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, GR Scott Budinger, Gökhan M. Mutlu, Toshio Miyata, Douglas E Vaughan*

*Corresponding author for this work

Research output: Contribution to journalArticle

61 Citations (Scopus)

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

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Plasminogen Activator Inhibitor 1
Proteolysis
Serine Proteinase Inhibitors
Cell Aging
Suppressor Genes
Phenotype
Arteriosclerosis
Emphysema
Proteins

Keywords

  • FGF23
  • IGFBP3
  • IL-6
  • TM5441

ASJC Scopus subject areas

  • General

Cite this

Eren, Mesut ; Boe, Amanda E. ; Murphy, Sheila B. ; Place, Aaron T. ; Nagpal, Varun ; Morales-Nebreda, Luisa ; Urich, Daniela ; Quaggin, Susan E ; Budinger, GR Scott ; Mutlu, Gökhan M. ; Miyata, Toshio ; Vaughan, Douglas E. / PAI-1-regulated extracellular proteolysis governs senescence and survival in Klotho mice. In: Proceedings of the National Academy of Sciences of the United States of America. 2014 ; Vol. 111, No. 19. pp. 7090-7095.
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PAI-1-regulated extracellular proteolysis governs senescence and survival in Klotho mice. / Eren, Mesut; Boe, Amanda E.; Murphy, Sheila B.; Place, Aaron T.; Nagpal, Varun; Morales-Nebreda, Luisa; Urich, Daniela; Quaggin, Susan E; Budinger, GR Scott; Mutlu, Gökhan M.; Miyata, Toshio; Vaughan, Douglas E.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 111, No. 19, 13.05.2014, p. 7090-7095.

Research output: Contribution to journalArticle

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AU - Murphy, Sheila B.

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AU - Morales-Nebreda, Luisa

AU - Urich, Daniela

AU - Quaggin, Susan E

AU - Budinger, GR Scott

AU - Mutlu, Gökhan M.

AU - Miyata, Toshio

AU - Vaughan, Douglas E

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