Intestinal homeostasis and aging

总结 胃肠道由一系列高度多样化的上皮细胞组成，这些上皮细胞具有重要的共同点， 要求（屏障功能，先天免疫功能，分泌和吸收功能），但 还具有独特且高度专业化的功能。长期维持肠道 稳态依赖于维持这种形态和功能多样性的过程， 在再生期重建它 乳腺癌相关的功能多样性丧失可导致化生性疾病，如Barrett's 食管，与肠道发育不良和癌症有关。衰老如何影响 肠道中的隔室维持，以及是否改善隔室维持 身份是否会延长寿命仍不清楚。在此，申请人提供了初步数据， 提示年龄相关性胃上皮化生是由慢性炎症引起的， 导致老化胃肠道内稳态的丧失。利用果蝇作为 在该模型系统中，申请人发现JAK/Stat信号传导途径被慢性激活， 分化的细胞老化的胃上皮，这种激活导致反式- 这些细胞分化为后中肠上皮细胞的特征性细胞类型。这 化生导致pH失衡、粘膜生态失调和上皮发育不良， 动物的寿命。因此，限制胃区域中的JAK/Stat活性就足够了 来延长寿命 了解全身性炎症、胃上皮化生和胃粘膜上皮细胞增生之间的复杂关系， 预期肠变性整合了衰老的病理生理学的各个方面， 为干预提供新的潜在途径。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所观察到的胃粘膜中的作用。 化生，（ii）表征胃细胞转分化为后分化的机制， 中肠细胞，（iii）评估生理后果（包括肠内的稳态 上皮和肠道细菌种群，以及寿命）的隔室 衰老的动物。 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蝇和脊椎动物之间是保守的， 可以预期，拟议的研究将为深入了解这种关系提供重要的见解， 在人类的全身炎症和再生稳态之间，并指出潜在的 改善老年人体内平衡、延长寿命和健康的干预策略。

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.