# Evolutionary Advantage of Heterozygous PAI-1 Deficiency in Humans

> **NIH NIH R56** · NORTHWESTERN UNIVERSITY · 2022 · $300,000

## Abstract

SUMMARY The number of Americans over age 65 years is growing and is projected to increase from
approximately 39 million in 2010 to an estimated 71 million in 2030 (2010 census). The prevalence of multi-
morbidity, including Alzheimer's dementia, emphysema, and presbycusis increases significantly with age. One
of the best validated molecular fingerprints of aging and senescence is the protein plasminogen activator
inhibitor-1 (PAI-1) (the protein product of the gene SERPINE1). Numerous studies demonstrate that PAI-1 is
evolutionarily conserved across mammalian and non-mammalian species. Further, PAI-1 is not just a marker
but also a mediator of senescence in vitro and in vivo. A remarkably robust and consistent body of experimental
evidence generated by laboratories from around the world have identified and reported a mechanistic link
between PAI-1 and aging-like pathology in every major organ system, including the brain and the lungs, among
others. In healthy human populations, higher levels of PAI-1 are associated with coronary artery disease,
increased vascular stiffness, obesity, diabetes, fatty liver disease, and emphysema/obstructive lung disease.
Recently, a DNA methylation estimator of plasma PAI-1 levels (DNAm PAI-1) was reported to be an
exceptionally robust predictor of lifespan (P=5.4E-28), comorbidity count (P= 7.3E-56), and type 2 diabetes
(P=2.0E-26), as well as other age-related maladies including hypertension, time to heart failure, and early
menopause. The protective effect of PAI-1 deficiency on biological aging appears to be operational in humans
as well. In a geographically and genetically constrained community of Old Order Amish, a remarkable “natural”
experiment has been underway for 8 generations. This community harbors a private loss-of-function (LOF)
mutation in SERPINE1, that can be traced back to a single ancestor that married into the community in the
early part of the 19th century. Heterozygous carriers of the null mutation in SERPINE1 have longer telomeres,
lower fasting insulin levels, protection from diabetes, preserved vascular flexibility, and a longer life span than
their unaffected (wildtype) kindred. In this proposal, we propose to test the hypothesis that lifelong PAI-1
deficiency provides multifaceted protection against aging-related multi-morbidity and is sufficient to
promote healthy longevity in mice and in man. This hypothesis will be tested through the two following
complimentary and coordinated Specific Aims that will test the association of genetic deficiency of PAI-1 in
human observational studies and in murine mechanistic studies. These studies will leverage the only known
kindred with a naturally occurring loss-of-function variants in PAI-1 with experimental studies in mice to translate
the generalizability of these findings. We anticipate that the studies proposed here will advance our
understanding of the pivotal role of PAI-1 in aging-related morbidity, the molecular mechanisms that explain
this...

## Key facts

- **NIH application ID:** 10686583
- **Project number:** 1R56AG077278-01
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Douglas E Vaughan
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $300,000
- **Award type:** 1
- **Project period:** 2022-09-15 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10686583

## Citation

> US National Institutes of Health, RePORTER application 10686583, Evolutionary Advantage of Heterozygous PAI-1 Deficiency in Humans (1R56AG077278-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10686583. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*