The number of Americans over age 65 is projected to increase from approximately 39 million in 2010 to an estimated 71 million in 2030 (2010 census). While only 13% of US population is 65 and older, they consume over 36% of personal health expenditures. Cardiovascular disease (CVD) is a major driver of morbidity, mortality, and health care costs in the elderly population. The cardiovascular system is prone to age-dependent deterioration even in the absence of traditional risk factors, and although these changes have been extensively characterized, the underlying mechanisms are incompletely understood. The functional and structural changes that occur during biological aging, including endothelial dysfunction, reduced vessel elasticity, and chronic vascular inflammation, ultimately result in decreased vascular compliance, systemic hypertension, arterial thrombosis and ischemic events. The previous iterations of this grant supported an investigative program that helped to define the molecular regulation of plasminogen activator inhibitor-1 (PAI-1) and its role in the development of vascular pathology. Based on work from this laboratory, PAI-1 is now recognized to have broad biologic relevance beyond its role in thrombosis. There is compelling evidence that senescent cells accumulate in tissues and contribute to the aging. In addition to contributing to the molecular fingerprint of senescence, PAI-1 is necessary and sufficient for the induction of replicative senescence in vitro. We have significantly advanced our understanding the role of PAI-1 as a potential driver of cellular and vascular senescence, as well as biological aging in murine models. Importantly, our initial characterization of lifespan, cardiovascular function, and markers of senescence in a unique kindred of Amish individuals harboring a loss of function mutation in the gene encoding PAI-1 (SERPINE1) reveals improved health span and longevity in humans with heterozygous PAI-1 deficiency compared to unaffected age-matched kindred. Based on these collective observations we hypothesize that PAI-1 promotes vascular senescence and aging-related cardiovascular morbidity. We propose a multifaceted phylogenetically diverse program using Drosophila, mice and humans, to delineate the involvement of PAI-1 in age-related vascular remodeling across species. We anticipate that these studies will not only establish the role of PAI-1 in senescence, but will also advance our knowledge of the mechanisms that drive physiological aging. Furthermore, understanding the molecular mechanism of PAI-1's role in senescence and aging may provide new insights into the prevention and treatment of aging-related dysfunction and frailty.

Public Health Relevance

Cardiovascular disease (CVD) is a leading cause of mortality and health care expenditure in the geriatric population. The vascular system is prone to age-dependent molecular and structural deterioration, leading to arterial dysfunction and CVD even in the absence of traditional risk factors. In this proposal, we will test the novel hypothesis that genetic deficiency and/or pharmacologic inhibition of PAI-1 (and its homolog Serpin 42De) delays vascular senescence and extends life span across multiple species (Drosophila, mice, and humans).

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL051387-23
Application #
9749219
Study Section
Hemostasis and Thrombosis Study Section (HT)
Program Officer
Reid, Diane M
Project Start
1994-07-01
Project End
2022-07-31
Budget Start
2019-08-01
Budget End
2020-07-31
Support Year
23
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Northwestern University at Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
Eren, Mesut; Place, Aaron T; Thomas, Paul M et al. (2017) PAI-1 is a critical regulator of FGF23 homeostasis. Sci Adv 3:e1603259
Rai, Rahul; Ghosh, Asish K; Eren, Mesut et al. (2017) Downregulation of the Apelinergic Axis Accelerates Aging, whereas Its Systemic Restoration Improves the Mammalian Healthspan. Cell Rep 21:1471-1480
Khan, Sadiya S; Shah, Sanjiv J; Klyachko, Ekaterina et al. (2017) A null mutation in SERPINE1 protects against biological aging in humans. Sci Adv 3:eaao1617
Afzal, Muhammad Zeeshan; Gartz, Melanie; Klyachko, Ekaterina A et al. (2017) Generation of human iPSCs from urine derived cells of a non-affected control subject. Stem Cell Res 18:33-36
Vaughan, Douglas E; Rai, Rahul; Khan, Sadiya S et al. (2017) Plasminogen Activator Inhibitor-1 Is a Marker and a Mediator of Senescence. Arterioscler Thromb Vasc Biol 37:1446-1452
Afzal, Muhammad Zeeshan; Gartz, Melanie; Klyachko, Ekaterina A et al. (2017) Generation of human iPSCs from urine derived cells of patient with a novel heterozygous PAI-1 mutation. Stem Cell Res 18:41-44
Flevaris, Panagiotis; Khan, Sadiya S; Eren, Mesut et al. (2017) Plasminogen Activator Inhibitor Type I Controls Cardiomyocyte Transforming Growth Factor-? and Cardiac Fibrosis. Circulation 136:664-679
Rai, Rahul; Verma, Suresh K; Kim, David et al. (2017) A novel acetyltransferase p300 inhibitor ameliorates hypertension-associated cardio-renal fibrosis. Epigenetics 12:1004-1013
Yahata, Takashi; Ibrahim, Abd Aziz; Muguruma, Yukari et al. (2017) TGF-?-induced intracellular PAI-1 is responsible for retaining hematopoietic stem cells in the niche. Blood 130:2283-2294
Bautista-NiƱo, Paula K; Portilla-Fernandez, Eliana; Vaughan, Douglas E et al. (2016) DNA Damage: A Main Determinant of Vascular Aging. Int J Mol Sci 17:

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