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

• 批准号: 10661517
• 负责人: Ming Xu
• 金额: $ 53.05万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 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/10661517
• 关键词: Adipocytes; 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 Control; 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; cell growth regulation; cell type; fecal microbiota; fecal transplantation; fortification; gut bacteria; gut microbiome; gut microbiota; human old age (65+); 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

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.

过去十年的研究已确定细胞衰老和肠道微生物组成的改变 促进衰老和各种与年龄相关的疾病的主要生理过程。因为他们的 它们对健康和疾病产生了深远的影响，它们代表了制定创新战略的两个有前途的想法 改善健康并延长寿命。然而，微生物组和细胞衰老之间的相互作用 相关的代谢功能障碍在很大程度上是未知的。这项研究的主要目标是阐明因果关系 代谢应激下老年小鼠细胞衰老与微生物组的联系。我们展现了高 脂肪饮食（HFD）诱导衰老细胞负荷，增加促炎性肠道细菌的丰度，以及 代谢功能恶化。相反，热量限制（CR）降低了与 人类和小鼠的衰老。模仿 CR 的间歇性禁食 (IF) 饮食可改善代谢功能， 并增加了已知具有强大抗炎和抗衰老特性的阿克曼氏菌的丰度。 使用我们的新型 p21-Cre 小鼠模型，我们发现表达高水平 p21 的衰老细胞的耗竭 (p21high) 显着增加了 Akkermansia 的相对丰度，并改善了代谢功能障碍 服用 HFD 的雄性小鼠。在目标 1 中，我们将检验细胞衰老调节微生物组的假设 组成和功能。这将通过直接移植或基因清除衰老细胞来实现 在老年雄性和雌性小鼠中进行实验，并确定它们对肠道微生物组和微生物代谢物的影响（Aim 1a).微生物组的变化将在群体水平和功能水平上确定，因为这些还没有被确定。 先前在衰老或与年龄相关的疾病中已有明确定义。使用我们的新型 p21-Cre 小鼠模型，我们将进一步 评估衰老诱导的微生物组改变是否是衰老细胞的一种新机制 影响代谢功能。我们还将检验 SASP 介导衰老诱导的假设 通过灭活 p21high 衰老细胞中的 NF-κB 来改变微生物组（目标 1b）。在目标 2 中，我们将测试 肠道微生物组调节衰老发展的假设。我们将研究发展 接受 HFD 粪便微生物群的小鼠出现衰老（目标 2a）。我们将确定潜力 通过粪便微生物群移植来自 IF 或 mono-的微生物群来抑制衰老细胞 Akkermansia 的定植（目标 2b）。微生物组和细胞相互调节的建立 衰老将加深我们对衰老和年龄相关病理生理学的基本理解 代谢疾病，并为开发针对衰老、微生物组或两者的强有力的干预措施铺平道路 改善健康并延长寿命。