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. 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 located in and near Adams County, Indiana, 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 confirm and extend our previous findings that heterozygous PAI-1 deficiency is sufficient to promote healthy longevity in man. These studies will leverage the only known kindred with a naturally occurring loss-of-function variants in PAI-1 in the world. 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 relationship, and provide proof of principle that pharmacological inhibition of PAI-1 is a rational therapeutic approach in preventing aging-related multi-morbidity in humans.
|Effective start/end date||1/1/22 → 12/31/24|
- Norn Group (Agmt 12/22/2021)
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