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

微生物的力量：线虫作为模型来识别微生物组对与年龄相关的肌肉功能的影响

• 批准号: BB/V011243/1
• 负责人: Marina Ezcurra
• 金额: $ 50.52万
• 依托单位: University of Kent
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FV011243%2F1
• 关键词: power; microbes; C.; elegans; model

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.

医疗保健和营养的改善意味着我们现在的寿命比以往任何时候都长，但随着衰老，生理功能的脆弱和恶化，给全球社会和医疗保健系统带来了巨大的负担。当前的大流行突出了老龄化期间健康和复原力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探索的途径是肠道微生物组，即我们肠道中的微生物群落。一系列研究将微生物组与宿主衰老联系起来。健康的肠道微生物组以细菌分类多样性为特征，但在衰老过程中，微生物组的组成发生变化，导致多样性降低，病原菌种类扩大和微生物功能改变。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组与年轻人的微生物组更相似。在模式生物中的工作（C。线虫、果蝇、鳉鱼、小鼠），包括使用粪便移植和细菌遗传操作，表明微生物组是宿主衰老的直接原因。考虑到这些物种之间的进化距离，这些研究表明微生物组也会影响人类衰老。最近，令人兴奋的研究表明，微生物组会影响肌肉功能和身体表现，但其潜在机制在很大程度上尚不清楚。我们研究的目的是确定宿主及其微生物组之间的分子相互作用，这些分子相互作用是微生物组对肌肉衰老的影响的基础，长期目标是找到改善老年人身体功能的方法。为了研究衰老过程中宿主-微生物组的相互作用，我们使用了一个简单易行的模型系统，C。优雅的C.秀丽隐杆线虫有许多优点，它的种植成本低，易于遗传，与人类共享许多基因，寿命短，能够进行高通量研究。重要的是，很容易对这些动物进行绝育，并在它们的肠道中定植所选的微生物。C.线虫在发现保守的衰老机制方面至关重要，彻底改变了我们对衰老的理解。最近的高调研究表明，在C。线虫也通过保守的途径发挥作用，我们预计，在未来几年中，宿主-微生物组相互作用的基本原理的许多重大发现将来自简单的模型。现在有机会扩大C的使用。elegans来提高我们对宿主-微生物组相互作用的理解。了解影响衰老的宿主-微生物相互作用最近，野生C。在实验室中分离并培养了秀丽线虫，使得能够研究易于处理的模型与其天然宿主之间的相互作用。我的团队已经建立了一个简化的天然微生物组，由来自C. elegans，使我们能够研究自然宿主-微生物组相互作用。使用这个系统，我们发现微生物组抑制了C.相对于在标准实验室条件下生长的动物，我们发现微生物组改变了肌肉中的线粒体，细胞的动力，并通过免疫系统影响与年龄相关的运动。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。该项目的目标是了解微生物组影响与年龄相关的运动的分子机制，并致力于创新方法，利用微生物组改善老年人的健康和生活质量。

项目成果

C. elegans ageing is accelerated by a self-destructive reproductive programme.

• DOI: 10.1038/s41467-023-40088-1
• 发表时间: 2023-07-20
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Kern, Carina C.;Srivastava, Shivangi;Ezcurra, Marina;Hsiung, Kuei Ching;Hui, Nancy;Townsend, StJohn;Maczik, Dominik;Zhang, Bruce;Tse, Victoria;Konstantellos, Viktoras;Bahler, Juerg;Gems, David
• 通讯作者: Gems, David