Current understanding of klotho

Abstract

Klotho is a new anti-aging gene. Genetic mutation of klotho causes multiple premature aging-like phenotypes and strikingly shortens lifespan. Overexpression of the klotho gene in mice suppresses aging and extends lifespan which may involve the mechanism of suppression of insulin signaling and oxidant stress. Klotho functions as a cofactor/coreceptor regulating fibroblast growth factor (FGF) 23 signaling. Klotho acts as a glucuronidase and activates ion channel TRPV5. Klotho protects against endothelial dysfunction and regulates the production of nitric oxide. Klotho also influences intracellular signaling pathways including p53/p21, cAMP, protein kinase C (PKC) and Wnt signaling pathways. The discovery of klotho has a great impact on aging research. The purpose of this review is to provide the recent progress and future directions of klotho research. Specifically, this review will cover: klotho and aging, structure and expression of the klotho gene, localization of klotho expression, source of circulating klotho, current understanding of klotho functions, and signaling pathways of klotho.

Figure 1

The mouse klotho gene structure and alternative RNA splicing. The mouse klotho gene is composed of 5- exons and 4-intron and resides on chromosome 13. Two transcripts arise from this alternative RNA splicing: a membrane or a secreted form of klotho protein.

Figure 2

The generation of secreted form klotho. The klotho protein can enter the circulation via three pathways: (1). Alternative RNA splicing. The klotho gene can directly generate secreted form klotho protein by an alternative RNA splicing. The secreted klotho protein is liberated into the extracellular space and subsequently the circulation. (2). Proteolytic cleavage. Klotho protein could be cleaved and released to the circulation system. (3). Na⁺, K⁺ -ATPase. Klotho can bind to Na⁺, K⁺ -ATPase, the complex of klotho and Na⁺, K⁺ -ATPase could be going up to the cell surface where klotho is cleaved and secreted into extracellular space and hence the circulation system.

Figure 3

The functional relationship of klotho and transient receptor potential vanilloid 5 (TRPV5) in kidneys. The β-glucuronidase activity plays an important role in activating TRPV5. Klotho in urine, as a β-glucuronidase, hydrolyzes the N-linked extracellular sugar residues of TRPV5, and then augments the retention of TRPV5 on the plasma membrane hence increase the influx of Ca₂⁺ in kidneys.