The power of microbes: C. elegans as a model to identify microbiome effects on age-related muscle function
Lead Research Organisation:
University of Kent
Department Name: Sch of Biosciences
Abstract
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 ORGANISM
To 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 AGEING
Recently, 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.
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 ORGANISM
To 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 AGEING
Recently, 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.
Technical Summary
Age-related decline is a major global challenge, and interventions that result in healthy ageing are in urgent need. New findings show that the gut microbiome affects ageing, and that the microbiome could be used to develop interventions to improve ageing, but the underlying mechanisms however are not understood. Our aim is to use a tractable model system to define molecular host-microbiome interactions underlying age-related health.
I have established a model consisting of C. elegans and a simplified microbiome based on the natural C. elegans microbiota, offering an opportunity to study how microbial species and molecules affect host ageing. This simplified microbiome has dramatic effects on motility and suppresses age-related motility decline. It also affects immunity and muscular mitochondrial network dynamics, suggesting routes of communication whereby gut microbes communicate through immunity and mitochondria to alter muscle function and metabolism. Moreover, extracellular molecules from the simplified microbiome suppress age-related amyloid aggregation toxicity in C. elegans muscle, and suppress amyloid aggregation in vitro, suggesting that molecules produced by the bacteria affect muscle proteostasis.
Our aim is to gain mechanistic understanding of host-microbiome interactions. We will address the following questions:
1. What are the effects of the microbiome on muscle function and muscle ageing?
2. What are the effects of the microbiome on mitochondrial function and mitochondrial signalling?
3. Which are the chemical signals by which the microbes alter host ageing?
We will advance the understanding of how molecular host-microbiome interactions affect healthspan, and work with collaborators to establish evolutionary conservation of our findings in other models and evaluate their translational potential.
I have established a model consisting of C. elegans and a simplified microbiome based on the natural C. elegans microbiota, offering an opportunity to study how microbial species and molecules affect host ageing. This simplified microbiome has dramatic effects on motility and suppresses age-related motility decline. It also affects immunity and muscular mitochondrial network dynamics, suggesting routes of communication whereby gut microbes communicate through immunity and mitochondria to alter muscle function and metabolism. Moreover, extracellular molecules from the simplified microbiome suppress age-related amyloid aggregation toxicity in C. elegans muscle, and suppress amyloid aggregation in vitro, suggesting that molecules produced by the bacteria affect muscle proteostasis.
Our aim is to gain mechanistic understanding of host-microbiome interactions. We will address the following questions:
1. What are the effects of the microbiome on muscle function and muscle ageing?
2. What are the effects of the microbiome on mitochondrial function and mitochondrial signalling?
3. Which are the chemical signals by which the microbes alter host ageing?
We will advance the understanding of how molecular host-microbiome interactions affect healthspan, and work with collaborators to establish evolutionary conservation of our findings in other models and evaluate their translational potential.
Organisations
People |
ORCID iD |
Marina Ezcurra (Principal Investigator) |
Publications
Hilton KLF
(2023)
Controlling the structure of supramolecular fibre formation for benzothiazole based hydrogels with antimicrobial activity against methicillin resistant Staphylococcus aureus.
in Journal of materials chemistry. B
Kern C
(2023)
C. elegans ageing is accelerated by a self-destructive reproductive programme
in Nature Communications
Description | UPCYCLED FOODS: GETTING THE GOODNESS OUT OF KENT CHERRIES |
Amount | £319,000 (GBP) |
Funding ID | 10027661 |
Organisation | Innovate UK |
Sector | Public |
Country | United Kingdom |
Start | 05/2022 |
End | 10/2023 |
Description | Waste wine and superfoods |
Amount | £80,000 (GBP) |
Organisation | University of Kent |
Sector | Academic/University |
Country | United Kingdom |
Start | 09/2023 |
End | 09/2026 |
Description | Dialogue with policy makers: MP Chris Skidmore |
Form Of Engagement Activity | A formal working group, expert panel or dialogue |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Policymakers/politicians |
Results and Impact | We and other researchers hosted RT Hon Chris Skidmore MP and discussed research relevant to the net zero review. |
Year(s) Of Engagement Activity | 2022 |
Description | Expert evidence for All Party Parliamentary Group on the Microbiome |
Form Of Engagement Activity | A formal working group, expert panel or dialogue |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Policymakers/politicians |
Results and Impact | Invited to witness as expert for the APPG Microbiome in Westminster. 5 MPs/Lords attended. |
Year(s) Of Engagement Activity | 2022 |
Description | Interview with BBC Politics South East |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Media (as a channel to the public) |
Results and Impact | Interview and filming with BBC crew and journalists on the topic of ageing research. |
Year(s) Of Engagement Activity | 2023 |
URL | https://www.bbc.co.uk/iplayer/episode/m001jpyb/politics-south-east-26022023 |
Description | Media coverage by ITV Meridian |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Media (as a channel to the public) |
Results and Impact | Media crew from ITV Meridian filmed and interviewed the research team on research related to healthy ageing. |
Year(s) Of Engagement Activity | 2022 |
URL | https://www.youtube.com/watch?v=LjSysmr0moQ |