Reciprocal Modulation of the Microbiome and Cellular Senescence in Metabolic Dysfunction

过去十年的研究已经确定细胞衰老和肠道微生物组成的改变是 促进衰老的主要生理过程和各种与年龄有关的疾病。因为他们的 对健康和疾病的深远影响，它们代表了制定创新战略的两个有前途的想法， 改善健康和延长寿命。然而，微生物组和细胞衰老的相互作用- 相关的代谢功能障碍在很大程度上未知。这项研究的主要目的是阐明 在代谢应激下，老年小鼠的细胞衰老和微生物组之间的联系。我们展示了一个高 高脂饮食（HFD）诱导衰老细胞负荷，增加促炎肠道细菌的丰度， 代谢功能恶化相比之下，热量限制（CR）降低了基因表达， 人类和小鼠的衰老。模拟CR的间歇性禁食（IF）饮食改善了代谢功能， 并增加了已知具有强抗炎和抗衰老特性的阿克曼氏菌的丰度。 使用我们新的p21-Cre小鼠模型，我们发现表达高水平p21的衰老细胞的耗竭， （p21 high）显著增加Akkermansia的相对丰度，并改善代谢功能障碍。 HFD的雄性小鼠。在目标1中，我们将测试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遗传清除衰老细胞来实现 老年雄性和雌性小鼠，并确定其对肠道微生物组和微生物代谢产物的影响（目的 1a）。微生物组的变化将在人群水平和功能水平上确定，因为这些水平尚未确定。 以前在衰老或与年龄有关的疾病中定义明确。使用我们新的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 影响代谢功能。我们还将检验SASP介导衰老诱导的细胞凋亡的假设。 p21高衰老细胞中的NF-κB失活导致微生物组改变（Aim 1 B）。在目标2中，我们将测试 假设肠道微生物组调节衰老发展。我们将研究 在接受来源于HFD的粪便微生物群的小鼠中的衰老（目标2a）。我们将确定潜在的 通过粪便微生物群移植来自IF或单核细胞的微生物群来抑制衰老细胞， Akkermansia的殖民化（Aim 2b）。建立微生物组和细胞的相互调节 衰老将加深我们对衰老和与年龄相关的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大干预措施铺平道路 来改善健康和延长寿命。

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.