Klotho and aging

Abstract

The klotho gene encodes a single-pass transmembrane protein that forms a complex with multiple fibroblast growth factor (FGF) receptors and functions as an obligatory co-receptor for FGF23, a bone-derived hormone that induces negative phosphate balance. Defects in either Klotho or Fgf23 gene expression cause not only phosphate retention but also a premature-aging syndrome in mice, unveiling a potential link between phosphate metabolism and aging. In addition, the extracellular domain of Klotho protein is clipped on the cell surface and secreted into blood stream, potentially functioning as an endocrine factor. The secreted Klotho protein has a putative sialidase activity that modifies glycans on the cell surface, which may explain the ability of secreted Klotho protein to regulate activity of multiple ion channels and growth factors including insulin, IGF-1, and Wnt. Secreted Klotho protein also protects cells and tissues from oxidative stress through a mechanism yet to be identified. Thus, the transmembrane and secreted forms of Klotho protein have distinct functions, which may collectively affect aging processes in mammals.

Figure 1

Function of Klotho protein. The transmembrane Klotho forms a complex with FGF receptor (FGFR) and functions as a co-receptor for FGF23 and plays a crucial role in the regulation of phosphate and vitamin D metabolism in the kidney. On the other hand, the transmembrane Klotho is clipped by membrane-anchored proteases ADAM10 and ADAM17 just above the plasma membrane. The entire extracellular domain of Klotho is then released into blood, urine, and cerebrospinal fluid. The secreted Klotho protein has a putative sialidase activity that modifies glycans of calcium channel TRPV5 on the cell surface. A similar mechanism may explain the inhibitory effect of secreted Klotho on growth factors including insulin, IGF-1, and Wnt. The ability of secreted Klotho to inhibit IGF-1 signaling may contribute to the anti-oxidative stress and anti-cancer properties of Klotho. See Section 4.

Figure 2

Endocrine axes that regulate vitamin D metabolism mediated by FGF23 and Klotho. Active vitamin D (1,25-dihydroxyvitamin D₃) binds to vitamin D receptor (VDR) in osteocytes, which in turn forms a heterodimer with a nuclear receptor RXR and directly binds to a promoter region of the FGF23 gene to transactivate its expression. FGF23 secreted from the bone acts on the Klotho-FGFR complex in the kidney (the bone-kidney axis) and parathyroid gland (the bone-parathyroid axis). In the kidney, FGF23 suppresses expression of Cyp27b1 gene that encodes 1α-hydroxylase and closes a negative feedback loop for vitamin D homeostasis. In the parathyroid gland, FGF23 suppresses expression of PTH. Since PTH is a potent inducer of Cyp27b1 gene expression, suppression of PTH by FGF23 reduces expression of Cyp27b1 gene as well as serum levels of 1,25-dihydroxyvitamin D₃, which closes another negative feedback loop for vitamin D homeostasis. Klotho and FGF23 are indispensable for the regulation of vitamin D metabolism, because defects in either Klotho or FGF23 cause hypervitaminosis D.

Figure 3

Klotho activates calcium channel TRPV5. The number of TRPV5 on the plasma membrane is determined by counterbalance between insertion by protein trafficking from Golgi and removal by endocytosis to endosomes. Terminals of sugar chains of cell-surface glycoproteins are capped with sialic acids (red). Secreted Klotho protein removes these sialic acids through its putative α2→6 sialidase activity and exposes underlying galactose residues (green) in the glycans. The exposed galactose then binds to galectin-1 (blue) in the extracellular matrix. Galectin-1 tethers TRPV5 on the cell surface and prevents its endocytosis, resulting in accumulation of TRPV5 on the plasma membrane and increase in calcium influx.