The host-microbe-metformin interplay in the aged gut

摘要 抗衰老药物的三个主要目标是“健康”、“恢复活力”和“长寿”。 二甲双胍就是这样一种药物，在临床试验中进行测试，并推广以实现一个甚至所有的承诺 抗衰老药物二甲双胍不仅是治疗糖尿病的最佳降糖药物， 2型糖尿病，但它可以调节与年龄相关的先天免疫变化，慢性疾病， 癌症和感染。代谢能改变肠道微生物群，从而改善代谢 参数，包括肥胖和胰岛素抵抗。在衰老过程中，肠道微生物群的变化 在某些情况下，可能会发生生物组成的变化，例如多样性降低，促进健康的细菌减少， 潜在的致病菌这种微生物群组成的失衡增加了肠道受损的风险。 屏障功能和炎症与年龄相关的慢性疾病。肠道屏障功能障碍可能是 不健康衰老的关键驱动因素-低水平的炎症和炎症。然而，知识 可能加强炎症的机制不完整;物理和免疫特性 人体微生物组和肠道屏障在衰老过程中的作用在很大程度上是未知的。尽管一系列潜在的 已经提出了二甲双胍的有益作用，使用二甲双胍作为 抗衰老药物仍然不太清楚。我们最近发现二甲双胍激活了专门的应激反应- 极性信号传导（SPS）途径与AMPK-GIV轴，这加强了上皮紧密连接[TJ]， 应力导致的坍塌AMPK对GIV的磷酸化作用可能是一种抑制GIV表达的机制。 生物标志物的慢性疾病，似乎是必要的和足够的屏障保护功能 的SPS途径。使用基于结肠类器官的模型，我们已经确定二甲双胍激活了 SPS-途径在结肠上皮中以AMPK依赖性方式表达，并在 微生物应激源的攻击在老化的肠道中，屏障被“打破”，SPS通路被抑制; 二甲双胍可以恢复TJ的完整性。根据初步研究，我们假设SPS- 二甲双胍可以靶向这一途径，以恢复衰老肠道中受损的上皮屏障， 炎症和恢复衰老相关蛋白sirtuins（SIRTs）的水平。使用单层 从小鼠和人类肠道衍生的肠类来自年轻人和老年人，我们将评估， 年龄相关微生物和二甲双胍对肠上皮细胞连接和炎症（Aim 1）的影响;确定 二甲双胍对老化肠道细胞衰老和氧化应激的影响（Aim 2）;确定 二甲双胍对慢性炎症的保护作用，使用具有微生物-上皮和 免疫细胞（Aim 3）。所获得的见解预计将制定一项全新的战略来应对老龄化， 通过二甲双胍与益生菌联合激活特定途径靶向肠道， 益生元或膳食成分，最终目的是促进健康衰老。

ABSTRACT The three main aims expected from the anti-aging drugs are-“healthspan,” “rejuvenation,” and “longevity.” Metformin is one such drug, tested in clinical trials and are propagated to fulfill one or even all of the promises of anti-aging drugs. Metformin is not only the best drug in lowering the blood glucose level in the treatment of type 2 diabetes, but it can modulate age-related changes in innate immunity, chronic diseases including cancers and infections. Metformin can alter the gut microbiota that leads to the improvement of metabolic parameters, including obesity and insulin resistance. During the aging process, changes in gut microbiota composition occur, such as decreased diversity, a decrease in health-promoting bacteria and an increase in potential pathobionts. This disturbed balance in microbiota composition increases the risk of impaired intestinal barrier function and inflammation linked to age-associated chronic diseases. Gut-barrier dysfunction may be a pivotal driver of an unhealthy aging-low level of inflammation and inflammaging. However, knowledge of mechanism(s) that might reinforce the inflammaging is incomplete; the physical and immunological properties of the human microbiome and gut barrier during aging are largely unknown. Although an array of the potential role of metformin’s beneficial action has been proposed, the underlying mechanisms to use metformin as an anti-aging drug is still less clear. We have recently identified that metformin activates the specialized stress- polarity signaling (SPS) pathway with the AMPK-GIV axis, which fortifies epithelial tight junctions [TJs] against stress-induced collapse. The phosphorylation of GIV by AMP-activated kinase [AMPK] could act as a biomarker for chronic diseases and appears to be necessary and sufficient for the barrier-protective functions of the SPS-pathway. Using the colonic organoid-based model, we have identified that metformin activates the SPS-pathway in the colon epithelium in an AMPK-dependent manner and reinforces the gut barrier following an attack with microbial stressors. In the aged gut, the barrier is ‘broken,’ the SPS-pathway is suppressed; and metformin can restore the TJ integrity. Based on the preliminary studies, we have hypothesized that the SPS- pathway can be targeted by metformin to restore the compromised epithelial barrier in the aging gut, to reduce inflammation and to restore the levels of the aging-related proteins sirtuins (SIRTs). Using monolayers generated from murine and human gut-derived enteroids from the young and old, we will assess, the effect of age-related microbes and metformin on intestinal epithelial cell junction and inflammation (Aim1); determine the impact of metformin on cellular senescence and oxidative stress in the aged gut (Aim2); determine the protective effect of metformin on chronic inflammation using gut-in-a-dish model with microbe-epithelial and immune cells (Aim3). The insights gained are expected to develop an entirely new strategy to tackle aging by targeting the gut through activation of a specialized pathway by metformin in conjunction with probiotics, prebiotics or dietary components, with an ultimate intent to promote healthy aging.