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PAI-1 Inhibitors; Will a genetic mutation unlock secrets to a longer life?


August 13th, 2022

Northwestern Medical Scientists have observed a rare genetic mutation in a small Amish group from Berne, Indiana, which was associated with a 10% longer lifepan, 10% longer telomeres, improved fasting insulin levels, lower blood pressure, and improved blood vessel elasticity. The average lifespan of this group is 85 years(compared with 78.6 years in the US population). This information has lead to impactful new research avenues and information.

One of the biggest differences between the Amish group and the rest of the population was in their low levels of PAI-1 (Plasminogen-Activator-Inhibitor-1), a protein that promotes blood clotting. High levels of PAI-1 are associated with Coronary Artery Disease, a leading cause of death. This finding has propagated the testing of new drugs which block PAI-1's activity, in hopes that it can increase human healthspan through benefits on insulin levels, cardiovascular health, and in other ways.

Research has domnstrated how olive oil and drugs of the statin class can decrease PAI-1 levels, and results from new drug trials are pending(1,2,3). Minerals such as nickel and copper have been shown to deactivate PAI-1, and the HIV drug class of non-nucleoside reverse transciptase inhibitors have also been correlated to lower PAI-1 in humans(4,5,6). Rodant studies show that PAI-1 protects organs and extends lifespan, along with improving memory and markers of Alzheimer's Disease. Other human studies demonostrate the association between lower PAI-1 levels, and improved overall health (7,8,9,10,11).

The other take away from this research is the importance of controlling and mitigating diabetes and blood vessel health.


By: Evan Redmond, Pharm.D.


References:

1. Lopez-Miranda J, Delgado-Lista J, Perez-Martinez P, Jimenez-Gómez Y, Fuentes F, Ruano J, Marin C. Olive oil and the haemostatic system. Mol Nutr Food Res. 2007 Oct;51(10):1249-59. doi: 10.1002/mnfr.200600307. PMID: 17879993.

2. Tzekaki EE, Tsolaki M, Pantazaki AA, Geromichalos G, Lazarou E, Kozori M, Sinakos Z. Administration of the extra virgin olive oil (EVOO) in mild cognitive impairment (MCI) patients as a therapy for preventing the progress to AD. Hell J Nucl Med. 2019 Sep-Dec;22 Suppl 2:181. PMID: 31802059.

3. Sahebkar A, Catena C, Ray KK, Vallejo-Vaz AJ, Reiner Ž, Sechi LA, Colussi G. Impact of statin therapy on plasma levels of plasminogen activator inhibitor-1. A systematic review and meta-analysis of randomised controlled trials. Thromb Haemost. 2016 Jul 4;116(1):162-71. doi: 10.1160/TH15-10-0770. Epub 2016 Mar 24. PMID: 27009446.

4. Thompson LC, Goswami S, Peterson CB. Metals affect the structure and activity of human plasminogen activator inhibitor-1. II. Binding affinity and conformational changes. Protein Sci. 2011 Feb;20(2):366-78. doi: 10.1002/pro.567. PMID: 21280128; PMCID: PMC3048421.

5. Thompson LC, Goswami S, Ginsberg DS, Day DE, Verhamme IM, Peterson CB. Metals affect the structure and activity of human plasminogen activator inhibitor-1. I. Modulation of stability and protease inhibition. Protein Sci. 2011 Feb;20(2):353-65. doi: 10.1002/pro.568. PMID: 21280127; PMCID: PMC3048420.

6. Gruevska A, Moragrega AB, Galindo MJ, Esplugues JV, Blas-Garcia A, Apostolova N. p53 and p53-related mediators PAI-1 and IGFBP-3 are downregulated in peripheral blood mononuclear cells of HIV-patients exposed to non-nucleoside reverse transcriptase inhibitors. Antiviral Res. 2020 Jun;178:104784. doi: 10.1016/j.antiviral.2020.104784. Epub 2020 Apr 6. PMID: 32272174.

7. Akhter H, Huang WT, van Groen T, Kuo HC, Miyata T, Liu RM. A Small Molecule Inhibitor of Plasminogen Activator Inhibitor-1 Reduces Brain Amyloid-β Load and Improves Memory in an Animal Model of Alzheimer's Disease. J Alzheimers Dis. 2018;64(2):447-457. doi: 10.3233/JAD-180241. PMID: 29914038.

8. Eren M, Boe AE, Murphy SB, Place AT, Nagpal V, Morales-Nebreda L, Urich D, Quaggin SE, Budinger GR, Mutlu GM, Miyata T, Vaughan DE. PAI-1-regulated extracellular proteolysis governs senescence and survival in Klotho mice. Proc Natl Acad Sci U S A. 2014 May 13;111(19):7090-5. doi: 10.1073/pnas.1321942111. Epub 2014 Apr 28. PMID: 24778222; PMCID: PMC4024885.

9. Goldstein S, Moerman EJ, Fujii S, Sobel BE. Overexpression of plasminogen activator inhibitor type-1 in senescent fibroblasts from normal subjects and those with Werner syndrome. J Cell Physiol. 1994 Dec;161(3):571-9. doi: 10.1002/jcp.1041610321. PMID: 7962138.

10. Cardoso AL, Fernandes A, Aguilar-Pimentel JA, de Angelis MH, Guedes JR, Brito MA, Ortolano S, Pani G, Athanasopoulou S, Gonos ES, Schosserer M, Grillari J, Peterson P, Tuna BG, Dogan S, Meyer A, van Os R, Trendelenburg AU. Towards frailty biomarkers: Candidates from genes and pathways regulated in aging and age-related diseases. Ageing Res Rev. 2018 Nov;47:214-277. doi: 10.1016/j.arr.2018.07.004. Epub 2018 Jul 30. PMID: 30071357.

11. Liberale L, Akhmedov A, Vlachogiannis NI, Bonetti NR, Nageswaran V, Miranda MX, Puspitasari YM, Schwarz L, Costantino S, Paneni F, Beer JH, Ruschitzka F, Montecucco F, Lüscher TF, Stamatelopoulos K, Stellos K, Camici GG. Sirtuin 5 promotes arterial thrombosis by blunting the fibrinolytic system. Cardiovasc Res. 2021 Aug 29;117(10):2275-2288. doi: 10.1093/cvr/cvaa268. PMID: 32931562.



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