Skip to main content

Role of Klotho Protein in Neuropsychiatric Disorders: A Narrative Review

Abstract

Neuropsychiatric disorders are comprised of diseases having both the neurological and psychiatric manifestations. The increasing burden of the disease on the population worldwide makes it necessary to adopt measures to decrease the prevalence. The Klotho is a single pass transmembrane protein that decreases with age, has been associated with various pathological diseases, like reduced bone mineral density, cardiac problems and cognitive impairment. However, multiple studies have explored its role in different neuropsychiatric disorders. A comprehensive search was undertaken in the Pubmed database for articles with the keywords “Klotho” and “neuropsychiatric disorders”. The available literature, based on the above search strategy, has been compiled in this brief narrative review to describe the emerging role of Klotho in various neuropsychiatric disorders. The Klotho levels were decreased in various neuropsychiatric disorders except for bipolar disorder. A suppressed Klotho protein levels induced oxidative stress and incited pro-inflammatory conditions significantly contributing to the pathophysiology of neuropsychiatric disorder. The increasing evidence of altered Klotho protein levels in cognition-decrement-related disorders warrants its consideration as a biomarker in various neuropsychiatric diseases. However, further evidence is required to understand its role as a therapeutic target.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3

References

  1. Miyoshi K, Morimura Y. Clinical Manifestations of Neuropsychiatric Disorders. Neuropsychiatric Disorders. Springer;2010:3–18. doi:https://doi.org/10.1007/978-4-431-53871-4.

  2. Kuro-o M, Matsumura Y, Aizawa H, Kawaguchi H, Suga T, Utsugi T, et al. Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature. 1997;390(6655):45–51.

    CAS  Article  Google Scholar 

  3. Kurosu H, Yamamoto M, Clark JD, Pastor JV, Nandi A, Gurnani P, et al. Suppression of aging in mice by the hormone Klotho. Science. 2005;309(5742):1829–33.

    CAS  Article  Google Scholar 

  4. Imura A, Tsuji Y, Murata M, Maeda R, Kubota K, Iwano A, et al. alpha-Klotho as a regulator of calcium homeostasis. Science. 2007;316(5831):1615–8. doi:https://doi.org/10.1126/science.1135901.

    CAS  Article  PubMed  Google Scholar 

  5. Chen CD, Podvin S, Gillespie E, Leeman SE, Abraham CR. Insulin stimulates the cleavage and release of the extracellular domain of Klotho by ADAM10 and ADAM17. Proc Natl Acad Sci U S A. 2007;104(50):19796–801. doi:https://doi.org/10.1073/pnas.0709805104.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Chen CD, Tung TY, Liang J, Zeldich E, Tucker Zhou TB, Turk BE, et al. Identification of cleavage sites leading to the shed form of the anti-aging protein klotho. Biochemistry. 2014;53(34):5579–87. doi:https://doi.org/10.1021/bi500409n.

    CAS  Article  PubMed  Google Scholar 

  7. van Loon EP, Pulskens WP, van der Hagen EA, Lavrijsen M, Vervloet MG, van Goor H, et al. Shedding of klotho by ADAMs in the kidney. Am J Physiol Renal Physiol. 2015;309(4):F359–68. doi:https://doi.org/10.1152/ajprenal.00240.2014.

    CAS  Article  PubMed  Google Scholar 

  8. Shiraki-Iida T, Aizawa H, Matsumura Y, Sekine S, Iida A, Anazawa H, et al. Structure of the mouse klotho gene and its two transcripts encoding membrane and secreted protein. FEBS Lett. 1998;424(1–2):6–10. doi:https://doi.org/10.1016/s0014-5793(98)00127-6.

    CAS  Article  PubMed  Google Scholar 

  9. Saito K, Ishizaka N, Mitani H, Ohno M, Nagai R. Iron chelation and a free radical scavenger suppress angiotensin II-induced downregulation of klotho, an anti-aging gene, in rat. FEBS Lett. 2003;551(1–3):58–62. doi:https://doi.org/10.1016/s0014-5793(03)00894-9.

    CAS  Article  PubMed  Google Scholar 

  10. Zhou Q, Lin S, Tang R, Veeraragoo P, Peng W, Wu R. Role of Fosinopril and Valsartan on Klotho Gene Expression Induced by Angiotensin II in Rat Renal Tubular Epithelial Cells. Kidney Blood Press Res. 2010;33(3):186–92. doi:https://doi.org/10.1159/000316703.

    CAS  Article  PubMed  Google Scholar 

  11. Li Y, Liu Y, Wang K, Huang Y, Han W, Xiong J, et al. Klotho is regulated by transcription factor Sp1 in renal tubular epithelial cells. BMC Mol Cell Biol. 2020;21(1):45. doi:https://doi.org/10.1186/s12860-020-00292-z.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  12. Moreno JA, Izquierdo MC, Sanchez-Niño MD, Suárez-Alvarez B, Lopez-Larrea C, Jakubowski A, et al. The inflammatory cytokines TWEAK and TNFα reduce renal klotho expression through NFκB. J Am Soc Nephrol. 2011;22(7):1315–25. doi:https://doi.org/10.1681/asn.2010101073.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  13. Hayden MS, Ghosh S. Regulation of NF-κB by TNF family cytokines. Semin Immunol. 2014;26(3):253–66.

    CAS  Article  Google Scholar 

  14. Asai O, Nakatani K, Tanaka T, Sakan H, Imura A, Yoshimoto S, et al. Decreased renal α-Klotho expression in early diabetic nephropathy in humans and mice and its possible role in urinary calcium excretion. Kidney Int. 2012;81(6):539–47. doi:https://doi.org/10.1038/ki.2011.423.

    CAS  Article  PubMed  Google Scholar 

  15. Choi BH, Kim CG, Lim Y, Lee YH, Shin SY. Transcriptional activation of the human Klotho gene by epidermal growth factor in HEK293 cells; role of Egr-1. Gene. 2010;450(1–2):121–7. doi:https://doi.org/10.1016/j.gene.2009.11.004.

    CAS  Article  PubMed  Google Scholar 

  16. Forster RE, Jurutka PW, Hsieh JC, Haussler CA, Lowmiller CL, Kaneko I, et al. Vitamin D receptor controls expression of the anti-aging klotho gene in mouse and human renal cells. Biochem Biophys Res Commun. 2011;414(3):557–62.

    CAS  Article  Google Scholar 

  17. Zhang H, Li Y, Fan Y, Wu J, Zhao B, Guan Y, et al. Klotho is a target gene of PPAR-gamma. Kidney Int. 2008;74(6):732–9.

    CAS  Article  Google Scholar 

  18. Zhang R, Zheng F. PPAR-gamma and aging: one link through klotho? Kidney Int. 2008;74(6):702–4. doi:https://doi.org/10.1038/ki.2008.382.

    CAS  Article  PubMed  Google Scholar 

  19. Narumiya H, Sasaki S, Kuwahara N, Irie H, Kusaba T, Kameyama H, et al. HMG-CoA reductase inhibitors up-regulate anti-aging klotho mRNA via RhoA inactivation in IMCD3 cells. Cardiovasc Res. 2004;64(2):331–6. doi:https://doi.org/10.1016/j.cardiores.2004.07.011.

    CAS  Article  PubMed  Google Scholar 

  20. Kuwahara N, Sasaki S, Kobara M, Nakata T, Tatsumi T, Irie H, et al. HMG-CoA reductase inhibition improves anti-aging klotho protein expression and arteriosclerosis in rats with chronic inhibition of nitric oxide synthesis. Int J Cardiol. 2008;123(2):84–90. doi:https://doi.org/10.1016/j.ijcard.2007.02.029.

    Article  PubMed  Google Scholar 

  21. Sugiura H, Yoshida T, Mitobe M, Shiohira S, Nitta K, Tsuchiya K. Recombinant human erythropoietin mitigates reductions in renal klotho expression. Am J Nephrol. 2010;32(2):137–44. doi:https://doi.org/10.1159/000315864.

    CAS  Article  PubMed  Google Scholar 

  22. Tang R, Zhou QL, Ao X, Peng WS, Veeraragoo P, Tang TF. Fosinopril and losartan regulate klotho gene and nicotinamide adenine dinucleotide phosphate oxidase expression in kidneys of spontaneously hypertensive rats. Kidney Blood Press Res. 2011;34(5):350–7. doi:https://doi.org/10.1159/000326806.

    CAS  Article  PubMed  Google Scholar 

  23. Tataranni T, Biondi G, Cariello M, Mangino M, Colucci G, Rutigliano M, et al. Rapamycin-induced hypophosphatemia and insulin resistance are associated with mTORC2 activation and Klotho expression. Am J Transplant. 2011;11(8):1656–64. doi:https://doi.org/10.1111/j.1600-6143.2011.03590.x.

    CAS  Article  PubMed  Google Scholar 

  24. Almeida OP, Morar B, Hankey GJ, Yeap BB, Golledge J, Jablensky A, et al. Longevity Klotho gene polymorphism and the risk of dementia in older men. Maturitas. 2017;101:1–5. doi:https://doi.org/10.1016/j.maturitas.2017.04.005.

    CAS  Article  PubMed  Google Scholar 

  25. Yokoyama JS, Marx G, Brown JA, Bonham LW, Wang D, Coppola G, et al. Systemic klotho is associated with KLOTHO variation and predicts intrinsic cortical connectivity in healthy human aging. Brain Imaging Behav. 2017;11(2):391–400. doi:https://doi.org/10.1007/s11682-016-9598-2.

    Article  PubMed  Google Scholar 

  26. de Vries CF, Staff RT, Noble KG, Muetzel RL, Vernooij MW, White T, et al. Klotho gene polymorphism, brain structure and cognition in early-life development. Brain Imaging Behav. 2020;14(1):213–25. doi:https://doi.org/10.1007/s11682-018-9990-1.

    Article  PubMed  Google Scholar 

  27. Belloy ME, Napolioni V, Han SS, Le Guen Y, Greicius MD, Alzheimer’s Disease Neuroimaging Initiative. Association of Klotho-vs heterozygosity with risk of alzheimer disease in individuals who carry apoe4. JAMA Neurol. 2020;77(7):849–62. doi:https://doi.org/10.1001/jamaneurol.2020.0414.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Erickson CM, Schultz SA, Oh JM, Darst BF, Ma Y, Norton D, et al. KLOTHO heterozygosity attenuates APOE4-related amyloid burden in preclinical AD. Neurology. 2019;92(16):e1878–89. doi:https://doi.org/10.1212/wnl.0000000000007323.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  29. Pereira RMR, Freitas TQ, Franco AS, Takayama L, Caparbo VF, Domiciano DS, et al. KLOTHO polymorphisms and age-related outcomes in community-dwelling older subjects: The São Paulo Ageing & Health (SPAH) Study. Sci Rep. 2020;10(1):8574. doi:https://doi.org/10.1038/s41598-020-65441-y.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  30. Zhu Z, Xia W, Cui Y, Zeng F, Li Y, Yang Z, et al. Klotho gene polymorphisms are associated with healthy aging and longevity: Evidence from a meta-analysis. Mech Ageing Dev. 2019;178:33–40. doi:https://doi.org/10.1016/j.mad.2018.12.003.

    CAS  Article  PubMed  Google Scholar 

  31. Hao Q, Ding X, Gao L, Yang M, Dong B. G-395A polymorphism in the promoter region of the KLOTHO gene associates with reduced cognitive impairment among the oldest old. Age (Dordr). 2016;38(1):7. doi:https://doi.org/10.1007/s11357-015-9869-7.

    Article  Google Scholar 

  32. Wolf EJ, Logue MW, Zhao X, Daskalakis NP, Morrison FG, Escarfulleri S, et al. PTSD and the klotho longevity gene: Evaluation of longitudinal effects on inflammation via DNA methylation. Psychoneuroendocrinology. 2020;117:104656.

    CAS  Article  Google Scholar 

  33. Yin S, Zhang Q, Yang J, Lin W, Li Y, Chen F, et al. TGFβ-incurred epigenetic aberrations of miRNA and DNA methyltransferase suppress Klotho and potentiate renal fibrosis. Biochim Biophys Acta Mol Cell Res. 2017;1864(7):1207–16.

    CAS  Article  Google Scholar 

  34. Nagai T, Yamada K, Kim HC, Kim YS, Noda Y. Cognition impairment in the genetic model of aging klotho gene mutant mice: a role of oxidative stress. FASEB J. 2003;17(1):50–2. doi:https://doi.org/10.1096/fj.02-0448fje.

    CAS  Article  PubMed  Google Scholar 

  35. Xiao NM, Zhang YM, Zheng Q, Gu J. Klotho is a serum factor related to human aging. Chin Med J (Engl). 2004;117(5):742–7.

    CAS  Google Scholar 

  36. Clinton SM, Glover ME, Maltare A, Laszczyk AM, Mehi SJ, Simmons RK, et al. Expression of klotho mRNA and protein in rat brain parenchyma from early postnatal development into adulthood. Brain Res. 2013;1527:1–14.

    CAS  Article  Google Scholar 

  37. Li SA, Watanabe M, Yamada H, Nagai A, Kinuta M, Takei K. Immunohistochemical localization of Klotho protein in brain, kidney, and reproductive organs of mice. Cell Struct Funct. 2004;29(4):91–9.

    CAS  Article  Google Scholar 

  38. German DC, Khobahy I, Pastor J, Kuro-O M, Liu X. Nuclear localization of Klotho in brain: an anti-aging protein. Neurobiol Aging. 2012;33(7):1483.e25-30.

    Article  Google Scholar 

  39. King GD, Rosene DL, Abraham CR. Promoter methylation and age-related downregulation of Klotho in rhesus monkey. Age (Dordr). 2012;34(6):1405–19.

    CAS  Article  Google Scholar 

  40. Lun MP, Monuki ES, Lehtinen MK. Development and functions of the choroid plexus-cerebrospinal fluid system. Nat Rev Neurosci. 2015;16(8):445–57. doi:https://doi.org/10.1038/nrn3921.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  41. Duce JA, Podvin S, Hollander W, Kipling D, Rosene DL, Abraham CR. Gene profile analysis implicates Klotho as an important contributor to aging changes in brain white matter of the rhesus monkey. Glia. 2008;56(1):106–17. doi:https://doi.org/10.1002/glia.20593.

    Article  PubMed  Google Scholar 

  42. Laszczyk AM, Fox-Quick S, Vo HT, Nettles D, Pugh PC, Overstreet-Wadiche L, et al. Klotho regulates postnatal neurogenesis and protects against age-related spatial memory loss. Neurobiol Aging. 2017;59:41–54. doi:https://doi.org/10.1016/j.neurobiolaging.2017.07.008.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  43. Chen CD, Li H, Liang J, Hixson K, Zeldich E, Abraham CR. The anti-aging and tumor suppressor protein Klotho enhances differentiation of a human oligodendrocytic hybrid cell line. J Mol Neurosci. 2015;55(1):76–90. doi:https://doi.org/10.1007/s12031-014-0336-1.

    CAS  Article  PubMed  Google Scholar 

  44. Chen CD, Sloane JA, Li H, Aytan N, Giannaris EL, Zeldich E, et al. The antiaging protein Klotho enhances oligodendrocyte maturation and myelination of the CNS. J Neurosci. 2013;33(5):1927–39. doi:https://doi.org/10.1523/jneurosci.2080-12.2013.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  45. Zeldich E, Chen CD, Avila R, Medicetty S, Abraham CR. The Anti-Aging Protein Klotho Enhances Remyelination Following Cuprizone-Induced Demyelination. J Mol Neurosci. 2015;57(2):185–96. doi:https://doi.org/10.1007/s12031-015-0598-2.

    CAS  Article  PubMed  Google Scholar 

  46. Shiozaki M, Yoshimura K, Shibata M, Koike M, Matsuura N, Uchiyama Y, et al. Morphological and biochemical signs of age-related neurodegenerative changes in klotho mutant mice. Neuroscience. 2008;152(4):924–41. doi:https://doi.org/10.1016/j.neuroscience.2008.01.032.

    CAS  Article  PubMed  Google Scholar 

  47. Dubal DB, Zhu L, Sanchez PE, Worden K, Broestl L, Johnson E, et al. Life extension factor klotho prevents mortality and enhances cognition in hAPP transgenic mice. J Neurosci. 2015;35(6):2358–71. doi:https://doi.org/10.1523/jneurosci.5791-12.2015.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  48. Toyama R, Fujimori T, Nabeshima Y, Itoh Y, Tsuji Y, Osamura RY, et al. Impaired regulation of gonadotropins leads to the atrophy of the female reproductive system in klotho-deficient mice. Endocrinology. 2006;147(1):120–9. doi:https://doi.org/10.1210/en.2005-0429.

    CAS  Article  PubMed  Google Scholar 

  49. Shahmoon S, Rubinfeld H, Wolf I, Cohen ZR, Hadani M, Shimon I, et al. The aging suppressor klotho: a potential regulator of growth hormone secretion. Am J Physiol Endocrinol Metab. 2014;307(3):E326–34. doi:https://doi.org/10.1152/ajpendo.00090.2014.

    CAS  Article  PubMed  Google Scholar 

  50. Medalia A, Saperstein AM. Does cognitive remediation for schizophrenia improve functional outcomes. Curr Opin Psychiatry. 2013;26(2):151–7. doi:https://doi.org/10.1097/yco.0b013e32835dcbd4.

    Article  PubMed  Google Scholar 

  51. Lystad JU, Falkum E, Haaland V, Bull H, Evensen S, McGurk SR, et al. Cognitive remediation and occupational outcome in schizophrenia spectrum disorders: A 2year follow-up study. Schizophr Res. 2017;185:122–9. doi:https://doi.org/10.1016/j.schres.2016.12.020.

    Article  PubMed  Google Scholar 

  52. Owen MJ, Sawa A, Mortensen PB. Schizophrenia. Lancet. 2016;388(10039):86–97. doi:https://doi.org/10.1016/S0140-6736(15)01121-6.

    Article  PubMed  PubMed Central  Google Scholar 

  53. Reyazuddin M, Azmi SA, Islam N, Rizvi A. Oxidative stress and level of antioxidant enzymes in drug-naive schizophrenics. Indian J Psychiatry. 2014;56(4):344–9. doi:https://doi.org/10.4103/0019-5545.146516.

    Article  PubMed  PubMed Central  Google Scholar 

  54. Zhang XY, Chen DC, Tan YL, Tan SP, Wang ZR, Yang FD, et al. The interplay between BDNF and oxidative stress in chronic schizophrenia. Psychoneuroendocrinology. 2015;51:201–8. doi:https://doi.org/10.1016/j.psyneuen.2014.09.029.

    CAS  Article  PubMed  Google Scholar 

  55. Sarandol A, Sarandol E, Acikgoz HE, Eker SS, Akkaya C, Dirican M. First-episode psychosis is associated with oxidative stress: Effects of short-term antipsychotic treatment. Psychiatry Clin Neurosci. 2015;69(11):699–707. doi:https://doi.org/10.1111/pcn.12333.

    CAS  Article  PubMed  Google Scholar 

  56. Miyaoka T, Ieda M, Hashioka S, Wake R, Furuya M, Liaury K, et al. Analysis of oxidative stress expressed by urinary level of biopyrrins and 8-hydroxydeoxyguanosine in patients with chronic schizophrenia. Psychiatry Clin Neurosci. 2015;69(11):693–8. doi:https://doi.org/10.1111/pcn.12319.

    CAS  Article  PubMed  Google Scholar 

  57. Dietrich-Muszalska A, Kwiatkowska A. Generation of superoxide anion radicals and platelet glutathione peroxidase activity in patients with schizophrenia. Neuropsychiatr Dis Treat. 2014;10:703–9. doi:https://doi.org/10.2147/ndt.S60034.

    Article  PubMed  PubMed Central  Google Scholar 

  58. Gonzalez-Liencres C, Tas C, Brown EC, Erdin S, Onur E, Cubukcoglu Z, et al. Oxidative stress in schizophrenia: a case-control study on the effects on social cognition and neurocognition. BMC Psychiatry. 2014;14:268. doi:https://doi.org/10.1186/s12888-014-0268-x.

    Article  PubMed  PubMed Central  Google Scholar 

  59. Morar B, Badcock JC, Phillips M, Almeida OP, Jablensky A. The longevity gene Klotho is differentially associated with cognition in subtypes of schizophrenia. Schizophr Res. 2018;193:348–53. doi:https://doi.org/10.1016/j.schres.2017.06.054.

    Article  PubMed  Google Scholar 

  60. Baumann N, Pham-Dinh D. Biology of oligodendrocyte and myelin in the mammalian central nervous system. Physiol Rev. 2001;81(2):871–927. doi:https://doi.org/10.1152/physrev.2001.81.2.871.

    CAS  Article  PubMed  Google Scholar 

  61. Chang A, Nishiyama A, Peterson J, Prineas J, Trapp BD. NG2-positive oligodendrocyte progenitor cells in adult human brain and multiple sclerosis lesions. J Neurosci. 2000;20(17):6404–12. doi:https://doi.org/10.1523/jneurosci.20-17-06404.2000.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  62. Rivers LE, Young KM, Rizzi M, Jamen F, Psachoulia K, Wade A, et al. PDGFRA/NG2 glia generate myelinating oligodendrocytes and piriform projection neurons in adult mice. Nat Neurosci. 2008;11(12):1392–401. doi:https://doi.org/10.1038/nn.2220.

    CAS  Article  PubMed  Google Scholar 

  63. Mensch S, Baraban M, Almeida R, Czopka T, Ausborn J, El Manira A, et al. Synaptic vesicle release regulates myelin sheath number of individual oligodendrocytes in vivo. Nat Neurosci. 2015;18(5):628–30. doi:https://doi.org/10.1038/nn.3991.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  64. Gibson EM, Purger D, Mount CW, Goldstein AK, Lin GL, Wood LS, et al. Neuronal activity promotes oligodendrogenesis and adaptive myelination in the mammalian brain. Science. 2014;344(6183):1252304. doi:https://doi.org/10.1126/science.1252304.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  65. Bošković M, Vovk T, KoresPlesničar B, Grabnar I. Oxidative stress in schizophrenia. Curr Neuropharmacol. 2011;9(2):301–12. doi:https://doi.org/10.2174/157015911795596595.

    Article  PubMed  PubMed Central  Google Scholar 

  66. Téllez-Zenteno JF, Hernández-Ronquillo L. A review of the epidemiology of temporal lobe epilepsy. Epilepsy Res Treat. 2012;2012:630853. doi:https://doi.org/10.1155/2012/630853.

    Article  PubMed  Google Scholar 

  67. Teocchi MA, Ferreira A, da Luz de Oliveira EP, Tedeschi H, D’Souza-Li L. Hippocampal gene expression dysregulation of Klotho, nuclear factor kappa B and tumor necrosis factor in temporal lobe epilepsy patients. J Neuroinflammation. 2013;10:53. doi:https://doi.org/10.1186/1742-2094-10-53.

  68. Margaret M, Esiri SA, Chance J, Debarros, Tim J Crow. Psychiatric Diseases. Greenfield’s Neuropathology. 6th edition. London: Arnold; 1997. ISBN 9781498721288.

  69. Foresti ML, Arisi GM, Shapiro LA. Role of glia in epilepsy-associated neuropathology, neuroinflammation and neurogenesis. Brain Res Rev. 2011;66(1–2):115–22. doi:https://doi.org/10.1016/j.brainresrev.2010.09.002.

    CAS  Article  PubMed  Google Scholar 

  70. Vezzani A, Friedman A. Brain inflammation as a biomarker in epilepsy. Biomark Med. 2011;5(5):607–14. doi:https://doi.org/10.2217/bmm.11.61.

    CAS  Article  PubMed  Google Scholar 

  71. Ravizza T, Balosso S, Vezzani A. Inflammation and prevention of epileptogenesis. Neurosci Lett. 2011;497(3):223–30. doi:https://doi.org/10.1016/j.neulet.2011.02.040.

    CAS  Article  PubMed  Google Scholar 

  72. Delorenzo RJ, Sun DA, Deshpande LS. Cellular mechanisms underlying acquired epilepsy: the calcium hypothesis of the induction and maintainance of epilepsy. Pharmacol Ther. 2005;105(3):229–66. doi:https://doi.org/10.1016/j.pharmthera.2004.10.004.

    CAS  Article  PubMed  Google Scholar 

  73. Choi DW. Glutamate neurotoxicity and diseases of the nervous system. Neuron. 1988;1(8):623–34. doi:https://doi.org/10.1016/0896-6273(88)90162-6.

    CAS  Article  PubMed  Google Scholar 

  74. Almilaji A, Munoz C, Pakladok T. Klotho suppresses TNF-alpha-induced expression of adhesion molecules in the endothelium and attenuates NF-kappaB activation. Endocrine. 2009;35(3):341–6. doi:https://doi.org/10.1007/s12020-009-9181-3.

    CAS  Article  Google Scholar 

  75. Maekawa Y, Ishikawa K, Yasuda O. Klotho suppresses TNF-alpha-induced expression of adhesion molecules in the endothelium and attenuates NF-kappaB activation. Endocrine. 2009;35(3):341–6. doi:https://doi.org/10.1007/s12020-009-9181-3.

    CAS  Article  PubMed  Google Scholar 

  76. Urakawa I, Yamazaki Y, Shimada T, Iijima K, Hasegawa H, Okawa K, et al. Klotho converts canonical FGF receptor into a specific receptor for FGF23. Nature. 2006;444(7120):770–4. doi:https://doi.org/10.1038/nature05315.

    CAS  Article  PubMed  Google Scholar 

  77. Kurosu H, Ogawa Y, Miyoshi M. Regulation of fibroblast growth factor-23 signaling by klotho. J Biol Chem. 2006;281(10):6120–3. doi:https://doi.org/10.1074/jbc.C500457200.

    CAS  Article  PubMed  Google Scholar 

  78. Stockmeier CA, Mahajan GJ, Konick LC, Overholser JC, Jurjus GJ, Meltzer HY, et al. Cellular changes in the postmortem hippocampus in major depression. Biol Psychiatry. 2004;56(9):640–50. doi:https://doi.org/10.1016/j.biopsych.2004.08.022.

    Article  PubMed  PubMed Central  Google Scholar 

  79. Kuro-o M. Klotho as a regulator of oxidative stress and senescence. Biol Chem. 2008;389(3):233–41. doi:https://doi.org/10.1515/bc.2008.028.

    CAS  Article  PubMed  Google Scholar 

  80. Paroni G, Seripa D, Fontana A. Klotho Gene and Selective Serotonin Reuptake Inhibitors: Response to Treatment in Late-Life Major Depressive Disorder. Mol Neurobiol. 2017;54(2):1340–51. doi:https://doi.org/10.1007/s12035-016-9711-y.

    CAS  Article  PubMed  Google Scholar 

  81. Prather AA, Epel ES, Arenander J. Longevity factor klotho and chronic psychological stress. Transl Psychiatry. 2015;5(6):e585. doi:https://doi.org/10.1038/tp.2015.81.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  82. Barbosa IG, Rocha NP, Alpak G. Klotho dysfunction: A pathway linking the aging process to bipolar disorder. J Psychiatr Res. 2017;95:80–3. doi:https://doi.org/10.1016/j.jpsychires.2017.08.007.

    Article  PubMed  Google Scholar 

  83. Rubinek T, Modan-Moses D. Klotho and the Growth Hormone/Insulin-Like Growth Factor 1 Axis: Novel Insights into Complex Interactions. Vitam Horm. 2016;101:85–118. doi:https://doi.org/10.1016/bs.vh.2016.02.009.

    CAS  Article  PubMed  Google Scholar 

  84. Mao S, Wang X, Wu L, Zang D, Shi W. Association between klotho expression and malignancies risk and progression: A meta-analysis. Clin Chim Acta. 2018;484:14–20. doi:https://doi.org/10.1016/j.cca.2018.05.033.

    CAS  Article  PubMed  Google Scholar 

  85. Tomo S, Birdi A, Yadav D, Chaturvedi M, Sharma P. Klotho: A Possible Role in the Pathophysiology of Nephrotic Syndrome. EJIFCC. 2022;33(1):3–10.

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Liu QF, Yu LX, Feng JH, Sun Q, Li SS, Ye JM. The Prognostic Role of Klotho in Patients with Chronic Kidney Disease: A Systematic Review and Meta-analysis. Dis Markers. 2019:6468729. doi:https://doi.org/10.1155/2019/6468729.

  87. Bora E. Peripheral inflammatory and neurotrophic biomarkers of cognitive impairment in schizophrenia: a meta-analysis. Psychol Med. 2019;49(12):1971–9. doi:https://doi.org/10.1017/s0033291719001685.

    Article  PubMed  Google Scholar 

  88. da Rosa MI, Simon C, Grande AJ, Barichello T, Oses JP, Quevedo J. Serum S100B in manic bipolar disorder patients: Systematic review and meta-analysis. J Affect Disord. 2016;206:210–5. doi:https://doi.org/10.1016/j.jad.2016.07.030.

    CAS  Article  PubMed  Google Scholar 

Download references

Funding

None.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Dharmveer Yadav.

Ethics declarations

Conflict of Interest

The authors declare no conflict of interest.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Birdi, A., Tomo, S., Yadav, D. et al. Role of Klotho Protein in Neuropsychiatric Disorders: A Narrative Review. Ind J Clin Biochem (2022). https://doi.org/10.1007/s12291-022-01078-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s12291-022-01078-0

Keywords

  • Klotho
  • Neuropsychiatry
  • Schizophrenia
  • Bipolar disorder
  • Depression