A potential link between phosphate and aging--lessons from Klotho-deficient mice

Abstract

Phosphate homeostasis is maintained primarily by a bone-kidney endocrine axis. When phosphate is in excess, fibroblast growth factor-23 (FGF23) is secreted from bone and acts on kidney to promote phosphate excretion into urine. FGF23 also reduces serum vitamin D levels to suppress phosphate absorption from intestine. Thus, FGF23 functions as a hormone that induces negative phosphate balance. One critical feature of FGF23 is that it requires Klotho, a single-pass transmembrane protein expressed in renal tubules, as an obligate co-receptor to bind and activate cognate FGF receptors. Importantly, defects in either FGF23 or Klotho not only cause phosphate retention but also a premature-aging syndrome in mice, which can be rescued by resolving hyperphosphatemia. In addition, changes in extracellular and intracellular phosphate concentration affect glucose metabolism, insulin sensitivity, and oxidative stress in vivo and in vitro, which potentially affect aging processes. These findings suggest an unexpected link between inorganic phosphate and aging in mammals.

Figure 1

The bone-kidney endocrine axes mediated by FGF23 and Klotho. In osteocytes, active form of vitamin D (1,25-dihydroxyvitamin D₃) binds to vitamin D receptor (VDR) and forms heterodimers with another nuclear receptor (RXR) to transactivate transcription of FGF23 gene. Phosphate (P) also increases expression of FGF23 in bone, but its mechanism remains to be determined. FGF23 secreted from bone acts on the Klotho-FGFR complex expressed in renal epithelium in the kidney. As a phosphaturic hormone, FGF23 inhibits transepithelial phosphate reabsorption by suppressing sodium-phosphate co-transporter type-IIa (NaPi-2a) on the apical brush-border membrane of renal tubules, thereby closing a negative feedback loop for phosphate homeostasis. As a counter-regulatory hormone for vitamin D, FGF23 reduces serum levels of 1,25-dihydroxyvitamin D₃ through suppressing its synthesis by down-regulating expression of the Cyp27b1 gene and promoting its inactivation by up-regulating expression of the Cyp24 gene, thereby closing a negative feedback loop for vitamin D homeostasis.

Figure 2

Relation between longevity and serum phosphate in mammals. 1: Klotho^−/− mouse, 2: Mouse, 3: Rat, 4: Hamster, 5: Gerbil, 6: Nutria, 7: Rabbit, 8: Guinea pig, 9: Sheep, 10: Squirrel, 11: Porcupine, 12: Naked mole rat, 13: Flying fox, 14: Bear, 15: Rhinoceros, 16: Elephant, 17: Human, 18: Human (centenarian). Serum phosphate leves are average or median values, whichever available in literatures (Asadi et al., 2007; Feldhamer et al., 2003; Field et al., 1998; Gorbunova et al., 2008; Heard et al., 2006; Holliday, 1995; Kuro-o et al., 1997; Moreau et al., 2003; Munson et al., 1998; Passeri et al., 2008; Pugh, 2002; Ramsay, 2003; Segawa et al., 2007; Thrall et al., 2004; Tuntasuvan et al., 2002; Yahav et al., 1993).