Tier 3 — preclinical

Cardioprotection and lifespan extension by the natural polyamine spermidine

Eisenberg T, Abdellatif M, Schroeder S, Primessnig U, Stekovic S, Pendl T, Harger A, Schipke J, Zimmermann A, Madeo F, et al.
Nature Medicine 2016 22(12):1428-1438

Bibliography

PubMed
PMID 27841876
PubMed Central
PMC5806691
DOI
10.1038/nm.4222
Funding
We thank N. Mizushima (University of Tokyo, Tokyo, Japan) for providing Atg5flox/flox mice and K. Chien (Harvard University, Cambridge, Massachusetts, USA) for providing MLC2a-Cre mice. We are grateful to R. Schreiber for assistance with high-resolution respirometry. FM is grateful to the Austrian Science Fund FWF (Austria) for grants P23490-B12, P24381, P 27893, I1000 and grant ‘SFB Lipotox’ and 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). TE is recipient of an APART fellowship of the Austrian Academy of Sciences. MA received funding from the FWF (P27637-B28) and was trained within the frame of the PhD Program Molecular Medicine of the Medical University of Graz. SB is supported by the Austrian Science Fund FWF (grant P27183-B24) and Swedish Research Council (grant 2015-05468). JD is supported by the DFG via CRC1140 and by the Swiss National Science Foundation, grant 31003A-166482/1. PR is supported by the Austrian Science Fund (FWF) project J3742-B28 and NAWI Graz. WAL is supported by EU (FP7) program MEDIA and German Research Foundation, SFB1002, TPA8 GK is supported by the LeDucq Foundation, Cancéropôle Ile-de-France; Institut National du Cancer (INCa); the European Research Council (ERC); the 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’ (JB), the Helmholtz Alliance ‘Imaging and Curing Environmental Metabolic Diseases (ICEMED)’ (JB) and by the German Federal Ministry of Education and Research (Infrafrontier grant 01KX1012.) (MHA). SJS was supported by grants from the Bundesministerium für Bildung und Forschung (Smartage, 01GQ1420A), from the Forschungszentrum für neurodegenerative Erkrankungen and from 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' 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.
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.

Study snapshot

DesignCombined preclinical (mouse/rat feeding and genetic knockout studies) and human cross-sectional dietary correlation analysis
ModelMice, Dahl salt-sensitive rats, cardiomyocyte cultures, and a human dietary-questionnaire cohort
SampleAnimal cohorts plus a human dietary-questionnaire correlation analysis (not an interventional human cohort)
InterventionOral spermidine supplementation (animal feeding); dietary spermidine intake assessed via food questionnaire (human arm)
DurationChronic feeding studies in animals; cross-sectional human dietary assessment
EndpointsCardiac hypertrophy; Diastolic function; Autophagy/mitophagy markers; Blood pressure; Human dietary spermidine correlation with cardiovascular disease incidence

What the study showed, in plain terms

Spermidine is a natural compound found in a variety of foods. In this study, researchers investigated whether adding spermidine to drinking water could improve heart health and extend lifespan. They discovered that oral spermidine supplementation significantly extended the median lifespan of wild-type mice, even when the treatment was started late in their lives.

The study demonstrated that spermidine protects the heart by triggering a cellular cleanup process known as autophagy, along with mitophagy, which removes damaged cellular components and dysfunctional energy powerhouses (mitochondria). In old mice, spermidine reversed age-associated heart enlargement and improved the heart's ability to relax and fill with blood (diastolic function). When the researchers genetically disabled the autophagy process in the heart muscle cells of mice, these protective benefits disappeared, confirming that cellular cleanup is the mechanism behind spermidine's success.

Beyond natural aging, spermidine also protected rats that were fed a high-salt diet to induce high blood pressure and heart failure. Additionally, the researchers analyzed human data from a 15-year prospective study and found that people who naturally consumed higher amounts of dietary spermidine had lower blood pressure and a significantly reduced risk of developing heart failure and other cardiovascular diseases.

Key findings

  • Spermidine supplementation in drinking water extended the median lifespan of wild-type mice; when administered late in life (starting at 18 months), median lifespan was prolonged by approximately 10%.
  • In aged mice (23–24 months old), spermidine reversed age-associated cardiac hypertrophy and improved diastolic function, significantly reducing left ventricular end-diastolic pressure and myocardial passive stiffness.
  • Spermidine enhanced autophagic flux and mitophagy in cardiomyocytes; its cardioprotective effects—including reduced left ventricular hypertrophy and improved ventricular-vascular coupling—were entirely abolished in mice lacking the essential autophagy gene Atg5.
  • In a rat model of salt-induced hypertension, spermidine supplementation delayed the rise in systemic blood pressure, attenuated cardiac hypertrophy, preserved diastolic function, and reduced signs of hypertensive renal injury.
  • In a prospective human cohort (the Bruneck Study, n=829), high dietary spermidine intake was inversely associated with systolic and diastolic blood pressure, and was linked to a roughly 40% reduction in the risk of fatal heart failure compared to low-intake groups.

What this study can and cannot tell us

The human data presented in this study is observational, relying on food frequency questionnaires to estimate dietary spermidine intake. This methodology cannot definitively establish a causal relationship between spermidine and reduced cardiovascular risk in humans, as it does not account for differences in food processing or unmeasured lifestyle factors.

While the study demonstrates significant lifespan extension and cardioprotection in rodent models, the exact doses used in the animal drinking water do not directly translate to human dietary guidelines or supplement dosages. Human clinical trials involving controlled spermidine supplementation are necessary to confirm therapeutic efficacy.

Although the research clearly proves that spermidine relies on autophagy to protect the heart, it is difficult to fully isolate how much of the lifespan extension in mice is driven specifically by these cardiac improvements versus other systemic, anti-inflammatory, or blood-pressure-lowering effects.

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Dr. Khaled Mahmoud, MBBChCritical Care Medicine, Longevity Science & Editorial Direction Dr. Amr Yasser, PhDCardiometabolic, Musculoskeletal, Gut & Bioavailability