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.