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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.

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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.

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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.

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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.

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Correspondence to Guido Kroemer, Simon Sedej or Frank Madeo.

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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.

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Eisenberg, T., Abdellatif, M., Schroeder, S. et al. Cardioprotection and lifespan extension by the natural polyamine spermidine. Nat Med 22, 1428–1438 (2016). https://doi.org/10.1038/nm.4222

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