Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

An excreted small molecule promotes C. elegans reproductive development and aging

Abstract

Excreted small-molecule signals can bias developmental trajectories and physiology in diverse animal species. However, the chemical identity of these signals remains largely obscure. Here we report identification of an unusual N-acylated glutamine derivative, nacq#1, that accelerates reproductive development and shortens lifespan in Caenorhabditis elegans. Produced predominantly by C. elegans males, nacq#1 hastens onset of sexual maturity in hermaphrodites by promoting exit from the larval dauer diapause and by accelerating late larval development. Even at picomolar concentrations, nacq#1 shortens hermaphrodite lifespan, suggesting a trade-off between reproductive investment and longevity. Acceleration of development by nacq#1 requires chemosensation and is dependent on three homologs of vertebrate steroid hormone receptors. Unlike ascaroside pheromones, which are restricted to nematodes, fatty acylated amino acid derivatives similar to nacq#1 have been reported from humans and invertebrates, suggesting that related compounds may serve signaling functions throughout metazoa.

This is a preview of subscription content

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Fig. 1: Excreted small molecules accelerate development in C. elegans.
Fig. 2: Identification of nacq#1, a signaling molecule primarily produced by males.
Fig. 3: Biological properties of nacq#1.
Fig. 4: nacq#1 and ascarosides are mutually antagonistic signals.
Fig. 5: nacq#1 signals via conserved signaling pathways.

Data availability

The authors declare that the data supporting the findings of this study are available within the article and its supplementary information files.

References

  1. von Reuss, S. H. & Schroeder, F. C. Combinatorial chemistry in nematodes: modular assembly of primary metabolism-derived building blocks. Nat. Prod. Rep. 32, 994–1006 (2015).

    Article  Google Scholar 

  2. Gendron, C. M. et al. Drosophila life span and physiology are modulated by sexual perception and reward. Science 343, 544–548 (2014).

    CAS  Article  PubMed  Google Scholar 

  3. Vandenbergh, J. G. Male odor accelerates female sexual maturation in mice. Endocrinology 84, 658–660 (1969).

    CAS  Article  PubMed  Google Scholar 

  4. Ludewig, A. H. et al. Larval crowding accelerates C. elegans development and reduces lifespan. PLoS Genet. 13, e1006717 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  5. Aprison, E. Z. & Ruvinsky, I. Sexually antagonistic male signals manipulate germline and soma of C. elegans hermaphrodites. Curr. Biol. 26, 2827–2833 (2016).

    CAS  Article  PubMed  Google Scholar 

  6. Ludewig, A. H. & Schroeder, F. C. in WormBook (ed. The C. elegans Research Community) https://doi.org/10.1895/wormbook.1.155.1 (2013).

  7. Schroeder, F. C. Modular assembly of primary metabolic building blocks: a chemical language in C. elegans. Chem. Biol. 22, 7–16 (2015).

    CAS  Article  PubMed  Google Scholar 

  8. Butcher, R. A. Small-molecule pheromones and hormones controlling nematode development. Nat. Chem. Biol. 13, 577–586 (2017).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  9. Frezal, L. & Felix, M. A. C. elegans outside the Petri dish. eLife 4, e05849 (2015).

    Article  PubMed Central  Google Scholar 

  10. Shi, C. & Murphy, C. T. Mating induces shrinking and death in Caenorhabditis mothers. Science 343, 536–540 (2014).

    CAS  Article  PubMed  Google Scholar 

  11. Maures, T. J. et al. Males shorten the life span of C. elegans hermaphrodites via secreted compounds. Science 343, 541–544 (2014).

    CAS  Article  PubMed  Google Scholar 

  12. Shi, C., Runnels, A. M. & Murphy, C. T. Mating and male pheromone kill Caenorhabditis males through distinct mechanisms. eLife 6, e23493 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  13. Artyukhin, A. B. et al. Metabolomic “dark matter” dependent on peroxisomal β-oxidation in Caenorhabditis elegans. J. Am. Chem. Soc. 140, 2841–2852 (2018).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  14. von Reuss, S. H. et al. Comparative metabolomics reveals biogenesis of ascarosides, a modular library of small molecule signals in C. elegans. J. Am. Chem. Soc. 134, 1817–1824 (2012).

    Article  Google Scholar 

  15. Forsberg, E. M. et al. Data processing, multi-omic pathway mapping, and metabolite activity analysis using XCMS Online. Nat. Protoc. 13, 633–651 (2018).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  16. Tautenhahn, R., Bottcher, C. & Neumann, S. Highly sensitive feature detection for high resolution LC/MS. BMC Bioinformatics 9, 504 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  17. Pungaliya, C. et al. A shortcut to identifying small molecule signals that regulate behavior and development in Caenorhabditis elegans. Proc. Natl Acad. Sci. USA 106, 7708–7713 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  18. Aprison, E. Z. & Ruvinsky, I. Counteracting ascarosides act through distinct neurons to determine the sexual identity of C. elegans pheromones. Curr. Biol. 27, 2589–2599 (2017).

    CAS  Article  PubMed  Google Scholar 

  19. He, J. et al. Distinct signals conveyed by pheromone concentrations to the mouse vomeronasal organ. J. Neurosci. 30, 7473–7483 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  20. Izrayelit, Y. et al. Targeted metabolomics reveals a male pheromone and sex-specific ascaroside biosynthesis in Caenorhabditis elegans. ACS Chem. Biol. 7, 1321–1325 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  21. Schulenburg, H. & Felix, M. A. The natural biotic environment of Caenorhabditis elegans. Genetics 206, 55–86 (2017).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  22. Gems, D. & Riddle, D. L. Genetic, behavioral and environmental determinants of male longevity in Caenorhabditis elegans. Genetics 154, 1597–1610 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Srinivasan, J. et al. A blend of small molecules regulates both mating and development in Caenorhabditis elegans. Nature 454, 1115–1118 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  24. Butcher, R. A., Fujita, M., Schroeder, F. C. & Clardy, J. Small-molecule pheromones that control dauer development in Caenorhabditis elegans. Nat. Chem. Biol. 3, 420–422 (2007).

    CAS  Article  PubMed  Google Scholar 

  25. Jeong, P. Y. et al. Chemical structure and biological activity of the Caenorhabditis elegans dauer-inducing pheromone. Nature 433, 541–545 (2005).

    CAS  Article  PubMed  Google Scholar 

  26. Ludewig, A. H. et al. Pheromone sensing regulates Caenorhabditis elegans lifespan and stress resistance via the deacetylase SIR-2.1. Proc. Natl Acad. Sci. USA 110, 5522–5527 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  27. Golden, J. W. & Riddle, D. L. A pheromone influences larval development in the nematode Caenorhabditis elegans. Science 218, 578–580 (1982).

    CAS  Article  PubMed  Google Scholar 

  28. Hu, P. J. in WormBook (ed. The C. elegans Research Community) https://doi.org/10.1895/wormbook.1.144.1 (2007).

  29. Kenyon, C. The plasticity of aging: insights from long-lived mutants. Cell 120, 449–460 (2005).

    CAS  Article  PubMed  Google Scholar 

  30. Kaplan, F. et al. Ascaroside expression in Caenorhabditis elegans is strongly dependent on diet and developmental stage. PLoS ONE 6, e17804 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  31. Fielenbach, N. & Antebi, A. C. elegans dauer formation and the molecular basis of plasticity. Genes Dev. 22, 2149–2165 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  32. Mangelsdorf, D. J. et al. The nuclear receptor superfamily: the second decade. Cell 83, 835–839 (1995).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  33. Antebi, A., Yeh, W. H., Tait, D., Hedgecock, E. M. & Riddle, D. L. daf-12 encodes a nuclear receptor that regulates the dauer diapause and developmental age in C. elegans. Genes Dev. 14, 1512–1527 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Ludewig, A. H. et al. A novel nuclear receptor/coregulator complex controls C. elegans lipid metabolism, larval development, and aging. Genes Dev. 18, 2120–2133 (2004).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  35. Magner, D. B. et al. The NHR-8 nuclear receptor regulates cholesterol and bile acid homeostasis in C. elegans. Cell Metab. 18, 212–224 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  36. Thondamal, M., Witting, M., Schmitt-Kopplin, P. & Aguilaniu, H. Steroid hormone signalling links reproduction to lifespan in dietary-restricted Caenorhabditis elegans. Nat. Commun. 5, 4879 (2014).

    CAS  Article  PubMed  Google Scholar 

  37. Bargmann, C. I. & Horvitz, H. R. Control of larval development by chemosensory neurons in Caenorhabditis elegans. Science 251, 1243–1246 (1991).

    CAS  Article  PubMed  Google Scholar 

  38. Schackwitz, W. S., Inoue, T. & Thomas, J. H. Chemosensory neurons function in parallel to mediate a pheromone response in C. elegans. Neuron 17, 719–728 (1996).

    CAS  Article  PubMed  Google Scholar 

  39. Alcedo, J. & Kenyon, C. Regulation of C. elegans longevity by specific gustatory and olfactory neurons. Neuron 41, 45–55 (2004).

    CAS  Article  PubMed  Google Scholar 

  40. Apfeld, J. & Kenyon, C. Regulation of lifespan by sensory perception in Caenorhabditis elegans. Nature 402, 804–809 (1999).

    CAS  Article  PubMed  Google Scholar 

  41. Park, D. et al. Interaction of structure-specific and promiscuous G-protein-coupled receptors mediates small-molecule signaling in Caenorhabditis elegans. Proc. Natl Acad. Sci. USA 109, 9917–9922 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  42. Maglich, J. M. et al. Comparison of complete nuclear receptor sets from the human, Caenorhabditis elegans and Drosophila genomes. Genome Biol. 2, research0029.1–research0029.7 (2001).

    Article  Google Scholar 

  43. Wollam, J. & Antebi, A. Sterol regulation of metabolism, homeostasis, and development. Annu. Rev. Biochem. 80, 885–916 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  44. Gems, D. & Partridge, L. Genetics of longevity in model organisms: debates and paradigm shifts. Annu. Rev. Physiol. 75, 621–644 (2013).

    CAS  Article  PubMed  Google Scholar 

  45. Maklakov, A. A. & Immler, S. The expensive germline and the evolution of ageing. Curr. Biol. 26, R577–R586 (2016).

    CAS  Article  PubMed  Google Scholar 

  46. Kuhn, F. & Natsch, A. Body odour of monozygotic human twins: a common pattern of odorant carboxylic acids released by a bacterial aminoacylase from axilla secretions contributing to an inherited body odour type. J. R. Soc. Interface 6, 377–392 (2009).

    CAS  Article  PubMed  Google Scholar 

  47. Long, J. Z. et al. The secreted enzyme PM20D1 regulates lipidated amino acid uncouplers of mitochondria. Cell 166, 424–435 (2016).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  48. Long, J. Z. et al. Ablation of PM20D1 reveals N-acyl amino acid control of metabolism and nociception. Proc. Natl Acad. Sci. USA 115, E6937–E6945 (2018).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  49. Schmelz, E. A., Engelberth, J., Alborn, H. T., Tumlinson, J. H. & Teal, P. E. A. Phytohormone-based activity mapping of insect herbivore-produced elicitors. Proc. Natl Acad. Sci. USA 106, 653–657 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  50. Weiss, L. C. et al. Identification of Chaoborus kairomone chemicals that induce defences in Daphnia. Nat. Chem. Biol. 14, 1133–1139 (2018).

    CAS  Article  PubMed  Google Scholar 

  51. Brenner, S. The genetics of Caenorhabditis elegans. Genetics 77, 71–94 (1974).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Sulston, J. & Hodgkin, J. in The Nematode Caenorhabditis elegans (ed. Wood, W. B.) 587–606 (Cold Spring Harbor Laboratory Press, 1988).

  53. Seydoux, G., Savage, C. & Greenwald, I. Isolation and characterization of mutations causing abnormal eversion of the vulva in Caenorhabditis elegans. Dev. Biol. 157, 423–436 (1993).

    CAS  Article  PubMed  Google Scholar 

  54. MacNeil, L., Watson, E., Arda, H. E., Zhu, L. J. & Walhout, A. J. M. Diet-induced developmental acceleration independent of TOR and insulin in C. elegans. Cell 153, 240–252 (2013).

    CAS  Article  PubMed  Google Scholar 

  55. Frand, A. R., Russel, S. & Ruvkun, G. Functional genomic analysis of C. elegans molting. PLoS Biol. 3, e312 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported in part by National Institutes of Health grants R01GM113692 (to F.C.S.), R01GM088290 (to F.C.S.) and T32GM008500 (to R.N.B.), R01GM126125 (to I.R.), and by National Science Foundation (NSF) grants IOS-1708518 and IOS-1755244 (to I.R.). F.C.S. is a faculty scholar of the Howard Hughes Medical Institute. This work made use of the Cornell University NMR Facility, which is supported, in part, by the NSF through MRI award CHE-1531632. We thank N. Movahed and D. Kiemle for assistance with MS and NMR spectroscopy and R. Smith and G. Horvath for technical support.

Author information

Authors and Affiliations

Authors

Contributions

I.R. and F.C.S. supervised the study. A.H.L., A.B.A., I.R. and F.C.S. designed experiments. A.H.L., A.B.A., E.Z.A., P.R.R., D.C.P., R.N.B., P.G. and O.P. performed chemical and biological experiments. R.N.B. and Y.K.Z. performed syntheses. I.R. and F.C.S. wrote the paper with input from the other authors.

Corresponding authors

Correspondence to Ilya Ruvinsky or Frank C. Schroeder.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Supplementary Information

Supplementary Tables 1–15 and Supplementary Figures 1–14

Reporting Summary

Supplementary Note

Synthetic procedures

Supplementary Data Set

Data for time-of-development assays based on morphological criteria. Includes data for time-of-development assays and molting curves shown in Figs. 1b and 3b,d, and Supplementary Figs. 5b, 7b,c, 9 and 12b,c.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Ludewig, A.H., Artyukhin, A.B., Aprison, E.Z. et al. An excreted small molecule promotes C. elegans reproductive development and aging. Nat Chem Biol 15, 838–845 (2019). https://doi.org/10.1038/s41589-019-0321-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41589-019-0321-7

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing