Klotho is an enzyme that in humans is encoded by the KL gene. There are three subfamilies of klotho: α-klotho, β-klotho, and γ-klotho. α-klotho activates FGF23, and β-klotho activates FGF19 and FGF21. When the subfamily is not specified, the word "klotho" generally means the α-klotho subfamily. Klotho can exist in a membrane-bound form or a soluble, circulating form. Proteases can convert the membrane-bound form into the circulating form. The KL gene encodes a type-I membrane protein that is related to β-glucuronidases. Reduced production of this protein has been observed in patients with chronic kidney failure, and this may be one of the factors underlying the degenerative processes seen in CKF. Also, mutations within this protein have been associated with ageing, bone loss and alcohol consumption. Transgenic mice that overexpress Klotho live longer than wild-type mice.
Function
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. The Klotho protein is a novel β-glucuronidase capable of hydrolyzing steroidβ-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 certain fibroblast growth factors to their fibroblast growth factor receptors, is promoted via their interactions as co-receptors with β-Klotho. α-klotho changes cellular calcium homeostasis, by both increasing the expression and activity of TRPV5 and decreasing that of TRPC6. α-klotho increases kidney calcium reabsorption by stabilizing TPRV5.
Clinical significance
α-klotho can suppress oxidative stress and inflammation, thereby reducing endothelial dysfunction and atherosclerosis. Blood plasma α-klotho is increased by aerobic exercise, thereby reducing endothelial dysfunction. 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 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. It has been found that the decreased Klotho expression may be due to DNA hypermethylation, which may have been induced by the overexpression of DNMT3a. 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 aging 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 NO production.
Effects on aging
Mice lacking either fibroblast growth factor 23 or the α-klotho enzyme display premature aging due to hyperphosphatemia. Many of these symptoms can be alleviated by feeding the mice a low phosphate diet. Although the vast majority of research has been based on lack of Klotho, it was demonstrated that an overexpression of Klotho in mice might extend their average life span between 19% and 31% compared to normal mice. In addition, variations in the Klotho gene are associated with both life extension and increased cognition in human populations. Klotho increases membrane expression of the inward rectifier ATP-dependent potassium channelROMK. Klotho-deficient mice show increased production of vitamin D, and altered mineral-ion homeostasis is suggested to be a cause of premature aging‑like phenotypes, because the lowering of vitamin D activity by dietary restriction reverses the premature aging‑like phenotypes and prolongs survival in these mutants. These results suggest that aging‑like phenotypes were due to klotho-associated vitamin D metabolic abnormalities. Klotho is an antagonist of the Wnt signaling pathway, and chronic Wnt stimulation can lead to stem cell depletion and aging.
