Novel Target : Klotho

First published in Nature in 1997, this single gene/protein is indispensable for human life processes.

Named after Clotho, the first of the three Fates in Greek mythology who determines lifespan, Klotho has recently emerged as a highly promising therapeutic target for AD, CKD, and longevity extension. 

Klotho (Goddess of Life)
Reference

Reference : Illustration of the 'Triumph of death over chastity' from Petrarch. The three ladies are the fates

Klotho Gene

Klotho (α-Klotho) is located on Chromosome 13, and has been described as an anti-aging gene. It has two major isoforms, a 135 kDa transmembrane protein and a 70 kDa secreted form[1]. The transmembrane form is primarily expressed in the kidneys, and the secreted form is most highly expressed in the brain, and is produced primarily by the choroid plexus[2]. The soluble form of Klotho includes both the cleaved (majority) and secreted (minority) forms and acts as a hormone with pleiotropic functions[3]

Reference

1. Chen C-D, Tung TY, Liang J et al. (2014) Identification of cleavage sites leading to the shed form of the anti-aging protein klotho. Biochemistry 53, 5579-5587.
https://Www.ncbi.nlm.nih.gov/pubmed/25110992

2. Massó A, Sánchez A, Gimenez-Llort L et al. (2015) Secreted and Transmembrane αKlotho Isoforms Have Different Spatio-Temporal Profiles in the Brain during Aging and Alzheimer's Disease Progression. PLoS One 10, e0143623- e0143623.
https://www.ncbi.nlm.nih.gov/pubmed/26599613

3.Dalton GD, Xie J, An S-W et al. (2017) New Insights into the Mechanism of Action of Soluble Klotho. Frontiers in Endocrinology
https://www.frontiersin.org/article/10.3389/fendo.2017.00323

Klotho protein deficiency and aging

In mice with the kl gene knocked out, lifespan was significantly shortened (around 60 days, approximately 10% of the normal lifespan of 2 years), and various degenerative diseases were induced.

Reference

Manya, H., Akasaka-Manya, K., & Endo, T. (2010). Klotho protein deficiency and aging. Geriatrics & gerontology international, 10 Suppl 1, S80–S87.
https://doi.org/10.1111/j.1447-0594.2010.00596.x

Klotho Subtypes

Klotho is classified into three subtypes

  • α-klotho: brain, kidney,

  • β-klotho: liver

  • Y-klotho: skin

Reference

Zou, D., Wu, W., He, Y., Ma, S., & Gao, J. (2018). The role of klotho in chronic kidney disease. BMC nephrology, 19(1), 285.
https://doi.org/10.1186/s12882-018-1094-z

Klotho proteins

a-klotho is the first discovered and the most well-known among[1]
klotho proteins. α-Klotho expression in various tissues. (Mouse Tissues)[2]

Reference

1. Hanson, K., Fisher, K., & Hooper, N. M. (2021). Exploiting the neuroprotective effects of α-klotho to tackle ageing- and neurodegeneration-related cognitive dysfunction. Neuronal signaling, 5(2), NS20200101

https://doi.org/10.1042/NS20200101

[2. Rao, Z., Zheng, L., Huang, H., Feng, Y., & Shi, R. (2019). α-Klotho Expression in Mouse Tissues Following Acute Exhaustive Exercise. Frontiers in physiology, 10, 1498.

https://doi.org/10.3389/fphys.2019.01498