A null mutation in
            <i>SERPINE1</i>
            protects against biological aging in humans

Khan, Sadiya S.; Shah, Sanjiv J.; Klyachko, Ekaterina; Baldridge, Abigail S.; Eren, Mesut; Place, Aaron T.; Aviv, Abraham; Puterman, Eli; Lloyd‐Jones, Donald M.; Heiman, Meadow; Miyata, Toshio; Gupta, Sweta; Shapiro, Amy D.; Vaughan, Douglas E.

doi:10.1126/sciadv.aao1617

Cited by 109 publications

(91 citation statements)

References 60 publications

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“…Although best known for its roles in regulating fibrinolysis and fibrosis, PAI‐1 is increasingly recognized as a mediator of metabolic diseases, including obesity, diabetes, and NAFLD . Heterozygosity of a null PAI‐1 mutation in humans is associated with lower fasting insulin levels and a lower prevalence of diabetes . Furthermore, a novel small molecule inhibitor of PAI‐1, TM5441, has recently been shown to attenuate high‐fat diet‐induced obesity and hepatic steatosis in mice .…”

mentioning

confidence: 99%

Inhibition of Plasminogen Activator Inhibitor 1 Attenuates Hepatic Steatosis but Does Not Prevent Progressive Nonalcoholic Steatohepatitis in Mice

Henkel

Khan²,

Olivares³

et al. 2018

Hepatol Commun

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Plasminogen activator inhibitor 1 (PAI‐1), an essential regulator of fibrinolysis, is increasingly implicated in the pathogenesis of metabolic disorders, such as obesity and nonalcoholic fatty liver disease (NAFLD). Pharmacologic inhibition of PAI‐1 is emerging as a highly promising therapeutic strategy for obesity and its sequelae. Given the well‐established profibrotic function of PAI‐1, we considered whether PAI‐1 may serve as a target for antifibrotic therapy in nonalcoholic steatohepatitis (NASH). We therefore determined the effect of genetic Pai‐1 deletion and pharmacologic PAI‐1 inhibition on the development of NASH‐related fibrosis in mice. Pai‐1 knockout (Pai‐1 –/–) and wild‐type control (Pai‐1 +/+) mice were fed a high‐fat/high‐cholesterol high‐sugar (HFHS) diet or a methionine‐ and choline‐deficient (MCD) diet to induce steatohepatitis with fibrosis. PAI‐1 was pharmacologically inhibited using the small molecule inhibitor TM5441 in wild‐type C57BL/6 mice fed an HFHS or MCD diet. Either genetic deletion of Pai‐1 or pharmacologic inhibition of PAI‐1 attenuated MCD diet‐induced hepatic steatosis but did not prevent hepatic inflammation or fibrosis. Targeted inhibition of PAI‐1 conferred transient protection from HFHS diet‐induced obesity and hepatic steatosis, an effect that was lost with prolonged exposure to the obesigenic diet. Neither genetic deletion of Pai‐1 nor pharmacologic inhibition of PAI‐1 prevented HFHS diet‐induced hepatic inflammation or fibrosis. Conclusion: Pai‐1 regulates hepatic lipid accumulation but does not promote NASH progression. The PAI‐1 inhibitor TM5441 effectively attenuates diet‐induced obesity and hepatic steatosis but does not prevent NASH‐related fibrosis in mice.

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mentioning

confidence: 99%

Inhibition of Plasminogen Activator Inhibitor 1 Attenuates Hepatic Steatosis but Does Not Prevent Progressive Nonalcoholic Steatohepatitis in Mice

Henkel

Khan²,

Olivares³

et al. 2018

Hepatol Commun

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“…TM5441 was selected for testing because it is an orally active, small‐molecule inhibitor of PAI‐1, the primary inhibitor of tissue and urokinase plasminogen activators, and thus a primary effector of fibrinolysis and extracellular proteolysis (Boe, ). PAI‐1 levels increase with age in mice and humans (Khan, ; Testa et al, ; Yamamoto et al, ) and are increased by obesity, insulin resistance, and inflammation (Alessi & Juhan‐Vague, ; Khan, ). PAI‐1 is present in atherosclerotic plaques and accumulates with age in murine heart muscle (Sobel, Lee, Pratley, & Schneider, ).…”

Section: Discussionmentioning

confidence: 99%

Glycine supplementation extends lifespan of male and female mice

et al. 2019

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Diets low in methionine extend lifespan of rodents, though through unknown mechanisms. Glycine can mitigate methionine toxicity, and a small prior study has suggested that supplemental glycine could extend lifespan of Fischer 344 rats. We therefore evaluated the effects of an 8% glycine diet on lifespan and pathology of genetically heterogeneous mice in the context of the Interventions Testing Program. Elevated glycine led to a small (4%–6%) but statistically significant lifespan increase, as well as an increase in maximum lifespan, in both males (p = 0.002) and females (p < 0.001). Pooling across sex, glycine increased lifespan at each of the three independent sites, with significance at p = 0.01, 0.053, and 0.03, respectively. Glycine‐supplemented females were lighter than controls, but there was no effect on weight in males. End‐of‐life necropsies suggested that glycine‐treated mice were less likely than controls to die of pulmonary adenocarcinoma (p = 0.03). Of the 40 varieties of incidental pathology evaluated in these mice, none were increased to a significant degree by the glycine‐supplemented diet. In parallel analyses of the same cohort, we found no benefits from TM5441 (an inhibitor of PAI‐1, the primary inhibitor of tissue and urokinase plasminogen activators), inulin (a source of soluble fiber), or aspirin at either of two doses. Our glycine results strengthen the idea that modulation of dietary amino acid levels can increase healthy lifespan in mice, and provide a foundation for further investigation of dietary effects on aging and late‐life diseases.

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“…A recent paper showed Older Amish individuals harbor a rare loss‐of‐function mutation in SERPINE1 gene that protects against effects of ageing. This mutation affects the function of plasminogen activator inhibitor‐1 (PAI‐1), which has a vital role in cellular senescence and is expressed at higher levels in senescent cells . This loss of function in “wellderly” individuals could be one of the factors that regulate PRLS.…”

Section: Discussionmentioning

confidence: 99%

“…This mutation affects the function of plasminogen activator inhibitor-1 (PAI-1), which has a vital role in cellular senescence and is expressed at higher levels in senescent cells. 86 This loss of function in "wellderly" individuals could be one of the factors that regulate PRLS. Further investigation is certainly warranted to decipher other factors regulating PRLS and future studies based on post-reproductive lifespan and correlation of genetic variants are required.…”

Section: F I G U R E 3 Correlation Of Cd33rsiglec Genes With Maximummentioning

confidence: 99%

Maximum reproductive lifespan correlates with CD33rSIGLEC gene number: Implications for NADPH oxidase‐derived reactive oxygen species in aging

et al. 2019

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Humans and orcas are among the very rare species that have a prolonged post-reproductive lifespan (PRLS), during which the aging process continues. Reactive oxygen species (ROS) derived from mitochondria and from the NADPH oxidase (NOX) enzymes of innate immune cells are known to contribute to aging, with the former thought to be dominant. CD33-related-Siglecs are immune receptors that recognize self-associated-molecular-patterns and modulate NOX-derived-ROS. We herewith demonstrate a strong correlation of lifespan with CD33rSIGLEC gene number in 26 species, independent of body weight or phylogeny. The correlation is stronger when considering total CD33rSIGLEC gene number rather than those encoding inhibitory and activating subsets, suggesting that lifetime balancing of ROS is important. Combining independent lines of evidence including the short half-life and spontaneous activation of neutrophils, we calculate that even without inter-current inflammation, a major source of lifetime ROS exposure may actually be neutrophil NOX-derived. However, genomes of human supercentenarians (>110 years) do not harbor a significantly higher number of functional CD33rSIGLEC genes. Instead, lifespan correlation with CD33rSIGLEC gene number was markedly strengthened by excluding the post-reproductive lifespan of humans and orcas (R 2 = 0.83; P < .0001). Thus, CD33rSIGLEC modulation of ROS likely contributes to maximum reproductive lifespan, but other unknown mechanisms could be important to PRLS. K E Y W O R D SCD33rSIGLEC, NADPH-oxidase, prolonged post-reproductive lifespan, reactive oxygen species | 1929 KHAN et Al. 1936 | KHAN et Al. ACKNOWLEDGMENTSWe thank members of the laboratory of AV for helpful discussions and suggestions.

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A null mutation in SERPINE1 protects against biological aging in humans

Abstract: Humans with a rare gene mutation in SERPINE1 live longer and show evidence of protection from aging-related morbidity.

Cited by 109 publications

References 60 publications

Inhibition of Plasminogen Activator Inhibitor 1 Attenuates Hepatic Steatosis but Does Not Prevent Progressive Nonalcoholic Steatohepatitis in Mice

Inhibition of Plasminogen Activator Inhibitor 1 Attenuates Hepatic Steatosis but Does Not Prevent Progressive Nonalcoholic Steatohepatitis in Mice

Glycine supplementation extends lifespan of male and female mice

Maximum reproductive lifespan correlates with CD33rSIGLEC gene number: Implications for NADPH oxidase‐derived reactive oxygen species in aging

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