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...
Background Long-term inhibition of nitric oxide synthase (NOS) by L-arginine analogues such as Nω-nitro-L-arginine methyl ester (L-NAME) has been shown to induce senescence in vitro and systemic hypertension and arteriosclerosis in vivo. We previously reported that PAI-1-deficient mice (PAI-1−/−) are protected against L-NAME-induced pathologies. In this study, we investigated whether a novel, orally active PAI-1 antagonist (TM5441) has a similar protective effect against L-NAME treatment. Additionally, we studied whether L-NAME can induce vascular senescence in vivo and investigated the role of PAI-1 in this process. Methods and Results Wild-type (WT) mice received either L-NAME or L-NAME and TM5441 for 8 weeks. Systolic blood pressure was measured every 2 weeks. We found that TM5441 attenuated the development of hypertension and cardiac hypertrophy compared to animals that had received L-NAME alone. Additionally, TM5441-treated mice had a 34% reduction in periaortic fibrosis relative to animals on L-NAME alone. Finally, we investigated the development of vascular senescence by measuring p16Ink4a expression and telomere length in aortic tissue. We found that L-NAME increased p16Ink4a expression levels and decreased telomere length, both of which were prevented with TM5441 co-treatment. Conclusions Pharmacological inhibition of PAI-1 is protective against the development of hypertension, cardiac hypertrophy, and periaortic fibrosis in mice treated with L-NAME. Furthermore, PAI-1 inhibition attenuates the arterial expression of p16Ink4a and maintains telomere length. PAI-1 appears to play a pivotal role in vascular senescence, and these findings suggest that PAI-1 antagonists may provide a novel approach in preventing vascular aging and hypertension.
The average age of the US population continues to increase. Age is the most important determinant of disease and disability in humans, but the fundamental mechanisms of aging remain largely unknown. Many age-related diseases are associated with an impaired fibrinolytic system. Elevated plasminogen activator inhibitor-1 (PAI-1) levels are reported in age-associated clinical conditions including cardiovascular diseases, type 2 diabetes, obesity and inflammation. PAI-1 levels are also elevated in animal models of aging. While the association of PAI-1 with physiological aging is well documented, it is only recently that its critical role in the regulation of aging and senescence has become evident. PAI-1 is synthesized and secreted in senescent cells and contributes directly to the development of senescence by acting downstream of p53 and upstream of insulin-like growth factor binding protein-3. Pharmacologic inhibition or genetic deficiency of PAI-1 was shown to be protective against senescence and the aging-like phenotypes in kl/kl and N(ω)-nitro-l-arginine methyl ester-treated wild-type mice. Further investigation into PAI-1's role in senescence and aging will likely contribute to the prevention and treatment of aging-related pathologies.
Nω-nitro-L-arginine methyl ester (L-NAME) treatment induces arteriosclerosis and vascular senescence. Here, we report that the systemic inhibition of nitric oxide (NO) production by L-NAME causes pulmonary emphysema. L-NAME-treated lungs exhibited both the structural (alveolar tissue destruction) and functional (increased compliance and reduced elastance) characteristics of emphysema development. Furthermore, we found that L-NAME-induced emphysema could be attenuated through both genetic deficiency and pharmacological inhibition of plasminogen activator inhibitor-1 (PAI-1). Because PAI-1 is an important contributor to the development of senescence both in vitro and in vivo, we investigated whether L-NAME-induced senescence led to the observed emphysematous changes. We found that L-NAME treatment was associated with molecular and cellular evidence of premature senescence in mice, and that PAI-1 inhibition attenuated these increases. These findings indicate that NO serves to protect and defend lung tissue from physiological aging.
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