Impact of dysbiosis on the development of age-related inflammation

项目总结 “衰老的支柱”假说认为，慢性未解决的炎症，加上代谢 功能障碍和大分子损伤是损害细胞更新和 导致衰老和慢性病的再生过程。炎症是一种保护性机制 它已经进化成能够抵御病原体和组织损伤，使宿主能够在威胁生命的情况下存活 动态平衡的恢复带来的挑战。那么，像炎症这样的保护性反应是如何成为 慢性的，会导致衰老并引发慢性病？在衰老过程中没有明显感染的情况下， 肠道微生物区系的改变(生物失调)或微生物区系衍生的PAMP可能转移到肝脏， 肠系膜和大网膜脂肪组织可能参与了年龄相关性炎症的发生机制。排队 在这种可能性下，最近的研究表明，与 并提示微生物群可能在炎症的某些方面起到因果作用。我们最近 发现衰老与第三级淋巴结构的形成有关，称为脂肪相关 淋巴团(FALC)，位于内脏脂肪组织中。与淋巴结节不同，FALC是杂乱无章的 与脂肪细胞相关的非囊化非经典淋巴组织含有T细胞、B细胞和 巨噬细胞。此外，我们还发现B细胞在FALC中随着年龄的增长而扩张，并表现出独特的 转录图谱使人联想到经历过抗原的B细胞。根据我们最初的调查结果，中央 这一应用的假设是肠道微生物移位到内脏脂肪组织导致Falc 形成和年龄相关的炎症导致代谢功能障碍。我们将测试这一机制是如何 防止微生物群的移位可以防止Falc的形成和发炎。

PROJECT SUMMARY The “pillars of aging” hypothesis entails that chronic unresolved inflammation, coupled with metabolic dysfunction and macromolecular damage are among the key mechanisms that impairs cellular renewal and regenerative processes that contribute to aging and chronic diseases. Inflammation is a protective mechanism that has evolved to protect against pathogens and tissue injury that enables a host to survive life-threatening challenges by restoration of homeostasis. How then does a protective response like inflammation become chronic, drive aging and serve as a trigger of chronic disease? In absence of overt infections in aging, alterations in the gut microbiota (dysbiosis) or potential translocation of microbiota derived PAMPs to liver, mesenteric and omental adipose tissue could contribute to the mechanism of age-related inflammation. In line with this possibility, recent studies have demonstrated profound changes in the microbiome associated with aging and suggest that the microbiome may play a causal role in certain aspects of inflammaging. We recently discovered that aging is associated with formation of tertiary lymphoid structures, called Fat-associated lymphoid clusters (FALCs), in the visceral adipose tissue. The FALCs, unlike lymph nodes are disorganized non-encapsulated non-classical lymphoid tissues associated to adipocytes contain T cells, B cell and macrophages. Moreover, we found that B cells expand with age in the FALCs and display a unique transcriptional profile reminiscent of antigen-experienced B cells. Based on our original findings, the central hypothesis of this application is that translocation of gut microbes to visceral adipose tissue results in FALC formation and age-related inflammation leading to metabolic dysfunction. We will test the mechanism of how preventing the translocation of microbiota protects against FALC formation and inflammaging.