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How Babraham Institute's study of nematode worms can help us understand human ageing

By Paul Brackley

It is a tiny worm that lives only for two or three weeks.

Caenorhabditis elegans, a free-living, transparent nematode (roundworm), about 1 mm in length. Green: neurons; red: digestive tract; yellow: bacteria. (7222368)
Caenorhabditis elegans, a free-living, transparent nematode (roundworm), about 1 mm in length. Green: neurons; red: digestive tract; yellow: bacteria. (7222368)

But Caenorhabditis elegans - a 1mm long transparent nematode - can help us learn about the process of human ageing.

Now international research led by the Babraham Institute has developed the best model for doing so, and used it to understand more about the link between ageing and metabolism.

Life is fuelled by metabolism, which is the processes involved in converting food to energy for cellular functions and the supply of building blocks for an organism.

Many of the genes that extend lifespan are known to do so by altering the flow of energy and signals in cells and across tissues.

We share many of the core metabolic pathways with C. elegans and many of the genetic influences on the lifespan of worms have been found to do the same in humans.

But researchers have faced a number of challenges. For example, chemical interventions used to prevent the worms having progeny have been shown to impact metabolism.

C.elegans (7222366)
C.elegans (7222366)

Janna Hastings, a PhD student at the Babraham Institute, explains: “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.

“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.”

Janna works in the Casanueva lab, which uses C. elegans to understand how metabolism changes during ageing and how interventions that alter metabolic fluxes can extend the length and quality of life.

Dr Olivia Casanueva, group leader in the epigenetics programme at the Babraham Institute, says: “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.”

The researchers reoptimised the modelling tool using data from multi-omic sources - both transcriptomics and metabolomics - so that they could study metabolic fluxes during ageing.

They validated the model by studying ageing worms, identifying a number of metabolites that change with age and a drop in mitochondrial function.

Caenorhabditis elegans, a free-living transparent nematode (roundworm), about 1mm in length. (7222370)
Caenorhabditis elegans, a free-living transparent nematode (roundworm), about 1mm in length. (7222370)

Mitochondria are the cell battery packs and their declining function in older humans could be key to ageing and many age-related diseases, such as Alzheimer’s.

The researchers explored whether their newly-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,” says 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 per cent.

“This reoptimisation 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.”

The work has published across a number of papers, the latest of which is in Frontiers in Molecular Biosciences.

“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,” says Dr Casanueva.

Read more

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