The parasitic worm product ES-62 promotes health- and life-span in a high calorie diet-accelerated mouse model of ageing
The parasitic worm product ES-62 promotes health- and life-span in a high calorie diet-accelerated mouse model of ageing
复制标题
DOI：
10.1371/journal.ppat.1008391
复制
发表时间：
2020-03-01
期刊：
影响因子：
6.7
通讯作者：
Harnett, Margaret M.
中科院分区：
文献类型：
--
作者：
Crowe, Jenny;Lumb, Felicity E.;Harnett, Margaret M.
寄生虫蠕虫越来越多地被认为可以预防慢性炎症性疾病，包括肥胖、2型糖尿病和心血管疾病。虽然以前与老年有关，但由于全球采用“西方”生活方式和高热量饮食（HCD;高糖高脂），这些疾病甚至在年轻人中也更加普遍。我们的方法不是开发活蠕虫疗法，而是专注于ES-62的潜力，ES-62是一种由寄生虫Acanthocheilonema viteae分泌的分子，我们以前已经证明可以防止小鼠过敏性哮喘和关节炎等炎症。我们发现，每周小剂量的ES-62促进了两种性别的HCD喂养小鼠的晚年健康，并大大延长了肥胖雄性小鼠的寿命（超过70天; >10%）。机器学习建模其对支持肥胖的复杂免疫代谢网络的影响表明，ES-62的健康促进作用不能简单地通过其抗炎作用来解释，而是包括对脂肪，肝脏和肠道病理的保护。因此，所确定的目标特征可能代表了开发基于ES-62的新方法以改善衰老期间的健康和延长人类寿命的起点。在过去50年中，卫生和健康管理的改善推动了人类寿命的显着增加。然而，令人沮丧的是，这种寿命的延长并没有与晚年健康的同等改善相匹配，尤其是由于2型糖尿病，肥胖和心血管疾病的全球流行，所有与衰老相关的疾病都因广泛采用高热量西方饮食而加剧和加速。最近，已经开始出现的证据表明，寄生虫感染可能会防止这种与年龄相关的合并症，作为其促生存，抗炎机制进化的偶然副作用。因此，作为一种新的治疗策略，我们研究了ES-62的潜力，ES-62是丝虫Acanthocheilonema viteae的抗炎分泌产物，通过靶向慢性炎症来改善健康寿命（衰老疾病出现之前的生命期），慢性炎症驱动代谢失调，从而导致衰老引起的健康状况不佳。我们给C57 BL/6 J小鼠皮下注射ES-62（剂量为1 μ g/周），使其在整个寿命期内经历HCD加速老化，同时在不同时间点对动物进行120次免疫代谢反应分析。ES-62改善了许多炎症参数，但值得注意的是，一系列衰老的病理生理学、代谢和微生物组参数也被成功靶向。值得注意的是，ES-62介导的促进雄性和雌性HCD小鼠的健康寿命与不同的机制相关，并且反映了这一点，机器学习建模确定了预测ES-62对抗HCD加速衰老的作用的性别特异性特征。值得注意的是，ES-62显著增加了雄性HCD小鼠的中位存活率。雌性动物的情况并非如此，出乎意料的是，两性之间的这种差异不能用抑制慢性炎症驱动衰老来解释，因为ES-62在减少雌性小鼠中的这种情况方面往往更有效。相反，这种差异似乎与ES-62在雄性动物中优先促进更健康的肠道代谢组织轴的额外能力有关。
Author summaryInfection with parasitic worms is increasingly considered to protect against chronic inflammatory disorders, including obesity, type-2 diabetes and cardiovascular disease. Although previously associated with old age, these ailments are ever more prevalent even in young people, due to the global adoption of the "Western" lifestyle and high calorie diet (HCD; high sugar and high fat). Rather than developing live worm therapies, our approach focuses on the potential of ES-62, a molecule secreted by the parasitic worm Acanthocheilonema viteae that we have previously shown to protect against inflammatory conditions like allergic asthma and arthritis in mice. We found that a small weekly dose of ES-62 promoted late-life wellbeing in HCD-fed mice of both sexes and substantially extended the life of obese male mice (by over 70 days; >10%). Machine learning modelling of its impact on the complex immunometabolic networks underpinning obesity showed that health-promoting effects of ES-62 could not simply be explained by its anti-inflammatory actions but encompassed protection against adipose, liver and gut pathology. The target signatures identified may thus represent a starting point for developing novel ES-62-based approaches to improving health during ageing and increasing lifespan in humans.Improvements in hygiene and health management have driven significant increases in human lifespan over the last 50 years. Frustratingly however, this extension of lifespan has not been matched by equivalent improvements in late-life health, not least due to the global pandemic in type-2 diabetes, obesity and cardiovascular disease, all ageing-associated conditions exacerbated and accelerated by widespread adoption of the high calorie Western diet (HCD). Recently, evidence has begun to emerge that parasitic worm infection might protect against such ageing-associated co-morbidities, as a serendipitous side-effect of their evolution of pro-survival, anti-inflammatory mechanisms. As a novel therapeutic strategy, we have therefore investigated the potential of ES-62, an anti-inflammatory secreted product of the filarial nematode Acanthocheilonema viteae, to improve healthspan (the period of life before diseases of ageing appear) by targeting the chronic inflammation that drives metabolic dysregulation underpinning ageing-induced ill-health. We administered ES-62 subcutaneously (at a dose of 1 mu g/week) to C57BL/6J mice undergoing HCD-accelerated ageing throughout their lifespan, while subjecting the animals to analysis of 120 immunometabolic responses at various time-points. ES-62 improved a number of inflammatory parameters, but markedly, a range of pathophysiological, metabolic and microbiome parameters of ageing were also successfully targeted. Notably, ES-62-mediated promotion of healthspan in male and female HCD-mice was associated with different mechanisms and reflecting this, machine learning modelling identified sex-specific signatures predictive of ES-62 action against HCD-accelerated ageing. Remarkably, ES-62 substantially increased the median survival of male HCD-mice. This was not the case with female animals and unexpectedly, this difference between the two sexes could not be explained in terms of suppression of the chronic inflammation driving ageing, as ES-62 tended to be more effective in reducing this in female mice. Rather, the difference appeared to be associated with ES-62's additional ability to preferentially promote a healthier gut-metabolic tissue axis in male animals.