Intestinal homeostasis and aging

摘要 胃肠道由一系列高度多样化的上皮构成，这些上皮共享重要的 需求(屏障功能、先天免疫功能、分泌和吸收功能)，但 也具有独特和高度专业化的功能。肠道的长期维护 动态平衡取决于维持这种形态和功能多样性的过程，以及 在再生期间重新建立它。 与年龄相关的功能多样性丧失可导致化生性疾病，如巴雷特氏症 食道，这与肠道发育不良和癌症有关。老龄化是如何影响的 肠道中的车厢维护，以及是否改善车厢维护 身份延长寿命尚不清楚。在这里，申请者提供了初步数据 提示年龄相关性胃化生是由慢性炎症引起的，而且它 导致老化的胃肠道的动态平衡丧失。利用果蝇作为 模型系统中，申请人发现JAK/Stat信号通路在 衰老的胃上皮细胞的分化，这种激活导致反式- 这些细胞分化成具有中肠后上皮特征的细胞类型。这 化生导致pH失衡、共生生物失调和上皮异型增生，并缩短 动物的寿命。因此，限制胃区的JAK/Stat活性就足够了 以延长寿命。 了解全身性炎症、胃化生和 肠道退行性变有望整合衰老病理生理学的各个方面， 为干预提供了新的潜在途径。申请人提出以下具体建议 目的：(I)确定全身和局部炎症信号在观察到的胃中的作用 化生，(II)胃细胞向后方转分化的机制 中肠细胞，(Iii)评估生理后果(包括肠道内稳态 上皮和共生细菌数量，以及寿命)的隔间 对衰老动物的干扰。 由于控制胃肠道再生的信号机制和 介导全身炎症反应的信号在苍蝇和脊椎动物之间是保守的， 可以预见的是，拟议的研究将对这一关系提供重要的见解 人类全身炎症和再生动态平衡之间的关系，并指出了潜在的 改善老年人动态平衡、延长寿命和健康寿命的干预策略。

Summary The gastrointestinal tract is lined by a series of highly diverse epithelia that share important requirements (barrier function, innate immune function, secretory and absorptive functions), but also have distinct and highly specialized functions. Long-term maintenance of intestinal homeostasis depends on processes that maintain this morphological and functional diversity and reestablish it during regenerative episodes. Age-related loss of functional diversity can lead to metaplastic diseases, such as Barrett’s esophagus, that are associated with intestinal dysplasias and cancers. How aging affects compartment maintenance in the gut, and whether improving maintenance of compartment identities increases lifespan remains unclear. Here, the applicant presents preliminary data suggesting that age-related gastric metaplasia is caused by chronic inflammation and that it contributes to the loss of homeostasis of the aging gastrointestinal tract. Using Drosophila as a model system, the applicant finds that the JAK/Stat signaling pathway is chronically activated in differentiated cells of the aging gastric epithelium, and that this activation results in trans- differentiation of these cells into cell types characteristic of the posterior midgut epithelium. This metaplasia results in pH imbalance, commensal dysbiosis, and epithelial dysplasia, and shortens the lifespan of the animal. Accordingly, limiting JAK/Stat activity in the gastric region is sufficient to extend lifespan. Understanding the complex relationship of systemic inflammation, gastric metaplasia, and intestinal degeneration is expected to integrate various aspects of the pathophysiology of aging, providing new potential avenues for intervention. The applicant proposes the following specific aims: (i) establish the role of systemic and local inflammatory signals in the observed gastric metaplasia, (ii) characterize the mechanism of trans-differentiation of gastric cells into posterior midgut cells, (iii) assess the physiological consequences (including homeostasis of the intestinal epithelium and the commensal bacterial population, as well as lifespan) of compartment disruption in aging animals. Since the signaling mechanisms controlling regeneration in the gastrointestinal tract and the signals mediating systemic inflammatory responses are conserved between flies and vertebrates, it can be anticipated that the proposed study will provide important insight into the relationship between systemic inflammation and regenerative homeostasis in humans, and point to potential intervention strategies to improve homeostasis in the elderly and extend life- and healthspan.