How does the immunomodulatory parasitic worm product ES-62 rewire bone marrow cells to increase healthspan and lifespan in obesity-accelerated ageing?

全球约有四分之一的人口感染了寄生蠕虫。虽然毫无疑问是一个公共卫生问题，但越来越多的人认为，这些传统上不受欢迎的访客实际上可能带来一些健康益处。特别是，来自对人类患者的研究和采用小鼠模型的实验的组合的证据表明，蠕虫感染可以防止一系列衰弱性疾病的发展，包括过敏性疾病（例如，哮喘）、自身免疫性疾病（例如RA）和心血管疾病。所有这些疾病的共同点是与持续的，不必要的炎症反应有关，因此寄生蠕虫提供的保护与它们分泌抗炎分子的能力有关，这可以解决这些问题。一个特别好表征的分子是ES-62，我们以前发现它可以防止RA，肾脏疾病和与系统性红斑狼疮相关的加速动脉粥样硬化以及肺和皮肤过敏的小鼠模型中的疾病发展。与有害炎症反应相关的许多疾病发展的风险因素是衰老，这本身与慢性低水平炎症有关，肥胖进一步增加了这种风险。随着人类人口逐渐变老和越来越肥胖，因此不可避免的是，这种疾病的患病率正在上升。因此，我们最近将注意力转向研究ES-62是否可以通过评估其对肥胖加速衰老的C57 BL/6 J小鼠模型的健康影响来对抗这一点，在该模型中，动物在其一生中被喂食高热量饮食（HCD）。毫不奇怪，我们发现ES-62可以抑制全身性肥胖诱导的炎症，但也注意到了许多其他保护作用，有趣的是，包括在衰老的骨髓（BM）生态位中。BM含有各种类型的细胞-“干细胞”-其在成熟过程之后具有补充体内某些细胞类型的作用，例如，免疫系统的细胞以及健康骨骼和其他组织所需的细胞。正如在人类中观察到的那样，肥胖和衰老导致我们的HCD喂养的衰老小鼠的干细胞群受损。然而，通过ES-62治疗，这在雄性小鼠中显著降低，此外，蠕虫产品还保护这些动物免受由肥胖加速老化期间发生的BM细胞变化引起的骨丢失。据我们所知，能够防止衰老对BM细胞的影响以前并没有归因于寄生虫产品。因此，我们的中心目标是利用我们的肥胖加速衰老小鼠模型来确定ES-62如何实现这一点。具体而言，我们将致力于实现以下目标：1.确定ES-62对BM细胞的影响是否反映了细胞内特定基因表达的变化，以及蠕虫产品如何“重新连接”控制这一点的细胞机制。2.定义ES-62介导的基因表达变化如何与拯救缺陷BM细胞相关。3.使用BM转移实验来确定ES-62条件BM是否促进受体小鼠的健康改善，并确定其保护作用是否是由于直接或间接（例如通过微生物组）与BM细胞的相互作用。我们的目标的成功实现将提供对ES-62的BM保护，抗炎作用的基础机制的知识和理解。ES-62的特性决定了它已经被认为对一系列与有害炎症相关的疾病具有治疗潜力，但我们的新BM数据清楚地表明，其潜在的疾病覆盖范围可能更广，例如，扩展到预防与衰老相关的退行性骨病，如骨质疏松症和恶性肿瘤，如白血病。

Around a quarter of the global human population is infected with parasitic worms. Although undoubtedly a public health problem, increasingly there is acceptance that these traditionally unwelcome visitors may actually confer some health benefits. In particular, the evidence, from a combination of studies on human patients and experiments employing mouse models, indicates that worm infection can protect against development of a range of debilitating diseases including allergic (e.g., asthma), autoimmune (e.g. RA) and cardiovascular conditions. What all these illnesses have in common is an association with persistent, unnecessary inflammatory responses and it is therefore not surprising that the protection afforded by parasitic worms has been correlated with their ability to secrete anti-inflammatory molecules, which can resolve these. One particularly well-characterised molecule is ES-62, which we have previously found to protect against disease development in mouse models of RA, kidney disease and accelerated atherosclerosis associated with systemic lupus erythematosus, and both lung and skin allergy. A risk factor for the development of many diseases linked with harmful inflammatory responses is ageing, which is itself associated with chronic low-level inflammation and this risk is further increased by obesity. As the human population is becoming both progressively older and increasingly obese, it is thus inevitable that the prevalence of such ailments is rising. We therefore recently turned our attention to investigating whether ES-62 could act to counter this by assessing its impact on well-being in a C57BL/6J mouse model of obesity-accelerated ageing where animals are fed high calorie diet (HCD) over their lifetime. Not surprisingly, we found ES-62 to inhibit systemic obesity-induced inflammation but a number of other protective effects were noted, intriguingly including within the ageing bone marrow (BM) niche. The BM contains various types of cells - "stem cells" - which following a process of maturation have the job of replenishing certain cell types in the body, e.g., cells of the immune system and those required for healthy bone and other tissues. As is observed in humans, obesity and ageing led to impairment of stem cell populations in our HCD-fed ageing mice. This however was significantly reduced in male mice by ES-62 treatment and furthermore, the worm product also protected against the bone loss arising from the changes in BM cells occurring during obesity-accelerated ageing in these animals. As far as we aware, being able to prevent the effects of ageing on BM cells has not previously been attributed to a parasitic worm product. Our central aim is thus to employ our mouse model of obesity-accelerated ageing to determine how ES-62 achieves this. In particular, we will address the following objectives:1. Determine whether ES-62's effects on BM cells reflect changes in the expression of particular genes within the cells and how the worm product "rewires" the cellular machinery controlling this. 2. Define how ES-62-mediated changes in gene expression are linked to rescue of defective BM cells. 3. Use BM transfer experiments to determine whether ES-62-conditioned BM promotes improved health in recipient mice and also establish whether its protective effects are due to direct or indirect, for example via the microbiome, interaction with BM cells.Successful achievement of our objectives will provide knowledge and understanding of the mechanisms underpinning the BM-protective, anti-inflammatory actions of ES-62. ES-62's properties dictate that it is already considered to possess therapeutic potential for a range of illnesses associated with harmful inflammation but our new BM-data clearly suggest that its potential disease-coverage may be even wider, for example, extending to protection against ageing-associated degenerative bone disorders like osteoporosis and malignancies such as leukemia.