Evolutionary Advantage of Heterozygous PAI-1 Deficiency in Humans

人类杂合 PAI-1 缺陷的进化优势

基本信息

批准号：
10686583
负责人：
Douglas E Vaughan
金额：
$ 30万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-15 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10686583
关键词：
Age Aging Alzheimer&apos s Disease American Amish Arteriosclerosis Back Biological Biological Aging Blood Vessels Brain Censuses Collection Communities Coronary Arteriosclerosis Coronary artery DNA Methylation Data Set Development Diabetes Mellitus Engineering Epigenetic Process Fasting Fatty Liver Fertility Fingerprint Gene Proteins Generations Genetic Genotype Geography Hearing Heart failure Human Hypertension In Vitro Indiana Insulin Investigation Investigative Reports Kidney Laboratories Link Liver Longevity Lung Measures Mediator of activation protein Metabolism Molecular Molecular Profiling Morbidity - disease rate Mus Natural experiment Non-Insulin-Dependent Diabetes Mellitus Obesity Observational Study Obstructive Lung Diseases Pathology Pharmacology Phenotype Physiological Plasma Plasminogen Activator Inhibitor 1 Population Premature Menopause Presbycusis Prevalence Privatization Proteins Pulmonary Emphysema Reporting Reproductive system Role SERPINE1 gene Skin Structure Testing Therapeutic Time Tissues Translating Variant age related body system cognitive function comorbidity comparative design experimental study fatty liver disease fertility preservation flexibility genetic association genetic variant human old age (65+)in vivo kindred loss of function loss of function mutation man multiple chronic conditions novel null mutation preservation prevent protective effect senescence telomere

项目摘要

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.

摘要 65 岁以上的美国人数量正在增长，预计将从 2010 年约为 3,900 万，到 2030 年估计为 7,100 万（2010 年人口普查）。发病率，包括阿尔茨海默氏痴呆、肺气肿和老年性耳聋，随着年龄的增长而显着增加。经验证的最佳衰老和衰老分子指纹是蛋白纤溶酶原激活剂抑制剂-1 (PAI-1)（SERPINE1 基因的蛋白质产物）。大量研究表明，PAI-1 是此外，PAI-1 在哺乳动物和非哺乳动物物种中都具有进化保守性。也是体外和体内衰老的介质，是一个令人惊讶的强大和一致的实验体。世界各地实验室产生的证据已确定并报告了机械联系 PAI-1 与每个主要器官系统（包括大脑和肺部）的类衰老病理学之间的关系在健康人群中，较高水平的 PAI-1 与冠状动脉疾病相关。血管僵硬度增加、肥胖、糖尿病、脂肪肝和肺气肿/阻塞性肺病。最近，据报道，血浆 PAI-1 水平的 DNA 甲基化估计器（DNAm PAI-1）是一种寿命 (P=5.4E-28)、合并症计数 (P=7.3E-56) 和 2 型糖尿病的异常稳健的预测因子 (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心力衰竭 PAI-1 缺乏对生物衰老的保护作用似乎在人类中发挥作用。在地理和基因上都受到限制的旧秩序阿米什人社区中，也有一个非凡的“自然”。该实验已经进行了 8 代。 SERPINE1 的突变，可以追溯到与社区联姻的单一祖先 19世纪早期，SERPINE1无效突变的杂合携带者具有更长的端粒，空腹胰岛素水平较低，预防糖尿病，保留血管灵活性，并且寿命比在本提案中，我们建议检验终生 PAI-1 的假设。缺乏可提供多方面的保护，预防与衰老相关的多种疾病，并且足以促进小鼠和人类的健康长寿该假设将通过以下两个方面进行检验。互补和协调的具体目标将测试 PAI-1 遗传缺陷与人类观察研究和小鼠机制研究将利用唯一已知的方法。与 PAI-1 中自然发生的功能丧失变体有亲缘关系，并在小鼠中进行了实验研究以转化我们预计这里提出的研究将推进我们的研究。了解 PAI-1 在衰老相关发病中的关键作用，解释其分子机制这种关系，并提供了原理证明，证明药物抑制 PAI-1 是一种合理的治疗方法预防人类与衰老相关的多种疾病的方法。