Reciprocal Modulation of the Microbiome and Cellular Senescence in Metabolic Dysfunction

代谢功能障碍中微生物组和细胞衰老的相互调节

基本信息

批准号：
10259812
负责人：
Ming Xu
金额：
$ 53.94万
依托单位：
UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-10 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10259812
关键词：
Affect Age Aging Agreement Anti-Inflammatory Agents Attenuated Bacteria Caloric Restriction Cell Aging Cell Proliferation Cells Chronic Disease Colon Development Diet Dietary Intervention Disease Exhibits Female Foundations Functional disorder Gene Expression Genetic Goals Gram-Negative Bacteria Health High Fat Diet Human In Vitro Inflammation Inflammatory Insulin Resistance Intermittent fasting Intervention Lipopolysaccharides Literature Longevity Mediating Metabolic Metabolic Diseases Metabolic dysfunction Metabolic stress Metagenomics Microbe Mucous Membrane Mus Obesity Pattern Phenotype Physiological Processes Play Population Production Progeria Property Proteobacteria Public Health Research Role Sample Size Shotgun Sequencing Solid Testing Tissues Transgenic Mice Transplantation age related anti aging base cell growth regulation cell type fecal microbiota fecal transplantation gut bacteria gut microbiome gut microbiota immune activation improved in vitro Assay in vivo innovation insight male metabolome microbial microbial composition microbiome microbiome alteration microbiome composition microbiota microbiota transplantation mouse model novel novel therapeutics senescence

项目摘要

Research from the last decade has identified cellular senescence and alteration of gut microbial composition as primary physiological processes that facilitate aging and a wide range of age-related diseases. Because of their profound impact on health and disease, they represent two promising ideas in developing innovative strategy to improve health and increase longevity. However, the interplay of the microbiome and cellular senescence in age- related metabolic dysfunction is largely unknown. The major goal of this proposed study is to elucidate the causal connection of cellular senescence and the microbiome in older mice under metabolic stress. We showed a high fat diet (HFD) induced senescent cell loads, increased the abundance of pro-inflammatory gut bacteria, and aggravated metabolic function. In contrast, caloric restriction (CR) decreased gene expression associated with senescence in humans and mice. An intermittent fasting (IF) diet that mimics CR improved metabolic function, and increased the abundance of Akkermansia known to have strong anti-inflammation and anti-aging property. Using our novel p21-Cre mouse model, we found that depletion of senescent cells expressing high levels of p21 (p21high) profoundly increased the relative abundance of Akkermansia, and improved metabolic dysfunction in male mice on a HFD. In Aim 1, we will test the hypothesis that cellular senescence modulates the microbiome composition and function. This will be achieved by directly transplanting or genetic clearance of senescent cells in older male and female mice, and determine their impact on the gut microbiome and microbial metabolites (Aim 1a). The microbiome changes will be determined at population level and functional level as these have not been well-defined previously in aging or age-related diseases. Using our novel p21-Cre mouse model, we will further assess if senescence induced alteration of the microbiome is a novel mechanism by which senescent cells influence metabolic function. We will also test the hypothesis that SASP mediates the senescence-induced microbiome changes by inactivating NF-κB in p21high senescent cells (Aim 1b). In Aim 2, we will test the hypothesis that the gut microbiome modulates senescence development. We will examine development of senescence in mice receiving fecal microbiota derived from a HFD (Aim 2a). We will determine the potential suppression of senescent cells by fecal microbiota transplantation of the microbiota derived from IF or mono- colonization of Akkermansia (Aim 2b). Establishment of reciprocal modulation of the microbiome and cellular senescence will deepen our fundamental understanding of the pathophysiology of aging and age-related metabolic diseases, and pave the way to develop robust interventions targeting senescence, microbiome or both to improve health and increase longevity.

过去十年的研究已经确定了肠道微生物组成的细胞感应和改变促进衰老和各种与年龄有关的疾病的主要物理过程。因为他们对健康和疾病的深远影响，它们代表着发展创新战略的两个有希望的思想改善健康并提高寿命。然而，微生物组和细胞感应年龄的相互作用 - 相关的代谢功能障碍在很大程度上未知。这项拟议的研究的主要目标是阐明因果关系在代谢应激下，老鼠的细胞感应和微生物组的连接。我们表现出很高的脂肪饮食（HFD）诱导感觉细胞负荷，增加促炎肠细菌的抽象，并增加汇总代谢功能。相反，热量限制（CR）降低了与人类和小鼠的感受。间歇性禁食（如果）模仿CR改善代谢功能的饮食，并增加了已知具有强大抗炎和抗衰老特性的Akkermansia的抽象。使用我们的新型P21-CRE小鼠模型，我们发现表达高水平P21的感觉细胞的耗竭（p21高）深刻地增加了阿克米亚的相对丰度，并改善了代谢功能障碍雄性老鼠在HFD上。在AIM 1中，我们将测试细胞感应调节微生物组的假设组成和功能。这将通过直接移植或遗传清除senscent细胞来实现在老年男性和雌性小鼠中，并确定它们对肠道微生物组和微生物代谢产物的影响（AIM 1A）。微生物组的变化将在人群级别和功能水平上确定，因为这些变化尚未先前在衰老或与年龄有关的疾病中定义明确。使用我们的新型P21-CRE鼠标模型，我们将进一步评估感应诱导的微生物组的改变是一种新型机制影响代谢功能。我们还将测试SASP介导感应诱导的假设微生物组通过在p21高的感觉细胞中灭活NF-κB而变化（AIM 1B）。在AIM 2中，我们将测试肠道微生物组调节衰老的发展的假设。我们将研究接收源自HFD的粪便菌群的小鼠（AIM 2A）的传感。我们将确定潜力通过粪便菌群移植源自if或单一的微生物群的粪便细胞抑制感官细胞 Akkermansia的殖民化（AIM 2B）。建立微生物组和细胞的相互调制感应将加深我们对衰老和与年龄有关的病理生理学的基本理解代谢性疾病，并为靶向靶向感受的良好干预措施铺平了道路改善健康并提高寿命。