Klotho

Klotho is a glycoprotein encoded by the KL gene and is part of the Klotho family of related proteins. It exists in two main forms: a membrane-bound isoform called α-Klotho, which can function as a co-receptor for fibroblast growth factor 23 (FGF23), and a soluble form produced by alternative splicing or proteolytic shedding that circulates in blood, urine, and cerebrospinal fluid.

Expression of α-Klotho is highest in the distal tubules of the kidney and the choroid plexus of the brain, with additional expression in other tissues. It participates in mineral ion metabolism and signaling via FGF23, helping to regulate phosphate excretion and vitamin D synthesis.

Mechanistically, the Klotho-FGFR1c complex enables FGF23 signaling, which lowers renal phosphate reabsorption by reducing NaPi-IIa/IIc transporters and decreases production of active vitamin D by downregulating CYP27B1 and upregulating CYP24A1. Soluble α-Klotho is proposed to act as an endocrine factor with antioxidative properties and the ability to influence insulin/IGF-1 signaling and Wnt signaling.

Genetically, KL encodes α-Klotho on chromosome 13q12 in humans. In mice, Kl knockout causes aging-like phenotypes, including vascular calcification, osteoporosis, and shortened lifespan, while overexpression of α-Klotho has been reported to mitigate aging features in some models.

Clinically, reduced Klotho levels are associated with aging and chronic kidney disease, and polymorphisms in KL have been studied for links to aging-related traits with mixed results. Klotho is investigated as a potential biomarker and therapeutic target for kidney, cardiovascular, and neurodegenerative diseases, with research exploring recombinant protein and gene-based approaches.