Klotho gene is composed of 5 exons and 4 introns and resides on chromosome 13q12 with a size of over 50 kb. Its promoter region lacks a TATA-box and contains four potential binding sites for Sp1 (a human transcription factor involved in gene expression in the early development of an organism). In the third exon, there is an alternative splicing at an internal splice donor site. Two transcripts arise from this alternative RNA splicing: a transmembrane and a secreted form of klotho protein. The transmembrane form of klotho has a full-length transcript and encodes 1014 amino acids. Once the short transmembrane domain is removed, this fragment can be released into the circulation (secreted form). An alternative mRNA splicing generates another transcript-secreted form of klotho protein. It has a half-length of the transcript and encodes 550 amino acids, which is a truncated klotho protein. In humans however, the major klotho gene product is the secreted protein.
Although genetic mutation of klotho causes multiple agingrelated disorders in nearly all organs and tissues, the klotho gene is only expressed in limited tissues in mice, rats and humans. klotho is primarily expressed in the kidney, although it is also detectable in the placenta, prostate, and small intestines. Some single nucleotide polymorphisms (SNP) in the human klotho gene are associated with altered lifespan, osteoporosis, stroke and altered risk for coronary artery disease. Klotho expression is influenced by many physiological and pathological conditions. Klotho protein itself or its metabolites may function as a humoral factor, inhibit insulin/IGF-1 signaling pathway (klotho-overexpressing transgenic mice can inhibit insulin/IGF- 1 signaling, and therefore lead to a decrease in phosphorylated FOXOs, activated FOXOs, and increased SOD2 expression, thus reducing oxidative stress.). Recently, the extracellular domain of klotho was demonstrated to bind directly to multiple FGF receptors and functions as the coreceptor in FGF23 signaling. Klotho acts as a b-glucuronidase that activates the ion channel TRPV5 by trimming its sugar moiety, leading to the up-regulation of Ca2+ reabsorption. Klotho may protect the cardiovascular system by increasing NO production and inhibiting oxidative stress.
The klotho gene plays a pivotal role in regulating aging and the development of age-related diseases in mammals: a loss of klotho results in multiple aging-like phenotypes and overexpression of klotho gene extends lifespan by 20– 30%.