Letter | Published:

Dauer-independent insulin/IGF-1-signalling implicates collagen remodelling in longevity

Nature volume 519, pages 97101 (05 March 2015) | Download Citation

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Abstract

Interventions that delay ageing mobilize mechanisms that protect and repair cellular components1,2,3, but it is unknown how these interventions might slow the functional decline of extracellular matrices4,5, which are also damaged during ageing6,7. Reduced insulin/IGF-1 signalling (rIIS) extends lifespan across the evolutionary spectrum, and in juvenile Caenorhabditis elegans also allows the transcription factor DAF-16/FOXO to induce development into dauer, a diapause that withstands harsh conditions1,2. It has been suggested that rIIS delays C. elegans ageing through activation of dauer-related processes during adulthood2,8,9, but some rIIS conditions confer robust lifespan extension unaccompanied by any dauer-like traits1,10,11. Here we show that rIIS can promote C. elegans longevity through a program that is genetically distinct from the dauer pathway, and requires the Nrf (NF-E2-related factor) orthologue SKN-1 acting in parallel to DAF-16. SKN-1 is inhibited by IIS and has been broadly implicated in longevity12,13,14, but is rendered dispensable for rIIS lifespan extension by even mild activity of dauer-related processes. When IIS is decreased under conditions that do not induce dauer traits, SKN-1 most prominently increases expression of collagens and other extracellular matrix genes. Diverse genetic, nutritional, and pharmacological pro-longevity interventions delay an age-related decline in collagen expression. These collagens mediate adulthood extracellular matrix remodelling, and are needed for ageing to be delayed by interventions that do not involve dauer traits. By genetically delineating a dauer-independent rIIS ageing pathway, our results show that IIS controls a broad set of protective mechanisms during C. elegans adulthood, and may facilitate elucidation of processes of general importance for longevity. The importance of collagen production in diverse anti-ageing interventions implies that extracellular matrix remodelling is a generally essential signature of longevity assurance, and that agents promoting extracellular matrix youthfulness may have systemic benefit.

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Acknowledgements

We thank C. Kenyon, S. Mitani, and J. Shim for strains, P. Sengupta for dauer pheromone, C. Obieglo, L. Moronetti, M. Bland, and K. Patel for assistance, and J. Apfeld, E. Greer, C. Kenyon, W. Mair, and Blackwell laboratory members for discussions or comments on the manuscript. Some strains were provided by the Caenorhabditis Genetics Center, which is funded by the National Institutes of Health Office of Research Infrastructure Programs (P40 OD010440). The work was supported by funding from the National Institutes of Health to T.K.B. (GM062891), C.T.M. (New Innovator), and J.P.A. (5T32DK007260), a Diabetes Research Center award to the Joslin Diabetes Center (P30DK036836), and fellowships from the National Science Foundation to J.N.L., and the Swiss National Science Foundation (PBSKP3_140135) to C.Y.E.

Author information

Author notes

    • Jess N. Landis
    •  & Jess Porter Abate

    These authors contributed equally to this work.

Affiliations

  1. Joslin Diabetes Center, One Joslin Place, Boston, Massachusetts 02215, USA

    • Collin Y. Ewald
    • , Jess Porter Abate
    •  & T. Keith Blackwell
  2. Harvard Stem Cell Institute, 7 Divinity Avenue, Cambridge, Massachusetts 02138, USA

    • Collin Y. Ewald
    • , Jess Porter Abate
    •  & T. Keith Blackwell
  3. Department of Genetics, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, Massachusetts 02215, USA

    • Collin Y. Ewald
    • , Jess Porter Abate
    •  & T. Keith Blackwell
  4. Department of Molecular Biology, Lewis-Sigler Institute for Integrative Genomics, Princeton University, 148 Carl Icahn Laboratory, Washington Road, Princeton, New Jersey 08544, USA

    • Jess N. Landis
    •  & Coleen T. Murphy

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Contributions

All authors participated in designing the experiments, and analysing and interpreting the data. J.N.L. and J.P.A. obtained samples for microarray analysis, performed the microarray experiments, analysed the expression profiling data, and performed the lifespan studies in Extended Data Fig. 2f–h and Supplementary Table 4. C.Y.E. performed all other experiments. C.Y.E. and T.K.B. wrote the manuscript in consultation with the other authors.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Coleen T. Murphy or T. Keith Blackwell.

Extended data

Supplementary information

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    Supplementary Information

    This file contains Supplementary Tables 1-2 and 4-17, a Supplementary Discussion and additional references (see separate file for Supplementary Table 3).

Excel files

  1. 1.

    Supplementary Table 3

    The file contains a complete list of daf-2; skn-1-up- and downregulated gene sets.

Videos

  1. 1.

    daf-2(e1370) (Class 2) mutants were grown and maintained at 15°C.

    When maintained at 15°C, daf-2(e1370) mutants (Class 2) are mobile throughout their lifespan as shown here at day 14 of adulthood (10 min; 8x speed).

  2. 2.

    daf-2(e1370) (Class 2) mutants were grown and maintained at 15°C.

    When upshifted from 15°C to 20°C at the first day of adulthood, daf-2(e1370) is typical of other Class 2 mutants in that it becomes relatively immobile during much of its adult lifespan, as shown here at day 14 (10 min; 8x speed).

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