Molecular basis of Klotho: from gene to function in aging

Abstract

The discovery of the Klotho (KL) gene, which was originally identified as a putative aging-suppressor gene, has generated tremendous interest and has advanced understanding of the aging process. In mice, the overexpression of the KL gene extends the life span, whereas mutations to the KL gene shorten the life span. The human KL gene encodes the α-Klotho protein, which is a multifunctional protein that regulates the metabolism of phosphate, calcium, and vitamin D. α-Klotho also may function as a hormone, although the α-Klotho receptor(s) has not been found. Point mutations of the KL gene in humans are associated with hypertension and kidney disease, which suggests that α-Klotho may be essential to the maintenance of normal renal function. Three α-Klotho protein types with potentially different functions have been identified: a full-length transmembrane α-Klotho, a truncated soluble α-Klotho, and a secreted α-Klotho. Recent evidence suggests that α-Klotho suppresses the insulin and Wnt signaling pathways, inhibits oxidative stress, and regulates phosphatase and calcium absorption. In this review, we provide an update on recent advances in the understanding of the molecular, genetic, biochemical, and physiological properties of the KL gene. Specifically, this review focuses on the structure of the KL gene and the factors that regulate KL gene transcription, the key sites in the regulation of α-Klotho enzyme activity, the α-Klotho signaling pathways, and the molecular mechanisms that underlie α-Klotho function. This current understanding of the molecular biology of the α-Klotho protein may offer new insights into its function and role in aging.

Figure 1.. Architecture of the Klotho gene and protein from the human, mouse, and rat.

A, The structure of the Klotho gene from the human, mouse, and rat. The upstream and downstream neighboring genes are highlighted in light brown. Introns and exons are highlighted in blue and green, respectively. B, Architecture of the human Klotho protein. Protein models were examined using the NCBI Conserved Domains and Protein Classification server.

Figure 2.. Structure of the Klotho promoter.

A comparison of the structure of the human (A) and mouse (B) Klotho promoter regions. The match program was used to analyze the transcription factor binding sites (underlined). The EMBOSS CpGPlot/CpGReport/Isochore program was used to screen the CpG islands (highlighted in blue). The transcription coding sequences are indicated in uppercase italic characters.

Figure 3.. Sequence alignment of selective Klotho sequences.

aa are colored according to their chemistry (blue = acidic; red = G or P; dark red = basic; green = hydrophobic), and conserved positions are highlighted when their aa occupants conform predominantly to a chemical type. The active site “E” is labeled with an asterisk (*). Positions of the starting aa in the total proteins are listed.

Figure 4.. Overview of the functions of Klotho.

a, Klotho inhibits the IGF signaling pathway. The downstream factors FOXO1, -3a, and -4 mediate the function of Klotho. b, Klotho suppresses the Wnt signaling pathway. c, Klotho regulates Trpv5 calcium channels. d, Klotho regulates PTH synthesis. e, The Klotho-FGF23 complex regulates Pi absorption, mineral metabolism, and vitamin D₃ expression and activity.