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

Area of Science:

• Biogerontology
• Molecular Biology
• Genetics

Background:

• Klotho gene mutations cause premature aging phenotypes in mice.
• Dietary phosphate restriction and vitamin D pathway ablation partially reverse aging in klotho mutant mice.
• Transgenic klotho overexpression extends lifespan by inhibiting insulin and IGF1 signaling.

Purpose of the Study:

• To investigate the therapeutic potential of recombinant soluble Klotho protein in treating premature aging-related phenotypes.
• To determine the effects of soluble Klotho protein administration on lifespan and aging markers in klotho mutant mice.

Main Methods:

• Intraperitoneal injection of recombinant soluble Klotho protein (0.02 mg/kg every other day) into klotho mutant mice (kl/kl).
• Assessment of lifespan, premature aging phenotypes (growth retardation, thymus involution, vascular calcification), urinary phosphate excretion, renal fibrosis, cellular senescence, and calcium deposits.

Main Results:

• Soluble Klotho protein administration extended kl/kl mouse lifespan by 17.4%.
• Treatment ameliorated aging phenotypes, enhanced urinary phosphate excretion, attenuated renal fibrosis via TGF-β signaling, and reduced cellular senescence (p21-cip1).
• Klotho treatment significantly reduced renal and aorta calcium deposits.

Conclusions:

• Soluble Klotho protein demonstrates therapeutic potential for treating age-related disorders.
• Klotho protein administration offers a promising strategy to combat premature aging phenotypes and associated pathologies in mice.