[12] The KL gene encodes a type-I single-pass transmembrane protein[7] that is related to β-glucuronidases.

[17] The other isoform is a truncated mRNA, that terminates after the KL1 domain and thus the transmembrane region gets cleaved off and the produced protein is excreted into the extracellular medium.

In order to distinguish the different circulating polypeptides (cleavage fragments and isoforms), newer papers follow the following nomenclature[20] mKL: mKL135 stands for the full-length, transmembrane form pKL: Processed Klotho (p-KL) comes from the processing of full-length transmembrane klotho protein.

This cleavage releases the ectodomains into the extracellular medium, while the transmembrane domain (with or without KL2) remains in the cell membrane.

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.[21] 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.

[31] 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,[31] but there is evidence against this mechanism.

[19] Klotho is required for oligodendrocyte maturation, myelin integrity, and can protect neurons from toxic effects.

[34] 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.

[36] An abnormal form of autophagy associated with reduced expression of klotho is linked to the pathogenesis of chronic obstructive pulmonary disease.

[7] The plasma (soluble) form of α-klotho is most easily measured, and has been shown to decrease after 40 years of age in humans.

[40] Lower plasma levels of α-klotho in older adults is associated with increased frailty and all-cause mortality.

[40] Mice lacking either fibroblast growth factor 23 or the α-klotho enzyme display premature aging due to hyperphosphatemia.

[27] Klotho-deficient mice show increased production of vitamin D, and altered mineral-ion homeostasis is suggested to cause premature aging‑like phenotypes, because reduced vitamin D activity from dietary restriction reverses the premature aging‑like phenotypes and prolongs survival in these mutants.

[48] This article incorporates text from the United States National Library of Medicine, which is in the public domain.