Pleiotropic Role of PAI-1 in Cardiovascular Aging

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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. The prevalence of multi-morbidity, including cardiovascular disease, Alzheimer's dementia, emphysema, and diabetes increases significantly with age. One of the best validated molecular fingerprints of aging and senescence is the protein plasminogen activatorinhibitor- 1 (PAI-1) (the protein product of the gene SERPINE1). A remarkably robust and consistent body of experimental evidence generated by laboratories from around the world have identified a mechanistic link between PAI-1 and aging-like pathology in every major organ system, including the heart, kidney and skin 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. Conversely, PAI-1 deficiency and/or pharmacological inhibition of PAI-1 provides substantial protection against aging-like cardiovascular pathology in mice. The protective effect of PAI-1 deficiency on biological aging appears to be operational in humans. 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 late 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 kindred. In this proposal, we will test the hypothesis that lifelong PAI-1 deficiency provides multifaceted protection against cardiovascular aging. This application is designed to investigate the pleiotropic effects of PAI-1 on cardiovascular resilience and aging and reveal the molecular mechanisms that explain these effects. These studies will leverage the only known kindred in the world with a naturally occurring loss-of-function variants in PAI-1 with experimental studies in mice and in iPSC-derived vascular cells 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 cardiovascular disease, 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