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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, G. R. Scott, Mutlu, Gökhan M., Miyata, Toshio, Vaughan, Douglas E.
- Proceedings of the National Academy of Sciences of the United States of America 2014 v.111 no.19 pp. 7090-7095
- cell senescence, genes, longevity, mice, phenotype, plasminogen activator inhibitors, proteinase inhibitors, proteolysis, serine proteinases
- 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.