Biology:Klotho

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Short description: Human enzyme


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example


Klotho is an enzyme that in humans is encoded by the KL gene.[1] The three subfamilies of klotho are α-klotho, β-klotho, and γ-klotho.[2] α-klotho activates FGF23, and β-klotho activates FGF19 and FGF21.[3] 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.[4][3]

α-klotho is highly expressed in the brain, liver and kidney.[5] β-klotho is predominantly expressed in the liver.[6][5] γ-klotho is expressed in the skin.[5]

Klotho can exist in a membrane-bound form or a (hormonal) soluble, circulating form.[7] Proteases can convert the membrane-bound form into the circulating form.[8]

The KL gene encodes a type-I single-pass transmembrane protein[3] 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 degenerative processes (e.g., arteriosclerosis, osteoporosis, and skin atrophy) seen in CKF. Mutations within the family have been associated with ageing, bone loss and alcohol consumption.[9][10] Transgenic mice that overexpress Klotho live longer than wild-type mice.[11]

Structure

The α-klotho gene is located on chromosome 13, and is translated into a single-pass integral membrane protein.[5] The intracellular portion of the α-klotho protein is short (11 amino acids), whereas the extracellular portion is long (980 amino acids).[5] The transmembrane portion is also comparatively short (21 amino acids).[5] The extracellular portion contains two repeat sequences, termed the KL1 (about 450 amino acids) and KL2 (about 430 amino acids) domains.[5][3] 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.[5] In humans, the secreted form of klotho is more dominant than the membrane form.[12]

The β-Klotho gene is located on chromosome 4. The protein shares homology (43.1% identity and 60.1% similarity) with α-klotho. [13] 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 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, who spins the thread of human life.[3]

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] and klotho protein has been shown to be a circulating factor detectable in serum that declines with age.[16]

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.[17][18][12][3] Loss of β-Klotho abolishes all effects of FGF21.[19]

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).[20] α-klotho increases kidney calcium reabsorption by stabilizing TPRV5.[21] 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.[22]

Clinical significance

α-klotho can suppress oxidative stress and inflammation, thereby reducing endothelial dysfunction and atherosclerosis.[4] Blood plasma α-klotho is increased by aerobic exercise, thereby reducing endothelial dysfunction.[23]

β-klotho activation of FGF21 protein has a protective effect on heart muscle cells.[24] 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,[24] but there is evidence against this mechanism.[12]

Klotho is required for oligodendrocyte maturation, myelin integrity, and can protect neurons from toxic effects.[25] Mice deficient in klotho have a reduced number of synapses and cognitive deficits, whereas mice overexpressing klotho have enhanced learning and memory.[26] Research with injections of klotho in primates demonstrates a positive effect on memory that lasts for as long as two weeks.[27]

Reduced klotho expression is seen in the lung macrophages of smokers.[28] An abnormal form of autophagy associated with reduced expression of klotho is linked to the pathogenesis of chronic obstructive pulmonary disease.[28] (Although normal autophagy helps maintain muscle, excessive autophagy causes loss of muscle mass.[28])

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.[29] 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.[12]

Klotho could play a protective role in Alzheimer's disease patients.[30][31]

Research with injections of α-klotho in primates suggests a positive effect on memory that could have implications for research with humans.[27] 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.[32]

Effects on aging

Reduced α-klotho or FGF23 can result in impaired phosphate excretion from the kidney, leading to hyperphosphatemia.[3] In mice, this leads to a phenotype characteristic of premature aging, which can be mitigated by feeding the mice a low phosphate diet.[3]

The plasma (soluble) form of α-klotho is most easily measured, and has been shown to decrease after 40 years of age in humans.[33] Lower plasma levels of α-klotho in older adults is associated with increased frailty and all-cause mortality.[33] Physical activity has been shown to increase plasma α-klotho.[33]

Mice lacking either fibroblast growth factor 23 or the α-klotho enzyme display premature aging due to hyperphosphatemia.[20] Many of these symptoms can be alleviated by feeding the mice a low phosphate diet.[3]

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.[11] 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.[34][5] The cognitive benefits of α-klotho are primarily seen late in life.[5]

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 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).[35][36][37][38]

Klotho is an antagonist of the Wnt signaling pathway, and chronic Wnt stimulation can lead to stem cell depletion and aging.[39] Klotho inhibition of Wnt signaling can inhibit cancer.[28] The anti-aging effects of klotho are also a consequence of increased resistance to inflammation and oxidative stress.[12]

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.[40]

The presence of senescent cells decreases α-klotho levels. Senolytic drugs reduce the level of these cells, allowing α-klotho levels to increase.[41]

References

  1. ↑ "Identification of the human klotho gene and its two transcripts encoding membrane and secreted klotho protein". Biochemical and Biophysical Research Communications 242 (3): 626–630. January 1998. doi:10.1006/bbrc.1997.8019. PMID 9464267. 
  2. ↑ "FGF19 subfamily members: FGF19 and FGF21". Journal of Physiology and Biochemistry 75 (2): 229–240. June 2019. doi:10.1007/s13105-019-00675-7. PMID 30927227. 
  3. ↑ 3.0 3.1 3.2 3.3 3.4 3.5 3.6 3.7 3.8 "The Klotho proteins in health and disease". Nature Reviews. Nephrology 15 (1): 27–44. January 2019. doi:10.1038/s41581-018-0078-3. PMID 30455427. 
  4. ↑ 4.0 4.1 "Klotho: A Major Shareholder in Vascular Aging Enterprises". International Journal of Molecular Sciences 20 (18): E4637. September 2019. doi:10.3390/ijms20184637. PMID 31546756. 
  5. ↑ 5.0 5.1 5.2 5.3 5.4 5.5 5.6 5.7 5.8 5.9 "Exploiting the neuroprotective effects of α-klotho to tackle ageing- and neurodegeneration-related cognitive dysfunction". Neuronal Signaling 5 (2): NS20200101. June 2021. doi:10.1042/NS20200101. PMID 34194816. 
  6. ↑ "Plasticity of renal endocrine function". American Journal of Physiology. Regulatory, Integrative and Comparative Physiology 308 (6): R455–R466. March 2015. doi:10.1152/ajpregu.00568.2013. PMID 25608752. 
  7. ↑ "Klotho Prevents Translocation of NFκB". Klotho. Vitamins & Hormones. 101. 2016. pp. 119–150. doi:10.1016/bs.vh.2016.02.005. ISBN 9780128048191. 
  8. ↑ "Soluble α-Klotho in Liver Cirrhosis and Alcoholism". Alcohol and Alcoholism 54 (3): 204–208. May 2019. doi:10.1093/alcalc/agz019. PMID 30860544. 
  9. ↑ "Entrez Gene: klotho". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=9365. 
  10. ↑ "KLB is associated with alcohol drinking, and its gene product β-Klotho is necessary for FGF21 regulation of alcohol preference". Proceedings of the National Academy of Sciences of the United States of America 113 (50): 14372–14377. December 2016. doi:10.1073/pnas.1611243113. PMID 27911795. Bibcode: 2016PNAS..11314372S. 
  11. ↑ 11.0 11.1 "Suppression of aging in mice by the hormone Klotho". Science 309 (5742): 1829–1833. September 2005. doi:10.1126/science.1112766. PMID 16123266. Bibcode: 2005Sci...309.1829K. 
  12. ↑ 12.0 12.1 12.2 12.3 12.4 "The metabolic, neuroprotective cardioprotective and antitumor effects of the Klotho protein". Neuro Endocrinology Letters 41 (2): 69–75. September 2020. PMID 33185993. 
  13. ↑ "Klotho Beta". https://www.genecards.org/cgi-bin/carddisp.pl?gene=KLB. 
  14. ↑ "Mutation of the mouse klotho gene leads to a syndrome resembling ageing". Nature 390 (6655): 45–51. November 1997. doi:10.1038/36285. PMID 9363890. Bibcode: 1997Natur.390...45K. 
  15. ↑ "Association of human aging with a functional variant of klotho". Proceedings of the National Academy of Sciences of the United States of America 99 (2): 856–861. January 2002. doi:10.1073/pnas.022484299. PMID 11792841. Bibcode: 2002PNAS...99..856A. 
  16. ↑ "Klotho is a serum factor related to human aging". Chinese Medical Journal 117 (5): 742–747. May 2004. PMID 15161545. http://www.cmj.org/Periodical/LinkIn.asp?journal=Chinese%20Medical%20Journal&linkintype=pubmed&year=2004&vol=117&issue=5&beginpage=742. [yes|permanent dead link|dead link}}]
  17. ↑ "Fibroblast growth factor receptor signaling in hereditary and neoplastic disease: biologic and clinical implications". Cancer and Metastasis Reviews 34 (3): 479–496. September 2015. doi:10.1007/s10555-015-9579-8. PMID 26224133. 
  18. ↑ "FGF21 Regulates Sweet and Alcohol Preference". Cell Metabolism 23 (2): 344–349. February 2016. doi:10.1016/j.cmet.2015.12.008. PMID 26724861. 
  19. ↑ "Metabolic Messengers: FGF21". Nature Metabolism 3 (3): 309–317. March 2021. doi:10.1038/s42255-021-00354-2. PMID 33758421. 
  20. ↑ 20.0 20.1 20.2 "Regulation of ion channels by secreted Klotho: mechanisms and implications". Kidney International 77 (10): 855–860. May 2010. doi:10.1038/ki.2010.73. PMID 20375979. 
  21. ↑ "TRP channels in calcium homeostasis: from hormonal control to structure-function relationship of TRPV5 and TRPV6". Biochimica et Biophysica Acta (BBA) - Molecular Cell Research 1864 (6): 883–893. June 2017. doi:10.1016/j.bbamcr.2016.11.027. PMID 27913205. 
  22. ↑ "Klotho up-regulates renal calcium channel transient receptor potential vanilloid 5 (TRPV5) by intra- and extracellular N-glycosylation-dependent mechanisms". The Journal of Biological Chemistry 289 (52): 35849–35857. December 2014. doi:10.1074/jbc.M114.616649. PMID 25378396. 
  23. ↑ "The effects of aerobic and anaerobic exercises on circulating soluble-Klotho and IGF-I in young and elderly adults and in CAD patients". Journal of Circulating Biomarkers 6: 1849454417733388. 2017. doi:10.1177/1849454417733388. PMID 29081845. 
  24. ↑ 24.0 24.1 "The Biological Role of Klotho Protein in the Development of Cardiovascular Diseases". BioMed Research International 2018: 5171945. 2018. doi:10.1155/2018/5171945. PMID 30671457. 
  25. ↑ "Klotho protein in neurodegenerative disorders". Neurological Sciences 39 (10): 1677–1682. October 2018. doi:10.1007/s10072-018-3496-x. PMID 30062646. 
  26. ↑ "Klotho, the Key to Healthy Brain Aging?". Brain Plasticity 3 (2): 183–194. August 2018. doi:10.3233/BPL-170057. PMID 30151342. 
  27. ↑ 27.0 27.1 "Anti-ageing protein injection boosts monkeys' memories". Nature 619 (7969): 234. 4 July 2023. doi:10.1038/d41586-023-02214-3. PMID 37402904. Bibcode: 2023Natur.619..234T. 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. 
  28. ↑ 28.0 28.1 28.2 28.3 "Klotho as Potential Autophagy Regulator and Therapeutic Target". Frontiers in Pharmacology 12: 755366. 2021. doi:10.3389/fphar.2021.755366. PMID 34737707. 
  29. ↑ "Immunohistochemical evaluation of Klotho and DNA methyltransferase 3a in oral squamous cell carcinomas". Medical Molecular Morphology 50 (3): 155–160. September 2017. doi:10.1007/s00795-017-0156-9. PMID 28303350. 
  30. ↑ "Klotho at the Edge of Alzheimer's Disease and Senile Depression". Molecular Neurobiology 56 (3): 1908–1920. March 2019. doi:10.1007/s12035-018-1200-z. PMID 29978424. 
  31. ↑ "Alignment of Alzheimer's disease amyloid β-peptide and klotho". World Academy of Sciences Journal 2 (6): 1. 2020. doi:10.3892/wasj.2020.68. PMID 32999998. 
  32. ↑ "Longevity factor klotho enhances cognition in aged nonhuman primates". Nature Aging 3 (8): 931–937. July 2023. doi:10.1038/s43587-023-00441-x. PMID 37400721. 
  33. ↑ 33.0 33.1 33.2 "Association of Klotho with physical performance and frailty in middle-aged and older adults: A systematic review". Experimental Gerontology 154: 111518. October 2021. doi:10.1016/j.exger.2021.111518. PMID 34407459. 
  34. ↑ "Life extension factor klotho enhances cognition". Cell Reports 7 (4): 1065–1076. May 2014. doi:10.1016/j.celrep.2014.03.076. PMID 24813892. 
  35. ↑ "Klotho and aging". Biochimica et Biophysica Acta (BBA) - General Subjects 1790 (10): 1049–1058. October 2009. doi:10.1016/j.bbagen.2009.02.005. PMID 19230844. 
  36. ↑ "FGF-23-Klotho signaling stimulates proliferation and prevents vitamin D-induced apoptosis". The Journal of Cell Biology 182 (3): 459–465. August 2008. doi:10.1083/jcb.200803024. PMID 18678710. 
  37. ↑ "Klotho, a gene related to a syndrome resembling human premature aging, functions in a negative regulatory circuit of vitamin D endocrine system". Molecular Endocrinology 17 (12): 2393–2403. December 2003. doi:10.1210/me.2003-0048. PMID 14528024. 
  38. ↑ "alpha-Klotho as a regulator of calcium homeostasis". Science 316 (5831): 1615–1618. June 2007. doi:10.1126/science.1135901. PMID 17569864. Bibcode: 2007Sci...316.1615I. 
  39. ↑ "Augmented Wnt signaling in a mammalian model of accelerated aging". Science 317 (5839): 803–806. August 2007. doi:10.1038/ki.2010.73. PMID 17690294. 
  40. ↑ ""Young blood" particles that help old mice fight aging identified" (in en-US). 2021-12-10. https://newatlas.com/medical/anti-aging-young-blood-particles/. 
  41. ↑ "Senolytic drugs boost protein that protects against effects of aging" (in en-US). 2022-03-16. https://newatlas.com/medical/senolytics-drugs-protein-age-related-disease/. 

Further reading

External links

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