The maintenance of proteostasis is crucial for any organism to survive and reproduce in an ever-changing environment, but its efficiency declines with age1. Post-transcriptional regulators such as micrRNAs (miRNAs) control protein translation of target mRNAs, with major consequences for development, physiology and longevity2,3. Here we show that food odour stimulates organismal proteostasis and promotes longevity in Caenorhabditis elegans through miR-71-mediated inhibition of tir-1 mRNA stability in olfactory AWC neurons. Screening a collection of miRNAs that control ageing3, we found that the miRNA miR-71 regulates lifespan and promotes ubiquitin-dependent protein turnover, particularly in the intestine. We show that miR-71 directly inhibits the Toll-receptor-domain protein TIR-1 in AWC olfactory neurons and that disruption of miR-71–tir-1 or loss of AWC olfactory neurons eliminates the influence of food source on proteostasis. miR-71-mediated regulation of TIR-1 controls chemotactic behaviour and is regulated by odour. Thus, odour perception influences cell-type-specific miRNA–target interaction, thereby regulating organismal proteostasis and longevity. We anticipate that the proposed mechanism of food perception will stimulate further research on neuroendocrine brain-to-gut communication and may open the possibility for therapeutic interventions to improve proteostasis and organismal health via the sense of smell, with potential implications for obesity, diabetes and ageing.
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The authors declare that the main data supporting the findings of this study are available within the article and its supplementary information files. RNA sequencing and microarray data have been deposited in the Gene Expression Omibus (GEO) with identifiers GSE124178 (RNA sequencing) and GSE124300 (microarray).
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We thank Y. Kohara and the Caenorhabditis Genetics Center (funded by the NIH National Center for Research Resources), the Dana-Farber Cancer Institute, Addgene and Geneservice for plasmids, cDNA and strains. We thank A. Segref (University of Cologne, Germany) for sharing unpublished strains and data on brain-to-gut regulation mechanisms. We thank the CECAD Imaging facility for support with confocal microscopy and the Cologne Center for Genomics for microarray analysis and RNA sequencing. This work is supported by grants from the Deutsche Forschungsgemeinschaft (DFG) (CECAD, FKZ: ZUK81/1 and SFB1218) and the European Research Council (ERC-CoG-616499) to T.H. and grants from the Austrian Science Fund (FWF) (W-1207-B09 and SFB-F43–23) and European Research Council (ERC-StG-337161) to L.C.
The authors declare no competing interests.
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Finger, F., Ottens, F., Springhorn, A. et al. Olfaction regulates organismal proteostasis and longevity via microRNA-dependent signalling. Nat Metab 1, 350–359 (2019). https://doi.org/10.1038/s42255-019-0033-z
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