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2015年增加到2016年。 2010年约为3 900万人，2030年估计为7 100万人（2010年人口普查）。多方面的普遍性- 包括阿尔茨海默氏痴呆、肺气肿和老年性耳聋在内的发病率随着年龄的增长而显著增加。一 最有效的老化和衰老的分子指纹是蛋白质纤溶酶原激活剂 抑制剂-1（派-1）（SERPINE 1基因的蛋白产物）。许多研究表明派-1是 在哺乳动物和非哺乳动物物种中进化保守。此外，派-1不仅仅是一种标志物， 而且是体外和体内衰老的介质。一个非常强大和一致的实验机构， 来自世界各地的实验室所产生的证据已经确定并报告了一种机械联系 派-1与包括大脑和肺部在内的每个主要器官系统中的衰老样病理学之间的关系， 他人在健康人群中，较高水平的派-1与冠状动脉疾病相关， 血管僵硬增加、肥胖、糖尿病、脂肪肝和肺气肿/阻塞性肺病。 最近，血浆派-1水平的DNA甲基化估计物（DNAm派-1）被报道是一种用于检测血浆PAI-1水平的DNA甲基化估计物。 寿命（P=5.4E-28）、合并症计数（P= 7.3E-56）和2型糖尿病的异常可靠的预测因子 （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 绝经派-1缺乏对生物衰老的保护作用似乎在人类中起作用 也在一个地理和遗传限制的旧秩序阿米什社区，一个显着的“自然” 实验已经进行了8代。这个社区有一个私人功能丧失（LOF） SERPINE 1的突变，可以追溯到一个单一的祖先，他们结婚进入社区， 19世纪早期。SERPINE 1无效突变的杂合携带者具有更长的端粒， 更低的空腹胰岛素水平，保护糖尿病，保持血管的灵活性，和更长的寿命比 他们的未受影响的（野生型）亲属。在这项提议中，我们提出测试假设，终身派-1 缺乏提供多方面的保护，防止与衰老有关的多种发病率，并足以 促进小鼠和人类的健康长寿。这一假设将通过以下两个测试 互补的和协调的特定目的，将测试派-1的遗传缺陷在 人类观察性研究和鼠机制研究。这些研究将利用唯一已知的 与派-1中自然发生的功能丧失变体的亲属在小鼠中进行实验研究，以翻译 这些发现的普遍性。我们预计这里提出的研究将推进我们的研究 了解派-1在衰老相关疾病中的关键作用，解释PAI-1的分子机制， 这种关系，并提供了原则上的证据，即派-1的药理学抑制是合理的治疗方法 预防人类与衰老有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.