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Klotho is a transmembrane glycoprotein encoded by the KLOTHO gene and structurally characterized by a short intracellular domain and a large extracellular region containing two internal repeat domains, KL1 and KL2. These domains share sequence homology with family 1 glycosidases, although classical glycosidase enzymatic activity has not been clearly demonstrated. Post-translational processing by membrane-associated proteases such as ADAM10 and ADAM17 enables the extracellular domain of Klotho to be released into circulation and biological fluids, generating soluble forms that exhibit distinct biochemical properties from the membrane-bound protein.

Expression analyses indicate that Klotho is most abundantly localized in renal distal convoluted tubules and the choroid plexus, with additional expression observed in the proximal tubule, parathyroid gland, reproductive tissues, vascular adventitia, and selected regions of the central nervous system. Beyond α-Klotho, homologous β- and γ-Klotho isoforms have been identified, each displaying tissue-specific distribution patterns and functional associations, particularly in relation to fibroblast growth factor (FGF) signaling pathways.

At the molecular level, transmembrane Klotho functions as a co-receptor for fibroblast growth factor 23 (FGF23), contributing to phosphate and vitamin D homeostasis. Soluble Klotho has been reported to influence multiple signaling cascades through glycan modification of cell-surface proteins, including ion channels and growth factor receptors. These interactions suggest a regulatory role in pathways linked to oxidative stress responses, autophagy-lysosomal dynamics, insulin-related signaling, and cellular metabolism.

Experimental models and observational studies have associated alterations in Klotho expression or genetic variation with processes related to aging biology, renal physiology, cardiovascular structure, metabolic regulation, and oncogenic signaling networks. In particular, Klotho has been examined in the context of phosphate metabolism, mitochondrial regulation, inflammatory signaling, and fibroblast growth factor resistance. Genetic polymorphisms within the KLOTHO locus have also been studied for their correlation with vascular and metabolic phenotypes.

Overall, Klotho represents a multifunctional protein of significant interest in molecular aging research, renal and cardiovascular biology, and intracellular signaling regulation. Ongoing investigation continues to clarify its structural biology, regulatory mechanisms, and role within complex physiological systems across diverse experimental contexts.