Klotho and calciprotein particles as therapeutic targets against accelerated ageing

Abstract

The klotho gene, named after a Greek goddess who spins the thread of life, was identified as a putative ‘ageing-suppressor’ gene. Klotho-deficient mice exhibit complex ageing-like phenotypes including hypogonadism, arteriosclerosis (vascular calcification), cardiac hypertrophy, osteopenia, sarcopenia, frailty, and premature death. Klotho protein functions as the obligate co-receptor for fibroblast growth factor-23 (FGF23), a bone-derived hormone that promotes urinary phosphate excretion in response to phosphate intake. Thus, Klotho-deficient mice suffer not only from accelerated ageing but also from phosphate retention due to impaired phosphate excretion. Importantly, restoration of the phosphate balance by placing Klotho-deficient mice on low phosphate diet rescued them from premature ageing, leading us to the notion that phosphate accelerates ageing. Because the extracellular fluid is super-saturated in terms of phosphate and calcium ions, an increase in the phosphate concentration can trigger precipitation of calcium-phosphate. In the blood, calcium-phosphate precipitated upon increase in the blood phosphate concentration is adsorbed by serum protein fetuin-A to form colloidal nanoparticles called calciprotein particles (CPPs). In the urine, CPPs appear in the renal tubular fluid when FGF23 increases phosphate load excreted per nephron. CPPs can induce cell damage, ectopic calcification, and inflammatory responses. CPPs in the blood can induce arteriosclerosis and non-infectious chronic inflammation, whereas CPPs in the urine can induce renal tubular damage and interstitial inflammation/fibrosis. Thus, we propose that CPPs behave like a pathogen that accelerates ageing and should be regarded as a novel therapeutic target against age-related disorders including chronic kidney disease.

Pathobiology of the Klotho Antiaging Protein and Therapeutic Considerations

“…It has been proposed that declining renal function, and associated low Klotho, accelerate or aggravate many of the pathologies found in old age. This may involve, for example, the precipitation of CPPs in tissue ( Kuro-o, 2021 ).…”

“…The activated FGFR signals through PI3K/Akt, phospholipase Cγ (PLCγ) and Ras/MAPK/ERK. The renal physiological functions of Klotho have been extensively reviewed ( Erben and Andrukhova, 2017 ; Kuro-o 2017 ; Zou et al, 2018 ; Kuro-o 2019 ; Kuro-o 2021 ; Neyra et al, 2021 ; Saar-Kovrov et al, 2021 ), and are only briefly described here. Activation of FGFR1c regulates phosphate and calcium exchange in the kidney.…”

“…A deficiency of either Klotho or FGF23 in mice results in excessive 1α-hydroxylase activity, overproduction of active vitamin D, and associated hyperphosphatemia and hypercalcemia. In Klotho-deficient mice, hypervitaminosis D and hyperphosphatemia both appear to contribute to the accelerated aging phenotype ( Kuro-o 2010 , 2018 , 2019 , 2021 ). However, a low phosphate diet ameliorates disease, even though vitamin D further increases, suggesting that the hyperphosphatemia is more important than vitamin D toxicity in the aging syndrome.…”

“…Nevertheless, ablation of vitamin D responses attenuated the lesions of Klotho-deficient mice ( Anour et al, 2012 ). It has been proposed that hypersaturation of phosphate and calcium ions in the blood leads to the formation of calciprotein particles (CPPs) ( Kuro-o, 2021 ). The CPPs precipitate in tissues, and are thought to accelerate the pathologic changes associated with aging.…”

“…Klotho can exist as a membrane-bound coreceptor for fibroblast growth factor 23 (FGF23) ( Urakawa et al, 2006 ), or a soluble endocrine mediator with many functions ( Figures 1 , 2 ) ( Dalton et al, 2017 ; Kuro-o, 2017 ). Age-related deterioration of renal function results in Klotho insufficiency, and hyperphosphatemia that contributes greatly to the aging phenotype ( Kuro-o 2010 , 2018 , 2021 ). Klotho protects the kidney and promotes phosphate elimination (phosphaturic effect).…”