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

Mesut Eren, Amanda E. Boe, Sheila B. Murphy, Aaron T. Place, Varun Nagpal, Luisa Morales-Nebreda, Daniela Urich, Susan E. Quaggin, G. R. Scott Budinger, Gökhan M. Mutlu, Toshio Miyata, Douglas E. Vaughan*

*Corresponding author for this work

Research output: Contribution to journalArticle

82 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)7090-7095
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number19
DOIs
StatePublished - May 13 2014

Keywords

  • FGF23
  • IGFBP3
  • IL-6
  • TM5441

ASJC Scopus subject areas

  • General

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