A potential link between phosphate and aging—Lessons from Klotho-deficient mice

Abstract

Phosphate homeostasis is maintained primarily by a bone-kidney endocrine axis. When phosphate is in excess, fibroblast growth factor-23 (FGF23) is secreted from bone and acts on kidney to promote phosphate excretion into urine. FGF23 also reduces serum vitamin D levels to suppress phosphate absorption from intestine. Thus, FGF23 functions as a hormone that induces negative phosphate balance. One critical feature of FGF23 is that it requires Klotho, a single-pass transmembrane protein expressed in renal tubules, as an obligate co-receptor to bind and activate cognate FGF receptors. Importantly, defects in either FGF23 or Klotho not only cause phosphate retention but also a premature-aging syndrome in mice, which can be rescued by resolving hyperphosphatemia. In addition, changes in extracellular and intracellular phosphate concentration affect glucose metabolism, insulin sensitivity, and oxidative stress in vivo and in vitro, which potentially affect aging processes. These findings suggest an unexpected link between inorganic phosphate and aging in mammals.

Role of nutrient transporters in lifestyle-related diseases

“…FGF23 is a novel phosphaturic factor, and strongly inhibits the activities of NaPi-IIa and NaPi-IIc through its specific receptor complex that consists of an FGF receptor and Klotho, which is an aging-related gene 43) . Mice that are null for either FGF23 or Klotho had the same premature aging-like phenotypes such as short lifespan, ectopic calcification, arteriosclerosis, and growth retardation that are induced by hyperphosphatemia.…”

“…Mice that are null for either FGF23 or Klotho had the same premature aging-like phenotypes such as short lifespan, ectopic calcification, arteriosclerosis, and growth retardation that are induced by hyperphosphatemia. Feeding a low phosphate diet or the simultaneous lack of the NaPiIIa gene can normalize serum phosphorus levels and cancel the premature aging-like phenotype of FGF23 or Klotho knockout mice 43) . It remains under investigation how hyperphosphatemia causes a premature aginglike phenotype.…”

Pathophysiology of the aging kidney and therapeutic interventions

“…92 Membrane-bound Klotho functions as the obligate coreceptor for fibroblast growth factor (FGF) 23, and any defects in the function of either Klotho or FGF23 in mice lead to phosphate accumulation and premature aging. 93 Patients with CKD eventually suffer premature death not from renal failure but as a result of the early onset of common aging-related diseases, such as cardiovascular disease and diabetes. 94 CKD patients exhibit remarkable declines in the kidney expression of Klotho, 95 which is associated with resistance to FGF23, 96 hyperphosphatemia and vascular calcification, symptoms similar to those of Klotho-deficient mice.…”

Cell Stress by Phosphate of Two Protozoa <i>Tetrahymena thermophile</i> and <i>Tetrahymena pyriformis</i>

“…In Humans, inorganic phosphate is involved in various pathological disorders such as bone, kidney, and vascular calcification [2]. Indeed, a deficiency of phosphate is found in rickets disease from children, osteomalacia in adults and…”