What is Klotho?

Klotho, named after the Greek mythological figure, is an enzyme that can be either circulating or bound to cell membranes [1,2]. It is expressed most highly in the kidneys [3]. There are three subfamilies of klotho (α-, ß-, and γ-klotho), with a-klotho being the most prominent.

α-klotho interacts with several proteins, such as activating FGF23 [4], ROMK [5], TRPV5 [5, 6], and TRPC6 [6] and antagonizing the Wnt signaling pathway [7]. It appears to play a major role in insulin sensitivity [4], calcium and phosphate homeostasis [5, 6], oxidative stress and inflammation [2, 8, 9], and cognitive function [10-13]. Reduced klotho accelerates the degenerative process of chronic kidney disease [5], may be an early sign of oral cancer [14], and contributes to atherosclerosis [8, 15].

Klotho has received particular attention due to its role in aging. Serum levels of klotho decrease with age in humans [16] and are predictive of mortality [17-19]. Reduced or absent klotho can be used as an accelerated aging model in mice [1]. On the other hand, an overexpression of klotho can increase mouse lifespan [20] and genetic variations of the human klotho gene are associated with longer lives [21].

Literature

[1] Kuro-O.M. et al. Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature (1997). https://doi.org/10.1038/36285

[2] Buendía, P. et al. Klotho Prevents Translocation of NFkB. Vitamins & Hormones (2016). https://doi.org/10.1016/bs.vh.2016.02.005

[3] Xu, Y. and Sun, Z. Molecular basis of Klotho: from gene to function in aging. Endocr Rev (2015). https://doi.org/10.1210/er.2013-1079

[4] Kuro-O.M. The Klotho proteins in health and disease. Nature Reviews Nephrology (2019). https://doi.org/10.1038/s41581-018-0078-3

[5] Huang, C.L. Regulation of ion channels by secreted Klotho: mechanisms and implications. Kidney International (2010). https://doi.org/10.1038/ki.2010.73

[6] van Goor, M.K. et al. TRP channels in calcium homeostasis: from hormonal control to structure-function relationship of TRPV5 and TRPV6. Biochimica et Biophysica Acta (BBA) – Molecular Cell Research (2017). https://doi.org/10.1016/j.bbamcr.2016.11.027

[7] Liu, H. et al. Augmented Wnt signaling in a mammalian model of accelerated aging. Science (2007). https://doi.org/10.1038/ki.2010.73

[8] Olejnik, A. et al. The Biological Role of Klotho Protein in the Development of Cardiovascular Diseases. BioMed Research International (2018). https://doi.org/10.1155/2018/5171945

[9] Amaro-Gahete, F.J. et al. Role of Exercise on S-Klotho Protein Regulation: A Systematic Review. Curr Aging Sci (2018). https://doi.org/10.2174/1874609811666180702101338

[10] Torbus-Paluszczak, M. et al. Klotho protein in neurodegenerative disorders. Neurological Sciences (2018). https://doi.org/10.1007/s10072-018-3496-x

[11] Vo, H.T., Laszczyk, A.M., and King, G.D. Klotho, the Key to Healthy Brain Aging? Brain Plasticity (2018). https://doi.org/10.3233/BPL-170057

[12] Paroni, G. et al. Klotho at the Edge of Alzheimer’s Disease and Senile Depression. Molecular Neurobiology (2019). https://doi.org/10.1007/s12035-018-1200-z

[13] Lehrer, S. and Rheinstein, P.H. Alignment of Alzheimer’s disease amyloid ß-peptide and klotho. World Academy of Sciences Journal (2020). https://doi.org/10.3892/wasj.2020.68</a 

[14] Adhikari, B.R. et al. Immunohistochemical evaluation of Klotho and DNA methyltransferase 3a in oral squamous cell carcinomas. Medical Molecular Morphology (2017). https://doi.org/10.1007/s00795-017-0156-9

[15] Saghiv, M.S. et al. 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 (2017). https://doi.org/10.1177/1849454417733388

[16] Xiao, N.M. et al. Klotho is a serum factor related to human aging. Chinese Medical Journal (2004). PMID: 15161545

[17] Charoenngam, N., Ponvilawan, B., and Ungprasert, P. Lower circulating soluble Klotho level is associated with increased risk of all-cause mortality in chronic kidney disease patients: a systematic review and meta-analysis. Int Urol Nephrol (2020). https://doi.org/10.1007/s11255-020-02510-1

[18] Semba, R.D. et al. Plasma klotho and mortality risk in older community-dwelling adults. J Gerontol A Biol Sci Med Sci (2011). https://doi.org/10.1093/gerona/glr058

[19] Kresovich, J.K. and Bulka, C.M. Low serum klotho associated with all-cause mortality among a nationally representative sample of American adults. J Gerontol A Biol Sci Med Sci (2021). https://doi.org/10.1093/gerona/glab308

[20] Kurosu, H. et al. Suppression of aging in mice by the hormone Klotho. Science (2005). https://doi.org/10.1126/science.1112766

[21]Dubal, D.B. et al. Life extension factor klotho enhances cognition. Cell Reports (2014). https://doi.org/10.1016/j.celrep.2014.03.076