Aging and FGF23-klotho system

Abstract

During the evolution of skeletons, vertebrates acquired the bone made of calcium phosphate. By keeping the extracellular fluid in a supersaturated condition regarding calcium and phosphate, vertebrates create the bone when and where they want simply by providing a cue for precipitation. To secure this strategy, a new endocrine system has evolved that strictly controls the extracellular phosphate concentration. In response to phosphate intake, fibroblast growth factor-23 (FGF23) is secreted from the bone and acts on the kidney through binding to its receptor Klotho to increase urinary phosphate excretion and maintain phosphate homeostasis. The FGF23-Klotho endocrine system, when disrupted, results in hyperphosphatemia and ectopic precipitation of calcium phosphate in mice and humans. In addition to disturbed phosphate homeostasis, mice lacking Klotho suffer from premature aging. They exhibit multiple organ atrophy, arteriosclerosis characterized by vascular calcification, cardiac hypertrophy, sarcopenia, cognition impairment, frailty, and a shortened life span associated with chronic non-infectious inflammation. Restoration of the phosphate balance by placing Klotho- or FGF23-deficient mice on low phosphate diet rescued them from the aging-like phenotypes, indicating that phosphate was responsible for the accelerated aging. The similar pathophysiology is universally observed in patients with chronic kidney disease (CKD), rendering advanced CKD a clinical model of accelerated aging. CKD patients bear colloidal nanoparticles containing calcium phosphate in the blood, which are termed calciprotein particles (CPPs). CPPs have the ability to induce cell damage and inflammation, potentially contributing to accelerated aging. Terrestrial vertebrates with the bone made of calcium phosphate may be destined to age due to ectopic calcium phosphate.

Keywords: 1,25-Dihydroxyvitamin D(3); Aging; Calciprotein particles; Chronic kidney disease; Fibroblast growth factor-21; Fibroblast growth factor-23; Klotho; Parathyroid hormone; Phosphate; βKlotho.