Klotho (biology)#Effects on aging

The α-klotho gene is located on chromosome 13, and is translated into a single-pass integral membrane protein.

The β-Klotho gene is located on chromosome 4. The protein shares homology (43.1% identity and 60.1% similarity) with α-klotho. {{cite web |title=Klotho Beta |url=https://www.genecards.org/cgi-bin/carddisp.pl?gene=KLB |access-date=12 September 2023}}

The β-Klotho gene and β-Klotho protein should not be confused with the alpha-cut and beta-cut of alpha-klotho, which releases KL1+KL2 and KL2 domain of α-klotho into the extracellular matrix and bloodstream, respectively.

There are two main isoforms.

One isoform is the full-length Klotho mRNA, that includes signal peptide, KL1 domain, linker region, KL2 domain, transmembrane region and intracellular domain. This gets produced into a full protein that is stuck in the membrane and subsequently is cleaved into soluble klotho proteins that are found in circulation in the bloodstream.{{cite web |title=Klotho Beta |url=https://pubmed.ncbi.nlm.nih.gov/26155844/B |access-date=30 October 2024}}

The other isoform is a truncated mRNA, that terminates after the KL1 domain and thus the transmembrane region gets cleaved off and the produced protein is excreted into the extracellular medium.{{cite web |title=Klotho Beta |url=https://www.nature.com/articles/s41598-023-31117-6#:~:text=Abstract,protein%20(s%2DKL). |access-date=30 October 2024}}

The intracellular portion of the α-klotho protein is short (11 amino acids), whereas the extracellular portion is long (980 amino acids). The transmembrane portion is also comparatively short (21 amino acids). The extracellular portion contains two repeat sequences, termed the KL1 (about 450 amino acids) and KL2 (about 430 amino acids) domains. In the kidney and the choroid plexus of the brain, the transmembrane protein can be proteolytically cleaved to produce a 130-Kilo-Dalton, soluble form of α-klotho protein, released into the circulation and cerebrospinal fluid, respectively. In humans, the secreted form of klotho is more dominant than the membrane form.

The nomenclature of physiologically appearing klotho polypeptide fragments can be confusing. In order to distinguish the different circulating polypeptides (cleavage fragments and isoforms), newer papers follow the following nomenclature{{cite web |title=Klotho Beta |url=https://www.nature.com/articles/s41598-023-31117-6#:~:text=Abstract,protein%20(s%2DKL). |access-date=30 October 2024}}

mKL:

mKL135 stands for the full-length, transmembrane form

pKL:

Processed Klotho (p-KL) comes from the processing of full-length transmembrane klotho protein. This cleavage releases the ectodomains into the extracellular medium, while the transmembrane domain (with or without KL2) remains in the cell membrane. This includes pKL65 (65 kDa in size) and pKL130 (130 kDa in size).

sKL:

The protein resulting from the shorter transcript for a putatively secreted protein (s-KL), which is produced as a soluble polypeptide without transmembrane domain.

It is important to keep in mind that previously, the processed (cleaved) fragments of klotho have also been named "sKL130" and "sKL65". in this case, the "s" stands for soluble.

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.{{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 }} The name of the gene comes from Klotho or Clotho, one of the Moirai, or Fates, in Greek mythology, who spins the thread of human life.{{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 }}

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,{{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 }} and klotho protein has been shown to be a circulating factor detectable in serum that declines with age.{{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 }}

β-Klotho: The binding of the endocrine 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.{{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 }}{{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 }} Loss of β-Klotho abolishes all effects of FGF21.{{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 }}

α-klotho, which binds to the endocrine FGF FGF23 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).{{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 }} α-klotho increases kidney calcium reabsorption by stabilizing TRPV5.{{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 }} About 95% to 98% of Ca²⁺ filtered from the blood by the kidney is normally reabsorbed by the kidney's renal tubule, which is mediated by TRPV5.{{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 }}

α-klotho can suppress oxidative stress and inflammation, thereby reducing endothelial dysfunction and atherosclerosis. Blood plasma α-klotho is increased by aerobic exercise, thereby reducing endothelial dysfunction.{{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 }}

β-klotho activation of FGF21 protein has a protective effect on heart muscle cells.{{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 }} 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, but there is evidence against this mechanism.{{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 }}

Klotho is required for oligodendrocyte maturation, myelin integrity, and can protect neurons from toxic effects.{{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 }} Mice deficient in klotho have a reduced number of synapses and cognitive deficits, whereas mice overexpressing klotho have enhanced learning and memory.{{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 }} Research with injections of klotho in primates demonstrates a positive effect on memory that lasts for as long as two weeks; this could have implications for research with humans.{{cite journal | vauthors = Tozer L | url = https://www.nature.com/articles/d41586-023-02214-3 | 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 | url-access=subscription }} Interestingly the cognitive effects in rhesus monkeys were observed even with subcutaneous injection despite previous results showing that klotho protein fails to cross the blood–brain barrier.{{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 }}

Reduced klotho expression is seen in the lung macrophages of smokers. An abnormal form of autophagy associated with reduced expression of klotho is linked to the pathogenesis of chronic obstructive pulmonary disease. (Although normal autophagy helps maintain muscle, excessive autophagy causes loss of muscle mass.)

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.{{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 }} 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 ageing 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 nitric oxide production.

Klotho could play a protective role in Alzheimer's disease patients.{{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 }}{{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 }}

Reduced α-klotho or FGF23 can result in impaired phosphate excretion from the kidney, leading to hyperphosphatemia. In mice, this leads to a phenotype characteristic of premature aging, which can be mitigated by feeding the mice a low phosphate diet.

The plasma (soluble) form of α-klotho is most easily measured, and has been shown to decrease after 40 years of age in humans.{{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 }} Lower plasma levels of α-klotho in older adults is associated with increased frailty and all-cause mortality. Physical activity has been shown to increase plasma α-klotho.

Mice lacking either fibroblast growth factor 23 or the α-klotho enzyme display premature aging due to hyperphosphatemia. Many of these symptoms can be alleviated by feeding the mice a low phosphate diet.

Although the majority of research has explored klotho's absence, it was demonstrated that klotho over-expression in mice extended their average lifespan between 19% and 31% compared to normal mice.{{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 }} 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 heterozygous, not homozygous.{{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 | author-link1 = Dena Dubal }} The cognitive benefits of α-klotho are primarily seen late in life.

Klotho increases membrane expression of the inward rectifier ATP-dependent potassium channel ROMK. 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).{{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 = 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 }}{{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 }}{{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 }}

Klotho is an antagonist of the Wnt signaling pathway, and chronic Wnt stimulation can lead to stem cell depletion and aging.{{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 }} Klotho inhibition of Wnt signaling can inhibit cancer.{{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 }} The anti-aging effects of klotho are also a consequence of increased resistance to inflammation and oxidative stress.

Extracellular vesicles (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.{{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}}

The presence of senescent cells decreases α-klotho levels. Senolytic drugs reduce the level of these cells, allowing α-klotho levels to increase.{{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}}

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• {{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}}

{{Portal|Biology}}

• {{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 }}

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Category:Biogerontology

Category:EC 3.2.1