Fluorescent blue wave reveals ‘cascade of death’ in worms

Fluorescent nematode worm
Since we don’t know exactly what ageing is, we can’t say definitively whether it is the same in worms as it is in higher animals. However...some of the ageing-control genes in worms function similarly in other organisms, including mice and perhaps even humans.
Professor David Gems
New research reveals that when the worm finally turns, death spreads like a wave from cell to cell until the entire organism is dead…

Biologists studying the final moments of a worm’s life have described how a wave of blue fluorescence illuminates a ‘cascade of death’ that spreads throughout the organism’s body before it expires.

The University College London (UCL) scientists, whose research has been published in the journal PLOS Biology, believe that their findings could offer fresh insights into ageing and death in humans.

Traditionally, scientists have hypothesised that death from ageing occurs when an organism’s cells ‘wear out’. However, the UCL study, which was funded by the Wellcome Trust and the Biotechnology and Biological Sciences Research Council (BBSRC), demonstrates that – in the case of worms – a chain reaction of death leads to the breakdown of cellular components and an accumulation of molecular debris.

To learn more about this cascade of death and the eerie blue fluorescence that accompanies it, I spoke to David Gems, lead author of the study and Professor of Biogerontology at UCL’s Institute of Healthy Ageing.

'One of the great unsolved questions'


"Ageing represents one of the great unsolved questions of modern science," he began. "It is now the major cause of disease in the developed world. It’s somewhat surprising, therefore, that we don’t actually understand a great deal about this process. For example, we don’t know much about the factors that drive ageing. This dearth of knowledge stems largely from the fact that it is so difficult to study the ageing process in mammals.

"It’s for these reasons that my colleagues and I chose to work with Caenorhabditis elegans nematode worms," Professor Gems continued. "C elegans is a model organism when it comes to the study of ageing. It’s a very simple animal, it’s cheap to work with, and it has a lifespan of just a couple of weeks. If we can understand the ageing process in just one animal, it will probably be in this worm. Moreover, a complete understanding of worm ageing could offer valuable insights into how the ageing process operates more broadly."

The simplicity of the nematode worm offers clear advantages in terms of understanding exactly what is happening during ageing and death. However, to what extent are these organisms analogous to human beings? Can the expiration of such a simple creature really teach us anything about the death of a complex mammal?

"That’s a good question," said Professor Gems. "Since we don’t know exactly what ageing is, we can’t say definitively whether it is the same in worms as it is in higher animals. However, previous studies have highlighted clear similarities. Some of the ageing-control genes in worms function similarly in other organisms, including mice and perhaps even humans. I am confident that if we can define what ageing is in one organism, we will be able to extrapolate some underlying principles."

'Chain reaction of cell death'


The chemical pathway of self-destruction observed by Professor Gems and his colleagues manifests itself as a fluorescent blue wave spreading throughout a worm during its final moments. Interestingly, the team discovered that the progress of this ominous glow – a side effect of necrosis – is dependent on calcium signalling.

By blocking the pathway, the biologists were able to temporarily stave off death when it was induced by a stress such as infection. However, they were unable to prevent the chain reaction from occurring when it stemmed from old age. I asked Professor Gems how much he and his colleagues understand about the mechanisms responsible for initiating this fatal cascade.

"Our study details the chain reaction of cell death that occurs within the nematode’s ‘intestine’," he replied. "In truth, this organ does a lot more than its name implies. Worms don’t have livers, kidneys, fat tissue, etc. All of these functions are carried out by a single large organ. Whilst we succeeded in characterising the pathway involved in the cascade, we still don’t know what causes it to begin in the first place."

Conventional wisdom states that ageing is a process of ‘wear and tear’. Scientists have long since believed that as organisms age, their cells suffer gradual but irreparable damage. However, the cascade of death observed by the UCL team suggests that the ‘wear-and-tear’ model might not be accurate after all.

Debunking the damage hypothesis


"Before we can begin to tackle ageing, we need to understand it," explained Professor Gems. "In order to do that, we must figure out which of the competing hypotheses is best. Essentially, this all boils down to two simple questions: what is life and what is death? According to the traditional damage model, ageing and death occur because of wear and tear. However, there is growing evidence to suggest that this is not the case.

"Sometimes, complex organisms suffer injuries that cause certain sections of their bodies to die," he continued. "A stroke, for example, might leave you with a lump of dead brain cells surrounded by living tissue. Consider what happens at the interface between these two areas. How does the dead tissue affect the living tissue? Studies show that in such instances, death actually spreads. Dead cells are capable of triggering death in living cells. Death, it seems, can be transmitted from cell to cell."

In mammals, the propagation of cell death in the brain is often accompanied by an influx of calcium into brain cells, leading to further cell death. Intercellular protein channels called 'connexins' allow ions to travel between cells. This is, essentially, the same process that the UCL researchers have observed within nematode intestines.

Understanding death


Professor Gems is hopeful that by learning how to manipulate this pathway, scientists will be able to develop new therapeutic techniques to counteract the damaging effects of ageing. So, what are the next steps for the researchers?

"Well, our main objective is to figure out what ageing is," he explained. "We will continue to scrutinise the damage hypothesis. People are finding, again and again, that this theory just doesn’t hold water. We also want to test the hyperfunction theory of ageing, which proposes that overactive biosynthetic processes during adulthood lead to pathologies responsible for increased mortality in old age.

"In terms of improving our understanding of death, we want to answer the question that you posed earlier," concluded Professor Gems. "By what mechanisms does ageing initiate the cascade of death that we have observed? This will be a big challenge, but major inroads are being made. People tend to think of death as something that can’t really be described. They see it as some chaotic event during which everything goes to hell. There is mounting evidence, however, to suggest that it is perfectly possible both to analyse and to understand death as a process."


If you'd like to find out more about the nematode worm's fluorescent cascade of cell death, check out the full paper: 'Anthranilate Fluorescence Marks a Calcium-Propagated Necrotic Wave That Promotes Organismal Death in C. elegans'...

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