Spermidine in health and disease

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Science  26 Jan 2018:
Vol. 359, Issue 6374, eaan2788
DOI: 10.1126/science.aan2788
  • Schematic outline of the mechanisms of spermidine-mediated health effects.

    The natural polyamine spermidine has prominent cardioprotective and neuroprotective effects, ameliorates aging-associated metabolic decline, and stimulates anticancer immunosurveillance in animal models. Autophagy is required for several of these health-promoting effects of spermidine. Spermidine also suppresses proinflammatory cytokines and improves the bioavailability of arginine required for NO biosynthesis. It remains an open question whether all these effects depend on the autophagy-stimulatory properties of spermidine.

  • Fig. 1 Regulation of the intracellular spermidine pool.

    Major routes and enzymes of mammalian polyamine metabolism. The cytosolic spermidine pool results from uptake, biosynthesis, catabolism, and transport. Spermidine is formed from its precursor putrescine or by degradation from spermine. Polyamine biosynthesis connects to arginine and NO metabolism via ornithine (as part of the urea cycle). Spermidine catabolism is mainly mediated through acetylation and subsequent oxidation reactions. Through the cofactors dcSAM (polyamine biosynthesis) and acetyl-CoA (polyamine catabolism), polyamine metabolism interrelates to protein/DNA methylation and protein acetylation, respectively, and thus indirectly influences epigenetic regulation of gene expression. ACLY, ATP-citrate synthase; ACSS2, acetyl-coenzyme A synthetase, cytoplasmic; AMD1, S-adenosylmethionine decarboxylase proenzyme; ARG1, arginase-1; ATP, adenosine triphosphate; CoA, coenzyme A; dcSAM, decarboxylated S-adenosylmethionine; MAT1/2A, S-adenosylmethionine synthase isoform type 1/2; NAA, N-acetylaspartate; NAT8L, N-acetylaspartate synthetase; NO, nitric oxide; ODC1, ornithine decarboxylase; PAOX, peroxisomal N(1)-acetyl-spermine/spermidine oxidase; SAM, S-adenosylmethionine; SMO, spermine oxidase; SAT1, spermidine/spermine N(1)-acetyltransferase 1; SMS, spermine synthase; Spd, spermidine; Spm, spermine SRM, spermidine synthase; VPAT, vesicular polyamine transporter.

  • Fig. 2 Sources of systemic spermidine.

    Scheme depicting the sources crucial for spermidine bioavailability in the whole organism. In addition to cellular metabolism (outlined in Fig. 1), spermidine is taken up orally from dietary sources or produced by commensal gut bacteria. Subsequently, spermidine can be resorbed by intestinal epithelial cells and is distributed through systemic circulation. Examples of spermidine-rich foods are enumerated. Food supplements, including the polyamine precursor arginine and probiotics (polyamine-producing bacteria), increase the intestinal production of polyamines.

  • Fig. 3 Spermidine-mediated health effects.

    (A) Summary of effects elicited by dietary or otherwise supplemented spermidine in different organ systems. Plus symbols indicate “improved.” (B) Spermidine-enhanced autophagy is required for several of the health-promoting effects presented in (A). Spermidine also suppresses proinflammatory cytokines and improves the bioavailability of arginine required for NO biosynthesis, mediating immunomodulatory and antihypertensive effects. It remains an open question to which extent autophagy contributes to spermidine-mediated changes in cytokine production and arginine or NO metabolism.

  • Fig. 4 Cellular and molecular mechanisms of spermidine-mediated health protection.

    Mechanistic models of the cellular and molecular effects elicited by spermidine through transcriptional, posttranslational (affecting protein acetylation and phosphorylation), as well as metabolic effects. (A) Rapid autophagy induction by spermidine administration through inhibition of the acetyl transferase EP300, primarily resulting in autophagy-relevant cytosolic protein deacetylation. Sustained autophagic control by spermidine is mediated through induction of autophagy-relevant gene transcription. This involves the regulation of FOXO transcription factor as well as inhibition of histone acetyl transferases, resulting in epigenetic transcriptional reprogramming. (B) Spermidine may suppress tumorigenesis through induction of autophagy in healthy cells. In autophagy-competent tumor cells, spermidine favors the autophagy-dependent release of ATP, which in turn favors immunosurveillance. (C) Anti-inflammatory effects of spermidine are explained through its effects on macrophages, promoting M2 polarization and the suppression of NFκB-dependent proinflammatory cytokines. These inhibitory macrophages then suppress autoimmune-reactive T cells. At the same time, spermidine favors formation of CD8+ memory T cells via induction of autophagy. (D) The suppression of circulatory cytokines, such as TNFα, also contributes to cardiovascular protection, possibly via a concerted action with arginine-derived nitric oxide, which leads to vasodilation and promotes the cGMP/cGMP-dependent protein kinase (PKG)–dependent phosphorylation status of titin. Spermidine-enhanced autophagy and mitophagy also contribute to cardiomyocyte elasticity and mitochondrial functionality. (E) The inhibitory effect of spermidine on autoimmune-reactive T cells (C) further translates into prevention of neurodegeneration by demyelination. Neuroprotection is also mediated via autophagy-dependent proteostasis of presynaptic active zones, assuring the maintenance of synaptic plasticity. (F) Suppression of stem cell senescence by spermidine depends on autophagy (in satellite cells), whereas spermidine promotes mitochondrial function and production of keratins in epithelial stem cells. These stemness-enhancing effects ensure muscle and hair follicle regeneration, respectively. Red arrows (up or down) indicate changes (increased or decreased, respectively) that are observed after spermidine supplementation.

Supplementary Materials

  • Spermidine in health and disease

    Frank Madeo, Tobias Eisenberg, Federico Pietrocola, Guido Kroemer

    Materials/Methods, Supplementary Text, Tables, Figures, and/or References

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    • Tables S1 and S2
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