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

Eren M1, Boe AE2, Murphy SB2, Place AT2, Nagpal V2, Morales-Nebreda L1, Urich D1, Quaggin SE2, Budinger GR1, Mutlu GM1, Miyata T3, Vaughan DE4.

Proc Natl Acad Sci U S A. 2014 ;111(19):7090-5.

1Department of Medicine and.

2Department of Medicine andFeinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, Chicago, IL 60611; and.

3United Centers for Advanced Research and Translational Medicine, Tohoku University Graduate School of Medicine, Miyagi 980-8575, Japan.and

4Department of Medicine andFeinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, Chicago, IL 60611; and [email protected]

 

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 inextracellular 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.

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