Daniel Piątek, Emilia Migryt, Kamila Tuzim, Joanna Szydełko, *Anna Boguszewska-Czubara
Klotho protein protects against aging and nicotine-induced chronic cellular stress
Department of Medical Chemistry, Medical University in Lublin, Poland
Summary
From 1997, when Klotho protein was first discovered and named “the anti-aging hormone”, scientists have been thoroughly investigating its biological properties. This protein plays an important role in numerous metabolic pathways that contribute to slower ageing processes. The prevalence of neurodegenerative diseases, impairment of cognitive functions and chronic stress increases with age. Additional factors, such as nicotine, rosiglitazone, statins, blood-pressure lowering drugs, calcitriol, magnesium, chronic psychosocial stress and aerobic exercises have an influence on Klotho protein plasma concentration. The research on proteins that increase Klotho plasma levels is important because of broad range of biological processes in which Klotho is engaged. Further studies on this substance could result in new possibilities of treatment for several common diseases.
Introduction
The KL gene is located on the long arm of human chromosome 13. Its product protein was discovered in 1997 and it immediately became of interest to many scientists due to its involvement in the mechanisms of ageing. The name of the protein is a reference to the Greek mythology, as Clotho was the youngest of the Three Moirai. She was responsible for spinning the thread of life from her distaff onto her spindle. By naming the protein after her, scientists wanted to emphasize the unique role of the protein. Soon after the discovery of the involvement of Klotho in ageing processes, it occurred that it is also involved in other vital processes and its effects are truly pleiotropic. From a biochemical point of view, Klotho is a novel β-glucuronidase, capable of activating the TRPV5 ion channel (1, 2). Thanks to the use of specific antibodies, it became possible to detect the secreted form of Klotho in the cerebrospinal fluid and serum (1). There are two forms of this protein: transmembrane (130kDa) and secretory (65kDa). They are synthesized in varying organs, but both have an ability to create oligomer complexes (1, 2). Transmembrane form is mainly produced by the brain (specifically, by the choroid plexus) and by the kidneys. The highest quantities of the secretory form are observed in the plasma and in the cerebrospinal fluid (3). The two forms have different functions. The transmembrane form is the co-receptor for fibroblast growth factor (FGF23) and the secretory form interacts with ion channels, transporters and receptors for growth factors (2). Among others, Klotho regulates the functions of the endothelium and the production of nitric oxide by the endothelium. It also affects many intracellular signaling pathways, including p53/p21 pathway, Wnt pathway, cAMP and protein kinase C pathway (2).
Klotho protein as ageing hormone
A mutation in the KL gene may cause faster progression of symptoms associated with senility, such as shorter life expectancy, infertility, arteriosclerosis, skin atrophy, osteoporosis and emphysema (4). As only some organs are able to produce the Klotho protein, researchers aimed to find target structures for Klotho in different human tissues. The results confirmed that Klotho protein functions as a humoral factor in cerebrospinal fluid and is engaged in hormonal regulation network (5). Recent studies have also underlined the role of the insulin and insulin-like growth factor (IGF) signaling pathway as one of the most important metabolic routes for the lifespan regulation. It has been discovered that even slight alterations weakening the insulin/IGF-1 signaling pathway can extend the lifespan of Caenorhabditis elegans even over two times (6). The Klotho protein suppresses intracellular pathways induced by insulin/IGF1 and finally enables the animals to remain active and young for a longer time (7). A relationship between Klotho serum levels and activities of daily living (ADL) in older people has been investigated. Lower levels of Klotho protein have been associated with ADL disability in elderly people (8). Furthermore, it has been suggested that the Klotho protein can be used as predictor of all-cause mortality (8, 9). Because the study has been conducted on a relatively small group, further research is required to verify if the concentration of Klotho protein may indeed be used as prognostic factor of ADL disability or mortality. The ageing process is strictly related to the overproduction of free radicals and impairment of cytoprotective mechanisms. It is probable that the Klotho protein owns the ability to prolong lifespan due to its capability of reducing oxidative stress (10). Some studies have indicated an increased expression of manganese superoxide dismutase as a result of activation FoxO – forkhead box transcription factors – in mice with high Klotho protein levels (10). Dismutase degrades free radicals and protects against small cellular damages, consequently, increasing the lifespan.
Klotho protein in neurological diseases
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Piśmiennictwo
1. Imura A, Iwano A, Tohyama O et al.: Secreted Klotho protein in sera and CSF: implication for post-translational cleavage in release of Klotho protein from cell membrane. FEBS Letters 2004; 565: 143-147. 2. Wang Y, Sun Z: Current understanding of klotho. Ageing Res Rev 2009; 8: 43-51. 3. Szymczyk A, Forma E: Structure and functions of Klotho protein. Folia Medica Lodziensia 2012; 39: 151-187. 4. Kuro-o M, Matsumura Y, Aizawa H et al.: Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature 1997; 390: 45-51. 5. Li SA, Watanabe M, Yamada H et al.: Immunohistochemical localization of Klotho protein in brain, kidney, and reproductive organs of mice. Cell Struct Funct 2004; 29: 91-99. 6. Heemst D: Insulin, IGF-1 and longevity. Aging Dis 2010; 1: 147-157. 7. Kurosu H, Yamamoto M, Clark JD et al.: Suppression of Aging in Mice by the Hormone Klotho. Science 2005; 309: 1829-1833. 8. Semba RD, Cappola AR, Sun K et al.: Plasma klotho and mortality risk in older community-dwelling adults. J Gerontol A Biol Sci Med Sci 2011; 66: 794-800. 9. Crasto CL, Semba RD, Sun K et al.: Relationship of low-circulating ‘anti-aging’ klotho hormone with disability in activities of daily living among older community-dwelling adults. Rejuvenation Res 2012; 15: 295-301. 10. Yamamoto M, Clark JD, Pastor JV et al.: Regulation of oxidative stress by the anti-aging hormone Klotho. J Biol Chem 2005; 280: 38029-38034. 11. Arking DE, Krebsova A, Macek M et al.: Association of human aging with a functional variant of Klotho. Proc Natl Acad Sci USA 2002; 99: 856-861. 12. Arking DE, Atzmon G, Arking A et al.: Association between a functional variant of the KLOTHO gene and high-density lipoprotein cholesterol, blood pressure, stroke, and longevity. Circ Res 2005; 96: 412-418. 13. Invidia L, Salvioli S, Altilia S et al.: 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. Biogerontology 2010; 11: 67-73. 14. Yokoyama JS, Sturm VE, Bonham LW et al.: Variation in longevity gene KLOTHO is associated with greater cortical volumes. Annals of Clinical and Translational Neurology 2015; 2: 215-230. 15. Chen CD, Sloane JA, Li H et al.: The antiaging protein Klotho enhances oligodendrocyte maturation and myelination of the CNS. J Neurosci 2013; 33: 1927-1939. 16. Duce JA, Podvin S, Hollander W et al.: Gene profile analysis implicates Klotho as an important contributor to aging changes in brain white matter of the rhesus monkey. Glia 2008; 56: 106-117. 17. Abraham CR, Chen C, Cuny GD et al.: Small-molecule Klotho enhancers as novel treatment of neurodegeneration. Future Med Chem 2012; 4: 1671-1679. 18. Kosakai A, Ito D, Nihei Y et al.: Degeneration of mesencephalic dopaminergic neurons in Klotho mouse related to vitamin D exposure. Brain Res 2011; 1382: 109-117. 19. Alzheimer’s Association: 2014 Alzheimer’s Disease Facts and Figures. Alzheimer’s & Dementia 2014; 10: 1-75. 20. Prather AA, Epel ES, Arenander J et al.: Longevity factor klotho and chronic psychological stress. Transl Psychiatry 2015; 16: 585. 21. Parrott AC, Murphy RS: Explaining the stress-inducing effects of nicotine to cigarette smokers. Hum Psychopharmacol 2012; 27: 150-155. 22. Morse DE: Neuroendocrine responses to nicotine and stress: enhancement of peripheral stress responses by the administration of nicotine. Psychopharmacology 1989; 98: 539-543. 23. Biała G, Pekala K, Boguszewska-Czubara A et al.: Behavioral and biochemical interaction between nicotine and chronic unpredictable mild stress in mice. Mol Neurobiol 2016 (online): 1-18. 24. Klein LC: Effects of adolescent nicotine exposure on opioid consumption and neuroendocrine responses in adult male and female rats. Exp Clin Psychopharmacol 2001; 9: 251-261. 25. Aleisa AM, Alzoubi KH, Alkadhi KA: Nicotine prevents stress-induced enhancement of long-term depression in hippocampal area CA1: electrophysiological and molecular studies. J Neurosci Res 2006; 83: 309-317. 26. Alkadhi KA: Chronic Stress and Alzheimer’s Disease-Like Pathogenesis in a Rat Model: Prevention by Nicotine. Curr Neuropharmacol 2011; 9: 587-597. 27. Nagai T, Yamada K, Kim HC et al.: Cognition impairment in the genetic model of aging klotho gene mutant mice: a role of oxidative stress. FASEB J 2003; 17: 50-52. 28. Dubal DB, Yokoyama JS, Zhu L et al.: Life Extension Factor Klotho Enhances Cognition. Cell Reports 2014; 7: 1065-1076. 29. Matsubara T, Miyaki A, Akazawa N et al.: Aerobic exercise training increases plasma Klotho levels and reduces arterial stiffness in postmenopausal women. Am J Physiol Heart Circ Physiol 2014; 306: 348-355. 30. Lau WL, Leaf EM, Hu MC et al.: Vitamin D receptor agonists increase klotho and osteopontin while decreasing aortic calcification in mice with chronic kidney disease fed a high phosphate diet. Kidney International 2012; 82: 1261-1270. 31. de Borst MH, Vervloet MG, ter Wee PM et al.: Cross talk between the renin-angiotensin-aldosterone system and vitamin D-FGF-23-klotho in chronic kidney disease. J Am SocNephrol 2011; 22: 1603-1609. 32. Yoon HE, Lim SW, Piao SG et al.: Statin upregulates the expression of klotho, an anti-aging gene, in experimental cyclosporine nephropathy. Nephron Exp Nephrol 2012; 120: 123-133. 33. Rodríguez-Ortiz ME, Canalejo A, Herencia C et al.: Magnesium modulates parathyroid hormone secretion and upregulates parathyroid receptor expression at moderately low calcium concentration. Nephrol Dial Transplant 2014; 29: 282-289.
