Recombinant human Klotho protein [His]

There are two molecular variants of the anti-aging protein produced by the Klotho gene which perform separate biological functions. The form of Klotho attached to cell membranes found mainly in the distal convoluted tubules of kidneys and brain choroid plexus epithelial cells binds with fibroblast growth factor receptor 1 (FGFR1) to enhance FGF23 signal transduction. The interaction suppresses renal phosphate reabsorption while increasing phosphate removal through urine which helps to maintain phosphate levels throughout the body. Expression levels remain comparatively lower in parathyroid glands, skeletal muscle, cardiac tissue, and reproductive organs. Alternative splicing of KL gene transcripts produces soluble Klotho which operates as an endocrine factor to influence multiple biological functions. The circulating form functions as a free radical-scavenging antioxidant while suppressing apoptotic pathways and promoting autophagy-mediated cell renewal and distant organ function regulation through systemic signaling. Soluble Klotho protects cells by stabilizing ion channels TRPV5/TRPC6 and blocking aging pathways TGF-β and IGF-1. Membrane-bound Klotho functions within certain tissues but the soluble version circulates through blood to deliver anti-aging effects throughout the body and affects organs without their own Klotho production. Renal tubules transport soluble Klotho from basolateral to luminal sides even though the substance does not pass through glomeruli before urinary excretion. Medical research demonstrates that reduced levels of Klotho correlate with chronic kidney disease and cardiovascular and neurodegenerative conditions which makes it a valuable biomarker and target for treatment.

Figure 1. Klotho structure
(Source: Prud'homme GJ, et al. 2022)

The anti-aging effects of Klotho operate through reducing activity in cytokine and growth factor signaling pathways. Klotho sustains mitochondrial integrity and reduces mitochondrial ROS production while protecting mitochondria from damage within cultured human renal tubular epithelial cells which results in delayed cellular aging. Research on plasma S-Klotho concentrations in AKI patients shows potential utility for diagnosis and treatment while showing disease progression alongside lower levels. Clinical studies show that the amount of circulating S-Klotho decreases progressively with CKD progression and the severity of disease stages correlates with lower levels of this marker which leads to worse kidney outcomes. The results as a whole suggest that S-Klotho serves as a potential prognostic marker to track the progress of CKD.