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Prostaglandin signals from adult germline stem cells delay somatic ageing of Caenorhabditis elegans

Nature Metabolism volume 1, pages 790–810 (2019)Cite this article

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Abstract

A moderate reduction in body temperature can induce a remarkable lifespan extension. Here we examine the link between cold temperature, germline fitness and organismal longevity. We show that low temperature reduces age-associated exhaustion of germline stem cells (GSCs) in Caenorhabditis elegans, a process modulated by thermosensory neurons. Notably, robust self-renewal of adult GSCs delays reproductive ageing and is required for extended lifespan at cold temperatures (10 °C, 15 °C). These cells release prostaglandin E2 (PGE2) to induce cbs-1 expression in the intestine, increasing the somatic production of hydrogen sulfide, a gaseous signalling molecule that prolongs lifespan. Loss of adult GSCs reduces intestinal cbs-1 expression and cold-induced longevity, whereas application of exogenous PGE2 rescues these phenotypes. Importantly, tissue-specific intestinal overexpression of cbs-1 mimics cold-temperature conditions and extends longevity even at warm temperatures (25 °C). Thus, our results indicate that GSCs communicate with somatic tissues to coordinate extended reproductive capacity with longevity.

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Fig. 1: The germline is essential for cold-induced longevity during adulthood.
Fig. 2: Cold temperature delays exhaustion of GSCs and reproductive ageing.
Fig. 3: Thermosensory neurons regulate cold-induced longevity and GSC proliferation.
Fig. 4: Adult GSC proliferation determines cold-induced longevity.
Fig. 5: cbs-1 and other factors modulate the long lifespan induced by adult GSCs at low temperatures.
Fig. 6: Tissue-specific knockdown of cbs-1 in the intestine or muscle reduces cold-induced longevity.
Fig. 7: GSCs induce cbs-1 expression in somatic tissues at cold temperatures.
Fig. 8: Release of PGE2 by GSCs promotes cold-induced longevity.
Fig. 9: Application of exogenous PGE2 rescues cbs-1 expression and cold-induced longevity in GSC-impaired worms.

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Data availability

The authors declare that the main data supporting the findings of this study are available within the article and its supplementary files. Transcriptome data have been deposited in Gene Expression Omnibus (GEO) under the accession code GSE123054. All the other data are also available from the corresponding author upon request.

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Acknowledgements

This work was supported by the European Research Council (ERC Starting Grant-677427 StemProteostasis) and the Deutsche Forschungsgemeinschaft (DFG) (VI742/1-2 and CECAD). We are grateful to E. Llamas for the graphical model and the germline scheme. We thank U. Pham and N. Fritsma for their help in BrdU and lifespan experiments, respectively. We thank J. P. Derks for data analysis and preparation of heatmap figures with R stats package of proteomics experiments. We also thank J. Horák for generation of the tissue-specific cbs-1 expression plasmids. We thank T. Hoppe for critical comments on the manuscript. We are grateful to the CECAD Proteomics and Imaging Facilities for their advice and contribution to proteomics and imaging experiments, respectively. We also thank P. Wagle from the CECAD Bionformatics Facility for data analysis of RNA-sequencing experiments. This work was also supported by the grant of the German Research Council through Collaborative Research Centre 1218 (SFB1218 - TP B01) to A.T.

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Authors and Affiliations

  1. Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany

    Hyun Ju Lee, Alireza Noormohammadi, Seda Koyuncu, Giuseppe Calculli, Marija Herholz, Aleksandra Trifunovic & David Vilchez

  2. Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA

    Milos S. Simic

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Contributions

H. J. L., A. N. and D. V. performed most of the experiments, data analysis and interpretation. S. K. assessed knockdown levels and contributed to lifespan assays and other experiments. G. C. performed some of the BrdU assays and helped with other experiments. M. S. S. generated the plasmids for tissue-specific overexpression that were used to clone cbs-1. M. H. performed oxygen consumption experiments. A. T. contributed expertise on metabolic rates and provided critical advice on the project. The manuscript was written by D. V. All authors discussed the results and commented on the manuscript.

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Correspondence to David Vilchez.

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Supplementary information

Supplementary Information

Supplementary Figures 1–33 and Supplementary Tables 1 and 2.

Reporting Summary

Supplementary Dataset 1

Differentially expressed proteins following iff-1 RNAi treatment or temperature increase. Log2-fold change of differentially expressed proteins in iff-1 RNAi-treated worms at 15 °C and EV RNAi-treated worms at 20 °C compared with EV RNAi-treated worms at 15 °C. The fer-15(b26);fem-1(hc17) control strain was raised at the restrictive temperature (25 °C) during development to obtain sterile worms with a proliferating germline, which were then shifted to the indicated temperatures and RNAi treatment until day 6 of adulthood. Statistical comparisons were made by two-tailed Student’s t-test (n=3, P value <0.05 was considered significant).

Supplementary Dataset 2

Transcriptome analysis of extruded germlines from worms following iff-1 RNAi treatment or temperature increase. Differentially expressed transcripts changed in the same direction in the germline of both iff-1 RNAi-treated worms at 15 °C and empty vector (EV) RNAi-treated worms at 20 °C compared with the germline of EV RNAi-treated worms at 15 °C. Statistical comparisons were made by two-tailed t-test, n=3 (each replicate contains 150 extruded germ lines from N2 wild-type worms), P <0.01 was considered significant. Germlines were extruded at day 6 of adulthood.

Supplementary Dataset 3

Statistical analysis and replicate data of lifespan experiments. All statistical comparisons were made by two-sided log-rank test, n=96 worms per condition.

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Lee, H.J., Noormohammadi, A., Koyuncu, S. et al. Prostaglandin signals from adult germline stem cells delay somatic ageing of Caenorhabditis elegans. Nat Metab 1, 790–810 (2019). https://doi.org/10.1038/s42255-019-0097-9

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