Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

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.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

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.

Similar content being viewed by others

Accession codes

Primary accessions

Gene Expression Omnibus

References

  1. Zile, 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, 1387–1393 (2002).

    PubMed  Google Scholar 

  2. Chiao, Y.A. & Rabinovitch, P.S. The aging heart. Cold Spring Harb. Perspect. Med. 5, a025148 (2015).

    PubMed  PubMed Central  Google Scholar 

  3. Redfield, M.M. et al. Burden of systolic and diastolic ventricular dysfunction in the community: appreciating the scope of the heart-failure epidemic. J. Am. Med. Assoc. 289, 194–202 (2003).

    Google Scholar 

  4. Bui, A.L., Horwich, T.B. & Fonarow, G.C. Epidemiology and risk profile of heart failure. Nat. Rev. Cardiol. 8, 30–41 (2011).

    PubMed  Google Scholar 

  5. Nakai, A. et al. The role of autophagy in cardiomyocytes in the basal state and in response to hemodynamic stress. Nat. Med. 13, 619–624 (2007).

    CAS  PubMed  Google Scholar 

  6. Taneike, M. et al. Inhibition of autophagy in the heart induces age-related cardiomyopathy. Autophagy 6, 600–606 (2010).

    CAS  PubMed  Google Scholar 

  7. Madeo, F., Zimmermann, A., Maiuri, M.C. & Kroemer, G. Essential role for autophagy in lifespan extension. J. Clin. Invest. 125, 85–93 (2015).

    PubMed  PubMed Central  Google Scholar 

  8. Eisenberg, T. et al. Induction of autophagy by spermidine promotes longevity. Nat. Cell Biol. 11, 1305–1314 (2009).

    CAS  PubMed  Google Scholar 

  9. Morselli, E. et al. Spermidine and resveratrol induce autophagy by distinct pathways converging on the acetylproteome. J. Cell Biol. 192, 615–629 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Gupta, V.K. et al. Restoring polyamines protects from age-induced memory impairment in an autophagy-dependent manner. Nat. Neurosci. 16, 1453–1460 (2013).

    CAS  PubMed  Google Scholar 

  11. Büttner, S. et al. Spermidine protects against α-synuclein neurotoxicity. Cell Cycle 13, 3903–3908 (2014).

    PubMed  PubMed Central  Google Scholar 

  12. Wang, I.-F. et al. Autophagy activators rescue and alleviate pathogenesis of a mouse model with proteinopathies of the TAR DNA-binding protein 43. Proc. Natl. Acad. Sci. USA 109, 15024–15029 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Weindruch, R., Walford, R.L., Fligiel, S. & Guthrie, D. The retardation of aging in mice by dietary restriction: longevity, cancer, immunity and lifetime energy intake. J. Nutr. 116, 641–654 (1986).

    CAS  PubMed  Google Scholar 

  14. Dai, D.-F. et al. Overexpression of catalase targeted to mitochondria attenuates murine cardiac aging. Circulation 119, 2789–2797 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Blackwell, B.N., Bucci, T.J., Hart, R.W. & Turturro, A. Longevity, body weight and neoplasia in ad libitum–fed and diet-restricted C57BL6 mice fed NIH-31 open-formula diet. Toxicol. Pathol. 23, 570–582 (1995).

    CAS  PubMed  Google Scholar 

  16. Treuting, P.M. et al. Reduction of age-associated pathology in old mice by overexpression of catalase in mitochondria. J. Gerontol. A Biol. Sci. Med. Sci. 63, 813–822 (2008).

    PubMed  Google Scholar 

  17. Soda, K., Kano, Y., Chiba, F., Koizumi, K. & Miyaki, Y. Increased polyamine intake inhibits age-associated alteration in global DNA methylation and 1,2-dimethylhydrazine-induced tumorigenesis. PLoS One 8, e64357 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Paulus, W.J. et al. How to diagnose diastolic heart failure: a consensus statement on the diagnosis of heart failure with normal left ventricular ejection fraction by the Heart Failure and Echocardiography Associations of the European Society of Cardiology. Eur. Heart J. 28, 2539–2550 (2007).

    PubMed  Google Scholar 

  19. Ky, B. et al. Ventricular-arterial coupling, remodeling and prognosis in chronic heart failure. J. Am. Coll. Cardiol. 62, 1165–1172 (2013).

    PubMed  PubMed Central  Google Scholar 

  20. Dai, D.-F. & Rabinovitch, P.S. Cardiac aging in mice and humans: the role of mitochondrial oxidative stress. Trends Cardiovasc. Med. 19, 213–220 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Heinzel, F.R., Hohendanner, F., Jin, G., Sedej, S. & Edelmann, F. Myocardial hypertrophy and its role in heart failure with preserved ejection fraction. J. Appl. Physiol. 119, 1233–1242 (2015).

    CAS  PubMed  Google Scholar 

  22. Linke, W.A. & Hamdani, N. Gigantic business: titin properties and function through thick and thin. Circ. Res. 114, 1052–1068 (2014).

    CAS  PubMed  Google Scholar 

  23. Borbély, A. et al. Cardiomyocyte stiffness in diastolic heart failure. Circulation 111, 774–781 (2005).

    PubMed  Google Scholar 

  24. López-Otín, C., Blasco, M.A., Partridge, L., Serrano, M. & Kroemer, G. The hallmarks of aging. Cell 153, 1194–1217 (2013).

    PubMed  PubMed Central  Google Scholar 

  25. Salvioli, S. et al. Inflamm-aging, cytokines and aging: state-of-the-art, new hypotheses on the role of mitochondria and new perspectives from systems biology. Curr. Pharm. Des. 12, 3161–3171 (2006).

    CAS  PubMed  Google Scholar 

  26. Duicu, O.M. et al. Ageing-induced decrease in cardiac mitochondrial function in healthy rats. Can. J. Physiol. Pharmacol. 91, 593–600 (2013).

    CAS  PubMed  Google Scholar 

  27. Liu, Y., Samuel, B.S., Breen, P.C. & Ruvkun, G. Caenorhabditis elegans pathways that surveil and defend mitochondria. Nature 508, 406–410 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Yeganeh, B. et al. Targeting the mevalonate cascade as a new therapeutic approach in heart disease, cancer and pulmonary disease. Pharmacol. Ther. 143, 87–110 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Paulus, W.J. & Tschöpe, C. A novel paradigm for heart failure with preserved ejection fraction: comorbidities drive myocardial dysfunction and remodeling through coronary microvascular endothelial inflammation. J. Am. Coll. Cardiol. 62, 263–271 (2013).

    PubMed  Google Scholar 

  30. Haspel, J. et al. Characterization of macroautophagic flux in vivo using a leupeptin-based assay. Autophagy 7, 629–642 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Hariharan, N., Zhai, P. & Sadoshima, J. Oxidative stress stimulates autophagic flux during ischemia–reperfusion. Antioxid. Redox Signal. 14, 2179–2190 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Shirakabe, A. et al. Drp1-dependent mitochondrial autophagy plays a protective role against pressure-overload-induced mitochondrial dysfunction and heart failure. Circulation 133, 1249–1263 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Gottdiener, J.S. et al. Predictors of congestive heart failure in the elderly: the Cardiovascular Health Study. J. Am. Coll. Cardiol. 35, 1628–1637 (2000).

    CAS  PubMed  Google Scholar 

  34. Doi, R. et al. Development of different phenotypes of hypertensive heart failure: systolic versus diastolic failure in Dahl salt-sensitive rats. J. Hypertens. 18, 111–120 (2000).

    CAS  PubMed  Google Scholar 

  35. Qu, P. et al. Time-course changes in left ventricular geometry and function during the development of hypertension in Dahl salt-sensitive rats. Hypertens. Res. 23, 613–623 (2000).

    CAS  PubMed  Google Scholar 

  36. Palmer, R.M., Ashton, D.S. & Moncada, S. Vascular endothelial cells synthesize nitric oxide from l-arginine. Nature 333, 664–666 (1988).

    CAS  PubMed  Google Scholar 

  37. Chen, P.Y. & Sanders, P.W. l-arginine abrogates salt-sensitive hypertension in Dahl/Rapp rats. J. Clin. Invest. 88, 1559–1567 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Tang, W.H.W., Wang, Z., Cho, L., Brennan, D.M. & Hazen, S.L. Diminished global arginine bioavailability and increased arginine catabolism as metabolic profile of increased cardiovascular risk. J. Am. Coll. Cardiol. 53, 2061–2067 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Sourij, H. et al. Arginine bioavailability ratios are associated with cardiovascular mortality in patients referred to coronary angiography. Atherosclerosis 218, 220–225 (2011).

    CAS  PubMed  Google Scholar 

  40. Ommen, S.R. et al. Clinical utility of Doppler echocardiography and tissue Doppler imaging in the estimation of left ventricular filling pressures: a comparative simultaneous Doppler–catheterization study. Circulation 102, 1788–1794 (2000).

    CAS  PubMed  Google Scholar 

  41. Kelly, R.P. et al. Effective arterial elastance as index of arterial vascular load in humans. Circulation 86, 513–521 (1992).

    CAS  PubMed  Google Scholar 

  42. Leoncini, G. et al. Renal and cardiac abnormalities in primary hypertension. J. Hypertens. 27, 1064–1073 (2009).

    CAS  PubMed  Google Scholar 

  43. Gori, M. et al. Association between renal function and cardiovascular structure and function in heart failure with preserved ejection fraction. Eur. Heart J. 35, 3442–3451 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Klotz, S. et al. Development of heart failure in chronic hypertensive Dahl rats: focus on heart failure with preserved ejection fraction. Hypertension 47, 901–911 (2006).

    CAS  PubMed  Google Scholar 

  45. Mori, K. & Nakao, K. Neutrophil gelatinase-associated lipocalin as the real-time indicator of active kidney damage. Kidney Int. 71, 967–970 (2007).

    CAS  PubMed  Google Scholar 

  46. Stegemann, C. et al. Lipidomics profiling and risk of cardiovascular disease in the prospective population-based Bruneck study. Circulation 129, 1821–1831 (2014).

    CAS  PubMed  Google Scholar 

  47. Schindler, C.E., Partap, U., Patchen, B.K. & Swoap, S.J. Chronic rapamycin treatment causes diabetes in male mice. Am. J. Physiol. Regul. Integr. Comp. Physiol. 307, R434–R443 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Miller, R.A. et al. Rapamycin-mediated lifespan increase in mice is dose and sex dependent and metabolically distinct from dietary restriction. Aging Cell 13, 468–477 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. LaRocca, T.J., Gioscia-Ryan, R.A., Hearon, C.M. Jr. & Seals, D.R. The autophagy enhancer spermidine reverses arterial aging. Mech. Ageing Dev. 134, 314–320 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. García-Prat, L. et al. Autophagy maintains stemness by preventing senescence. Nature 529, 37–42 (2016).

    PubMed  Google Scholar 

  51. Hara, T. et al. Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature 441, 885–889 (2006).

    CAS  PubMed  Google Scholar 

  52. Wettschureck, N. et al. Absence of pressure-overload-induced myocardial hypertrophy after conditional inactivation of Gαq–Gα11 in cardiomyocytes. Nat. Med. 7, 1236–1240 (2001).

    CAS  PubMed  Google Scholar 

  53. Sedej, S. et al. Na+-dependent SR Ca2+ overload induces arrhythmogenic events in mouse cardiomyocytes with a human CPVT mutation. Cardiovasc. Res. 87, 50–59 (2010).

    CAS  PubMed  Google Scholar 

  54. Miller, R.A. et al. An Aging Interventions Testing Program: study design and interim report. Aging Cell 6, 565–575 (2007).

    CAS  PubMed  Google Scholar 

  55. Yuan, R. et al. Aging in inbred strains of mice: study design and interim report on median lifespans and circulating IGF1 levels. Aging Cell 8, 277–287 (2009).

    CAS  PubMed  Google Scholar 

  56. Kastenmayer, R.J., Fain, M.A. & Perdue, K.A. A retrospective study of idiopathic ulcerative dermatitis in mice with a C57BL/6 background. J. Am. Assoc. Lab. Anim. Sci. 45, 8–12 (2006).

    CAS  PubMed  Google Scholar 

  57. Rozman, J. et al. Glucose tolerance tests for systematic screening of glucose homeostasis in mice. Curr. Protoc. Mouse Biol. 5, 65–84 (2015).

    CAS  PubMed  Google Scholar 

  58. Sedej, S. et al. Subclinical abnormalities in sarcoplasmic reticulum Ca2+ release promote eccentric myocardial remodeling and pump failure death in response to pressure overload. J. Am. Coll. Cardiol. 63, 1569–1579 (2014).

    CAS  PubMed  Google Scholar 

  59. Troy, B.L., Pombo, J. & Rackley, C.E. Measurement of left ventricular wall thickness and mass by echocardiography. Circulation 45, 602–611 (1972).

    CAS  PubMed  Google Scholar 

  60. Pacher, P., Nagayama, T., Mukhopadhyay, P., Bátkai, S. & Kass, D.A. Measurement of cardiac function using pressure–volume conductance catheter technique in mice and rats. Nat. Protoc. 3, 1422–1434 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Abdellatif, M. et al. Spectral transfer function analysis of respiratory hemodynamic fluctuations predicts end-diastolic stiffness in preserved ejection fraction heart failure. Am. J. Physiol. Heart Circ. Physiol. 310, H4–H13 (2016).

    PubMed  Google Scholar 

  62. Tournoux, F. et al. Validation of noninvasive measurements of cardiac output in mice using echocardiography. J. Am. Soc. Echocardiogr. 24, 465–470 (2011).

    PubMed  PubMed Central  Google Scholar 

  63. Wolf, D. et al. CD4+CD25+ regulatory T cells inhibit experimental anti–glomerular basement membrane glomerulonephritis in mice. J. Am. Soc. Nephrol. 16, 1360–1370 (2005).

    CAS  PubMed  Google Scholar 

  64. Saeed, A.I. et al. TM4: a free, open-source system for microarray data management and analysis. Biotechniques 34, 374–378 (2003).

    CAS  PubMed  Google Scholar 

  65. Sturn, A., Quackenbush, J. & Trajanoski, Z. Genesis: cluster analysis of microarray data. Bioinformatics 18, 207–208 (2002).

    CAS  PubMed  Google Scholar 

  66. Shevchenko, A., Tomas, H., Havlis, J., Olsen, J.V. & Mann, M. In-gel digestion for mass spectrometric characterization of proteins and proteomes. Nat. Protoc. 1, 2856–2860 (2006).

    CAS  PubMed  Google Scholar 

  67. Rappsilber, J., Mann, M. & Ishihama, Y. Protocol for micropurification, enrichment, prefractionation and storage of peptides for proteomics using StageTips. Nat. Protoc. 2, 1896–1906 (2007).

    CAS  PubMed  Google Scholar 

  68. Sprenger, A., Küttner, V., Bruckner-Tuderman, L. & Dengjel, J. Global proteome analyses of SILAC-labeled skin cells. Methods Mol. Biol. 961, 179–191 (2013).

    CAS  PubMed  Google Scholar 

  69. Cox, J. & Mann, M. MaxQuant enables high peptide identification rates, individualized p.p.b.-range mass accuracies and proteome-wide protein quantification. Nat. Biotechnol. 26, 1367–1372 (2008).

    CAS  PubMed  Google Scholar 

  70. Magnes, C. et al. Polyamines in biological samples: rapid and robust quantification by solid-phase extraction online-coupled to liquid chromatography–tandem mass spectrometry. J. Chromatogr. A 1331, 44–51 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Yuan, M., Breitkopf, S.B., Yang, X. & Asara, J.M. A positive/negative ion-switching, targeted mass-spectrometry-based metabolomics platform for bodily fluids, cells, and fresh and fixed tissue. Nat. Protoc. 7, 872–881 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Braun, R.J. et al. Accumulation of basic amino acids at mitochondria dictates the cytotoxicity of aberrant ubiquitin. Cell Rep. 10, 1557–1571 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Buescher, J.M., Moco, S., Sauer, U. & Zamboni, N. Ultrahigh-performance liquid chromatography–tandem mass spectrometry method for fast and robust quantification of anionic and aromatic metabolites. Anal. Chem. 82, 4403–4412 (2010).

    CAS  PubMed  Google Scholar 

  74. Roth, M. Fluorescence reaction for amino acids. Anal. Chem. 43, 880–882 (1971).

    CAS  PubMed  Google Scholar 

  75. Schwarz, E.L., Roberts, W.L. & Pasquali, M. Analysis of plasma amino acids by HPLC with photodiode array and fluorescence detection. Clin. Chim. Acta 354, 83–90 (2005).

    CAS  PubMed  Google Scholar 

  76. Shirakabe, A. et al. Evaluating mitochondrial autophagy in the mouse heart. J. Mol. Cell. Cardiol. 92, 134–139 (2016).

    CAS  PubMed  Google Scholar 

  77. Neagoe, C. et al. Titin isoform switch in ischemic human heart disease. Circulation 106, 1333–1341 (2002).

    PubMed  Google Scholar 

  78. Hamdani, N. et al. Crucial role for Ca2+–calmodulin-dependent protein kinase II in regulating diastolic stress of normal and failing hearts via titin phosphorylation. Circ. Res. 112, 664–674 (2013).

    CAS  PubMed  Google Scholar 

  79. Mayhew, T.M. Taking tissue samples from the placenta: an illustration of principles and strategies. Placenta 29, 1–14 (2008).

    CAS  PubMed  Google Scholar 

  80. Mühlfeld, C., Nyengaard, J.R. & Mayhew, T.M. A review of state-of-the-art stereology for better quantitative 3D morphology in cardiac research. Cardiovasc. Pathol. 19, 65–82 (2010).

    PubMed  Google Scholar 

  81. Méndez, J. & Keys, A. Density and composition of mammalian muscle. Metabolism 9, 184–188 (1960).

    Google Scholar 

  82. Willett, W.C. et al. Reproducibility and validity of a semiquantitative food-frequency questionnaire. Am. J. Epidemiol. 122, 51–65 (1985).

    CAS  PubMed  Google Scholar 

  83. McKee, P.A., Castelli, W.P., McNamara, P.M. & Kannel, W.B. The natural history of congestive heart failure: the Framingham study. N. Engl. J. Med. 285, 1441–1446 (1971).

    CAS  PubMed  Google Scholar 

  84. Willeit, P. et al. Discrimination and net reclassification of cardiovascular risk with lipoprotein(a): prospective 15-year outcomes in the Bruneck Study. J. Am. Coll. Cardiol. 64, 851–860 (2014).

    PubMed  Google Scholar 

  85. Willett, W. & Stampfer, M.J. Total energy intake: implications for epidemiologic analyses. Am. J. Epidemiol. 124, 17–27 (1986).

    CAS  PubMed  Google Scholar 

  86. Assarsson, E. et al. Homogenous 96-plex PEA immunoassay exhibiting high sensitivity, specificity and excellent scalability. PLoS One 9, e95192 (2014).

    PubMed  PubMed Central  Google Scholar 

  87. Wei, J., Carroll, R.J., Harden, K.K. & Wu, G. Comparisons of treatment means when factors do not interact in two-factorial studies. Amino Acids 42, 2031–2035 (2012).

    CAS  PubMed  Google Scholar 

  88. Burkhoff, D., Mirsky, I. & Suga, H. Assessment of systolic and diastolic ventricular properties via pressure–volume analysis: a guide for clinical, translational and basic researchers. Am. J. Physiol. Heart Circ. Physiol. 289, H501–H512 (2005).

    CAS  PubMed  Google Scholar 

Download references

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

Authors and Affiliations

Authors

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.

Corresponding authors

Correspondence to Guido Kroemer, 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 Figures

Supplementary Figures 1–18, Supplementary Tables 1–16, Supplementary Notes (PDF 16921 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

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

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing