C. elegans is a tiny, transparent roundworm that scientists have used to study how life works at its most basic level for over 60 years.
But Prof. Nektarios Tavernarakis, research director at Institute of Molecular Biology and Biotechnology, told delegates in Dublin they could offer very specific potential to current solutions as regulatory and ethical restrictions over animal testing come into play - noting research should be striving to achieve the ‘three R’s’.
“The goal of the three R’s —replacement, reduction and refinement— is to reduce the number of animals used, to replace them where possible with alternative systems such as cellular models or simpler organisms, and to refine experimental designs so that fewer animals are required,” Tavernarakis said.
“The three R’s are becoming increasingly relevant for biomedical research and recent research is advancing the understanding that C. elegans offers a platform that can help alleviate some of the regulatory restrictions that are likely to be imposed in the future.”
Organisms such as C. elegans can be used without the bioethical restrictions associated with mice or other higher organisms, Tavernarakis explained. They adapt easily to different experimental conditions, and importantly, many fundamental biological processes are highly conserved between these organisms and humans.
“This evolutionary conservation allows us to draw conclusions that are relevant to human health,” he said.
C. elegans: Studying aging at single-cell resolution
C.elegans develop rapidly, reaching reproductive adulthood in roughly 2.5 days, and reproduce clonally, enabling the study of genetically identical populations.
Researchers have identified the species’ exact cell lineage, accounting for all 959 somatic cells, and fully reconstructed its nervous system, which comprises 302 neurons and approximately 6,000 synapses.
“This unmatched level of anatomical and cellular detail makes it possible to investigate aging and neurodegeneration with single-cell resolution,” Tavernarakis said.
“In C. elegans, we can monitor the gradual accumulation of damaged mitochondria in vivo, and we can even distinguish functional from damaged mitochondria with remarkable precision.
“This makes C. elegans an ideal system to study mitochondrial dynamics during aging and to uncover the molecular mechanisms underlying mitochondrial accumulation.”
Mechanisms behind neurodegenerative diseases
Aging is associated with numerous pathologies, some of them devastating and currently incurable, Tavernarakis noted. “These include neurodegenerative diseases, cardiovascular diseases, and metabolic disorders.”
He referred to statistics that more than 130 million people are projected to be affected by dementia or Alzheimer’s disease in the coming decades.
“This poses a tremendous challenge for the biomedical community to understand disease mechanisms well enough to develop effective interventions,” Tavernarakis said.
This conundrum has centred his work around why neuronal homeostatic systems that function for decades eventually fail.
“Neurons are among the longest-lived cells in the human body; they are born before we are and often persist long after other cells have died,” Tavernarakis said. “They must survive for decades, potentially over a century, which means they require exceptionally robust detoxification and repair mechanisms to cope with damage accumulated during aging. Therefore, understanding why and how these mechanisms fail is central to our work.”
Mitophagy activation in C. elegans shows promise for treating neurodegenerative diseases
As Tavernarakis noted, mitophagy is a critical protective mechanism in neurons during aging and neurodegeneration. As neurons age, they tend to accumulate damaged mitochondria due to reduced mitophagy and increased oxidative stress. This accumulation accelerates when mitophagy becomes impaired.
Tavernarakis presented a C. elegans study of Parkinson’s disease, where the worms were made to produce alpha-synuclein (a protein common in the human brain) in their neurons, causing dopaminergic neurodegeneration and motor impairment. When the process that induces mitophagy was blocked or reduced, the neurons died faster and the symptoms got worse.
This established mitophagy as an active defense mechanism that limits α-synuclein–induced toxicity in dopaminergic neurons, Tavernarakis explained.
In another study on Alzheimer’s disease, worms’ neurons were made to produce human β-amyloid and tau proteins. This blocked mitophagy, which left neurons vulnerable to mitochondrial damage and functional decline. Results showed that pharmacological activation of mitophagy helped remove the damaged mitochondria and partially improved learning and memory in these worms, Tavernarakis noted.
The study also found that urolithin A, known to induce mitophagy, reactivated mitochondrial turnover in neurons expressing toxic human proteins. Results demonstrated that mitophagy activation can reverse key aspects of neurodegenerative pathology, Tavernarakis noted.
“Results we are seeing position mitophagy as a promising therapeutic target and validate C. elegans as a powerful, scalable platform for discovering interventions relevant to human neurodegenerative diseases,” Tavernarakis said.
Alternatives to animal testing in probiotic research
As Tavernarakis noted, regulations are already being implemented in many European countries and will present an increasing challenge for the biomedical community in the future as the global effort continues to significantly reduce the number of animals sacrificed for research.
“First of all, the usual bioethical restrictions that apply to models such as mice or primates do not apply to C. elegans,” Tavernarakis noted. “It is an invertebrate species that is not endangered, not pathogenic, and not threatened with extinction, and this allows for a great deal of flexibility in laboratory use.
“Secondly, C. elegans is ideally suited for high-throughput studies, and this is particularly important when we want to identify specific compounds responsible for probiotic effects in humans - it enables large-scale compound screening that simply isn’t feasible in more complex organisms.
“So, not only do we bypass increasingly strict regulatory frameworks, but we also gain unique experimental advantages that cannot be achieved with mice or other higher organisms,” he said.
These constraints are only going to become stricter in the future, Tavernarakis noted, and as a result, alternative organisms such as C. elegans will continue to emerge as viable and attractive solutions.
“I believe they will become increasingly popular, particularly in probiotic research,” he said.
