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Proc Natl Acad Sci U S A. 2014 May 13;111(19):7090-5. doi: 10.1073/pnas.1321942111. Epub 2014 Apr 28.

PAI-1-regulated extracellular proteolysis governs senescence and survival in Klotho mice.

Author information

1
Department of Medicine and.
2
Department of Medicine andFeinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, Chicago, IL 60611; and.
3
United Centers for Advanced Research and Translational Medicine, Tohoku University Graduate School of Medicine, Miyagi 980-8575, Japan.
4
Department of Medicine andFeinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, Chicago, IL 60611; and d-vaughan@northwestern.edu.

Abstract

Cellular senescence restricts the proliferative capacity of cells and is accompanied by the production of several proteins, collectively termed the "senescence-messaging secretome" (SMS). As senescent cells accumulate in tissue, local effects of the SMS have been hypothesized to disrupt tissue regenerative capacity. Klotho functions as an aging-suppressor gene, and Klotho-deficient (kl/kl) mice exhibit an accelerated aging-like phenotype that includes a truncated lifespan, arteriosclerosis, and emphysema. Because plasminogen activator inhibitor-1 (PAI-1), a serine protease inhibitor (SERPIN), is elevated in kl/kl mice and is a critical determinant of replicative senescence in vitro, we hypothesized that a reduction in extracellular proteolytic activity contributes to the accelerated aging-like phenotype of kl/kl mice. Here we show that PAI-1 deficiency retards the development of senescence and protects organ structure and function while prolonging the lifespan of kl/kl mice. These findings indicate that a SERPIN-regulated cell-nonautonomous proteolytic cascade is a critical determinant of senescence in vivo.

KEYWORDS:

FGF23; IGFBP3; IL-6; TM5441

PMID:
24778222
PMCID:
PMC4024885
DOI:
10.1073/pnas.1321942111
[Indexed for MEDLINE]
Free PMC Article

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