Klotho mutant mouse (kl-/-), a mouse model for human aging, exhibits various 
phenotypes in a wide range of organs including arteriosclerosis, neural 
degeneration, skin and gonadal atrophy, pulmonary emphysema, calcification of 
soft tissues, and cognition impairment. Klotho mRNA, however, is expressed only 
in brain, kidney, reproductive organs, pituitary gland, and parathyroid gland. 
Therefore it remains to be elucidated how lack of Klotho protein in these 
limited organs leads to the variety of phenotypes. To shed light on mechanisms 
by which Klotho protein acts on distant targets, we examined localization of 
Klotho protein in brain, kidney, and reproductive organs, and analyzed brain and 
kidney in kl-/- mice searching for changes in target regions in these organs. In 
brain, Klotho proteins were localized at choroid plexus, where the proteins were 
dominantly localized at the apical plasma membrane of ependymal cells. In kl-/- 
brain, reduction of synapses was evident in hippocampus, suggesting a role of 
Klotho as a humoral factor in cerebrospinal fluid. Klotho proteins in kidney 
localized at distal renal tubules. Interestingly, in kl-/-mice, type IIa 
Na/phosphate (Pi) cotransporters, which function at the proximal renal tubules 
in reabsorption of phosphate ions, were translocated. This suggests that Klotho 
protein in kidney is implicated in calcium homeostasis which regulates 
localization of type IIa Na/Pi cotransporters via parathyroid hormone (PTH). 
Klotho proteins in reproductive organs were expressed only in mature germ cells, 
although in kl-/- mice germ cell maturation was arrested at earlier stages. 
Thus, Klotho proteins not only function as a humoral factor, but also are 
implicated in hormonal regulation, which may explain why mutation of klotho gene 
results in a variety of phenotypes.