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

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.A dvanced age contributes to the development of frailty and disease in humans, but the fundamental mechanisms that drive physiological aging are incompletely understood (1, 2). Cellular senescence, which halts the proliferative capacity of cells, is associated with the manifestation of the senescenceassociated secretory phenotype (3) and the production and secretion of a distinct set of proteins (2, 4), including insulin-like growth factor-binding proteins (IGFBPs), interleukins (ILs), transforming growth factor type β (TGF-β), and plasminogen activator inhibitor-1 (PAI-1) (5), collectively termed the "senescence-messaging secretome" (SMS) (6). In addition to this pattern of protein production and secretion, senescent cells display a distinctive morphology, and can be identified by increased expression of senescence-associated β-galactosidase (7). The tumor suppressor and proapoptotic protein p53 plays a central role in inducing replicative senescence by regulating the transcription of genes involved in cell cycle arrest and apoptosis, including the cyclindependent kinase inhibitors p16Ink4a and p21 (8). Senescence can be triggered by a number of factors, including DNA damage (9), oncogene induction (10), and oxidative stress (11). Although the relationship between cellular senescence and physiological aging remains an area of intense investigation, it is becoming increasingly evident that the two processes are fundamentally linked. Senescent cells accumulate in aging tissues and have been hypothesized to disrupt tissue regeneration, which may reflect cell-nonautonomous effects of the SMS (6).In the last decade, numerous examples of genetically modified mice with phenotypes reminiscent of human aging have been described and investigated. These include the BubR1 H/H progeroid (12) and Klotho-deficient (kl/kl) mice (13). BubR1H/H progeroid mice exhibit an age-dependent increase in the expression levels of PAI-1...

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Inorganic Phosphate Activates the AKT/mTORC1 Pathway and Shortens the Life Span of an α‑Klotho–Deficient Model

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