Strengthening gut barrier integrity with beneficial microbes to increase lifespan and healthspan

许多与年龄相关的疾病(ARD)，如结直肠癌和阿尔茨海默病，以及衰老过程 这与我们肠道中微生物组成的变化有关。此外，我们的直觉有能力 排除血液中的有毒微生物成分(所谓的肠道屏障功能)会随着 随着年龄的增长，会导致炎症，而炎症反过来又会加速衰老，促进各种ARDS。我们的 长期目标是识别具有抗炎特性的细菌，因此可以促进健康，以及 以了解它们的作用机制。我们发现了一种正常的稻纵卷叶蝉Parabacteroidesdisasonis(PD) 肠道细菌，降低炎症，增强小鼠的肠道屏障功能。此外，帕金森病还增加了 果蝇的寿命和延缓与年龄相关的活力丧失。此应用程序的目标是确定 帕金森病能否延长寿命、保持活力、减缓与阿尔茨海默病和/或阿尔茨海默病相关的认知衰退 目的：研究阿尔茨海默病相关痴呆(AD/ADRD)在小鼠衰老过程中的作用，并了解其中的机制。 此外，要了解肠道屏障功能在机体活力丧失和发育中的重要性。 衰老过程中AD/ADRD相关的病理改变。我们假设在衰老过程中肠道屏障功能会恶化。 由于ZO-1表达减弱，导致细菌毒素泄漏到血液中，导致炎症 以及AD/ADRD相关病理的活力丧失和发展。此外，特定的肠道细菌，如 帕金森病，可以预防或延缓与年龄相关的肠道屏障功能障碍，从而减少炎症，保持健康 预防AD/ADRD相关的病理改变。研究的具体目的是：1)确定帕金森病是否可以 延长小鼠寿命，保持活力，防止AD/ADRD相关标志物；1a)了解蛋白质是如何 参与肠道屏障维护的基因因衰老和PD暴露而改变；2)确定是否改变ZO-1 肠道中的表达影响小鼠的寿命、活力和AD/ADRD相关标志物；3)识别活跃的 PD的因子；3a)检测PD的ZO-1上调因子是否促进长寿和健康；以及3b) 识别PD的鼠标目标。这项研究的目标将通过进行几个相互关联的 在细胞培养、小鼠和果蝇方面的实验。首先，我们将比较寿命，肠道屏障功能， 炎症、虚弱和认知健康的测量，包括记忆和大脑的几个测量 与AD/ADRD直接相关的炎症，在喂食添加或不添加PD的饮食的小鼠之间进行。接下来，我们将 比较肠道中ZO-1表达正常、缺失和高表达的小鼠的相同读数。至 鉴定PD的活性因子，我们将鉴定其他种类的能够上调ZO-1的细菌 找出他们和帕金森病的共同点。然后这些细菌将发生突变或转移到其他细菌中 一个接一个。确定帕金森病能否延长寿命、保持活力并预防AD/ADRD相关 小鼠的病理学，以及鉴定其活性因子，将为这种细菌或其活性因子， 用于治疗以延长健康寿命，并将ZO-1确立为此类治疗的目标。

Many age-related diseases (ARD) like colorectal cancer and Alzheimer’s disease, as well as the process of aging itself, have been linked to changes in the composition of microbes in our gut. Moreover, the ability of our gut to exclude toxic microbial components from our bloodstream (so-called gut barrier function) deteriorates with increasing age and results in inflammation which, in-turn, can accelerate aging and promote various ARDs. Our long-term goal is to identify bacteria with anti-inflammatory properties, and could therefore promote health, and to understand their mechanism of action. We have discovered that Parabacteroides distasonis (Pd), a normal gut bacterium, lowers inflammation and strengthens gut barrier function in mice. Furthermore, Pd increased lifespan and slowed age-related loss of vigor in fruit flies. The objectives of this application are to determine whether Pd can extend lifespan, preserve vigor and slow cognitive decline relevant to Alzheimer’s disease and/or Alzheimer’s-related dementias (AD/ADRD) during aging in mice and to understand the mechanisms involved. Furthermore, to understand the importance of gut barrier function in the loss of vigor and development of AD/ADRD-related pathologies during aging. We hypothesize that gut barrier function deteriorates during aging due to diminished ZO-1 expression, resulting in leakage of bacterial toxins into the bloodstream, inflammation and loss of vigor and development of AD/ADRD-related pathologies. Furthermore, specific gut bacteria, such as Pd, can prevent or slow age-related gut barrier dysfunction, thereby reducing inflammation, preserving health and preventing AD/ADRD-related pathologies. The specific aims of the study are to: 1) determine if Pd can increase lifespan, preserve vigor and prevent AD/ADRD-related markers in mice; 1a) understand how proteins involved in gut barrier maintenance are altered by aging and Pd exposure; 2) determine whether altering ZO-1 expression in the intestine affects lifespan, vigor and AD/ADRD-related markers in mice; 3) identify the active factor of Pd; 3a) test whether the ZO-1 upregulating factor of Pd promotes longevity and healthspan and 3b) identify the mouse target of Pd. The aims of this study will be addressed by conducting several inter-related experiments in cell culture, mice and fruit flies. Firstly, we will compare the lifespan, gut barrier function, inflammation and measures of frailty and cognitive health, including several measures of memory and brain inflammation directly relevant to AD/ADRD, between mice fed diet with or without with added Pd. Next, we will compare the same readouts between mice with normal, deleted and high ZO-1 expression in the intestine. To identify the active factor of Pd, we will identify additional species of bacteria that are able to up-regulate ZO-1 and find the genes they have in common with Pd. These will then be mutated or transferred to other bacteria one by one. Determining whether Pd can extend lifespan, preserve vigor and prevent AD/ADRD related pathologies in mice, as well as identifying its active factor, will pave the way for this bacterium, or its active factor, to be utilized in therapies to extend the healthy lifespan and establish ZO-1 as a target for such therapies.