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Abstract

Age-dependent memory impairment is known to occur in several organisms, including Drosophila, mouse and human. However, the fundamental cellular mechanisms that underlie these impairments are still poorly understood, effectively hampering the development of pharmacological strategies to treat the condition. Polyamines are among the substances found to decrease with age in the human brain. We found that levels of polyamines (spermidine, putrescine) decreased in aging fruit flies, concomitant with declining memory abilities. Simple spermidine feeding not only restored juvenile polyamine levels, but also suppressed age-induced memory impairment. Ornithine decarboxylase-1, the rate-limiting enzyme for de novo polyamine synthesis, also protected olfactory memories in aged flies when expressed specifically in Kenyon cells, which are crucial for olfactory memory formation. Spermidine-fed flies showed enhanced autophagy (a form of cellular self-digestion), and genetic deficits in the autophagic machinery prevented spermidine-mediated rescue of memory impairments. Our findings indicate that autophagy is critical for suppression of memory impairments by spermidine and that polyamines, which are endogenously present, are candidates for pharmacological intervention.

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Acknowledgements

We would like to thank T. Neufeld (University of Minnesota), L. Luo (Stanford University) and the Bloomington Stock Center for fly stocks, and S. Gaumer (University Versailles) for ref(2)P antibody. We are also grateful to M.G. Holt and B. Gerber for critically reading the manuscript. This work was supported by grants from the Deutsche Forschungsgemeinschaft to S.J.S. (Exc257, FOR1363), as well as A6/SFB 958 and DynAge Focus Area (Freie Universität Berlin) to S.J.S., the European Union (FP7 Gencodys HEALTH-241995) to H.G.S. and A.S., a VIDI grant from the Netherlands Organization for Scientific Research (917-96-346) to A.S., the BMBF (BCCNII, grant number 01GQ1005A) to A.F., and the Emmy Noether Program to M.S. F.M. is grateful to the FWF for grants LIPOTOX, P23490, P24381 and I1000 (DACH). T.E. is recipient of an APART fellowship of the Austrian Academy of Sciences.

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Affiliations

  1. Institute for Biology/Genetics, Freie Universität Berlin, Berlin, Germany.

    • Varun K Gupta
    • , Lisa Scheunemann
    • , Sara Mertel
    • , Anuradha Bhukel
    • , Karen S Y Liu
    • , Martin Schwaerzel
    •  & Stephan J Sigrist
  2. NeuroCure, Charité, Berlin, Germany.

    • Varun K Gupta
    • , Anuradha Bhukel
    • , Karen S Y Liu
    •  & Stephan J Sigrist
  3. Institute of Molecular Biosciences, University of Graz, Graz, Austria.

    • Tobias Eisenberg
    • , Sabrina Schroeder
    •  & Frank Madeo
  4. Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences, Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.

    • Tom S Koemans
    • , Jamie M Kramer
    •  & Annette Schenck
  5. Department of Molecular Biology, Faculty of Science, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen, Nijmegen, The Netherlands.

    • Hendrik G Stunnenberg
  6. Health Institute for Biomedicine and Health Sciences, Joanneum Research Forschungs GesmBH, Graz, Austria.

    • Frank Sinner
    • , Christoph Magnes
    •  & Thomas R Pieber
  7. Department of Internal Medicine, Division of Endocrinology and Metabolism, Medical University of Graz, Austria.

    • Frank Sinner
    •  & Thomas R Pieber
  8. Georg-August-Universität Göttingen, Molecular Neurobiology of Behavior, Göttingen, Germany.

    • Shubham Dipt
    •  & André Fiala

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Contributions

V.K.G., F.M. and S.J.S. designed the study. V.K.G., L.S., T.E., C.M., S.M., T.S.K., J.M.K., A.B., S.D., K.S.Y.L., S.S. and C.M. performed the experiments. V.K.G., L.S., T.E., T.S.K., J.M.K., A.B., K.S.Y.L., S.S., S.D., C.M., F.M. and S.J.S. analyzed the data. F.S., M.S., T.R.P., A.F. and H.G.S. provided protocols, reagents and advice. All of the authors commented on the manuscript. V.K.G., A.S., F.M. and S.J.S. wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Frank Madeo or Stephan J Sigrist.

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DOI

https://doi.org/10.1038/nn.3512