Sniffing Out Longevity: Aversion to Harmful Odors May Affect Lifespan

Summary: Nematodes from the species Caenorhabditis elegans show aversion to harmful odors, which might be an indicator of their enhanced longevity.

A new study reveals that these odor molecules from pathogenic bacteria not only induce avoidance behaviors in the nematodes but also stimulate a protective neural circuit in other tissues. This circuit boosts the efficient processing of toxic proteins, akin to proteins linked to human neurodegenerative diseases.

The study suggests that sensing environmental dangers via odors may be an evolutionary mechanism extending lifespan.

Key Facts:

  1. When exposed to the odor molecule 1-undecene, nematodes demonstrated increased lifespan and improved protein processing in their intestines.
  2. Activation of the endoplasmic reticulum unfolded protein response (UPRER) in the nematode’s intestine plays a crucial role in processing toxic proteins when exposed to the odorant.
  3. The protein DAF-7, equivalent to the human TGF-β, is essential in the aversion response and might provide insights for human research.

Source: FAPESP

Aversion to an offending smell can be an indicator of the organism’s capacity to protect itself from harmful substances and live longer. This at least is what happens in the case of nematodes of the species Caenorhabditis elegans.

Although nematodes (roundworms or threadworms) do not look remotely like humans, for about 50 years they have been used as a model for biological studies. The advantages include a simple nervous system, few cells and genes, many of which have the same functions as our own, and a short lifespan averaging 17 days, which is ideal for research on aging.

This shows an older man smelling a flower.
This is a defense the organism uses to trigger repair mechanisms or eliminate defective proteins. Credit: Neuroscience News

An article published in the journal Nature Aging reports the findings of a study showing that odorant molecules secreted by pathogenic bacteria not only produced an aversive response in C. elegans, which retreated to avoid the threat but also triggered a neural circuit that induced a response in other tissues of the nematode.

This response includes more efficient processing of toxic proteins, and control of the aggregation of these and other proteins produced by the worms. The relevance of this is that in humans a buildup of these proteins is one of the factors associated with neurodegenerative diseases such as Alzheimer’s and Parkinson’s.

“They can sense danger in the environment by smell, heightening their stress responses even before they locate any pathogenic bacteria. Smell also prevents aggregation of proteins involved in disease, potentially extending their lifespan,” said Evandro Araújo de Souza, first author of the article.

The study was part of his postdoctoral research at the Neurobiology Division of the Medical Research Council Laboratory of Molecular Biology (MRC-LMB) in Cambridge in the United Kingdom.

Souza is one of 32 scientists selected for FAPESP’s Project Generation, which supports research based on bold ideas conducted by early-career researchers with outstanding potential. In September, he embarked on the next stage of the study at the State University of Campinas’s Institute of Biology (IB-UNICAMP) in Brazil, where he will conduct the project “Mechanisms of regulation of proteostasis in peripheral tissues by the nervous system”. 

Scenting danger

In the study, nematodes exposed to 1-undecene, an odorant molecule, lived longer than those that had no contact with the odor secreted by bacteria. Responses to the stimulus could be seen in the intestine, evidencing the existence of a circuit connecting olfactory perception to the rest of the body. 

“These findings suggest that manipulating perceptions of chemical substances could one day be a route to intervention in neurodegenerative and age-related diseases. However, more research is needed to establish whether similar cell signaling pathways and mechanisms also operate in humans,” said Rebecca Taylor, a researcher at MRC-LMB and last author of the article.

According to the researchers, other studies had already shown that mice have a neural circuit linking brain to liver when these animals smell certain kinds of food, and it makes sense to hypothesize that the mammalian nervous system could trigger a response by other organs when stimulated, as is the case in nematodes.

“If we find a molecule that can mediate this circuit connecting the perception of odor to the organism’s response, we could have a promising route to develop novel treatments,” Souza said.

Partially revealed circuit

In the study, the nematodes were placed on different plates from those containing the odorants to demonstrate that it was not direct contact between the worms and the substances that caused aversion but only their smell.

The odorants used were those secreted by pathogenic bacteria such as Pseudomonas aeruginosa and Staphylococcus aureus, which are harmful to nematodes. Three of these compounds including 1-undecene were associated with aversive responses in C. elegans. The researchers decided to focus on 1-undecene in subsequent experiments as it induced aversion without being toxic. 

When they analyzed the worms exposed to the substance, they observed activation of the endoplasmic reticulum unfolded protein response (UPRER) in the intestine. This is a defense the organism uses to trigger repair mechanisms or eliminate defective proteins.

In worms with mutations in two genes that regulate the UPRER (ire-1 and xbp-1), the response was not activated by 1-undecene, showing that this cellular signaling pathway was essential to activation of UPRER by the substance. Other experiments confirmed this result.

Another group of mutant nematodes exposed to 1-undecene failed to produce neurotransmitters such as serotonin, dopamine and glutamate, among others, but the researchers were unable to identify a role for any of these molecules. 

Next, they focused on DAF-7, a protein and gene equivalent to transforming growth factor-beta (TGF-β) in mammals, where it plays an important role in the neural circuits that govern behavior such as aversion to pathogens.

When production of DAF-7 was inhibited, odorant-induced UPRER was not activated, evidencing its role in this response. “We now know the route we need to follow, especially because the protein has an equivalent in humans,” Souza said.

About this longevity research news

Author: Heloisa Reinert
Source: FAPESP
Contact: Heloisa Reinert – FAPESP
Image: The image is credited to Neuroscience News

Original Research: Open access.
Olfactory chemosensation extends lifespan through TGF-β signaling and UPR activation” by Evandro Araújo de Souza et al. Nature Aging


Olfactory chemosensation extends lifespan through TGF-β signaling and UPR activation

Animals rely on chemosensory cues to survive in pathogen-rich environments. In Caenorhabditis elegans, pathogenic bacteria trigger aversive behaviors through neuronal perception and activate molecular defenses throughout the animal. This suggests that neurons can coordinate the activation of organism-wide defensive responses upon pathogen perception.

In this study, we found that exposure to volatile pathogen-associated compounds induces activation of the endoplasmic reticulum unfolded protein response (UPRER) in peripheral tissues after xbp-1 splicing in neurons.

This odorant-induced UPRER activation is dependent upon DAF-7/transforming growth factor beta (TGF-β) signaling and leads to extended lifespan and enhanced clearance of toxic proteins. Notably, rescue of the DAF-1 TGF-β receptor in RIM/RIC interneurons is sufficient to significantly recover UPRER activation upon 1-undecene exposure.

Our data suggest that the cell non-autonomous UPRER rewires organismal proteostasis in response to pathogen detection, pre-empting proteotoxic stress. Thus, chemosensation of particular odors may be a route to manipulation of stress responses and longevity.

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