# PAI-1 and Vascular Senescence

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2021 · $546,166

## Abstract

PROJECT SUMMARY
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.

## Key facts

- **NIH application ID:** 10221762
- **Project number:** 5R01HL051387-25
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Douglas E Vaughan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $546,166
- **Award type:** 5
- **Project period:** 1994-07-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10221762

## Citation

> US National Institutes of Health, RePORTER application 10221762, PAI-1 and Vascular Senescence (5R01HL051387-25). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10221762. Licensed CC0.

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