Evolutionary Advantage of Heterozygous PAI-1 Deficiency in Humans

65岁以上的美国人的数量正在增长，预计将从 2010年约为3900万人，到2030年(2010年人口普查)估计为7100万人。多发性硬化症的流行 发病率，包括阿尔茨海默氏症、肺气肿和老年性耳聋，随着年龄的增长而显著增加。一 最能证实衰老和衰老的分子指纹之一是蛋白质纤溶酶原激活剂 抑制物-1(PAI-1)(SERPINE1基因的蛋白质产物)。大量研究表明，PAI-1是 在哺乳动物和非哺乳动物物种中进化保守。此外，PAI-1不仅仅是一个标志物 而且在体外和体内也是衰老的调节剂。一个非常强大和一致的实验机构 来自世界各地的实验室产生的证据已经确定并报告了一种机械联系 PAI-1与包括大脑和肺在内的每个主要器官系统的类衰老病理之间的关系，其中 其他。在健康人群中，PAI-1水平较高与冠状动脉疾病有关， 血管僵硬、肥胖、糖尿病、脂肪肝和肺气肿/阻塞性肺病。 最近，血浆PAI-1水平的DNA甲基化估计(dNaM PAI-1)被报道为 非常可靠的寿命(P=5.4E-28)、合并症计数(P=7.3E-56)和2型糖尿病的预测因子 (P=2.0E-26)，以及其他与年龄相关的疾病，包括高血压、心力衰竭时间和早期 更年期。PAI-1缺乏对人类生物衰老的保护作用似乎是可行的 也是。在一个受地理和基因限制的旧亚米希人社区中，一个非凡的“天然” 实验已经进行了8代。这个社区有一个私人功能丧失(LOF) SERPINE1中的突变，可以追溯到一个单一的祖先，这个祖先在 19世纪初的一段时间。SERPINE1零突变杂合携带者的端粒更长， 更低的空腹胰岛素水平，预防糖尿病，保持血管灵活性，并比 他们未受影响的(野生型)亲属。在这项提议中，我们建议检验终生PAI-1的假设 缺乏提供多方面的保护，防止与衰老相关的多种疾病，并足以 促进小鼠和人的健康长寿。这一假设将通过以下两个方面进行检验 互补和协调的特定目标，将测试PAI-1基因缺陷与 人类观察性研究和小鼠机制研究。这些研究将利用唯一已知的 与自然发生的PAI-1功能丧失变异体亲缘关系与小鼠实验研究翻译 这些发现的概括性。我们预计，这里提出的研究将推动我们的 了解PAI-1在衰老相关疾病中的关键作用及其解释的分子机制 这种关系，并提供了药理抑制PAI-1是一种合理的治疗原则的证据 预防人类与衰老相关的多种疾病的方法。

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.