The host-microbe-metformin interplay in the aged gut

衰老肠道中宿主-微生物-二甲双胍的相互作用

• 批准号: 10228423
• 负责人: Soumita Das
• 金额: $ 39.4万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10228423
• 关键词: 5' -AMP-activated protein kinase; Age; Aging; Antidiabetic Drugs; Apical; Bacteria; Bifidobacterium; Biological Assay; Biological Markers; Blood Glucose; Butyrates; CCL2 gene; CDKN1A gene; CDKN2A gene; Cell Aging; Cell Cycle Arrest; Cell surface; Cells; Chronic; Chronic Disease; Clinical Trials; Colon; DNA Damage; Data; Dextrans; Diet; Dietary Component; Disease; Electrical Resistance; Enzyme-Linked Immunosorbent Assay; Epigenetic Process; Epithelial; Epithelial Cell Junction; Epithelial Cells; Epithelium; Exposure to; Fatty Acids; Functional disorder; G1 Phase; Genes; Genetic; Glutamine; Growth Factor; Health Promotion; Human; Human Microbiome; IL8 gene; Immune; Immunologics; Impairment; Infection; Inflammaging; Inflammation; Inflammatory; Inflammatory Response Pathway; Innate Immune Response; Insulin Resistance; Insulin-Like Growth-Factor-Binding Proteins; Interleukin-6; Knowledge; Leaky Gut; Link; Longevity; Malignant Neoplasms; Measures; Metabolic; Metformin; Microbe; Modeling; Molecular; Mus; Natural Immunity; Non-Insulin-Dependent Diabetes Mellitus; Nutritional; Obesity; Organoids; Oxidative Stress; Pathway interactions; Pharmaceutical Preparations; Phenotype; Phosphorylation; Physiological; Population; Probiotics; Process; Property; Proteins; Quantitative Reverse Transcriptase PCR; Reagent; Rejuvenation; Risk; Role; SIRT1 gene; Side; Signal Pathway; Sirtuins; Specialized Epithelial Cell; Specimen; Stains; Stress; TP53 gene; Testing; Tight Junctions; Tissues; Triad Acrylic Resin; Tumor Necrosis Factor Receptor; Urokinase Plasminogen Activator Receptor; Western Blotting; age effect; age related; aged; anti aging; base; beta-Galactosidase; chemokine; cognitive function; confocal imaging; cytokine; drug testing; equilibration disorder; gut microbiota; healthspan; healthy aging; improved; inflammatory marker; insight; intercellular cell adhesion molecule; intestinal barrier; intestinal epithelium; lifestyle factors; microbial; microbiota; monocyte; monolayer; occludin; oxidative damage; pathobiont; pathogen; prebiotics; prevent; protective effect; recruit; senescence; side effect; stem cells; stressor; telomere

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.

抽象的 抗衰老药物的三个主要目标是“健康寿命”、“返老还童”和“长寿”。 二甲双胍就是这样一种药物，经过临床试验测试，并进行推广以实现一项甚至所有承诺 的抗衰老药物。二甲双胍不仅是治疗糖尿病的最佳降血糖药物 2 型糖尿病，但它可以调节与年龄相关的先天免疫、慢性疾病，包括 癌症和感染。二甲双胍可以改变肠道微生物群，从而改善代谢 参数，包括肥胖和胰岛素抵抗。在衰老过程中，肠道微生物群发生变化 成分发生变化，例如多样性下降、促进健康的细菌减少以及细菌数量增加 潜在的病原体。微生物群组成的平衡被破坏会增加肠道受损的风险 屏障功能和炎症与年龄相关的慢性疾病有关。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 可能增强炎症的机制不完整；物理和免疫学特性 人类微生物组和肠道屏障在衰老过程中的变化在很大程度上是未知的。尽管潜力无穷 二甲双胍的有益作用的作用已经被提出，使用二甲双胍作为药物的潜在机制 抗衰老药物目前还不太清楚。我们最近发现二甲双胍可以激活专门的应激- AMPK-GIV 轴的极性信号 (SPS) 通路，可强化上皮紧密连接 [TJ] 应力引起的塌陷。 AMP 激活激酶 [AMPK] 对 GIV 的磷酸化可以作为 慢性疾病的生物标志物，似乎对于屏障保护功能是必要和充分的 SPS 途径的。使用基于结肠类器官的模型，我们发现二甲双胍激活 结肠上皮中的 SPS 通路以 AMPK 依赖性方式增强肠道屏障 微生物应激源的攻击。在老化的肠道中，屏障被“破坏”，SPS 通路受到抑制；和 二甲双胍可以恢复 TJ 完整性。根据初步研究，我们假设 SPS- 二甲双胍可以靶向该途径来恢复老化肠道中受损的上皮屏障，从而减少 炎症并恢复衰老相关蛋白去乙酰化酶 (SIRT) 的水平。使用单层细胞 从年轻人和老年人的小鼠和人类肠道来源的肠类中产生，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的影响（Aim1）；决定 二甲双胍对衰老肠道细胞衰老和氧化应激的影响（Aim2）；确定 使用微生物上皮和肠道模型研究二甲双胍对慢性炎症的保护作用 免疫细胞（目标3）。所获得的见解预计将制定出一种全新的战略来应对老龄化问题 通过二甲双胍与益生菌结合激活专门途径来靶向肠道， 益生元或膳食成分，最终目的是促进健康衰老。