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

Evandro A. De-Souza, Maximillian A. Thompson, Rebecca C. Taylor

Preprint posted on 13 October 2022

Article now published in Nature Aging at

Danger ahead – trust your gut feeling! Metabolites from pathogenic bacteria triggers a stress response in the worm’s gut.

Selected by Chee Kiang Ewe

Updated 1 September 2023 with a postLight by Chee Kiang Ewe

This work was recently published in Nature Aging. It has been great to follow the journey of this paper from preprint to published article. Notably, the key conclusions presented in the revised paper largely mirror those from the preprint. The preprint demonstrated that TGFβ signaling is required for the cell non-autonomous UPRER activation in response to pathogen perception as knocking out daf-7 or daf-1 inhibits 1-undecene-induced UPRER activation.

In the revised paper, the authors provide additional support to the claim by rescuing daf-1 expression specifically in the RIM/RIC interneurons, which recovers UPRER activation in daf-1(-) mutant. Furthermore, the authors found that ablating ASI using a split caspase system effectively blocks 1-undecene-induced UPRER activation.

The original preprint reported that exposure to 1-undecene extends the animals’ lifespan through the activation of the UPRER. The revised article goes even further by demonstrating that this lifespan extension induced by 1-undecene depends on daf-7 and daf-1.

These new findings significantly substantiate the claim that the ASI-RIM/RIC neuronal circuit mediated by TGFβ signaling regulates 1-undecene-induced UPRER activation. This paper elegantly demonstrates how sensing bacterial metabolites can enhance the worms’ immune defense which may in turn promoting their survival. Congratulations to all the authors involved in this beautiful study!


Stress-induced accumulation of misfolded proteins in the endoplasmic reticulum (ER) triggers the conserved unfolded protein response (UPRER), a complex signaling network that promotes proteostasis (or triggers cell death if the ER damage is irreversible) (Todd et al., 2008). In the nematode C. elegans, UPRER is required for the innate immune response to microbes (Richardson et al., 2010). In this exciting preprint, the researchers found that the perception of a specific pathogen-associated odorant molecule activates cell non-autonomous UPRER as a defense mechanism. As well, they could show that lifespan and proteostasis can be modulated by sensory inputs. This study, therefore, provides an intriguing connection between sensory perception, cellular stress response, and longevity.

Major findings:

1) Bacterial odorants activate UPRER in the intestine

To investigate whether pathogen-associated odors may trigger a stress response in C. elegans, the authors exposed the animals to various odorants secreted by pathogenic microbes, including Pseudomonas aeruginosa and Staphylococcus aureus, and monitored the expression of hsp-4 (which encodes the homolog of BiP, a conversed sensor of UPRER). They found that exposure to 1-undecene, 2-nonanone, and pyrrole strongly upregulated hsp-4 in the intestine.

ER stress leads to the activation of IRE-1 which cleaves the mRNA encoding the bZIP transcription factor XBP-1 into its active form, XBP-1s, which subsequently controls a wide range of targets that mediate ER proteostasis. The authors report that knocking out ire-1 or xbp-1 blocked 1-undecene-induced hsp-4 upregulation, and that the expression of xbp-1s was increased in the intestine in the presence of 1-undecene, suggesting that olfactory input may trigger cell non-autonomous UPRER (Figure 1).

2) 1-undecene exposure induces TGFβ signaling in ASI chemosensory neurons

To further investigate how neuronal signals mediate inter-tissue UPRER in response to 1-undecene, the authors eliminated UNC-13, a presynaptic protein required for synaptic vesicle exocytosis, and found that 1-undecene failed to induce UPRER in these mutant worms. In addition, the authors showed that daf-7 (which encodes a TGFβ homolog) was upregulated in ASI chemosensory neurons upon 1-undecene exposure. Moreover, worms lacking daf-7 or daf-1 (encoding a DAF-7 receptor expressed in RIM/RIC interneurons) failed to respond to 1-undecene, indicating that the activation of TGFβ signaling in the nervous system triggers cell non-autonomous UPRER (Figure 1).

3) 1-undecene exposure promotes longevity and proteostasis

Interestingly, the authors found that 1-undecene exposure prolongs the lifespan of worms. This effect was abrogated in the absence of xbp-1, demonstrating the requirement of UPRER activation. In addition, the authors could demonstrate that worms exposed to 1-undecene show reduced expression of YFP-tagged polyglutamine (polyQ) repeats, suggesting enhanced proteostasis in 1-undecene-treated worms (Figure 1).

Figure 1: 1-undecene exposure leads to TGF-β signaling in sensory neurons and inter-tissue regulation of UPRER. Adapted from De-Souza, Thompson, Taylor (2022).

What I liked about this preprint:

This preprint convincingly demonstrates how neuronal perception of odorants may elicit a cellular stress response in peripheral tissue. This indicates that sensing bacterial metabolites may prime the worms’ immune defense – an adaptive strategy that promotes survival. As well, this and other previous studies demonstrate the regulation of longevity pathway by sensory inputs, providing an exciting avenue to manipulate lifespan in animals. Overall, the genetic experiments in this preprint were exhaustive and the conclusions were nicely supported by the results.

Questions for the authors:

Do you know how RIM/RIC communicates with the intestine? It would be interesting to see if 1-undecene could prime the worms for future infection and increase survival during infection.


Richardson, C. E., Kooistra, T., & Kim, D. H. (2010). An Essential Role for XBP-1 in Host Protection against Immune Activation in C. elegans. Nature, 463(7284), 1092.

Todd, D. J., Lee, A. H., & Glimcher, L. H. (2008). The endoplasmic reticulum stress response in immunity and autoimmunity. Nature Reviews Immunology 2008 8:9, 8(9), 663–674.

Tags: neuronal perception, tgf beta, upr

Posted on: 5 December 2022 , updated on: 1 September 2023


Read preprint (No Ratings Yet)

Author's response

Maximilian A Thompson shared

Do you know how RIM/RIC communicates with the intestine?

We have shown in an earlier study that tyramine synthesis by the RIM/RIC interneurons mediates communication of UPR activation to the intestine (PMID: 33232669). Interestingly, though, tyramine synthesis does not seem to be required for UPR activation by 1-undecene. We are currently interested in determining whether RIM/RIC neurons really are needed for 1-undecene-mediated UPR activation in intestinal cells, and if so, how they do this in the context of chemosensory stimulation.

It would be interesting to see if 1-undecene could prime the worms for future infection and increase survival during infection.

In fact, we know that 1-undecene can do just that, as shown by Varsha Singh’s lab in 2021 (PMID: 34086368). Their work focused on the activation of the immune response by 1-undecene. However, we have found that the activation of the UPR which we see is not downstream of the immune pathways that were shown to be activated in the Singh lab study, and we think this UPR activation is probably happening in parallel to the immune response. So it seems that you can achieve a hormesis-like boost to the UPR by basically tricking the worm into reacting to stress which never arrives, rather than subjecting it to actual stress. It would be really interesting to see if this logic extends to other stresses.

Have your say

Your email address will not be published. Required fields are marked *

This site uses Akismet to reduce spam. Learn how your comment data is processed.

Sign up to customise the site to your preferences and to receive alerts

Register here

Also in the genetics category:

9th International Symposium on the Biology of Vertebrate Sex Determination

This preList contains preprints discussed during the 9th International Symposium on the Biology of Vertebrate Sex Determination. This conference was held in Kona, Hawaii from April 17th to 21st 2023.


List by Martin Estermann

Alumni picks – preLights 5th Birthday

This preList contains preprints that were picked and highlighted by preLights Alumni - an initiative that was set up to mark preLights 5th birthday. More entries will follow throughout February and March 2023.


List by Sergio Menchero et al.

Semmelweis Symposium 2022: 40th anniversary of international medical education at Semmelweis University

This preList contains preprints discussed during the 'Semmelweis Symposium 2022' (7-9 November), organised around the 40th anniversary of international medical education at Semmelweis University covering a wide range of topics.


List by Nándor Lipták

20th “Genetics Workshops in Hungary”, Szeged (25th, September)

In this annual conference, Hungarian geneticists, biochemists and biotechnologists presented their works. Link:


List by Nándor Lipták

2nd Conference of the Visegrád Group Society for Developmental Biology

Preprints from the 2nd Conference of the Visegrád Group Society for Developmental Biology (2-5 September, 2021, Szeged, Hungary)


List by Nándor Lipták

EMBL Conference: From functional genomics to systems biology

Preprints presented at the virtual EMBL conference "from functional genomics and systems biology", 16-19 November 2020


List by Jesus Victorino

TAGC 2020

Preprints recently presented at the virtual Allied Genetics Conference, April 22-26, 2020. #TAGC20


List by Maiko Kitaoka et al.

ECFG15 – Fungal biology

Preprints presented at 15th European Conference on Fungal Genetics 17-20 February 2020 Rome


List by Hiral Shah


Preprints on autophagy and lysosomal degradation and its role in neurodegeneration and disease. Includes molecular mechanisms, upstream signalling and regulation as well as studies on pharmaceutical interventions to upregulate the process.


List by Sandra Malmgren Hill

Zebrafish immunology

A compilation of cutting-edge research that uses the zebrafish as a model system to elucidate novel immunological mechanisms in health and disease.


List by Shikha Nayar