International Business Department           Liu Bojia           October 30, 2023

  Some people are extraordinarily sensitive to odours; the smell of sweat, faeces, vomit, rotting fish and shrimp ...... can't stand a bit of it. Typically, being disgusted by odours and stench allows organisms to retreat away from harmful substances and avoid poisoning. And scientists have recently discovered in animal experiments that there's a long-term benefit to being disgusted by odours.

  According to a newly published research paper in Nature Aging, the aversion response that occurs after smelling a foul odour directly triggers specific neural circuits in the animal's body, which promotes the organism to actively remove toxic proteins from the body, resulting in a longer lifespan.

  The researchers chose the showy cryptic rod nematode (C. elegans) for their observations. Although the tiny worms look very different from humans, they share many genes and highly conserved gene regulatory mechanisms with humans, and have long been classic model organisms for studying development and aging.

  Nematodes feed mainly on bacteria, such as E. coli. However, some bacteria are the equivalent of "rotten fish and shrimp" and are not edible, such as pathogens like Pseudomonas aeruginosa and Staphylococcus aureus. Nematodes do not need to come into direct contact with such pathogens, but will show an aversion to smelling them and avoid them.

  In the experiment, the researchers tested the nematodes on a molecule called 1-undecene, a compound secreted by the pathogenic bacteria. This volatile substance itself is non-toxic to nematodes, but it has a nasty odour to them.

  Something interesting happened: the nematodes that smelled 1-undecene for hours lived longer compared to the nematodes that had not been exposed to the odour of the pathogen.

  At the same time, the researchers found, through fluorescent reporter genes and tracking of neuronal signals, that a response to the odour molecules appeared within the nematode's intestinal tissue: the endoplasmic reticulum unfolded protein response (UPR) was activated.

  The endoplasmic reticulum is the site of protein processing, where proteins can only be transported to fulfil their proper function if they are correctly folded. Proteins that are not folded or are folded incorrectly need to be destroyed, and if they accumulate in large amounts in the endoplasmic reticulum, endoplasmic reticulum damage can result. Neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease, which affect human health and longevity, are closely related to the accumulation of misfolded proteins.

  And the UPR response is activated to induce repair mechanisms that help cells process defective proteins more efficiently. For nematodes that smell of 1-undecene, activation of the UPR response resulted in enhanced cellular clearance of toxic proteins, which prevented disease-related proteins from aggregating, potentially increasing the animal's resilience and extending its lifespan.

  "Nematodes can sense dangers in their environment through odour and enhance stress responses even before pathogenic bacteria are detected." Dr Evandro Araújo de Souza, first author of the research paper, concludes that the aversion to "bad smells" demonstrates the organism's ability to protect itself from harmful substances.

  The researchers further revealed in the paper that the DAF-7 protein and its downstream factors in specific neurons of nematodes play a key role in mediating odour-induced aversion and the UPR response, and that these molecules are essential for the longevity of nematodes smelling 1-undecene. Human cells, on the other hand, have an equivalent protein to DAF-7, the transforming growth factor TGF-β. Whether UPR repair mechanisms can be triggered by following the TGF-β signalling pathway in human cells are questions that need to be followed up.