The klotho gene (KL) was identified first as a putative aging-suppressor gene 
that extended life span when overexpressed and accelerated aging-like phenotypes 
when disrupted in mice. It encodes a single-pass transmembrane protein and is 
expressed predominantly in kidney, where it functions as an obligate coreceptor 
for fibroblast growth factor 23 (FGF-23). FGF-23 is a bone-derived hormone that 
suppresses phosphate reabsorption and 1,25 dihydroxyvitamin D(3) (vitamin D) 
synthesis in the kidney. Klotho also is expressed in the parathyroid gland, 
where FGF-23 decreases parathyroid hormone expression and secretion, further 
suppressing vitamin D synthesis in kidney. Thus, FGF-23 functions as a 
phosphaturic hormone and a counter-regulatory hormone for vitamin D, thereby 
inducing negative phosphate balance. Mice lacking either FGF-23 or Klotho show 
hyperphosphatemia in addition to developing multiple aging-like phenotypes, 
which can be rescued by resolving phosphate retention. These findings have 
unveiled an unexpected link between aging and phosphate. In patients with 
chronic kidney disease (CKD), phosphate retention is seen universally and has 
been associated with increased mortality risk. Patients with CKD have high serum 
FGF-23 levels with decreased klotho expression in the kidney and parathyroid, 
rendering FGF-23 and Klotho as potential biomarkers and therapeutic targets for 
CKD. The Klotho protein not only serves as a coreceptor for FGF-23, but also 
functions as a humoral factor. Klotho's extracellular domain is released into 
blood and urine by ectodomain shedding and exerts various functions 
independently of FGF-23, including regulation of multiple ion channels and 
transporters. Decreased urinary Klotho protein level has been identified as one 
of the earliest biomarkers of CKD progression. This review focuses on the 
current understanding of Klotho protein function, with emphasis on its potential 
involvement in the pathophysiologic process of CKD.