Abstract 17023: PAI-1 Deficiency Protects Against Accelerated Aging in Klotho-Deficient Mice

Abstract

The klotho gene encodes a single-pass transmembrane protein and functions as an aging-suppressor gene, which extends life span when overexpressed and accelerates the development of aging-like phenotypes when disrupted in mice. Klotho protein and FGF receptor function as co-receptors for FGF23 and regulate phosphate and vitamin D metabolism. Klotho also plays a role in the regulation of calcium channel TRPV5, insulin, IGF-1, and Wnt. Klotho deficient (kl -/- ) mice display a phenotype consistent with accelerated aging, including a markedly truncated lifespan (approx. 10 weeks), infertility, osteoporosis, renal sclerosis and obstructive pulmonary disease. The biochemical hallmarks of kl -/- include elevated plasma levels of FGF23, phosphate, calcium, vitamin D, and plasma PAI-1. Given the relationship between elevated PAI-1 and nephrosclerosis and tissue fibrosis, we hypothesized that PAI-1 deficiency would attenuate the phenotype of kl -/- mice. Partial or complete PAI-1 deficiency had no significant effects on serum levels of calcium, phosphate, and creatinine levels, while plasma levels of FGF23 were reduced more than 60-fold in kl -/- -pai-1 -/- (P=0.01) and kl -/- -pai-1 +/- (P=0.004) mice. Furthermore, both kl -/- -pai-1 -/- and kl -/- -pai-1 +/- mice exhibit normal fertility. Most importantly, partial and complete PAI-1 deficiency more than doubled the lifespan of kl -/- mice, with kl -/- -pai-1 -/- living 148±79 days, (n=9, p=0.009)) and kl -/- -pai-1 +/- surviving 208±155 days (n=17, p=0.002). These findings indicate that PAI-1 contributes to some of the critical components of the kl -/- phenotype. These results suggest that drugs that either directly or indirectly reduce PAI-1 might have beneficial effects in delaying age-related pathologies.