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⇱ Induction of autophagy by spermidine promotes longevity | Nature Cell Biology

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Abstract

Ageing results from complex genetically and epigenetically programmed processes that are elicited in part by noxious or stressful events that cause programmed cell death. Here, we report that administration of spermidine, a natural polyamine whose intracellular concentration declines during human ageing, markedly extended the lifespan of yeast, flies and worms, and human immune cells. In addition, spermidine administration potently inhibited oxidative stress in ageing mice. In ageing yeast, spermidine treatment triggered epigenetic deacetylation of histone H3 through inhibition of histone acetyltransferases (HAT), suppressing oxidative stress and necrosis. Conversely, depletion of endogenous polyamines led to hyperacetylation, generation of reactive oxygen species, early necrotic death and decreased lifespan. The altered acetylation status of the chromatin led to significant upregulation of various autophagy-related transcripts, triggering autophagy in yeast, flies, worms and human cells. Finally, we found that enhanced autophagy is crucial for polyamine-induced suppression of necrosis and enhanced longevity.

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Figure 1: Application of spermidine extends the lifespan of yeast, flies and human immune cells, and inhibits oxidative stress in ageing mice.
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Figure 2: Polyamine depletion shortens yeast chronological lifespan evoking markers of oxidative stress and necrosis.
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Figure 3: Spermidine application suppresses necrotic cell death.
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Figure 4: Lifespan extension by spermidine application is accompanied by epigenetic hypoacetylation of histone H3.
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Figure 5: Spermidine-induced longevity is mediated by inhibition of HAT activity and correlates with upregulation of autophagy-related genes.
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Figure 6: Autophagy is induced by spermidine and critical for maximal life span extension in yeast.
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Figure 7: Autophagy is essential for spermidine-induced life span extension in flies and worms.
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Acknowledgements

We thank Ulrike Potocnik, Silvia Dichtinger, Arno Absenger and Elfgard Heintz for assistance. We are grateful to the Austrian Science Fund FWF (Austria) for grant S-9304-B05 (to F.M., S.B. and D.C.-G.), grant S-9303-B05 (to K.-U.F. and H.K.), grant LIPOTOX (to F.M. and S.B.), and grant S-9301-B05 (to B.G.-L.) and to the European Commission for project TransDeath (to K.-U.F. and C.R.), project APOSYS (to F.M., T.E. and G.K.) and project Lifespan (FP6 036894 to B.G.-L.). We are grateful to the Austrian Science Fund FWF (Vienna, Austria) for grants S9302-B05 (to M.B.) and to the European Commission (Brussels, Europe) for project MIMAGE (contract no. 512020; to M.B.).

Author information

Author notes

  1. Nadege Minois

    Present address: Current address: School of Biology, University of St Andrews, St Andrews, Scotland, Fife KY16 9AJ, UK.,

Authors and Affiliations

  1. Institute of Molecular Biosciences, University of Graz, Graz, 8010, Austria

    Tobias Eisenberg, Heide Knauer, Alexandra Schauer, Sabrina BΓΌttner, Christoph Ruckenstuhl, Didac Carmona-Gutierrez, Julia Ring, Sabrina Schroeder, Lucia Antonacci, Heike Fussi, Kai-Uwe FrΓΆhlich & Frank Madeo

  2. Institute of Medical Technologies and Health Management, Joanneum Research, Graz, Austria

    Christoph Magnes & Frank Sinner

  3. Research Institute of Molecular Pathology (IMP), Vienna, Austria

    Luiza Deszcz, Regina Hartl & Nadege Minois

  4. Institute of Molecular Biotechnology (IMBA), Austrian Academy of Sciences, Vienna, Austria

    Luiza Deszcz, Regina Hartl & Nadege Minois

  5. Institute of Applied Microbiology, University of Natural Resources and Applied Life Sciences, Vienna, Austria

    Elisabeth Schraml

  6. INSERM, U848,

    Alfredo Criollo & Guido Kroemer

  7. Villejuif, 94805, France

    Alfredo Criollo & Guido Kroemer

  8. Institut Gustave Roussy, Villejuif, 94805, France

    Alfredo Criollo & Guido Kroemer

  9. University Paris Sud, Paris-11, Villejuif, 94805, France

    Alfredo Criollo & Guido Kroemer

  10. Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology-Hellas, Heraklion, 70013, Crete, Greece

    Evgenia Megalou & Nektarios Tavernarakis

  11. Institute for Biomedical Ageing Research, Austrian Academy of Sciences, Innsbruck, 6020, Austria

    Daniela Weiskopf & Beatrix Grubeck-Loebenstein

  12. Department of Cell Biology, Division of Genetics, University of Salzburg, Salzburg, 5020, Austria

    Peter Laun, Gino Heeren & Michael Breitenbach

  13. Gladstone Institute of Virology and Immunology, San Francisco, 94158, CA, USA

    Eva Herker

  14. M.E. Mueller Institute for Structural Biology, Biozentrum, University of Basel, Basel, 4056, Switzerland

    Birthe Fahrenkrog

Authors
  1. Tobias Eisenberg
  2. Heide Knauer
  3. Alexandra Schauer
  4. Sabrina BΓΌttner
  5. Christoph Ruckenstuhl
  6. Didac Carmona-Gutierrez
  7. Julia Ring
  8. Sabrina Schroeder
  9. Christoph Magnes
  10. Lucia Antonacci
  11. Heike Fussi
  12. Luiza Deszcz
  13. Regina Hartl
  14. Elisabeth Schraml
  15. Alfredo Criollo
  16. Evgenia Megalou
  17. Daniela Weiskopf
  18. Peter Laun
  19. Gino Heeren
  20. Michael Breitenbach
  21. Beatrix Grubeck-Loebenstein
  22. Eva Herker
  23. Birthe Fahrenkrog
  24. Kai-Uwe FrΓΆhlich
  25. Frank Sinner
  26. Nektarios Tavernarakis
  27. Nadege Minois
  28. Guido Kroemer
  29. Frank Madeo

Contributions

T.E., G.K. and F.M. designed and organized this study and wrote the manuscript. T.E. performed the largest part of the yeast and mouse experiments and contributed significantly to the fly and PBMC cell culture data. H.K., A.S., S.B., C.R., D.C-G., J.R., S.S., H.F., L.A. and B.A. contributed to the yeast experiments. C.M. and F.S. performed polyamine measurements by MassSpec. L.D., R.H. and N.M. performed the fly experiments. E.S. contributed to mouse data. A.C. performed HELA cell culture experiments. E.M. and N.T. contributed the worm data. D.W. and B.G-L. performed PBMC experiments. P.L., G.H. and M.B. determined yeast replicative life spans. N.M., E.H., K.-U.F., S.B., C.R. and D.C-G. contributed with decisive discussions and helped to design experiments.

Corresponding authors

Correspondence to Guido Kroemer or Frank Madeo.

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Competing interests

The authors declare no competing financial interests.

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Eisenberg, T., Knauer, H., Schauer, A. et al. Induction of autophagy by spermidine promotes longevity. Nat Cell Biol 11, 1305–1314 (2009). https://doi.org/10.1038/ncb1975

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