The study investigates the relationship between Klotho, an aging suppressor gene, and fibroblast growth factor-23 (FGF23) signaling. Klotho-deficient mice exhibit aging-like phenotypes, including shortened lifespan and muscle atrophy, which are similar to those observed in FGF23-deficient mice. To explore whether Klotho and FGF23 function in a common signaling pathway, the researchers examined the interaction between Klotho and FGF receptors (FGFRs). They found that Klotho directly binds to multiple FGFR isoforms, and the Klotho-FGFR complex binds to FGF23 with higher affinity than FGFR or Klotho alone. Additionally, Klotho significantly enhances the ability of FGF23 to induce phosphorylation of FGF receptor substrate and ERK in various cell types. These findings suggest that Klotho functions as a cofactor essential for the activation of FGF signaling by FGF23. The study also highlights the potential role of Klotho in regulating FGF signaling in non-kidney cells and the possibility that Klotho may act as a paracrine factor in the kidney to inhibit phosphate reabsorption.The study investigates the relationship between Klotho, an aging suppressor gene, and fibroblast growth factor-23 (FGF23) signaling. Klotho-deficient mice exhibit aging-like phenotypes, including shortened lifespan and muscle atrophy, which are similar to those observed in FGF23-deficient mice. To explore whether Klotho and FGF23 function in a common signaling pathway, the researchers examined the interaction between Klotho and FGF receptors (FGFRs). They found that Klotho directly binds to multiple FGFR isoforms, and the Klotho-FGFR complex binds to FGF23 with higher affinity than FGFR or Klotho alone. Additionally, Klotho significantly enhances the ability of FGF23 to induce phosphorylation of FGF receptor substrate and ERK in various cell types. These findings suggest that Klotho functions as a cofactor essential for the activation of FGF signaling by FGF23. The study also highlights the potential role of Klotho in regulating FGF signaling in non-kidney cells and the possibility that Klotho may act as a paracrine factor in the kidney to inhibit phosphate reabsorption.