{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n Klotho is a multifunctional protein that plays a central role in regulating mineral metabolism, aging, and cellular signaling. The membrane‐bound form complexes with fibroblast growth factor receptors (FGFRs) to form a high‐affinity receptor for FGF23, thereby orchestrating phosphate, calcium, and vitamin D homeostasis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": " Equally important, the secreted form—generated by proteolytic shedding mediated by enzymes such as ADAM10 and ADAM17—acts as a circulating hormone that modulates the activity and cell‐surface retention of key proteins. For instance, secreted Klotho enhances calcium channel activity by modifying the glycan moieties on TRPV5"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": "and directly regulates the principal renal phosphate transporter NaPi‑2a."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Beyond its established role in mineral metabolism, Klotho exerts broad anti–aging and protective effects by interacting with multiple signaling pathways. Overexpression of Klotho extends lifespan by inhibiting insulin/IGF‑1 signaling"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}, {"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": ", while its ability to bind Wnt ligands suppresses aberrant Wnt/β‑catenin activity"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}, {"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": ", thereby contributing to enhanced oxidative stress resistance and preservation of stem cell function. Furthermore, secreted Klotho directly interferes with profibrotic TGF‑β signaling"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "and counteracts vascular calcification"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": ", which together underline its renoprotective and cardioprotective properties.\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Genetic studies have revealed that polymorphic variants in the Klotho gene (such as the KL‑VS allele) are associated with differences in aging phenotypes and cardiovascular risk."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": " In addition, the process of Klotho shedding—as shown by its regulation via specific secretases"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": "—is critical for its availability and function as a systemic modulator. Finally, inflammatory cytokines can downregulate Klotho expression through NF‑κB–dependent mechanisms"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": ", highlighting its role at the intersection of inflammation, aging, and chronic kidney disease.\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Collectively, these findings establish Klotho as a pivotal regulator of endocrine FGF signaling and as a multifunctional anti–aging protein with far‐reaching implications for metabolic, vascular, and renal health.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Itaru Urakawa, Yuji Yamazaki, Takashi Shimada, et al. 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