Klotho (biology)

Human enzyme

Klotho is an enzyme that in humans is encoded by the KL gene. The three subfamilies of klotho are α klotho, β klotho, and γ klotho. α klotho activates FGF23, and β klotho activates FGF19 and FGF21. β klotho is predominantly expressed in the liver. Proteases can convert the membrane bound form into the circulating form. The KL gene encodes a type I single pass transmembrane protein Transgenic mice that overexpress Klotho live longer than wild type mice. It should not be confused with the alpha cut and beta cut of alpha klotho, which releases KL1+KL2 and KL2 domain, respectively.

Klotho is a transmembrane protein that, in addition to other effects, provides some control over the sensitivity of the organism to insulin and appears to be involved in ageing. Its discovery was documented in 1997 by Makoto Kuro o et al. The name of the gene comes from Klotho or Clotho, one of the Moirai, or Fates, in Greek mythology, who spins the thread of human life. The klotho protein is a novel β glucuronidase (EC number 3.2.1.31) capable of hydrolyzing steroid β glucuronides. Genetic variants in KLOTHO have been associated with human aging, and klotho protein has been shown to be a circulating factor detectable in serum that declines with age. The binding of the endocrine fibroblast growth factors (FGF's, viz., FGF19 and FGF21) to their fibroblast growth factor receptors, is promoted via their interactions as co receptors with β klotho. α klotho, which binds to the endocrine FGF FGF23 changes cellular calcium homeostasis, by both increasing the expression and activity of TRPV5 (decreasing phosphate reabsorption in the kidney) and decreasing that of TRPC6 (decreasing phosphate absorption from the intestine). α klotho increases kidney calcium reabsorption by stabilizing TPRV5. About 95% to 98% of Ca2+ filtered from the blood by the kidney is normally reabsorbed by the kidney's renal tubule, which is mediated by TRPV5.

α klotho can suppress oxidative stress and inflammation, thereby reducing endothelial dysfunction and atherosclerosis. β klotho activation of FGF21 protein has a protective effect on heart muscle cells. Obesity is characterized by FGF21 resistance, believed to be caused by the inhibition of β klotho by the inflammatory cell signalling protein (cytokine) tumor necrosis factor alpha,

Klotho is required for oligodendrocyte maturation, myelin integrity, and can protect neurons from toxic effects. Mice deficient in klotho have a reduced number of synapses and cognitive deficits, whereas mice overexpressing klotho have enhanced learning and memory. Research with injections of klotho in primates demonstrates a positive effect on memory that lasts for as long as two weeks. Klotho may be a reliable gene for early detection of methylation changes in oral tissues, and can be used as a target for therapeutic modification in oral cancer during the early stages. Klotho deficient mice manifest a syndrome resembling accelerated human ageing and display extensive and accelerated arteriosclerosis. Additionally, they exhibit impaired endothelium dependent vasodilation and impaired angiogenesis, suggesting that klotho protein may protect the cardiovascular system through endothelium derived nitric oxide production. Research with injections of α klotho in primates suggests a positive effect on memory that could have implications for research with humans. Interestingly the cognitive effects in rhesus monkeys were observed even with subcutaneous injection despite previous results showing that klotho protein fails to cross the blood–brain barrier.

Reduced α klotho or FGF23 can result in impaired phosphate excretion from the kidney, leading to hyperphosphatemia. Lower plasma levels of α klotho in older adults is associated with increased frailty and all cause mortality. In addition, variations in the Klotho gene (SNP Rs9536314) are associated with both life extension and increased cognition in human populations and mice, but only if the gene expression was heterozygous, not homozygous. Klotho is an antagonist of the Wnt signaling pathway, and chronic Wnt stimulation can lead to stem cell depletion and aging. Klotho inhibition of Wnt signaling can inhibit cancer. The anti aging effects of klotho are also a consequence of increased resistance to inflammation and oxidative stress. The presence of senescent cells decreases α klotho levels. Senolytic drugs reduce the level of these cells, allowing α klotho levels to increase.