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Klotho increases membrane expression of the inward rectifier [[Adenosine triphosphate|ATP]]-dependent [[potassium channel]] [[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 = 1049–58 | date = Oct 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 | title = FGF-23-Klotho signaling stimulates proliferation and prevents vitamin D-induced apoptosis | journal = The Journal of Cell Biology | volume = 182 | issue = 3 | pages = 459–65 | date = Aug 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 = 2393–403 | date = Dec 2003 | pmid = 14528024 | doi = 10.1210/me.2003-0048 | doi-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 | title = alpha-Klotho as a regulator of calcium homeostasis | journal = Science | volume = 316 | issue = 5831 | pages = 1615–8 | date = Jun 2007 | pmid = 17569864 | doi = 10.1126/science.1135901 | bibcode = 2007Sci...316.1615I | s2cid = 40529168 }}</ref>
Klotho increases membrane expression of the inward rectifier [[Adenosine triphosphate|ATP]]-dependent [[potassium channel]] [[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 = 1049–58 | date = Oct 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 | title = FGF-23-Klotho signaling stimulates proliferation and prevents vitamin D-induced apoptosis | journal = The Journal of Cell Biology | volume = 182 | issue = 3 | pages = 459–65 | date = Aug 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 = 2393–403 | date = Dec 2003 | pmid = 14528024 | doi = 10.1210/me.2003-0048 | doi-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 | title = alpha-Klotho as a regulator of calcium homeostasis | journal = Science | volume = 316 | issue = 5831 | pages = 1615–8 | date = Jun 2007 | pmid = 17569864 | doi = 10.1126/science.1135901 | bibcode = 2007Sci...316.1615I | s2cid = 40529168 }}</ref>


Klotho is an antagonist of the [[Wnt signaling pathway]], and chronic Wnt stimulation can lead to [[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 TL | title=Augmented Wnt signaling in a mammalian model of accelerated aging | journal=[[Science (journal)|Science]] | volume=317 | issue=5839 | pages=803–806 | year=2007 | doi = 10.1038/ki.2010.73 | pmid=17690294 | doi-access=free }}</ref>
Klotho is an antagonist of the [[Wnt signaling pathway]], and chronic Wnt stimulation can lead to [[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 TL | title=Augmented Wnt signaling in a mammalian model of accelerated aging | journal=[[Science (journal)|Science]] | volume=317 | issue=5839 | pages=803–806 | year=2007 | doi = 10.1038/ki.2010.73 | pmid=17690294 | doi-access=free }}</ref> Klotho inhibition of Wnt signaling can inhibit [[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 | doi = 10.3389/fphar.2021.755366 | pmc=8560683 | pmid=34737707 }}</ref>


[[Extracellular vesicle|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.<ref>{{Cite web|last=Irving|first=Michael|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/|url-status=live|access-date=2021-12-11|website=New Atlas|language=en-US}}</ref>
[[Extracellular vesicle|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.<ref>{{Cite web|last=Irving|first=Michael|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/|url-status=live|access-date=2021-12-11|website=New Atlas|language=en-US}}</ref>

Revision as of 15:12, 1 February 2022

KL
Identifiers
AliasesKL, entrez:9365, klotho, HFTC3, KLA
External IDsOMIM: 604824; MGI: 1101771; HomoloGene: 68415; GeneCards: KL; OMA:KL - orthologs
Orthologs
SpeciesHumanMouse
Entrez

9365

16591

Ensembl

ENSG00000133116

ENSMUSG00000058488

UniProt

Q9UEF7

O35082

RefSeq (mRNA)

NM_004795
NM_153683

NM_013823

RefSeq (protein)

NP_004786

NP_038851

Location (UCSC)Chr 13: 33.02 – 33.07 MbChr 5: 150.88 – 150.92 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Klotho is an enzyme that in humans is encoded by the KL gene.[5] There are three subfamilies of klotho: α-klotho, β-klotho, and γ-klotho.[6] α-klotho activates FGF23, and β-klotho activates FGF19 and FGF21.[7] When the subfamily is not specified, the word "klotho" generally means the α-klotho subfamily.[8]

Klotho can exist in a membrane-bound form or a (hormonal) soluble, circulating form.[9] Proteases can convert the membrane-bound form into the circulating form.[10]

The KL gene encodes a type-I membrane protein 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 the degenerative processes (e.g., arteriosclerosis, osteoporosis, and skin atrophy) seen in CKF. Also, mutations within the Klotho protein family have been associated with ageing, bone loss and alcohol consumption.[11][12] Transgenic mice that overexpress Klotho live longer than wild-type mice.[13]

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.[citation needed]

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][16] and klotho protein has been shown to be a circulating factor detectable in serum that declines with age.[17]

The binding of certain 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.[18][19]

α-klotho 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]

Clinical significance

α-klotho can suppress oxidative stress and inflammation, thereby reducing endothelial dysfunction and atherosclerosis.[8] Blood plasma α-klotho is increased by aerobic exercise, thereby reducing endothelial dysfunction.[22]

β-klotho activation of FGF21 protein has a protective effect on heart muscle cells.[23] 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.[23]

Klotho is required for oligodendrocyte maturation, myelin integrity, and can protect neurons from toxic effects.[24] Mice deficient in klotho have a reduced number of synapses and cognitive deficits, whereas mice overexpressing klotho have enhanced learning and memory.[25]

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.[26] 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 NO production.

Klotho could play a protective role in Alzheimer's disease patients.[27][28]

Effects on aging

Mice lacking either fibroblast growth factor 23 or the α-klotho enzyme display premature aging due to hyperphosphatemia.[29] Many of these symptoms can be alleviated by feeding the mice a low phosphate diet.[7]

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.[13] 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.[30]

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).[31][32][33][34]

Klotho is an antagonist of the Wnt signaling pathway, and chronic Wnt stimulation can lead to stem cell depletion and aging.[35] Klotho inhibition of Wnt signaling can inhibit cancer.[36]

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.[37]

References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000133116 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000058488 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ Matsumura Y, Aizawa H, Shiraki-Iida T, Nagai R, Kuro-o M, Nabeshima Y (January 1998). "Identification of the human klotho gene and its two transcripts encoding membrane and secreted klotho protein". Biochemical and Biophysical Research Communications. 242 (3): 626–30. doi:10.1006/bbrc.1997.8019. PMID 9464267.
  6. ^ Dolegowska K, Marchelek-Mysliwiec M, Nowosiad-Magda M, Slawinski M, Dolegowska B (June 2019). "FGF19 subfamily members: FGF19 and FGF21". Journal of Physiology and Biochemistry. 75 (2): 229–240. doi:10.1007/s13105-019-00675-7. PMC 6611749. PMID 30927227.
  7. ^ a b Kuro-O M (January 2019). "The Klotho proteins in health and disease". Nature Reviews. Nephrology. 15 (1): 27–44. doi:10.1038/s41581-018-0078-3. PMID 30455427. S2CID 53872296.
  8. ^ a b Lim K, Halim A, Lu TS, Ashworth A, Chong I (September 2019). "Klotho: A Major Shareholder in Vascular Aging Enterprises". International Journal of Molecular Sciences. 20 (18): E4637. doi:10.3390/ijms20184637. PMC 6770519. PMID 31546756.
  9. ^ Buendía P, Ramírez R, Aljama P, Carracedo J (2016). "Klotho Prevents Translocation of NFκB". Klotho. Vitamins & Hormones. Vol. 101. pp. 119–150. doi:10.1016/bs.vh.2016.02.005. ISBN 9780128048191. PMID 27125740.
  10. ^ Martín-González C, González-Reimers E, Quintero-Platt G, Martínez-Riera A, Santolaria-Fernández F (2019). "Soluble α-Klotho in Liver Cirrhosis and Alcoholism". Alcohol and Alcoholism. 54 (3): 204–208. doi:10.1093/alcalc/agz019. PMC 6731336. PMID 30860544.
  11. ^ "Entrez Gene: klotho".
  12. ^ Schumann G, Liu C, O'Reilly P, Gao H, Song P, Xu B, et al. (2016). "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. doi:10.1073/pnas.1611243113. PMC 5167198. PMID 27911795.
  13. ^ a b 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 (Sep 2005). "Suppression of aging in mice by the hormone Klotho". Science. 309 (5742): 1829–33. Bibcode:2005Sci...309.1829K. doi:10.1126/science.1112766. PMC 2536606. PMID 16123266.
  14. ^ 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 (Nov 1997). "Mutation of the mouse klotho gene leads to a syndrome resembling ageing". Nature. 390 (6655): 45–51. Bibcode:1997Natur.390...45K. doi:10.1038/36285. PMID 9363890. S2CID 4428141.
  15. ^ Arking DE, Krebsova A, Macek M, Macek M, Arking A, Mian IS, Fried L, Hamosh A, Dey S, McIntosh I, Dietz HC (Jan 2002). "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): 856–61. Bibcode:2002PNAS...99..856A. doi:10.1073/pnas.022484299. PMC 117395. PMID 11792841.
  16. ^ Rodriguez T (2015). "Identifying significant biological markers in Klotho gene variants across wide ranging taxonomy". Journal of Molecular Biology Research. 5 (1): 11. doi:10.5539/jmbr.v5n1p11.
  17. ^ Xiao NM, Zhang YM, Zheng Q, Gu J (May 2004). "Klotho is a serum factor related to human aging". Chinese Medical Journal. 117 (5): 742–7. PMID 15161545.[permanent dead link]
  18. ^ Helsten T, Schwaederle M, Kurzrock R (2015). "Fibroblast growth factor receptor signaling in hereditary and neoplastic disease: biologic and clinical implications". Cancer and Metastasis Reviews. 34 (3): 479–96. doi:10.1007/s10555-015-9579-8. PMC 4573649. PMID 26224133.
  19. ^ 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 (February 2016). "FGF21 Regulates Sweet and Alcohol Preference". Cell Metabolism. 23 (2): 344–9. doi:10.1016/j.cmet.2015.12.008. PMC 4749404. PMID 26724861.
  20. ^ a b Huang CL (May 2010). "Regulation of ion channels by secreted Klotho: mechanisms and implications". Kidney International. 77 (10): 855–60. doi:10.1038/ki.2010.73. PMID 20375979.
  21. ^ van Goor MK, Hoenderop JG, van der Wijst J (2017). "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. doi:10.1016/j.bbamcr.2016.11.027. PMID 27913205.
  22. ^ Saghiv MS, Sira DB, Goldhammer E, Sagiv M (2017). "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. doi:10.1177/1849454417733388. PMC 5644364. PMID 29081845.
  23. ^ a b Olejnik A, Franczak A, Krzywonos-Zawadzka A, Kałużna-Oleksy M, Bil-Lula I (2018). "The Biological Role of Klotho Protein in the Development of Cardiovascular Diseases". BioMed Research International. 2018: 5171945. doi:10.1155/2018/5171945. PMC 6323445. PMID 30671457.
  24. ^ Torbus-Paluszczak M, Bartman W, Adamczyk-Sowa M (2018). "Klotho protein in neurodegenerative disorders". Neurological Sciences. 39 (10): 1677–1682. doi:10.1007/s10072-018-3496-x. PMC 6154120. PMID 30062646.
  25. ^ Vo HT, Laszczyk AM, King GD (2018). "Klotho, the Key to Healthy Brain Aging?". Brain Plasticity. 3 (2): 183–194. doi:10.3233/BPL-170057. PMC 6091049. PMID 30151342.
  26. ^ Adhikari BR, Uehara O, Matsuoka H, Takai R, Harada F, Utsunomiya M, et al. (September 2017). "Immunohistochemical evaluation of Klotho and DNA methyltransferase 3a in oral squamous cell carcinomas". Medical Molecular Morphology. 50 (3): 155–160. doi:10.1007/s00795-017-0156-9. PMID 28303350. S2CID 22810635.
  27. ^ Paroni G, Panza F, De Cosmo S, Greco A, Seripa D, Mazzoccoli G (March 2019). "Klotho at the Edge of Alzheimer's Disease and Senile Depression". Molecular Neurobiology. 56 (3): 1908–1920. doi:10.1007/s12035-018-1200-z. PMID 29978424. S2CID 49567009.
  28. ^ Lehrer S, Rheinstein PH (2020). "Alignment of Alzheimer's disease amyloid β-peptide and klotho". World Academy of Sciences Journal. 2 (6). doi:10.3892/wasj.2020.68. PMC 7521834. PMID 32999998.
  29. ^ Huang CL (2010). "Regulation of ion channels by secreted Klotho: mechanisms and implications". Kidney International. 77 (10): 855–860. doi:10.1038/ki.2010.73. PMID 20375979.
  30. ^ Dubal DB, Yokoyama JS, Zhu L, Broestl L, Worden K, Wang D, et al. (May 2014). "Life extension factor klotho enhances cognition". Cell Reports. 7 (4): 1065–76. doi:10.1016/j.celrep.2014.03.076. PMC 4176932. PMID 24813892.
  31. ^ Kuro-o M (Oct 2009). "Klotho and aging". Biochimica et Biophysica Acta (BBA) - General Subjects. 1790 (10): 1049–58. doi:10.1016/j.bbagen.2009.02.005. PMC 2743784. PMID 19230844.
  32. ^ Medici D, Razzaque MS, Deluca S, Rector TL, Hou B, Kang K, Goetz R, Mohammadi M, Kuro-O M, Olsen BR, Lanske B (Aug 2008). "FGF-23-Klotho signaling stimulates proliferation and prevents vitamin D-induced apoptosis". The Journal of Cell Biology. 182 (3): 459–65. doi:10.1083/jcb.200803024. PMC 2500132. PMID 18678710.
  33. ^ Tsujikawa H, Kurotaki Y, Fujimori T, Fukuda K, Nabeshima Y (Dec 2003). "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): 2393–403. doi:10.1210/me.2003-0048. PMID 14528024.
  34. ^ 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 (Jun 2007). "alpha-Klotho as a regulator of calcium homeostasis". Science. 316 (5831): 1615–8. Bibcode:2007Sci...316.1615I. doi:10.1126/science.1135901. PMID 17569864. S2CID 40529168.
  35. ^ 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 TL (2007). "Augmented Wnt signaling in a mammalian model of accelerated aging". Science. 317 (5839): 803–806. doi:10.1038/ki.2010.73. PMID 17690294.
  36. ^ Zhou H, Pu S, Zhou H, Guo Y (2021). "Klotho as Potential Autophagy Regulator and Therapeutic Target". Frontiers in Pharmacology. 12: 755366. doi:10.3389/fphar.2021.755366. PMC 8560683. PMID 34737707.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  37. ^ Irving, Michael (2021-12-10). ""Young blood" particles that help old mice fight aging identified". New Atlas. Retrieved 2021-12-11.{{cite web}}: CS1 maint: url-status (link)

Further reading

This article incorporates text from the United States National Library of Medicine, which is in the public domain.

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