One Mutation, Ten Extra Years

There’s a delicate balance in the body between blood clotting and the resolution of clotting. Blood clot formation is a dynamic, ever-changing process. Plasminogen activator inhibitor-1 (PAI-1) is part of these dynamic mechanisms in clotting.

When you form a clot to stop bleeding, your body continually breaks it down and remodels it. The breakdown process is called fibrinolysis. PAI-1 prevents this breakdown from happening too quickly by blocking the enzymes (tPA and uPA) that would normally dissolve the clot. This balance is crucial: too little PAI-1 results in excessive bleeding, while too much PAI-1 prevents clots from dissolving, increasing the risk of heart attacks, strokes, and microvascular clot formation.

PAI-1 levels rise with age, starting after middle age and correlating with increased cardiovascular risk and frailty. This makes PAI-1 a protective protein when balanced and a harmful aging accelerator if elevated.

To get a little more technical, PAI-1 is a serine protease inhibitor (serpin), and the SERPINE1 gene codes for it. Common variants in the SERPINE1 gene can make you a little more or less susceptible to having clot-related problems like strokes or heart attacks. Rare mutations in SERPINE1 can cause PAI-1 to be significantly impaired, and looking at how these mutations affect longevity is really interesting.

PAI-1 is primarily produced in the endothelial cells lining blood vessels, but is also produced in platelets and released upon platelet activation. Fat cells and the liver can also produce PAI-1. Inflammatory cytokines (TNF-alpha) can increase PAI-1 levels, as can high blood glucose or low oxygen (hypoxia). PAI-1 is also elevated significantly in infections, such as Covid or sepsis.

Beyond blood clots, or rather, preventing blood clots, PAI-1 has more recently been discovered to play a role in promoting fibrosis, such as liver or lung fibrosis. This is because PAI-1 can prevent the degradation of urokinase plasminogen activator, which is involved in breaking down fibrosis in tissues. This leads to higher levels of fibrosis with higher PAI-1 levels.

Since PAI-1 levels naturally increase with age, what happens if PAI-1 is inhibited?

Genetic studies on rare mutations can show what the extreme - a significantly increased function or decreased function of a gene - does to the body.

2017 Amish study on PAI-1 mutation:
A null mutation in SERPINE1 protects against biological aging in humans, Science, 2017

Researchers studied 177 members of the Berne Amish community, including 43 carriers of a rare null mutation in SERPINE1 (encoding PAI-1, plasminogen activator inhibitor-1), to determine if reduced PAI-1 affects human aging.

Here’s what they found:

• Lower PAI-1: Circulating PAI-1 levels were 50% lower in heterozygous mutation carriers and completely undetectable in homozygotes.

• Longer telomeres: Heterozygous carriers showed 10% longer telomere length compared to noncarriers after adjusting for age, sex, and family structure.

• Better metabolic health: They also had 28% lower fasting insulin levels and zero diabetes prevalence versus 7% in noncarriers.

• Extended lifespan: Analysis of 56 deceased relatives with known genotypes revealed carriers lived a median of 85 years versus 75 years in noncarriers—a 10-year lifespan extension.

This 2017 study shows multiple benefits for lower PAI-1 levels over the course of a lifetime from carrying one copy of a non-functioning mutation. Mice with the same mutation as seen in the Amish study above also live longer.

PAI-1 inhibitor drugs and mechanisms have been studied in multiple contexts - from preventing clot-related heart attacks and strokes to decreasing pulmonary fibrosis to increasing the release of hematopoietic stem cells. Inhibiting PAI-1 also helps to prevent T cell exhaustion by inhibiting the PD-1 checkpoint. Overall, studies on PAI-1 inhibitors show that they have anti-thrombotic effects, anti-fibrotic effects, anti-inflammatory effects, anti-aging effects, and immune checkpoint inhibitory effects.

The obvious drawback to inhibiting PAI-1 is that excessive inhibition could increase bleeding risk; however, the animal studies show that PAI-1 inhibitors don’t extend bleeding time as much as antiplatelet drugs.

So, where is the research at today?

New study: Silencing of PAI-1 using siRNA-lipid nanoparticles reduces thrombosis and prolongs life span in murine models

There’s a brand new study out showing that using one dose of a small interfering RNA (siRNA) that targets PAI-1 could reduce plasma PAI-1 levels by 90% for 10 days. There was no ‘overt toxicity’ noticed in the mouse study, but obviously, that is a long way from human trials. The study also looked at the effect of inhibiting PAI-1 in aged mice and found that it prolonged lifespan in a fast-aging mouse model.

If you have genetic raw data, you can check to see whether you have higher or lower PAI-1 activity based on your genes. Keep in mind that in addition to genetic variants, factors such as hypoxia, high TNF, or high blood glucose can also increase PAI-1 levels.

These studies bring me to the idea that inhibiting PAI-1 is likely beneficial in longevity — assuming that the individual doesn’t have a risk of excessive bleeding.

As always, this is just an overview of natural supplements shown in literature to have an effect. Talk with your doctor if you are unsure whether a supplement is a good idea for you.

Hesperidin is a natural flavonoid found in citrus fruits and readily available as a supplement. It is a natural TNF inhibitor. A cell study found that hesperidin significantly decreased PAI-1 levels.

Resveratrol: In cell studies, resveratrol inhibits the upregulation of PAI-1. A randomized placebo-controlled trial of resveratrol showed that 350 mg/day for one year resulted in decreased PAI-1 levels.

Olive oil and oleuropein: Olive oil is a mild PAI-1 inhibitor. Olive leaf extract is also a good source of oleuropein.

Aspirin is a COX inhibitor that affects platelet aggregation and clotting in several ways. One effect of aspirin (650 mg) is a reduction in PAI-1 levels. The reduction peaked at 2 hours.

Vitamins C and E are natural ways to attenuate PAI-1 expression in animals with high cholesterol.

Baicalin (skullcap): The herbal supplement baicalin has been shown in animals to reduce PAI-1 levels and airway inflammation caused by cigarette smoke.

References:

Chen, Xiangqi, et al. “Endothelial H2S-AMPK Dysfunction Upregulates the Angiocrine Factor PAI-1 and Contributes to Lung Fibrosis.” Redox Biology, vol. 70, Apr. 2024, p. 103038. DOI.org (Crossref), https://doi.org/10.1016/j.redox.2024.103038.

Ferraresso, Francesca, Chad W. Skaer, Zimu Wei, Woosuk S. Hur, Hongyin Y, et al. “Age-Associated Increases in PAI-1 Silenced with siRNA-Lipid Nanoparticles Reduces Thrombosis and Prolongs Lifespan.” Blood, vol. 147, no. 18, Apr. 2026, pp. 2053–63. PubMed Central, https://doi.org/10.1182/blood.2025029834.

Ferraresso, Francesca, Chad W. Skaer, Zimu Wei, Woosuk S. Hur, Hongyin Yu, et al. “Silencing of PAI-1 Using siRNA-Lipid Nanoparticles Reduces Thrombosis and Prolongs Life Span in Murine Models.” Blood, vol. 147, no. 18, Apr. 2026, pp. 2053–63. PubMed, https://doi.org/10.1182/blood.2025029834.

Giménez-Bastida, Juan Antonio, et al. “Hesperetin and Its Sulfate and Glucuronide Metabolites Inhibit TNF-α Induced Human Aortic Endothelial Cell Migration and Decrease Plasminogen Activator Inhibitor-1 (PAI-1) Levels.” Food & Function, vol. 7, no. 1, Jan. 2016, pp. 118–26. PubMed, https://doi.org/10.1039/c5fo00771b.

Khan, Sadiya S., et al. “A Null Mutation in SERPINE1 Protects against Biological Aging in Humans.” Science Advances, vol. 3, no. 11, Nov. 2017, p. eaao1617. DOI.org (Crossref), https://doi.org/10.1126/sciadv.aao1617.

Moon, Deborah. “Plasminogen Activator Inhibitor-1 (PAI-1): Regulator of Clotting.” Genetic Lifehacks, 27 July 2023, https://www.geneticlifehacks.com/plasminogen-activator-inhibitor-1-pai-1/.

Mousa, Shaker A., et al. “Effect of Single Oral Dose of Aspirin on Human Platelet Functions and Plasma Plasminogen Activator Inhibitor-1.” Cardiology, Nov. 2008, pp. 367–73. DOI.org (Crossref), https://doi.org/10.1159/000175993.

Ohkura, Naoki, and Riyo Morimoto-Kamata. “Antithrombotic Natural Products That Inhibit Plasminogen Activator Inhibitor 1 (PAI-1).” BPB Reports, vol. 7, no. 2, 2024, pp. 51–55. J-Stage, https://doi.org/10.1248/bpbreports.7.2_51.

Orbe, J. “Vitamins C and E Attenuate Plasminogen Activator Inhibitor-1 (PAI-1) Expression in a Hypercholesterolemic Porcine Model of Angioplasty.” Cardiovascular Research, vol. 49, no. 2, Feb. 2001, pp. 484–92. DOI.org (Crossref), https://doi.org/10.1016/S0008-6363(00)00260-1.

Smokovitis, A., et al. “Great Variation in the Response of Tissue Plasminogen Activator Activity, Plasminogen Activator Inhibition and Plasmin Inhibition to Endotoxin, Aspirin and Endotoxin after Administration of Aspirin.” Thrombosis Research, vol. 50, no. 4, May 1988, pp. 495–505. DOI.org (Crossref), https://doi.org/10.1016/0049-3848(88)90198-3.

Tzekaki, Elena E., et al. “Oleuropein Is a Natural Inhibitor of PAI-1-Mediated Proliferation in Human ER-/PR- Breast Cancer Cells.” Breast Cancer Research and Treatment, vol. 186, no. 2, Apr. 2021, pp. 305–16. Springer Link, https://doi.org/10.1007/s10549-020-06054-x.

Zagotta, Ivana, et al. “Resveratrol Suppresses PAI-1 Gene Expression in a Human in Vitro Model of Inflamed Adipose Tissue.” Oxidative Medicine and Cellular Longevity, vol. 2013, 2013, p. 793525. PubMed, https://doi.org/10.1155/2013/793525.

Zhang, Hu, et al. “Baicalin Ameliorates Cigarette Smoke-Induced Airway Inflammation in Rats by Modulating HDAC2/NF-κB/PAI-1 Signalling.” Pulmonary Pharmacology & Therapeutics, vol. 70, Oct. 2021, p. 102061. PubMed, https://doi.org/10.1016/j.pupt.2021.102061.

———. “Baicalin Ameliorates Cigarette Smoke-Induced Airway Inflammation in Rats by Modulating HDAC2/NF-κB/PAI-1 Signalling.” Pulmonary Pharmacology & Therapeutics, vol. 70, Oct. 2021, p. 102061. PubMed, https://doi.org/10.1016/j.pupt.2021.102061.