Can studying the mechanism of action of the parasitic worm-derived immunomodulator ES-62, inform on how to slow ageing and improve healthspan?

采用疫苗和药物来控制疾病，再加上更容易获得食物和改善卫生条件，意味着人们现在的寿命要长得多。目前，这一增长是惊人的，相当于每十年多活2.5年。然而，预期寿命的提高本身就是一个巨大的新问题，因为它并没有伴随着健康和福祉的类似增长。这既反映了像汽车发动机这样的机械机器，老化过程自然与其系统由于“磨损”而丧失功能有关，也反映了财富的增加导致了现代西方生活方式，包括高脂肪饮食（HFD），导致与年龄相关的疾病，如2型糖尿病（T2 D），中风和心脏病。寿命延长的影响伴随着健康不良，由于其日益全球化的规模，产生了巨大的社会经济影响，需要从健康的角度更好地了解老龄化过程，世界人口约有四分之一感染寄生蠕虫。令人感兴趣的是，最近的几份报告表明，这种感染在小鼠模型中提供了针对诸如肥胖、心血管疾病和T2 D等病症的发展的保护，并且在人类中也可以看到类似的保护。我们一直在研究一种单独的寄生虫成分- ES-62，它是从丝状线虫（Acanthocheilonema viteae）的分泌产物中分离出来的，与这些研究一致，ES-62在减少高敏感小鼠品系中出现的心血管疾病方面非常有效，特别是在对高脂肪饮食做出反应时。此外，我们有一些初步数据显示，ES-62可以提供一些保护，防止与T2 D发展相关的肥胖症的发展。迄今为止，我们对ES-62的研究还表明，它在抑制过敏、类风湿性关节炎和系统性红斑狼疮小鼠模型中的疾病发展方面是有效的。所有这些疾病与心血管疾病和T2 D的共同点是，人们越来越认识到它们与不必要的炎症有关。这立即为ES-62的保护作用提供了解释，因为寄生虫衍生的分子具有一系列抗炎特性。此外，由于衰老现在也被认为是慢性低度炎症环境中的生物学问题，这增加了研究ES-62对衰老过程和晚年健康和福祉（healthspan）的影响的可能性。因此，我们特别计划使用高脂肪饮食+/- ES-62喂养小鼠的范例来确定ES-62是否可以减缓衰老并改善健康寿命。我们将使用这个模型来评估ES-62治疗对衰老的影响，其背景是促进已知与衰老/炎症相关的基因签名和信号通路，而不是与长寿和健康相关的基因签名和信号通路。除了使我们能够确定ES-62的抗炎特性是否如预测的那样在分子水平上影响衰老过程外，这种策略还可以使我们验证衰老的新生物标志物，甚至是潜在的治疗干预部位。关于后者，我们在我们对过敏和自身免疫模型的研究中生产了ES-62的合成药物样小分子类似物（SMA），以期将其用作这些疾病的新药开发的起点。因此，尽管目前的应用程序旨在增加对衰老生物学的理解，而不是药物开发，但我们将在项目的最后一年使用其中一种SMA进行小型试验，以期提交未来的拨款申请，以获得影响资金，用于开发潜在的治疗方法。

The introduction of vaccines and drugs to control disease, in combination with greater access to food and improved sanitation, means that people are now living much longer. Currently this increase is staggering, equating to an extra 2.5 years of life per decade. However, improved life expectancy itself amounts to a huge new problem, in that it is not being accompanied by a similar increase in health and wellbeing. This reflects both that like a mechanical machine such as a car engine, the ageing process is naturally associated with a loss of function of its systems due to "wear and tear", but also that improved wealth has resulted in a modern Western life-style, incorporating a high fat diet (HFD) that contributes to age-associated ailments such as type-2 diabetes (T2D), stroke and heart disease. This impact of increased lifespan presenting with associated ill-health has enormous socio-economic implications due to its increasingly global scale, arguing for a need to better understand the process of ageing in the context of health.Approximately one quarter of the world's population is infected with parasitic worms. Of interest, several recent reports indicate that such infections offer protection against development of conditions such as obesity, cardiovascular disease and T2D in mouse models and that similar protection may also be seen in humans. We have been studying one individual parasitic worm component - ES-62, isolated from the secretory products of the filarial nematode, Acanthocheilonema viteae, and consistent with these studies, ES-62 is highly effective in reducing the cardiovascular disease that arises in a highly susceptible strain of mouse, particularly in response to a high fat diet. Moreover, we have some preliminary data showing that ES-62 may offer some protection against development of the obesity that is associated with development of T2D. Our studies to date with ES-62 also show it to be effective in inhibiting the development of disease in mouse models of allergy, rheumatoid arthritis and systemic lupus erythematosus. What all of these diseases have in common with cardiovascular disease and T2D is the increasing realization that they are associated with unwanted inflammation. This immediately offers an explanation for ES-62's protective effects, as the parasitic worm-derived molecule possesses a range of anti-inflammatory properties. Furthermore, as ageing is also now being considered as a biological problem in the setting of chronic low-grade inflammation, this raises the possibility of investigating the effect of ES-62 on the ageing process and late-life health and well being (healthspan). Thus, we specifically plan to determine whether ES-62 can slow ageing and improve healthspan using a paradigm where mice will be fed on a high fat diet +/- ES-62. We will use this model to assess the effect of ES-62 treatment on ageing in the context of promotion of gene signatures and signalling pathways known to be associated with ageing/inflammation versus those associated with longevity and healthspan. In addition to enabling us to establish whether ES-62's anti-inflammatory properties are impacting on the ageing process at the molecular level as predicted, this strategy might allow us to validate novel biomarkers for ageing and even potential sites of therapeutic intervention. With respect to the latter, we have produced synthetic drug-like small molecule analogues (SMAs) of ES-62 during our work on the allergy and autoimmunity models, with a view to using these as a starting point in novel drug development for these conditions. Thus, although the current application is designed to increase understanding of the biology of ageing rather than drug development, we will conduct a small trial with one of these SMAs towards the final year of the project with a view to submitting future grant applications for impact funding for their development as potential therapies.