Phosphate as a Pathogen of Arteriosclerosis and Aging.

During the evolution of skeletons, terrestrial vertebrates acquired strong bones made of calcium-phosphate. By keeping the extracellular fluid in a supersaturated condition regarding calcium and phosphate ions, they created the bone when and where they wanted simply by providing a cue for precipitation. To secure this strategy, they acquired a novel endocrine system to strictly control 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, thereby maintaining phosphate homeostasis. The FGF23-Klotho endocrine system, when disrupted in mice, results in hyperphosphatemia and vascular calcification. Besides, mice lacking Klotho or FGF23 suffer from complex aging-like phenotypes, which are alleviated by placing them on a low- phosphate diet, indicating that phosphate is primarily responsible for the accelerated aging. Phosphate acquires the ability to induce cell damage and inflammation when precipitated with calcium. In the blood, calcium-phosphate crystals are adsorbed by serum protein fetuin-A and prevented from growing into large precipitates. Consequently, nanoparticles that comprised calcium-phosphate crystals and fetuin-A, termed calciprotein particles (CPPs), are generated and dispersed as colloids. CPPs increase in the blood with an increase in serum phosphate and age. Circulating CPP levels correlate positively with vascular stiffness and chronic non-infectious inflammation, raising the possibility that CPPs may be an endogenous pro-aging factor. Terrestrial vertebrates with the bone made of calcium- phosphate may be destined to age due to calcium-phosphate in the blood.