The power of microbes: C. elegans as a model to identify microbiome effects on age-related muscle function

医疗保健和营养的改善意味着我们现在比以往任何时候都活得更长，但随着老龄化而来的是虚弱和生理功能的恶化，这给全球社会和医疗体系带来了沉重的负担。目前的大流行突显了老龄化期间健康和韧性的重要性，以及改善晚年健康的紧迫性。肠道微生物会影响我们衰老的方式吗？促进健康老龄化的一个非常有希望但基本上未被探索的途径是肠道微生物群，即我们肠道中的微生物群落。一系列研究将微生物群与宿主衰老联系起来。健康的肠道微生物群的特点是细菌分类多样性，但在老化过程中微生物群的组成发生变化，导致多样性减少，致病细菌种类扩大，微生物功能改变。人类的年龄和虚弱与某些物种/属有关，而百岁老人的微生物群与年轻人的微生物群更相似。在模式生物体(线虫、果蝇、千里鱼、老鼠)中的研究，包括使用粪便移植和细菌的遗传操作，表明微生物群是宿主老化的直接原因。考虑到这些物种之间的进化距离，这些研究表明微生物群也影响人类的衰老。最近，令人兴奋的研究表明，微生物群影响肌肉功能和身体表现，但其潜在的机制在很大程度上是未知的。我们研究的目的是确定宿主与其微生物群之间的分子相互作用，这些微生物群对肌肉衰老的影响，长期目标是找到改善老年人身体功能的方法。c.优雅-一个理想的模型组织为了研究衰老过程中宿主与微生物群的相互作用，我们使用了一个简单易处理的模型系统，秀丽线虫。线虫有许多优势：种植成本低，基因适应性强，与人类有许多共同的基因，寿命短，能够进行高通量研究。重要的是，很容易给这些动物绝育，并用选择的微生物在它们的肠道上定居。线虫在发现保守的衰老机制方面起到了至关重要的作用，彻底改变了我们对衰老的理解。最近备受瞩目的研究表明，线虫中的宿主-微生物组相互作用也通过保守的途径发挥作用，我们预计未来几年宿主-微生物组相互作用的基础的许多重大发现将来自简单的模型。现在有机会扩大线虫的使用，以提高我们对宿主-微生物组相互作用的理解。了解影响衰老的宿主-微生物群相互作用最近，野生线虫的自然微生物群在实验室中被分离和培养，使研究一个易处理的模型与其自然共生体之间的相互作用成为可能。我的团队已经建立了一个简化的自然微生物组，由11个来自线虫自然微生物组的代表性细菌物种组成，使我们能够研究自然宿主-微生物组的相互作用。使用这个系统，我们发现微生物组抑制了与年龄相关的线虫活力下降，相对于在标准实验室条件下生长的动物。我们发现，微生物群改变了肌肉中细胞的动力源线粒体，并通过免疫系统影响与年龄相关的运动性。这些结果表明，微生物组通过线粒体和免疫信号影响肌肉功能。本项目的目标是了解微生物组对年龄相关运动的潜在分子机制，并努力寻找创新的方法，利用微生物组来改善老年人的健康和生活质量。

Improvements in healthcare and nutrition mean that we now live longer than ever before, but with ageing comes frailty and deterioration of physiological functions, leading to large burdens for societies and healthcare systems globally. The current pandemic highlights the importance of health and resilience during ageing and the urgency of improving late-life health. DO GUT MICROBES AFFECT THE WAY WE AGE? One very promising but largely unexplored avenue to promote healthy ageing is the gut microbiome, the community of microbes in our guts. A series of studies link the microbiome to host ageing. Healthy gut microbiomes are characterised by bacterial taxonomic diversity, but during ageing the composition of the microbiome changes, resulting in decreased diversity, expansion of pathogenic bacterial species and alterations in microbial functions. Human age and frailty are associated with certain species/genera while the microbiomes of centenarians are more similar to those of young adults. Work in model organisms (C. elegans, Drosophila, killifish, mice), including the use of faecal transplants and genetic manipulation of bacteria, show that the microbiome is a direct cause of host ageing. Considering the evolutionary distance between these species, these studies suggest the microbiome also affects human ageing. Recently, exciting studies have shown that the microbiome affects muscle function and physical performance, but the underlying mechanisms are largely unknown. The aim of our study is to determine the molecular interactions between the host and its microbiome underlying the microbiome effects on muscle ageing, with the long term goal of finding ways to improve physical function in the elderly.C. ELEGANS - AN IDEAL MODEL ORGANISMTo study host-microbiome interactions during ageing we are using a simple and tractable model system, C. elegans. C. elegans offers many advantages; it is cheap to grow, genetically amenable, shares many of its genes with humans, is short-lived and enables high-throughput research. Importantly, it is easy to sterilise these animals and colonise their guts with microbes of choice. C. elegans has been crucial in the discovery of conserved ageing mechanisms, revolutionising our understanding of ageing. Recent high-profile studies show that host-microbiome interactions in C. elegans also act through conserved pathways, and we anticipate that many major discoveries of the fundamentals of host-microbiome interactions in the coming years will come from simple models. There is now an opportunity to expand the use of C. elegans to improve our understanding of host-microbiome interactions. UNDERSTANDING THE HOST-MICROBIOME INTERACTIONS AFFECTING AGEINGRecently, the natural microbiome of wild C. elegans was isolated and cultivated in the lab, enabling the study of interactions between a tractable model and its natural commensals. My group has established a simplified natural microbiome consisting of 11 representative bacterial species from the natural microbiome of C. elegans, allowing us to study natural host-microbiome interactions. Using this system, we find that the microbiome suppresses age-related decline in motility in C. elegans relative to animals grown in standard laboratory conditions. We find that the microbiome alters the mitochondria, the cells' powerhouses, in muscle and affects age-related motility through the immune system. These results suggest that the microbiome affects muscle function through the mitochondria and immune signalling.The goal of this project is to understand the molecular mechanisms underlying microbiome effects on age-related motility, and to work towards innovative ways to use the microbiome to improve health and quality of life for ageing people.