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Cardioprotection and lifespan extension by the natural polyamine spermidine

Nature Medicine volume 22, pages 14281438 (2016) | Download Citation

Abstract

Aging is associated with an increased risk of cardiovascular disease and death. Here we show that oral supplementation of the natural polyamine spermidine extends the lifespan of mice and exerts cardioprotective effects, reducing cardiac hypertrophy and preserving diastolic function in old mice. Spermidine feeding enhanced cardiac autophagy, mitophagy and mitochondrial respiration, and it also improved the mechano-elastical properties of cardiomyocytes in vivo, coinciding with increased titin phosphorylation and suppressed subclinical inflammation. Spermidine feeding failed to provide cardioprotection in mice that lack the autophagy-related protein Atg5 in cardiomyocytes. In Dahl salt-sensitive rats that were fed a high-salt diet, a model for hypertension-induced congestive heart failure, spermidine feeding reduced systemic blood pressure, increased titin phosphorylation and prevented cardiac hypertrophy and a decline in diastolic function, thus delaying the progression to heart failure. In humans, high levels of dietary spermidine, as assessed from food questionnaires, correlated with reduced blood pressure and a lower incidence of cardiovascular disease. Our results suggest a new and feasible strategy for protection against cardiovascular disease.

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Acknowledgements

We thank N. Mizushima (University of Tokyo) for providing Atg5fl/fl mice and K. Chien (Harvard University) for providing MLC2a-Cre mice. We are grateful to R. Schreiber for assistance with high-resolution respirometry. F.M. is grateful to the Austrian Science Fund FWF (Austria) for grants P23490-B12, P24381, P 27893, I1000 and 'SFB Lipotox', as well as to BMWFW and the Karl-Franzens University for grant 'Unkonventionelle Forschung'. S. Sedej is supported by the Austrian Science Fund FWF through grant P27637-B28 and by a grant from the Austrian Heart Foundation (Österreichischer Herzfonds). T.E. is recipient of an APART fellowship from the Austrian Academy of Sciences. M.A. received funding from the FWF (grant P27637-B28) and was trained within the frame of the Ph.D Program Molecular Medicine of the Medical University of Graz. S.B. is supported by the Austrian Science Fund FWF (grant P27183-B24) and the Swedish Research Council (grant 2015-05468). J.D. is supported by the DFG via grant CRC1140 and by the Swiss National Science Foundation, grant 31003A-166482/1. P.R. is supported by the Austrian Science Fund (FWF) project J3742-B28 and NAWI Graz. W.A.L. is supported by EU (FP7) program MEDIA and the German Research Foundation grant SFB1002, TPA8. G.K. is supported by the LeDucq Foundation, the Cancéropôle Ile-de-France, the Institut National du Cancer (INCa), the European Research Council (ERC), LabEx Immuno-Oncology and the Paris Alliance of Cancer Research Institutes (PACRI). The project was supported by grants from the Helmholtz Portfolio Theme 'Metabolic Dysfunction and Common Disease' (J.B.), the Helmholtz Alliance ('Imaging and Curing Environmental Metabolic Diseases (ICEMED)'; J.B.) and the German Federal Ministry of Education and Research (Infrafrontier grant 01KX1012) (M.H.d.A.). S.J.S. was supported by grants from the Bundesministerium für Bildung und Forschung (Smartage, 01GQ1420A), the Forschungszentrum für neurodegenerative Erkrankungen and the Deutsche Forschungsgemeinschaft (Exc 257). S.K., J.W., R.P., P.W. and M.M. are supported by an excellence initiative (Competence Centers for Excellent Technologies; COMET) of the Austrian Research Promotion Agency FFG: 'Research Center of Excellence in Vascular Ageing–Tyrol, VASCage' (K-Project Nr. 843536) funded by the BMVIT, BMWFW, the Wirtschaftsagentur Wien and the Standortagentur Tirol. This work was supported by the National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy's and St Thomas's NHS Foundation Trust and King's College London in partnership with King's College Hospital. M.M. is a Senior Research fellow of the British Heart Foundation. The authors are grateful for the support by staff members of the animal facilities of the Institutes of Biomedical Research (IBF, Medical University of Graz) and Molecular Biosciences (IMB, University of Graz) and acknowledge the Center for Medical Research (ZMF) of the Medical University of Graz for assistance.

Author information

Author notes

    • Tobias Eisenberg
    •  & Mahmoud Abdellatif

    These authors contributed equally to this work.

    • Guido Kroemer
    • , Simon Sedej
    •  & Frank Madeo

    These authors jointly directed this work.

Affiliations

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

    • Tobias Eisenberg
    • , Sabrina Schroeder
    • , Slaven Stekovic
    • , Tobias Pendl
    • , Alexandra Harger
    • , Andreas Zimmermann
    • , Christoph Ruckenstuhl
    • , Christopher Dammbrueck
    • , Angelina S Gross
    • , Didac Carmona-Gutierrez
    • , Sabrina Büttner
    • , Oskar Knittelfelder
    • , Patrick Rockenfeller
    • , Tarek Moustafa
    • , Guenter Haemmerle
    •  & Frank Madeo
  2. BioTechMed Graz, Graz, Austria.

    • Tobias Eisenberg
    • , Simon Sedej
    •  & Frank Madeo
  3. Department of Cardiology, Medical University of Graz, Graz, Austria.

    • Mahmoud Abdellatif
    • , Uwe Primessnig
    • , Albrecht Schmidt
    • , Viktoria Herbst
    • , Corinna Simonini
    • , Burkert Pieske
    •  & Simon Sedej
  4. Department of Internal Medicine and Cardiology, Campus Virchow-Klinikum, Charité–University Medicine Berlin, Berlin, Germany.

    • Uwe Primessnig
    •  & Burkert Pieske
  5. Department of Internal Medicine, Medical University of Graz, Graz, Austria.

    • Alexandra Harger
    • , Tarek Moustafa
    •  & Thomas Pieber
  6. Institute of Functional and Applied Anatomy, Hannover Medical School, Hannover, Germany.

    • Julia Schipke
    • , Alexandros Rahn
    •  & Christian Mühlfeld
  7. Cluster of Excellence REBIRTH (From Regenerative Biology to Reconstructive Therapy), Hannover, Germany.

    • Julia Schipke
    •  & Christian Mühlfeld
  8. Department of Cell Biology and Molecular Medicine, Rutgers–New Jersey Medical School, Newark, USA.

    • Mingming Tong
    •  & Junichi Sadoshima
  9. Joanneum Research Forschungsgesellschaft m.b.H., HEALTH, Institute for Biomedicine and Health Sciences, Graz, Austria.

    • Christoph Magnes
    • , Gert Trausinger
    • , Sophie Narath
    •  & Thomas Pieber
  10. Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria.

    • Andreas Meinitzer
  11. FRIAS Freiburg Institute for Advanced Studies, Department of Dermatology, Medical Center, ZBSA Center for Biological Systems Analysis, BIOSS Centre for Biological Signalling Studies, University of Freiburg, Freiburg, Germany.

    • Zehan Hu
    •  & Joern Dengjel
  12. Department of Biology, University of Fribourg, Fribourg, Switzerland.

    • Zehan Hu
    •  & Joern Dengjel
  13. Clinical division of Nephrology, Medical University of Graz, Graz, Austria.

    • Alexander Kirsch
    •  & Kathrin Eller
  14. Department of Molecular Biosciences, Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.

    • Sabrina Büttner
  15. Equipe 11 Labellisée Ligue Contre le Cancer, Centre de Recherche des Cordeliers, Paris, France.

    • Federico Pietrocola
    •  & Guido Kroemer
  16. Cell Biology and Metabolomics Platforms, Gustave Roussy Comprehensive Cancer Center, Villejuif, France.

    • Federico Pietrocola
    •  & Guido Kroemer
  17. INSERM, U1138, Paris, France.

    • Federico Pietrocola
    •  & Guido Kroemer
  18. Université Paris Descartes, Sorbonne Paris Cité, Paris, France.

    • Federico Pietrocola
    •  & Guido Kroemer
  19. Université Pierre et Marie Curie, Paris, France.

    • Federico Pietrocola
    •  & Guido Kroemer
  20. Department of Biology, University of Padua, Padua, Italy.

    • Emilie Schrepfer
    •  & Luca Scorrano
  21. Dulbecco-Telethon Institute, Venetian Institute of Molecular Medicine, Padua, Italy.

    • Emilie Schrepfer
    •  & Luca Scorrano
  22. Kent Fungal Group, School of Biosciences, University of Kent, Canterbury, UK.

    • Patrick Rockenfeller
  23. German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.

    • Marion Horsch
    • , Kristin Moreth
    • , Johannes Beckers
    • , Helmut Fuchs
    • , Valerie Gailus-Durner
    • , Frauke Neff
    • , Dirk Janik
    • , Birgit Rathkolb
    • , Jan Rozman
    •  & Martin Hrabe de Angelis
  24. Chair of Experimental Genetics, School of Life Science Weihenstephan, Technische Universität München, Freising, Germany.

    • Johannes Beckers
    •  & Martin Hrabe de Angelis
  25. German Center for Diabetes Research (DZD), Neuherberg, Germany.

    • Johannes Beckers
    • , Birgit Rathkolb
    • , Jan Rozman
    •  & Martin Hrabe de Angelis
  26. Institute of Pathology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.

    • Frauke Neff
    •  & Dirk Janik
  27. Institute of Molecular Animal Breeding and Biotechnology, Gene Center, Ludwig–Maximilians University München, Munich, Germany.

    • Birgit Rathkolb
  28. King's British Heart Foundation Centre, King's College London, London, UK.

    • Manuel Mayr
  29. Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria.

    • Peter Willeit
    • , Raimund Pechlaner
    • , Johann Willeit
    •  & Stefan Kiechl
  30. Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.

    • Peter Willeit
  31. Department of Cardiovascular Physiology, Ruhr University Bochum, Bochum, Germany.

    • Marion von Frieling-Salewsky
    •  & Wolfgang A Linke
  32. Department of Internal Medicine and Cardiology, German Heart Center Berlin, Berlin, Germany.

    • Burkert Pieske
  33. Institute for Biology, Freie Universität Berlin, Berlin, Germany.

    • Stephan J Sigrist
  34. NeuroCure, Charité, Berlin, Germany.

    • Stephan J Sigrist
  35. Pôle de Biologie, Hôpital Européen Georges Pompidou, Paris, France.

    • Guido Kroemer
  36. Karolinska Institute, Department of Women's and Children's Health, Karolinska University Hospital, Stockholm, Sweden.

    • Guido Kroemer

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Contributions

T.E., S. Sedej, G.K. and F.M. designed and supervised the study; T.E., M.A., G.K., S. Sedej and F.M. wrote the manuscript; T.E., M.A., S. Schroeder, U.P., S. Stekovic, T. Pendl, A.H., J. Schipke, A.Z., A.S., M.T., C.R., C.D., A.S.G., V.H., C. Magnes, G.T., S.N., A.M., Z.H., A.K., D.C.-G., S.B., F.P., O.K., E.S., P.R., C.S., A.R., M.H., F.N., D.J., B.R., J.R, T.M., M.M., P.W., M.v.F.-S., R.P. and S. Sedej performed experiments and analyzed and discussed data; K.E., K.M., J.B., H.F., V.G.-D., M.H.d.A., G.H., B.P., L.S., T. Pieber, J.W., S.J.S., W.A.L., C. Mühlfeld, J. Sadoshima, J.D. and S.K. discussed and analyzed data and gave conceptual advice.

Competing interests

F.M., T.E., D.C.-G., S.J.S. and S. Stekovic have equity interests in TLL, a company founded in 2016 that will develop natural food extracts.

Corresponding authors

Correspondence to Guido Kroemer or Simon Sedej or Frank Madeo.

Supplementary information

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    Supplementary Text and Figures

    Supplementary Figures 1–18, Supplementary Tables 1–16, Supplementary Notes

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DOI

https://doi.org/10.1038/nm.4222