Klotho and the aging process

Abstract

The klotho gene was originally identified as a putative age-suppressing gene in mice that extends life span when overexpressed. It induces complex phenotypes resembling human premature aging syndromes when disrupted. The gene was named after a Greek goddess Klotho who spun the thread of life. Since then, various functional aspects of the klotho gene have been investigated, leading to the identification of multiple novel endocrine axes that regulate various metabolic processes and an unexpected link between mineral metabolism and aging. The purposes of this review were to overview recent progress on Klotho research and to discuss a novel aging mechanism.

Keywords: Fibroblast growth factor; Klotho; Phosphate; Vitamin D.

Figure 1

Membrane Klotho and secreted Klotho. Membrane Klotho forms a complex with the fibroblast growth factor receptor (FGFR) to create a de novo high-affinity binding site for FGF23. Membrane Klotho is subject to ectodomain shedding by α- and β-secretases to release secreted Klotho.

Figure 2

Endocrine regulation of phosphate homeostasis (modified from [30,31]). Parathyroid hormone (PTH) increases synthesis of calcitriol (1,25-dihydroxyvitamin D₃) in the kidney (a). Calcitriol in turn decreases PTH (b), thereby closing a negative feedback loop. The fibroblast growth factor 23 (FGF23)-Klotho system has emerged as the principal phosphate-regulating endocrine axes. FGF23 is secreted from bone and acts on kidney to reduce calcitriol synthesis (c). Because calcitriol increases FGF23 expression in bone (d), a negative feedback loop exists between FGF23 and calcitriol. FGF23 also acts on the parathyroid to reduce PTH (e). Because PTH increases FGF23 expression (f), another negative feedback loop exists between PTH and FGF23.

Figure 3

Changes in the phosphate-regulating endocrine system during progression of chronic kidney disease (CKD) (modified from [30,31]). (A) Vicious cycles leading to high fibroblast growth factor 23 (FGF23), high parathyroid hormone (PTH), low vitamin D, and low Klotho in CKD. (B) Increases in serum FGF23 and serum PTH levels and decreases in serum vitamin D and urine Klotho levels precede hyperphosphatemia during CKD progression from stage 1 to stage 5.

Figure 4

Feedback regulation of activity and expression of endocrine fibroblast growth factor (FGFs). (A) The bone-kidney endocrine axis (modified from [69]). The active form of vitamin D (calcitriol or 1,25-dihydroxyvitamin D₃) binds to vitamin D receptor (VDR). The ligand-bound VDR forms a heterodimer with retinoid X receptor (RXR) and functions as a transcription factor that increases FGF23 expression in osteocytes. Secreted FGF23 activates FGFR1c, 3c and/or 4 bound by Klotho in renal tubular cells, and suppresses CYP27B1 gene expression, which encodes an enzyme that synthesizes calcitriol. Additionally, FGF23 increases expression of the CYP24 gene, which encodes an enzyme that hydrolyzes and inactivates calcitriol. Thus, FGF23 reduces serum calcitriol levels. (B) The intestine-liver endocrine axis. Feeding increases the release of bile acids that bind to farnesoid X receptor (FXR). The ligand-bound FXR forms a heterodimer with RXR and functions as a transcription factor that increases expression of FGF19 in intestinal epithelial cells. Secreted FGF19 activates FGFR4 bound by βKlotho in hepatocytes and suppresses expression of the CYP7A1 gene, which encodes the rate-limiting enzyme for bile acid synthesis. Thus, FGF19 reduces bile acid synthesis in the liver. (C) The liver-white adipose tissue (WAT) endocrine axis. Fasting increases the release of fatty acids that bind to peroxisome proliferator-activated receptor α (PPARα). The ligand-bound PPARα forms a heterodimer with RXR and functions as a transcription factor that increases expression of FGF21 in hepatocytes. Secreted FGF21 activates FGFR1c bound by βKlotho in adipocytes and promotes lipolysis. A CYP gene (s) regulated by the FGF21-βKlotho system in adipocytes remains to be identified.