Researchers using nematode worms discovered that exposure to a particular chemical generated by pathogenic bacteria caused the worms to activate a brain circuit. The worms’ longevity increased as a result of this activation, and protein aggregation—which is thought to play a role in the emergence of neurodegenerative diseases—was decreased.
An organism’s ability to defend itself against dangerous substances and prolong its life can be inferred from its response to offensive smells. In the case of Caenorhabditis elegans nematodes, at least, this is what occurs.
Nematodes, often known as roundworms or threadworms, are not even remotely similar to humans, yet for the past 50 years or more, they have been utilised as models in biological research. A short lifespan of 17 days on average, which is perfect for ageing studies, a simple nervous system, and a small number of cells and genes—many of which perform the same roles as human genes—are among the benefits.
The results of a study are reported in a journal article called Nature Ageing. The study demonstrated that pathogenic bacteria’s odorant molecules not only caused C. elegans to retreat in order to avoid the threat but also set off a neural circuit that caused a response in other nematode tissues.
This reaction entails controlling the aggregation of these and other proteins the worms make, as well as digesting hazardous proteins more effectively. This is relevant since one of the things linked to neurodegenerative illnesses like Alzheimer’s and Parkinson’s in humans is an accumulation of these proteins.
They have the ability to smell dangerous substances in their surroundings, which causes them to become more stressed even before they come across any harmful bacteria. Additionally, smell delays the aggregation of disease-causing proteins, which may prolong their life, according to the article’s primary author, Evandro Araújo de Souza. His postdoctoral research at the Medical Research Council Laboratory of Molecular Biology (MRC-LMB) in Cambridge, United Kingdom, included the study.
Souza is one of the thirty-two scientists that were chosen for FAPESP’s Project Generation programme, which funds research based on audacious concepts carried out by early-career scientists with exceptional promise. He started the second phase of his research in September at the Institute of Biology (IB-UNICAMP) of the State University of Campinas in Brazil. His project is titled “Mechanisms of regulation of proteostasis in peripheral tissues by the nervous system.”
Dangerous Substances scent
In the experiment, nematodes exposed to the odorant molecule 1-undecene outlived those that were not in contact with the bacterially generated odour. There was evidence of intestinal responses to the stimuli, suggesting that there is a circuit that links the olfactory system to the rest of the body.
These results imply that one day, treating age-related and neurodegenerative disorders may include changing people’s perceptions of chemicals. But further investigation is required to determine whether comparable cell signalling pathways and mechanisms also function in people, according to Rebecca Taylor, the article’s final author and an MRC-LMB researcher.
The researchers reasoned that since previous research had demonstrated that mice have a neural circuit connecting the brain to the liver when these animals smell particular foods, it stands to reason that the mammalian nervous system could also cause other organs to react when stimulated, as nematodes do.
“We may have a promising path to creating new treatments if we identify a molecule that can mediate this circuit linking the organism’s response to odour perception,” Souza stated.
Circuit partially displayed
To show that the worms’ aversion was only due to their fragrance and not due to any actual interaction with the chemicals, the nematodes were isolated from the odorant-containing plates in the study.
The pathogenic bacteria that cause injury to nematodes, like Pseudomonas aeruginosa and Staphylococcus aureus, released the odorants that were utilised. In C. elegans, three of these dangerous substances—including 1-undecene—were linked to negative reactions. In further trials, the researchers chose to concentrate on 1-undecene because it produced aversion without being hazardous.
Upon examining the worms exposed to the material, they saw that the intestinal endoplasmic reticulum unfolded protein response (UPRER) had been activated. The organism uses this defence to start repair processes or get rid of faulty proteins.
The response was not triggered by 1-undecene in worms with mutations in the two UPRER-regulating genes (ire-1 and xbp-1), indicating that this cellular signalling pathway was necessary for the substance’s activation of UPRER. This result was validated by several experiments.
How Smell, Taste & Pheromone-Like Dangerous Substances Control You
Researchers were unable to determine the function of any of the neurotransmitters produced by another batch of mutant worms exposed to 1-undecene, including glutamate, serotonin, and dopamine.
Subsequently, scientists turned their attention to DAF-7, a protein and gene that functions similarly to TGF-β in mammals and is crucial for the brain circuits that control behaviour, including immunity to infections.
Odorant-induced UPRER was not activated when DAF-7 synthesis was suppressed, indicating its function in this response. “We now know the path we must take, particularly since humans have an equivalent of the protein,” Souza stated.
Reference: “Olfactory chemosensation extends lifespan through TGF-β signaling and UPR activation” by Evandro A. De-Souza, Maximillian A. Thompson and Rebecca C. Taylor, 27 July 2023, Nature Aging.
DOI: 10.1038/s43587-023-00467-1
The study was funded by the São Paulo Research Foundation.
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