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 μg/week) to C57BL/6 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 markers, 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.

过去 50 年来，卫生和健康管理的改进推动了人类寿命的显着延长。然而令人沮丧的是，寿命的延长并没有伴随晚年健康的同等改善，尤其是由于2型糖尿病、肥胖和心血管疾病在全球流行，所有与衰老相关的疾病都因广泛采用高热量西方饮食（HCD）。最近，有证据表明，寄生虫感染可能可以预防此类与衰老相关的并发症，这是其促生存、抗炎机制进化的偶然副作用。因此，作为一种新颖的治疗策略，我们研究了 ES-62（一种丝虫线虫Acanthocheilonema viteae的抗炎分泌产物）通过针对慢性炎症来改善健康寿命（衰老疾病出现之前的生命周期）的潜力。导致代谢失调，导致衰老引起的健康不良。我们对在整个生命周期中经历 HCD 加速衰老的 C57BL/6 小鼠皮下注射 ES-62（剂量为 1 μg/周），同时对动物在不同时间点进行 120 种免疫代谢反应分析。 ES-62 改善了许多炎症标志物，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 介导的雄性和雌性 HCD 小鼠健康寿命的促进与不同的机制相关，并反映了这一点，机器学习模型确定了预测 ES-62 对抗 HCD 加速衰老作用的性别特异性特征。 值得注意的是，ES-62 显着增加了雄性 HCD 小鼠的中位生存期。雌性动物的情况并非如此，而且出乎意料的是，两种性别之间的这种差异无法用抑制导致衰老的慢性炎症来解释，因为 ES-62 在雌性小鼠中往往更有效地减少这种炎症。相反，这种差异似乎与 ES-62 优先促进雄性动物肠道代谢组织轴更健康的额外能力有关。