Reciprocal Modulation of the Microbiome and Cellular Senescence in Metabolic Dysfunction

过去十年的研究发现，细胞衰老和肠道微生物组成的变化是 促进衰老和一系列与年龄相关的疾病的主要生理过程。因为他们的 对健康和疾病产生深远影响，它们代表了制定创新战略的两个有希望的想法 增进健康，延长寿命。然而，微生物组和细胞衰老的相互作用在年龄- 相关的代谢功能障碍在很大程度上是未知的。这项拟议研究的主要目标是阐明因果关系。 代谢应激下老龄小鼠细胞衰老与微生物群的关系。我们表现出了很高的 脂肪饮食(HFD)诱导衰老细胞负荷，增加促炎肠道细菌的丰度，以及 代谢功能加重。相比之下，热量限制(CR)减少了与以下相关的基因表达 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， 并增加了已知具有较强抗炎和抗衰老作用的阿克曼属植物的丰度。 使用我们新的p21-CRE小鼠模型，我们发现高水平表达p21的衰老细胞枯竭 (P21High)显著增加阿克曼草属的相对丰度，并改善体内代谢紊乱。 在HFD上的雄性小鼠。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遗传清除衰老细胞来实现。 在老年雄性和雌性小鼠中，并确定它们对肠道微生物群和微生物代谢物的影响(目的 1a)。微生物组的变化将在种群水平和功能水平上确定，因为这些还没有 以前对衰老或与年龄相关的疾病有很好的定义。使用我们的新型p21-Cre小鼠模型，我们将进一步 评估衰老诱导微生物组的改变是否是衰老细胞的一种新机制 影响新陈代谢功能。我们还将检验SASP介导衰老诱导的假说 通过灭活p21高衰老细胞中的NF-κB来改变微生物组(目标1b)。在目标2中，我们将测试 肠道微生物群调节衰老发育的假说。我们将研究一下 接受来自HFD的粪便微生物群的小鼠的衰老(目标2a)。我们将确定潜在的 通过粪便微生物区系移植IF或Mono-1来源的微生物区系抑制衰老细胞 阿克曼西亚的殖民化(目标2b)。微生物组与细胞间相互调控机制的建立 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认识 代谢性疾病，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 增进健康，延年益寿。

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.