PAI-1-regulated extracellular proteolysis governs senescence and survival in Klotho mice.
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.
Department of Medicine and.
Mesut
M
Eren
Department of Medicine andFeinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, Chicago, IL 60611; and.
Amanda E
AE
Boe
Department of Medicine andFeinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, Chicago, IL 60611; and.
Sheila B
SB
Murphy
Department of Medicine andFeinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, Chicago, IL 60611; and.
Aaron T
AT
Place
Department of Medicine andFeinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, Chicago, IL 60611; and.
Varun
V
Nagpal
Department of Medicine and.
Luisa
L
Morales-Nebreda
Department of Medicine and.
Daniela
D
Urich
Department of Medicine andFeinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, Chicago, IL 60611; and.
Susan E
SE
Quaggin
Department of Medicine and.
G R Scott
GR
Budinger
Department of Medicine and.
Gökhan M
GM
Mutlu
United Centers for Advanced Research and Translational Medicine, Tohoku University Graduate School of Medicine, Miyagi 980-8575, Japan.
Toshio
http://orcid.org/0000-0001-9153-5024
T
Miyata
Department of Medicine andFeinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, Chicago, IL 60611; and d-vaughan@northwestern.edu.
Douglas E
DE
Vaughan
D000375:Aging / Q000502:physiology*; D000818:Animals; D016922:Cellular Senescence / Q000502:physiology; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism; D005110:Extracellular Space / Q000378:metabolism; D005260:Female; D000089703:Fibroblast Growth Factor-23; D005966:Glucuronidase / Q000235:genetics* / Q000378:metabolism*; D006474:Hemorrhagic Disorders / Q000235:genetics / Q000378:metabolism / Q000401:mortality; D000090265:Klotho Proteins; D008136:Longevity / Q000502:physiology; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D017395:Plasminogen Activator Inhibitor 1 / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D059748:Proteolysis; D058258:Serpin E2 / Q000235:genetics* / Q000378:metabolism*; D016615:Telomere / Q000502:physiology
C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; C000717428:Fgf23 protein, mouse; D017395:Plasminogen Activator Inhibitor 1; D058258:Serpin E2; C511869:Serpine2 protein, mouse; D000089703:Fibroblast Growth Factor-23; D005966:Glucuronidase; D000090265:Klotho Proteins
FGF23; IGFBP3; IL-6; TM5441