Cardioprotection and lifespan extension by the natural polyamine spermidine
Open accessAbstract
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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Spermidine inhibits histone acetyltransferases, resulting in higher resistance to oxidative stress, increased autophagy, and markedly reduced subclinical inflammation and rates of cell necrosis during aging.
“Spermidine is known to inhibit histone acetyltransferases, which results in higher resistance to oxidative stress, to increase autophagy as well as to markedly reduce subclinical inflammation and the rates of cell necrosis during aging (60).”
From Health Benefits of the Mediterranean Diet: Metabolic and Molecular Mechanisms (2018) · cites this paper as [60]
Spermidine, contained in the germ of whole grains, has been shown to extend chronological life span in flies, nematodes, rodents, and human cells.
“Moreover, the germ of whole grains contain a polyamine, called spermidine, which has been shown to extend chronological life span in flies, nematodes, rodents, and human cells (60).”
From Health Benefits of the Mediterranean Diet: Metabolic and Molecular Mechanisms (2018) · cites this paper as [60]
Conditional cardiomyocyte-specific deletion of Atg5 exacerbates cardiac abnormalities and premature death, linked to increased ubiquitination and mitochondrial misalignment.
“| Cardiomyopathies | Conditional cardiomyocyte‐specific deletion of Atg5 | Exacerbated cardiac abnormalities and premature death, linked to increased ubiquitination and mitochondrial misalignment | Nakai et al (2007), Taneike et al (2010), Eisenberg et al (2016) |”
From Autophagy in major human diseases (2021) · cites this paper as Eisenberg et al (2016)
Spermidine provides cardioprotection and extends life in mice through activation of autophagy and mitophagy.
“It was shown to provide cardioprotection and to extend life in mice through the activation of autophagy and mitophagy [276].”
From The mitochondrial permeability transition: Nexus of aging, disease and longevity (2021) · cites this paper as [276]
Spermidine is an effective antiaging agent.
“and has been shown to be an effective antiaging agent [275,276,277].”
From The mitochondrial permeability transition: Nexus of aging, disease and longevity (2021) · cites this paper as [276]
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- Authors
- Eisenberg, T., Abdellatif, M., Schroeder, S., Primessnig, U., Stekovic, S., Pendl, T., Harger, A., Schipke, J., Zimmermann, A., Schmidt, A., Tong, M., Ruckenstuhl, C., Dammbrueck, C., Gross, A. S., Herbst, V., Magnes, C., Trausinger, G., Narath, S., Meinitzer, A., Hu, Z., Kirsch, A., Eller, K., Carmona-Gutierrez, D., Büttner, S., Pietrocola, F., Knittelfelder, O., Schrepfer, E., Rockenfeller, P., Simonini, C., Rahn, A., Horsch, M., Moreth, K., Beckers, J., Fuchs, H., Gailus-Durner, V., Neff, F., Janik, D., Rathkolb, B., Rozman, J., de Angelis, M. H., Moustafa, T., Haemmerle, G., Mayr, M., Willeit, P., von Frieling-Salewsky, M., Pieske, B., Scorrano, L., Pieber, T., Pechlaner, R., Willeit, J., Sigrist, S. J., Linke, W. A., Mühlfeld, C., Sadoshima, J., Dengjel, J., Kiechl, S., Kroemer, G., Sedej, S., & Madeo, F.
- Affiliations
- University of Graz (AT)
- Medical University of Graz (AT)
- Medizinische Hochschule Hannover (DE)
- Rutgers New Jersey Medical School (US)
- Joanneum Research (AT)
- University of Fribourg (CH)
- Inserm (FR)
- University of Padua (IT)
- Helmholtz Munich (DE)
- King's College London (GB)
- Innsbruck Medical University (AT)
- Freie Universität Berlin (DE)
- Ruhr University Bochum (DE)
- Karolinska University Hospital (SE)
- Corresponding author
- Kroemer, Guido
- Sedej, Simon
- Madeo, Frank
- ORCID
- Eisenberg, Tobias
- Abdellatif, Mahmoud
- Primessnig, Uwe
- Pendl, Tobias
- Schipke, Julia
- Zimmermann, Andreas
- Schmidt, Albrecht
- Tong, Mingming
- Ruckenstuhl, Christoph
- Gross, Angelina S
- Magnes, Christoph
- Meinitzer, Andreas
- Hu, Zehan
- Kirsch, Alexander
- Eller, Kathrin
- Büttner, Sabrina
- Pietrocola, Federico
- Knittelfelder, Oskar
- Rockenfeller, Patrick
- Simonini, Corinna
- Rahn, Alexandros
- Moreth, Kristin
- Beckers, Johannes
- Fuchs, Helmut
- Janik, Dirk
- Rathkolb, Birgit
- Rozman, Jan
- de Angelis, Martin Hrabe
- Moustafa, Tarek
- Haemmerle, Guenter
- Mayr, Manuel
- Willeit, Peter
- Pieske, Burkert
- Scorrano, Luca
- Pieber, Thomas
- Pechlaner, Raimund
- Willeit, Johann
- Sigrist, Stephan J
- Linke, Wolfgang A
- Mühlfeld, Christian
- Sadoshima, Junichi
- Kiechl, Stefan
- Kroemer, Guido
- Sedej, Simon
- Madeo, Frank
- Venue
- Nature Medicine
- Published
- 2016-11-14
- Volume
- 22
- Issue
- 12
- Pages
- 1428-1438
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC5806691
- OpenAlex
- W2554740475
- Cited by
- 1,168
- References
- 91
- Citations by year
- 2026: 127 · 2025: 116 · 2024: 124 · 2023: 112 · 2022: 146 · 2021: 148 · 2020: 139 · 2019: 96 · 2018: 96 · 2017: 54 · 2016: 5 · 2012: 1
- FWCI
- 43.47
- Type
- journal article
- Language
- en
- Open access
- green
- kar.kent.ac.uk
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- Kent Academic Repository (University of Kent) (acceptedVersion)
- PubMed Central (acceptedVersion)
- HAL (submittedVersion, other-oa)
- mediaTUM (Technical University of Munich) (submittedVersion, other-oa)
- Site cant be reached (submittedVersion)
- PuSH - Publication Server of Helmholtz Zentrum München (submittedVersion)
- Padua Research Archive (University of Padova) (submittedVersion)
- Funders
- National Science Foundation
- Harvard University
- INFRAFRONTIER (01KX1012)
- National Institute for Health and Care Research
- British Heart Foundation (FS/13/2/29892, FS/11/29/28759)
- King's College London
- Deutsche Forschungsgemeinschaft (CRC1140, SFB 1002, 01KX1012)
- Agence Nationale de la Recherche (ANR-10-LABX-0015)
- Fondation Leducq
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (27893, 31003A-166482/1, 31003A, 166482)
- Österreichischen Akademie der Wissenschaften
- Bundesministerium für Bildung und Forschung (01GQ1420A, 01KX1012)
- Austrian Science Fund (P27183, P 27637, P 24381, P 27893, I1000, P 23490, J 3742)
- Bundesministerium für Wissenschaft, Forschung und Wirtschaft (843536)
- Vetenskapsrådet (2015-05468)
- Österreichische Forschungsförderungsgesellschaft (843536)
- Bundesministerium für Verkehr, Innovation und Technologie (843536)
- Institut National Du Cancer
- Karl-Franzens-Universität Graz
- Medizinische Universität Graz
- Standortagentur Tirol (843536)
- Wirtschaftsagentur Wien (843536)
- Labex Immuno-Oncology
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Polyamine Metabolism and Applications
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- spermidine, polyamines, lifespan extension, cardioprotection, cardiac hypertrophy, diastolic function, cardiac autophagy, mitophagy, mitochondrial respiration, titin phosphorylation, subclinical inflammation, ATG5, Dahl salt-sensitive rats, hypertension, congestive heart failure, high-salt diet, dietary intake, blood pressure, cardiovascular disease, aging
- MeSH terms
- Autophagy-Related Protein 5, Adult, Aged, Aging, Animals, Autophagy, Blood Pressure, Cardiotonic Agents, Cardiovascular Diseases, Chromatography, High Pressure Liquid, Diastole, Diet, Echocardiography, Female, Glucose Tolerance Test, Heart, Cardiomegaly, Heart Failure, Humans, Inflammation, Longevity, Male, Middle Aged, Mitochondria, Heart, Phosphorylation, Prospective Studies, Surveys and Questionnaires, Mass Spectrometry, Spermidine, Immunoblotting, Gene Expression, Cytokines, Rats, Inbred Dahl, Myocytes, Cardiac, Mice, Rats, Mitophagy, Connectin
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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