Differential toxicity profile of secreted and processed α-Klotho expression over mineral metabolism and bone...

Area of Science:

• Gerontology
• Molecular Biology
• Biochemistry

Background:

• The aging-protective gene α-Klotho (KL) has two main transcripts: full-length mRNA producing processed Klotho (p-KL) and a shorter transcript for secreted Klotho (s-KL).
• While KL has beneficial properties, exogenous p-KL administration has shown negative impacts on mineral homeostasis.

Purpose of the Study:

• To investigate the effects of the secreted Klotho (s-KL) isoform on mineral metabolism independently of the processed Klotho (p-KL) isoform.
• To assess the safety and efficacy of s-KL as a therapeutic strategy for anti-aging effects.

Main Methods:

• Independent expression of s-KL and p-KL isoforms using gene transfer vectors in mice.
• Analysis of kidney ion channel expression, blood mineral levels (Pi, Ca2+), and bone gene expression (Fgf23).
• Evaluation of bone microstructure parameters.

Main Results:

• Mice treated with p-KL showed altered kidney ion channel expression and blood mineral levels (Pi, Ca2+), alongside a fourfold increase in bone Fgf23 expression.
• p-KL treatment significantly worsened bone microstructure parameters.
• s-KL treated mice exhibited mineral and bone parameters comparable to control groups, with an unexpected increase in trabecular thickness and cortical mineral density.

Conclusions:

• The secreted Klotho (s-KL) isoform is a safe therapeutic strategy for harnessing KL's anti-aging effects.
• Unlike p-KL, s-KL does not negatively impact mineral metabolism or bone microstructure.
• s-KL demonstrates potential for therapeutic applications without adverse effects on mineral homeostasis and bone health.