What can worms tell us about human ageing? A lot more than you’d think; as research led by the Babraham Institute but involving researchers from multiple disciplines drawn together from across the world has shown. In a cluster of papers, the latest of which is published today in Frontiers in Molecular Biosciences, the researchers describe how a collaborative effort has developed a single agreed model of metabolic flux in a tiny worm called C. elegans, and how Babraham Institute researchers have used this model to understand more about the link between metabolism and ageing.
Metabolism fuels life; converting food to energy for cellular processes and ensuring a supply of building blocks to meet the organism’s needs. Importantly, metabolism plays a key role in modulating longevity, as many of the genes that are known to extend lifespan do so by altering the flow of energy and signals in cells and across tissues. There is demonstration of this relationship shown by the influence of diet and severe calorie restriction on lifespan in many organisms, including humans.
C. elegans is one of the best model organisms to investigate the process of ageing because of its short lifespan (2-3 weeks) and readily available genetic tools. It also shares many of its core metabolic pathways with humans and many of the key genetic players in determining the lifespan of worms have been found to do the same in humans.
“One major barrier for fully exploiting the potential of C. elegans as a research tool was the lack of a model uniting everything that was known about C. elegans metabolism,” says Janna Hastings, a PhD student in the Casanueva lab at the Babraham Institute. “To overcome this, we initiated a global team effort to reconcile existing and conflicting information on metabolic pathways in C. elegans into a single community-agreed model and launched the resulting WormJam resource in 2017.”
The Casanueva lab at the Babraham Institute use C. elegans to understand how metabolism changes during the normal course of ageing and how a variety of interventions that change metabolic fluxes can extend the length and quality of life. Physical changes evident in ageing worms point towards the loss of central metabolic capabilities as the worms age. The developed metabolic model was valuable to their research but had one key limitation; it best reflected what was happening during the growing phase of C.elegans, not the ageing phase.
“One of the key challenges that we face when studying ageing is that the modelling tools available are optimised for animals or cells that are in the process of growing, which is not happening in aged animals,” explains Dr Olivia Casanueva, group leader in the Epigenetics programme at the Babraham Institute.
Confronted with this challenge, the researchers re-optimised the modelling tool using data from multi-omic sources (both transcriptomics and metabolomics) and were able to adapt the tool to study metabolic fluxes during ageing.
The relevance of the model to understanding the metabolic changes that occur during ageing was validated in the lab by studying ageing worms. The research identified a number of metabolites that significantly change with age and revealed a drop in mitochondrial function with age.
Mitochondria are the powerhouse of energy production in the cell and their declining function in older humans may be central to ageing and many age-related diseases such as Alzheimer’s. The researchers asked whether the new optimised tools could predict which metabolites produced by the mitochondria might be most affected by age.
“The model prediction was quite accurate, as it predicted that Oxaloacetate, a key resource for the production of energy, was becoming limiting in aged worms,” said Dr Casanueva. "We know that of all metabolites that can be supplemented to the food source for ageing worms, Oxaloacetate is the one metabolite that produces the most robust effect - extending lifespan by up to 20%.”
So, what can worms tell us about human ageing? A lot more now, thanks to the WormJam model and the subsequent development to adapt this for ageing studies.
“This re-optimisation of the model for ageing animals represents a significant technical advance for the field and will allow more accurate predictions of metabolic fluxes during the course of ageing,” concludes Dr Casanueva. “By developing our understanding of the experimental model of ageing, we can gain valuable insight into what’s happening in humans – taking a step towards achieving healthier ageing.”
Hastings et al. Multi-omics and genome-scale modeling reveal a metabolic shift during C. elegans aging. Frontiers in Molecular Biosciences. DOI: 10.3389/fmolb.2019.00002
Witting et al. The WormJam Consensus Model as Basis for Metabolic Studies in the Model Organism Caenorhabditis elegans. Frontiers in Molecular Biosciences (2018)
Hastings*, Suriyalakash* & Casanueva. Flow with the flux: how systems biology tools predict novel metabolic drivers of ageing in C. elegans Current Opinion in Systems Biology (* first authors).
This work was supported by funding from the ERC, the BBSRC and a MRC UKRI Rutherford Fund Fellowship to Abraham Mains.
The WormJam community project was funded by the EU GENiE COST action and received support from the Babraham Institute's BBSRC Knowledge Exchange and Commercialisation grant.
Dr Louisa Wood, Institute Communications Manager, firstname.lastname@example.org, 01223 496230
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Image description:C. elegans worms labelled with a fluorescent protein and imaged using a confocal microscope. The image shows worms that are genetically identical but that exhibit inter-individual variability in stress response gene expression. Credit: Dr Laetitia Chauve, Babraham Institute.
Affiliated authors (in author order):
Janna Hastings, PhD student, Casanueva group
Abraham Mains, PhD student, Casanueva group
Bhupinder Virk, postdoctoral researcher, Casanueva group
Nicolas Rodriguez, senior technical support, SysBio group
Sharlene Murdoch, senior research assistant, Casanueva group
Juliette Pierce, PhD student, Reik group
Olivia Casanueva, group leader, Epigenetics research programme
Animal research statement:
As a publicly funded research institute, the Babraham Institute is committed to engagement and transparency in all aspects of its research. The research described here used nematode worms called Caenorhabditis elegans (shortened to C. elegans) which is used as a model organism by researchers to understand human development and disease. The use of C. elegans in research is one of the ways by which we aim to reduce the numbers of animals we use in research.
Please follow the link to find out more about ways we work to meet the 3Rs principles: reduction, refinement and replacement in our research and when using animals in research.
About the Babraham Institute
The Babraham Institute undertakes world-class life sciences research to generate new knowledge of biological mechanisms underpinning ageing, development and the maintenance of health. Our research focuses on cellular signalling, gene regulation and the impact of epigenetic regulation at different stages of life. By determining how the body reacts to dietary and environmental stimuli and manages microbial and viral interactions, we aim to improve wellbeing and support healthier ageing. The Institute is strategically funded by the Biotechnology and Biological Sciences Research Council (BBSRC), part of UK Research and Innovation, through an Institute Core Capability Grant and also receives funding from other UK research councils, charitable foundations, the EU and medical charities.
06 February 2019