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

作者：Eren Mesut; Boe Amanda E; Murphy Sheila B; Place Aaron T; Nagpal Varun; Morales Nebreda Luisa; Urich Daniela; Quaggin Susan E; Budinger G R Scott; Mutlu Goekhan M; Miyata Toshio; Vaughan Douglas E^*

来源：Proceedings of the National Academy of Sciences, 2014, 111(19): 7090-7095.

DOI：10.1073/pnas.1321942111

• FGF23
• IGFBP3
• IL-6
• TM5441

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.

• 出版日期2014-5-13
• 单位西北大学