AbstractAging 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. Subscription info for Chinese customersWe have a dedicated website for our Chinese customers. Please go to naturechina.com to subscribe to this journal.Go to naturechina.comRent or Buy articleGet time limited or full article access on ReadCube.from$8.99Rent or BuyAll prices are NET prices. Figure 1: Spermidine extends lifespan and improves cardiac diastolic function in mice.Figure 2: Spermidine improves cardiomyocyte composition and mitochondrial function in mice.Figure 3: Spermidine ameliorates cardiac function through induction of autophagy.Figure 4: Spermidine ameliorates salt-induced hypertension and heart failure in Dahl salt-sensitive rats.Figure 5: Dietary spermidine intake inversely correlates with human cardiovascular disease.Figure 6: Mechanistic model of spermidine-mediated cardioprotection in aging and hypertensive heart failure. References1Zile, M.R. Brutsaert, D.L. New concepts in diastolic dysfunction and diastolic heart failure: part I: diagnosis, prognosis and measurements of diastolic function. Circulation 105, 1387鈥?393 (2002).PubMed聽Google Scholar聽 2Chiao, Y.A. Rabinovitch, P.S. The aging heart. Cold Spring Harb. Perspect. Med. 5, a025148 (2015).PubMed聽 PubMed Central聽Google Scholar聽 3Redfield, M.M. et al. 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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 (脰sterreichischer 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 Canc茅rop么le 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 f眉r Bildung und Forschung (Smartage, 01GQ1420A), the Forschungszentrum f眉r 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鈥揟yrol, 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 informationAuthor notesTobias Eisenberg and Mahmoud Abdellatif: These authors contributed equally to this work.Guido Kroemer, Simon Sedej and Frank Madeo: These authors jointly directed this work.AffiliationsInstitute of Molecular Biosciences, NAWI Graz, University of Graz, Graz, AustriaTobias Eisenberg,聽Sabrina Schroeder,聽Slaven Stekovic,聽Tobias Pendl,聽Alexandra Harger,聽Andreas Zimmermann,聽Christoph Ruckenstuhl,聽Christopher Dammbrueck,聽Angelina S Gross,聽Didac Carmona-Gutierrez,聽Sabrina B眉ttner,聽Oskar Knittelfelder,聽Patrick Rockenfeller,聽Tarek Moustafa,聽Guenter Haemmerle聽 聽Frank MadeoBioTechMed Graz, Graz, AustriaTobias Eisenberg,聽Simon Sedej聽 聽Frank MadeoDepartment of Cardiology, Medical University of Graz, Graz, AustriaMahmoud Abdellatif,聽Uwe Primessnig,聽Albrecht Schmidt,聽Viktoria Herbst,聽Corinna Simonini,聽Burkert Pieske聽 聽Simon SedejDepartment of Internal Medicine and Cardiology, Campus Virchow-Klinikum, Charit茅鈥揢niversity Medicine Berlin, Berlin, GermanyUwe Primessnig聽 聽Burkert PieskeDepartment of Internal Medicine, Medical University of Graz, Graz, AustriaAlexandra Harger,聽Tarek Moustafa聽 聽Thomas PieberInstitute of Functional and Applied Anatomy, Hannover Medical School, Hannover, GermanyJulia Schipke,聽Alexandros Rahn聽 聽Christian M眉hlfeldCluster of Excellence REBIRTH (From Regenerative Biology to Reconstructive Therapy), Hannover, GermanyJulia Schipke聽 聽Christian M眉hlfeldDepartment of Cell Biology and Molecular Medicine, Rutgers鈥揘ew Jersey Medical School, Newark, USAMingming Tong聽 聽Junichi SadoshimaJoanneum Research Forschungsgesellschaft m.b.H., HEALTH, Institute for Biomedicine and Health Sciences, Graz, AustriaChristoph Magnes,聽Gert Trausinger,聽Sophie Narath聽 聽Thomas PieberClinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, AustriaAndreas MeinitzerDepartment of Dermatology, FRIAS Freiburg Institute for Advanced Studies, Medical Center, ZBSA Center for Biological Systems Analysis, BIOSS Centre for Biological Signalling Studies, University of Freiburg, Freiburg, GermanyZehan Hu聽 聽Joern DengjelDepartment of Biology, University of Fribourg, Fribourg, SwitzerlandZehan Hu聽 聽Joern DengjelClinical division of Nephrology, Medical University of Graz, Graz, AustriaAlexander Kirsch聽 聽Kathrin EllerDepartment of Molecular Biosciences, Wenner-Gren Institute, Stockholm University, Stockholm, SwedenSabrina B眉ttnerEquipe 11 Labellis茅e Ligue Contre le Cancer, Centre de Recherche des Cordeliers, Paris, FranceFederico Pietrocola聽 聽Guido KroemerCell Biology and Metabolomics Platforms, Gustave Roussy Comprehensive Cancer Center, Villejuif, FranceFederico Pietrocola聽 聽Guido KroemerINSERM, U1138, Paris, FranceFederico Pietrocola聽 聽Guido KroemerUniversit茅 Paris Descartes, Sorbonne Paris Cit茅, Paris, FranceFederico Pietrocola聽 聽Guido KroemerUniversit茅 Pierre et Marie Curie, Paris, FranceFederico Pietrocola聽 聽Guido KroemerDepartment of Biology, University of Padua, Padua, ItalyEmilie Schrepfer聽 聽Luca ScorranoDulbecco-Telethon Institute, Venetian Institute of Molecular Medicine, Padua, ItalyEmilie Schrepfer聽 聽Luca ScorranoKent Fungal Group, School of Biosciences, University of Kent, Canterbury, UKPatrick RockenfellerGerman Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum M眉nchen, German Research Center for Environmental Health, Neuherberg, GermanyMarion Horsch,聽Kristin Moreth,聽Johannes Beckers,聽Helmut Fuchs,聽Valerie Gailus-Durner,聽Frauke Neff,聽Dirk Janik,聽Birgit Rathkolb,聽Jan Rozman聽 聽Martin Hrabe de AngelisChair of Experimental Genetics, School of Life Science Weihenstephan, Technische Universit盲t M眉nchen, Freising, GermanyJohannes Beckers聽 聽Martin Hrabe de AngelisGerman Center for Diabetes Research (DZD), Neuherberg, GermanyJohannes Beckers,聽Birgit Rathkolb,聽Jan Rozman聽 聽Martin Hrabe de AngelisInstitute of Pathology, Helmholtz Zentrum M眉nchen, German Research Center for Environmental Health, Neuherberg, GermanyFrauke Neff聽 聽Dirk JanikInstitute of Molecular Animal Breeding and Biotechnology, Gene Center, Ludwig鈥揗aximilians University M眉nchen, Munich, GermanyBirgit RathkolbKing\'s British Heart Foundation Centre, King\'s College London, London, UKManuel MayrDepartment of Neurology, Medical University of Innsbruck, Innsbruck, AustriaPeter Willeit,聽Raimund Pechlaner,聽Johann Willeit聽 聽Stefan KiechlDepartment of Public Health and Primary Care, University of Cambridge, Cambridge, UKPeter WilleitDepartment of Cardiovascular Physiology, Ruhr University Bochum, Bochum, GermanyMarion von Frieling-Salewsky聽 聽Wolfgang A LinkeDepartment of Internal Medicine and Cardiology, German Heart Center Berlin, Berlin, GermanyBurkert PieskeInstitute for Biology, Freie Universit盲t Berlin, Berlin, GermanyStephan J SigristNeuroCure, Charit茅, Berlin, GermanyStephan J SigristP么le de Biologie, H么pital Europ茅en Georges Pompidou, Paris, FranceGuido KroemerDepartment of Women\'s and Children\'s Health, Karolinska Institute, Karolinska University Hospital, Stockholm, SwedenGuido KroemerAuthorsTobias EisenbergView author publicationsYou can also search for this author in PubMed聽Google ScholarMahmoud AbdellatifView author publicationsYou can also search for this author in PubMed聽Google ScholarSabrina SchroederView author publicationsYou can also search for this author in PubMed聽Google ScholarUwe PrimessnigView author publicationsYou can also search for this author in PubMed聽Google ScholarSlaven StekovicView author publicationsYou can also search for this author in PubMed聽Google ScholarTobias PendlView author publicationsYou can also search for this author in PubMed聽Google ScholarAlexandra HargerView author publicationsYou can also search for this 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PubMed聽Google ScholarSimon SedejView author publicationsYou can also search for this author in PubMed聽Google ScholarFrank MadeoView author publicationsYou can also search for this author in PubMed聽Google ScholarContributionsT.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. M眉hlfeld, J. Sadoshima, J.D. and S.K. discussed and analyzed data and gave conceptual advice.Corresponding authorsCorrespondence to Guido Kroemer or Simon Sedej or Frank Madeo.Ethics declarations 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. Supplementary information Supplementary Text and FiguresSupplementary Figures 1鈥?8, Supplementary Tables 1鈥?6, Supplementary Notes (PDF 16921 kb)Rights and permissionsReprints and PermissionsAbout this articleCite this articleEisenberg, T., Abdellatif, M., Schroeder, S. et al. Cardioprotection and lifespan extension by the natural polyamine spermidine. Nat Med 22, 1428鈥?438 (2016). https://doi.org/10.1038/nm.4222Download citationReceived: 08 June 2015Accepted: 24 September 2016Published: 14 November 2016Issue Date: December 2016DOI: https://doi.org/10.1038/nm.4222 Hui-min Li, Xin Liu, Zi-yu Meng, Lei Wang, Li-min Zhao, Hui Chen, Zhi-xia Wang, Hao Cui, Xue-qing Tang, Xiao-han Li, Wei-na Han, Xue Bai, Yuan Lin, Heng Liu, Yong Zhang Bao-feng Yang Acta Pharmacologica Sinica (2021) Atsuo Nakamura, Shin Kurihara, Daisuke Takahashi, Wakana Ohashi, Yutaka Nakamura, Shunsuke Kimura, Masayoshi Onuki, Aiko Kume, Yukiko Sasazawa, Yukihiro Furusawa, Yuuki Obata, Shinji Fukuda, Shinji Saiki, Mitsuharu Matsumoto Koji Hase Nature Communications (2021) Xudong Zhu, Zhiyang Chen, Weiyan Shen, Gang Huang, John M. Sedivy, Hu Wang Zhenyu Ju Signal Transduction and Targeted Therapy (2021) Miho Nozue, Taichi Shimazu, Hadrien Charvat, Nagisa Mori, Michihiro Mutoh, Norie Sawada, Motoki Iwasaki, Taiki Yamaji, Manami Inoue, Yoshihiro Kokubo, Kazumasa Yamagishi, Hiroyasu Iso Shoichiro Tsugane European Journal of Clinical Nutrition (2021) Sign up for the Nature Briefing newsletter 鈥?what matters in science, free to your inbox daily.