The secreted Klotho protein restores phosphate retention and suppresses accelerated aging in Klotho mutant mice

Tso Hsiao Chen, Makoto Kuro-O, Cheng Hsien Chen, Yuh Mou Sue, Yen Cheng Chen, Ho Han Wu, Chung Yi Cheng

Research output: Contribution to journalArticle

49 Citations (Scopus)

Abstract

Klotho was identified as the responsible gene in a mutant mouse line whose disruption results in a variety of premature aging-related phenotypes. Nonetheless, the related mechanisms were still unknown. Many studies report that dietary phosphate restriction and genetic ablation of vitamin D pathways indirectly reverse premature aging processes in these mice. Furthermore, transgenic overexpression of klotho in mice extends their life span through inhibition of insulin and IGF1 signaling. We found that intraperitoneal injection of recombinant soluble Klotho protein at dose of 0.02 mg/kg every other day effectively extends the life span of kl/kl mice by 17.4%. Soluble Klotho administration also ameliorated premature aging-related phenotype, such as growth retardation, premature thymus involution and vascular calcification, and effectively enhanced urinary phosphate excretion in kl/kl mice. Klotho treatment attenuated renal fibrosis through down-regulation of transforming growth factor-β signaling as well as reduced cellular senescence through down-regulation of p21-cip1 mRNA levels. In addition, soluble Klotho treatment significantly reduced both renal and aorta calcium deposits. In conclusion, our study shows the therapeutic potential of soluble Klotho protein to treat age-related disorders in mice.

Original languageEnglish (US)
Pages (from-to)67-73
Number of pages7
JournalEuropean Journal of Pharmacology
Volume698
Issue number1-3
DOIs
StatePublished - Jan 5 2013

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Phosphates
Premature Aging
Down-Regulation
Vascular Calcification
Phenotype
Kidney
Cell Aging
Transforming Growth Factors
Intraperitoneal Injections
Vitamin D
Thymus Gland
Aorta
klotho protein
Fibrosis
Therapeutics
Insulin
Calcium
Messenger RNA
Growth
Genes

Keywords

  • IGF1
  • Insulin
  • Klotho
  • Phosphate
  • Vascular calcification

ASJC Scopus subject areas

  • Pharmacology

Cite this

The secreted Klotho protein restores phosphate retention and suppresses accelerated aging in Klotho mutant mice. / Chen, Tso Hsiao; Kuro-O, Makoto; Chen, Cheng Hsien; Sue, Yuh Mou; Chen, Yen Cheng; Wu, Ho Han; Cheng, Chung Yi.

In: European Journal of Pharmacology, Vol. 698, No. 1-3, 05.01.2013, p. 67-73.

Research output: Contribution to journalArticle

Chen, Tso Hsiao ; Kuro-O, Makoto ; Chen, Cheng Hsien ; Sue, Yuh Mou ; Chen, Yen Cheng ; Wu, Ho Han ; Cheng, Chung Yi. / The secreted Klotho protein restores phosphate retention and suppresses accelerated aging in Klotho mutant mice. In: European Journal of Pharmacology. 2013 ; Vol. 698, No. 1-3. pp. 67-73.
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