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A short introduction to worms in ageing research

What are C. elegans?

Caenorhabditis elegans is a type of nematode, or roundworm, commonly used in biological research. They are small, about 1mm long, made up of almost 1,000 cells, transparent, and are found primarily in the soil on rotting fruit but they can also survive in liquid. The use of C. elegans in research took off after Sydney Brenner began using them in neurobiology studies in the 1960s, their simplicity suited scientific research, and they could be kept in vast quantities. Despite their simplicity, they share many biological characteristics with more complex organisms, including humans.  Their transparent and simple body plans in combination with their well-mapped genetics make them ideal for studying fundamental biological processes.

What is a worm lifecycle like and how does ageing work in C. elegans?

The lifecycle of C. elegans is straightforward and short, typically lasting around 2-3 weeks and is split into three main stages:

1. Embryo: Development begins from a fertilised egg.
2. Larval stages: There are four larval stages (which researchers refer to as L1, L2, L3, and L4), each lasting around 12 hours under optimal conditions. However, under adverse conditions such as overcrowding, limited food and high temperature the worms can exit their normal developmental pathway into a stage called ‘Dauer’ where they can live for several months! When the food supply increases or the population density decreases they can exit this ‘paused’ stage and continue their development.
3. Adult: After the final molt, where the old cuticle detaches at the end of the L4 stage, the worms become adults capable of reproduction. The adult stage accounts for the rest of their lifetime.

Once C. elegans reach adulthood they start to exhibit many different signs of ageing that are also observed in other organisms, such as reduced movement, fertility decline, and increased susceptibility to stress. Studying their ageing process helps us to try and decipher the basic mechanisms of aging that might be conserved across species.

Why are worms used in research?

Worms like C. elegans are used in research for several reasons:

• Genetic simplicity: They have a simple genome with around 20,000 genes, many of which have human equivalents and fully grown adults have exactly 959 cells.
• Transparency: Their transparent bodies allow easy observation of internal processes.
• Rapid lifecycle: Their short lifecycle allows for quick generation turnover and rapid experiments.
• Well-mapped nervous system: All 302 neurons in C. elegans are well-mapped, aiding neuroscience studies.
• Ease of cultivation: They are easy and inexpensive to maintain in a laboratory setting.
• Hermaphrodites: The worms exist mainly as hermaphrodites meaning they self-fertilise and are genetically identical. However, putting adults into a high temperature environment causes them to produce males. The worms are kept on plates of agar and eat E. coli.

[1] There have been three Nobel Prizes which used C. elegans:

1. In 2002, the Nobel Prize in Physiology or Medicine was awarded to Sydney Brenner,  Robert Horvitz, and John Sulston for their work on the genetics of organ development and programmed cell death in C. elegans.
2. The 2006 Nobel Prize in Physiology or Medicine was awarded to Andrew Fire and Craig Mello for their discovery of RNA interference in C. elegans.
3. In 2008, Martin Chalfie shared a Nobel Prize in Chemistry for his work on green fluorescent protein which is widely used in microscopy today; some of the research involved the use of C. elegans.

How similar are worms and humans?

While humans and worms appear very different, they share many genetic and biochemical pathways. Approximately 40% of C. elegans genes have human equivalents, making them a valuable model for studying human biology and disease. Their simplicity allows researchers to manipulate genes and observe outcomes that can provide insights into human genetics and development. It is important to study things in the context of whole organisms to see the effects in other parts of the body, as tissues are intricately linked together to allow an organism to function.

What are the limitations of using C. elegans in ageing studies? How are they overcome?

While C. elegans are a powerful tool for ageing research, as with all model systems they have limitations. These limitations stem from their relative simplicity. C. elegans lack many organs and systems present in humans, such as respiratory and circulatory systems. Additionally, some physiological processes and environmental responses differ between worms and humans, potentially limiting the direct application of findings to human ageing. However, different strategies have been developed to overcome these limitations. One approach is to use C. elegans alongside human cells or more complex models like mice. This complementary approach allows findings to be cross-validated. Additionally, the advantage of studying C. elegans lies in the availability of a plethora of different advanced genetic tools. These tools allow for detailed study of specific genes, including human genes, which can then be examined in more complex organisms. Finally, focusing on fundamental ageing processes offers valuable insights as many of these processes are conserved across species, meaning studying them in worms can provide a strong foundation for understanding human ageing.

Why can’t we just use cells?

While cultured cells are useful for many types of research, they lack the complexity of a whole organism. C. elegans provide a middle ground between cell cultures and more complex animal models, allowing for the study of:

• Development: How a complete organism grows and develops from a single cell.
• System interactions: How different biological systems interact within an organism.
• Behaviour: Observing how genetic changes affect behaviour, which isn't possible with isolated cells.

Despite their simplicity, they provide critical insights that are often applicable to more complex organisms, including humans. In summary, C. elegans are a powerful model organism that has significantly advanced our understanding of biology.

What have we learnt from worms already that is relevant to studying ageing-related diseases?

So far, a lot of different fascinating discoveries have been made using C. elegans. They have been used to identify genes and pathways that influence lifespan, like the insulin pathway, where tweaking a single gene in C. elegans can double their life! This research offers clues for potential future interventions in humans. C. elegans studies have also shed light on how proteins malfunction in diseases like Alzheimer’s and Parkinson's, and how cells naturally die off, a process important for understanding cancer. They can also be used in special machines that test thousands of potential drugs at once, helping scientists quickly identify promising candidates for treating ageing and related diseases and evaluate their toxicity.

What are researchers at the Babraham Institute studying by using worms?

I am doing my PhD in Della David’s group which is so far the only C. elegans group at the Babraham Institute. The ultimate goal of the lab is to discover mechanisms to promote healthy ageing and alleviate age-related diseases. We aim to understand the molecular basis of ageing by focusing on a pathological adaptation to ageing, namely protein aggregation, or clumps of protein that can cause damage to a cell. Our research in C. elegans reveals that protein aggregates contribute to the decline in muscle function with age. Therefore, identifying ways to keep proteins in their correct shape will likely promote healthy ageing.

 My project is centred around trying to understand what makes certain tissues more vulnerable to protein aggregation with age and how to promote resilience to protein aggregation.

What are the potential implications of C. elegans research on human ageing?

Ageing research is extremely complicated as there are many contributing factors that are all interlinked. However, research using C. elegans has the potential to significantly impact our understand of human ageing and age-related diseases. For example, ageing pathways have been discovered in C. elegans that are conserved in humans (the insulin/IGF-1 pathway) and subsequent longevity genes that are now known to influence lifespan. By looking at simpler organisms we can try and understand how the complete system works and how it becomes more complicated in more sophisticated species. Much more research is needed to fully understand the human equivalents!

 

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Image description: ‘Colourful C.elegans’ by Célia Raimondi, DNA staining (DAPI) of D1 in adulthood of mutant strain (glp-1(e2144)) of Caenorhabditis elegans.