title: Cardioprotection and lifespan extension by the natural polyamine spermidine.
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.
authors.affiliation: Institute of Molecular Biosciences, NAWI Graz, University of Graz, Graz, Austria.|BioTechMed Graz, Graz, Austria.
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authors.lastname: Eisenberg
authors.affiliation: Department of Cardiology, Medical University of Graz, Graz, Austria.
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authors.affiliation: Institute of Molecular Biosciences, NAWI Graz, University of Graz, Graz, Austria.
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authors.affiliation: Department of Cardiology, Medical University of Graz, Graz, Austria.|Department of Internal Medicine and Cardiology, Campus Virchow-Klinikum, Charité-University Medicine Berlin, Berlin, Germany.
authors.forename: Uwe
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authors.lastname: Primessnig
authors.affiliation: Institute of Molecular Biosciences, NAWI Graz, University of Graz, Graz, Austria.
authors.forename: Slaven
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authors.affiliation: Institute of Molecular Biosciences, NAWI Graz, University of Graz, Graz, Austria.
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authors.affiliation: Institute of Molecular Biosciences, NAWI Graz, University of Graz, Graz, Austria.|Department of Internal Medicine, Medical University of Graz, Graz, Austria.
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authors.affiliation: Institute of Functional and Applied Anatomy, Hannover Medical School, Hannover, Germany.|Cluster of Excellence REBIRTH (From Regenerative Biology to Reconstructive Therapy), Hannover, Germany.
authors.forename: Julia
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authors.lastname: Schipke
authors.affiliation: Institute of Molecular Biosciences, NAWI Graz, University of Graz, Graz, Austria.
authors.forename: Andreas
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authors.affiliation: Department of Cardiology, Medical University of Graz, Graz, Austria.
authors.forename: Albrecht
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authors.affiliation: Department of Cell Biology and Molecular Medicine, Rutgers-New Jersey Medical School, Newark, USA.
authors.forename: Mingming
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authors.affiliation: Institute of Molecular Biosciences, NAWI Graz, University of Graz, Graz, Austria.
authors.forename: Christoph
authors.initials: C
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authors.affiliation: Institute of Molecular Biosciences, NAWI Graz, University of Graz, Graz, Austria.
authors.forename: Christopher
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authors.affiliation: Institute of Molecular Biosciences, NAWI Graz, University of Graz, Graz, Austria.
authors.forename: Angelina S
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authors.affiliation: Department of Cardiology, Medical University of Graz, Graz, Austria.
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authors.affiliation: Joanneum Research Forschungsgesellschaft m.b.H., HEALTH, Institute for Biomedicine and Health Sciences, Graz, Austria.
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authors.affiliation: Joanneum Research Forschungsgesellschaft m.b.H., HEALTH, Institute for Biomedicine and Health Sciences, Graz, Austria.
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authors.affiliation: Joanneum Research Forschungsgesellschaft m.b.H., HEALTH, Institute for Biomedicine and Health Sciences, Graz, Austria.
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authors.affiliation: Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria.
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authors.affiliation: 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.|Department of Biology, University of Fribourg, Fribourg, Switzerland.
authors.forename: Zehan
authors.initials: Z
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authors.affiliation: Clinical division of Nephrology, Medical University of Graz, Graz, Austria.
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authors.affiliation: Clinical division of Nephrology, Medical University of Graz, Graz, Austria.
authors.forename: Kathrin
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authors.affiliation: Institute of Molecular Biosciences, NAWI Graz, University of Graz, Graz, Austria.
authors.forename: Didac
authors.initials: D
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authors.affiliation: Institute of Molecular Biosciences, NAWI Graz, University of Graz, Graz, Austria.|Department of Molecular Biosciences, Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.
authors.forename: Sabrina
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authors.affiliation: Equipe 11 Labellisée Ligue Contre le Cancer, Centre de Recherche des Cordeliers, Paris, France.|Cell Biology and Metabolomics Platforms, Gustave Roussy Comprehensive Cancer Center, Villejuif, France.|INSERM, U1138, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Paris, France.|Université Pierre et Marie Curie, Paris, France.
authors.forename: Federico
authors.initials: F
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authors.affiliation: Institute of Molecular Biosciences, NAWI Graz, University of Graz, Graz, Austria.
authors.forename: Oskar
authors.initials: O
authors.lastname: Knittelfelder
authors.affiliation: Department of Biology, University of Padua, Padua, Italy.|Dulbecco-Telethon Institute, Venetian Institute of Molecular Medicine, Padua, Italy.
authors.forename: Emilie
authors.initials: E
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authors.affiliation: Institute of Molecular Biosciences, NAWI Graz, University of Graz, Graz, Austria.|Kent Fungal Group, School of Biosciences, University of Kent, Canterbury, UK.
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authors.initials: P
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authors.affiliation: Department of Cardiology, Medical University of Graz, Graz, Austria.
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authors.affiliation: Institute of Functional and Applied Anatomy, Hannover Medical School, Hannover, Germany.
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authors.affiliation: German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.|Chair of Experimental Genetics, School of Life Science Weihenstephan, Technische Universität München, Freising, Germany.|German Center for Diabetes Research (DZD), Neuherberg, Germany.
authors.forename: Johannes
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authors.affiliation: German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
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authors.affiliation: German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.|Institute of Pathology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
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authors.initials: F
authors.lastname: Neff
authors.affiliation: German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.|Institute of Pathology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Janik
authors.affiliation: German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.|German Center for Diabetes Research (DZD), Neuherberg, Germany.|Institute of Molecular Animal Breeding and Biotechnology, Gene Center, Ludwig-Maximilians University München, Munich, Germany.
authors.forename: Birgit
authors.initials: B
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authors.affiliation: German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.|German Center for Diabetes Research (DZD), Neuherberg, Germany.
authors.forename: Jan
authors.identifier: 0000-0002-8035-8904
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authors.affiliation: German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.|Chair of Experimental Genetics, School of Life Science Weihenstephan, Technische Universität München, Freising, Germany.|German Center for Diabetes Research (DZD), Neuherberg, Germany.
authors.forename: Martin Hrabe
authors.identifier: 0000-0002-7898-2353
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authors.affiliation: Institute of Molecular Biosciences, NAWI Graz, University of Graz, Graz, Austria.|Department of Internal Medicine, Medical University of Graz, Graz, Austria.
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authors.affiliation: Institute of Molecular Biosciences, NAWI Graz, University of Graz, Graz, Austria.
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authors.forename: Marion
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authors.affiliation: Department of Cardiology, Medical University of Graz, Graz, Austria.|Department of Internal Medicine and Cardiology, Campus Virchow-Klinikum, Charité-University Medicine Berlin, Berlin, Germany.|Department of Internal Medicine and Cardiology, German Heart Center Berlin, Berlin, Germany.
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authors.initials: B
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authors.affiliation: Department of Biology, University of Padua, Padua, Italy.|Dulbecco-Telethon Institute, Venetian Institute of Molecular Medicine, Padua, Italy.
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authors.identifier: 0000-0002-8515-8928
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authors.affiliation: Department of Internal Medicine, Medical University of Graz, Graz, Austria.|Joanneum Research Forschungsgesellschaft m.b.H., HEALTH, Institute for Biomedicine and Health Sciences, Graz, Austria.
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authors.affiliation: Institute of Functional and Applied Anatomy, Hannover Medical School, Hannover, Germany.|Cluster of Excellence REBIRTH (From Regenerative Biology to Reconstructive Therapy), Hannover, Germany.
authors.forename: Christian
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authors.affiliation: Department of Cell Biology and Molecular Medicine, Rutgers-New Jersey Medical School, Newark, USA.
authors.forename: Junichi
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authors.affiliation: 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.|Department of Biology, University of Fribourg, Fribourg, Switzerland.
authors.forename: Joern
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authors.forename: Stefan
authors.initials: S
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authors.affiliation: Equipe 11 Labellisée Ligue Contre le Cancer, Centre de Recherche des Cordeliers, Paris, France.|Cell Biology and Metabolomics Platforms, Gustave Roussy Comprehensive Cancer Center, Villejuif, France.|INSERM, U1138, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Paris, France.|Université Pierre et Marie Curie, Paris, France.|Pôle de Biologie, Hôpital Européen Georges Pompidou, Paris, France.|Karolinska Institute, Department of Women's and Children's Health, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Guido
authors.initials: G
authors.lastname: Kroemer
authors.affiliation: BioTechMed Graz, Graz, Austria.|Department of Cardiology, Medical University of Graz, Graz, Austria.
authors.forename: Simon
authors.identifier: 0000-0002-4419-6821
authors.initials: S
authors.lastname: Sedej
authors.affiliation: Institute of Molecular Biosciences, NAWI Graz, University of Graz, Graz, Austria.|BioTechMed Graz, Graz, Austria.
authors.forename: Frank
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mesh_terms: D000328:Adult; D000368:Aged; D000375:Aging / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D000071187:Autophagy-Related Protein 5 / Q000235:genetics; D001794:Blood Pressure / Q000187:drug effects*; D006332:Cardiomegaly / Q000000981:diagnostic imaging; D002316:Cardiotonic Agents / Q000494:pharmacology; D002318:Cardiovascular Diseases / Q000453:epidemiology; D002851:Chromatography, High Pressure Liquid; D064211:Connectin / Q000187:drug effects / Q000378:metabolism; D016207:Cytokines / Q000187:drug effects / Q000276:immunology; D003971:Diastole; D004032:Diet / Q000706:statistics & numerical data; D004452:Echocardiography; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D005951:Glucose Tolerance Test; D006321:Heart / Q000000981:diagnostic imaging / Q000187:drug effects*; D006333:Heart Failure; D006801:Humans; D015151:Immunoblotting; D007249:Inflammation; D008136:Longevity / Q000187:drug effects*; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D008875:Middle Aged; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000378:metabolism; D063306:Mitophagy / Q000187:drug effects*; D032383:Myocytes, Cardiac / Q000187:drug effects*; D010766:Phosphorylation / Q000187:drug effects; D011446:Prospective Studies; D051381:Rats; D020303:Rats, Inbred Dahl; D013095:Spermidine / Q000494:pharmacology*; D011795:Surveys and Questionnaires
chemical_list: C495773:Atg5 protein, mouse; D000071187:Autophagy-Related Protein 5; D002316:Cardiotonic Agents; D064211:Connectin; D016207:Cytokines; D013095:Spermidine