8 | pages = e6641 | date = August 2009 | pmid = 19680556 | pmc = 2722017 | doi = 10.1371/journal.pone.0006641 | veditors = Bridger JM | doi-access = free | bibcode = 2009PLoSO...4.6641H }}
* {{cite journal | vauthors = Shimoyama Y, Nishio K, Hamajima N, Niwa T | title = 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 | journal = Clinica Chimica Acta; International Journal of Clinical Chemistry | volume = 406 | issue = 1–2 | pages = 134–138 | date = August 2009 | pmid = 19539617 | doi = 10.1016/j.cca.2009.06.011 }}
* {{cite journal | vauthors = Wang HL, Xu Q, Wang Z, Zhang YH, Si LY, Li XJ, Yang QH, Xiao H | display-authors = 6 | title = A potential regulatory single nucleotide polymorphism in the promoter of the Klotho gene may be associated with essential hypertension in the Chinese Han population | journal = Clinica Chimica Acta; International Journal of Clinical Chemistry | volume = 411 | issue = 5–6 | pages = 386–390 | date = March 2010 | pmid = 20005218 | doi = 10.1016/j.cca.2009.12.004 }}
* {{cite journal | vauthors = 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 | display-authors = 6 | title = High-density association study of 383 candidate genes for volumetric BMD at the femoral neck and lumbar spine among older men | journal = Journal of Bone and Mineral Research | volume = 24 | issue = 12 | pages = 2039–2049 | date = December 2009 | pmid = 19453261 | pmc = 2791518 | doi = 10.1359/jbmr.090524 }}
* {{cite journal | vauthors = Torres PU, Prié D, Molina-Blétry V, Beck L, Silve C, Friedlander G | title = Klotho: an antiaging protein involved in mineral and vitamin D metabolism | journal = Kidney International | volume = 71 | issue = 8 | pages = 730–737 | date = April 2007 | pmid = 17332731 | doi = 10.1038/sj.ki.5002163 | doi-access = free }}
* {{cite journal | vauthors = Kurosu H, Kuro-o M | title = The Klotho gene family and the endocrine fibroblast growth factors | journal = Current Opinion in Nephrology and Hypertension | volume = 17 | issue = 4 | pages = 368–372 | date = July 2008 | pmid = 18660672 | doi = 10.1097/MNH.0b013e3282ffd994 | s2cid = 23104131 }}
* {{cite journal | vauthors = Kuro-o M | title = Klotho and aging | journal = Biochimica et Biophysica Acta (BBA) - General Subjects | volume = 1790 | issue = 10 | pages = 1049–1058 | date = October 2009 | pmid = 19230844 | pmc = 2743784 | doi = 10.1016/j.bbagen.2009.02.005 }}
* {{cite journal | vauthors = 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 | display-authors = 6 | title = Functional variant of KLOTHO: a breast cancer risk modifier among BRCA1 mutation carriers of Ashkenazi origin | journal = Oncogene | volume = 29 | issue = 1 | pages = 26–33 | date = January 2010 | pmid = 19802015 | doi = 10.1038/onc.2009.301 | doi-access = free }}
* {{cite journal | vauthors = Invidia L, Salvioli S, Altilia S, Pierini M, Panourgia MP, Monti D, De Rango F, Passarino G, Franceschi C | display-authors = 6 | title = 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 | journal = Biogerontology | volume = 11 | issue = 1 | pages = 67–73 | date = February 2010 | pmid = 19421891 | doi = 10.1007/s10522-009-9229-z | s2cid = 25150050 | url = https://zenodo.org/record/1066843 }}
* {{cite journal | vauthors = Nabeshima Y | title = [Discovery of alpha-Klotho and FGF23 unveiled new insight into calcium and phosphate homeostasis] | journal = Clinical Calcium | volume = 18 | issue = 7 | pages = 923–934 | date = July 2008 | pmid = 18591743 }}
* {{cite journal | vauthors = Chen SN, Cilingiroglu M, Todd J, Lombardi R, Willerson JT, Gotto AM, Ballantyne CM, Marian AJ | display-authors = 6 | title = Candidate genetic analysis of plasma high-density lipoprotein-cholesterol and severity of coronary atherosclerosis | journal = BMC Medical Genetics | volume = 10 | pages = 111 | date = October 2009 | pmid = 19878569 | pmc = 2775733 | doi = 10.1186/1471-2350-10-111 | doi-access = free }}
* {{cite journal | vauthors = Zhang R, Zheng F | title = PPAR-gamma and aging: one link through klotho? | journal = Kidney International | volume = 74 | issue = 6 | pages = 702–704 | date = September 2008 | pmid = 18756295 | doi = 10.1038/ki.2008.382 | doi-access = free }}
* {{cite journal | vauthors = Kim JH, Hwang KH, Park KS, Kong ID, Cha SK | title = Biological Role of Anti-aging Protein Klotho | journal = Journal of Lifestyle Medicine | volume = 5 | issue = 1 | pages = 1–6 | date = March 2015 | pmid = 26528423 | pmc = 4608225 | doi = 10.15280/jlm.2015.5.1.1 }}
{{refend}}

== External links ==
* {{Cite web |title=KL klotho [Homo sapiens (human)] - Gene  | work = NCBI | publisher = U.S. National Library of Medicine |url=https://www.ncbi.nlm.nih.gov/gene?cmd=Retrieve&dopt=Graphics&list_uids=9365 |access-date=2023-03-20 }}
* {{cite web | url = http://genomics.senescence.info/genes/entry.php?hugo=KL | title = GenAge entry for KL (Homo sapiens) | work = Human Ageing Genomic Resources }}

{{NLM content}}
{{Sugar hydrolases}}
{{Enzymes}}

[[Category:EC 3.2.1]]

{{Sourceattribution|Klotho (biology)|1}}