Evolutionary Advantage of Heterozygous PAI-1 Deficiency in Humans

65岁以上的美国人数量正在增长，预计将从

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 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.