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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.

SUBMITTER: Eisenberg T

PROVIDER: S-EPMC5806691 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Cardioprotection and lifespan extension by the natural polyamine spermidine.

Eisenberg Tobias T Abdellatif Mahmoud M Schroeder Sabrina S Primessnig Uwe U Stekovic Slaven S Pendl Tobias T Harger Alexandra A Schipke Julia J Zimmermann Andreas A Schmidt Albrecht A Tong Mingming M Ruckenstuhl Christoph C Dammbrueck Christopher C Gross Angelina S AS Herbst Viktoria V Magnes Christoph C Trausinger Gert G Narath Sophie S Meinitzer Andreas A Hu Zehan Z Kirsch Alexander A Eller Kathrin K Carmona-Gutierrez Didac D Büttner Sabrina S Pietrocola Federico F Knittelfelder Oskar O Schrepfer Emilie E Rockenfeller Patrick P Simonini Corinna C Rahn Alexandros A Horsch Marion M Moreth Kristin K Beckers Johannes J Fuchs Helmut H Gailus-Durner Valerie V Neff Frauke F Janik Dirk D Rathkolb Birgit B Rozman Jan J de Angelis Martin Hrabe MH Moustafa Tarek T Haemmerle Guenter G Mayr Manuel M Willeit Peter P von Frieling-Salewsky Marion M Pieske Burkert B Scorrano Luca L Pieber Thomas T Pechlaner Raimund R Willeit Johann J Sigrist Stephan J SJ Linke Wolfgang A WA Mühlfeld Christian C Sadoshima Junichi J Dengjel Joern J Kiechl Stefan S Kroemer Guido G Sedej Simon S Madeo Frank F

Nature medicine 20161114 12

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 ph ...[more]

PMID: 27841876

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Project description:BACKGROUND:Tau stabilizes microtubules; however, in Alzheimer's disease (AD) and tauopathies, tau becomes hyperphosphorylated, aggregates, and results in neuronal death. Our group recently uncovered a unique interaction between polyamine metabolism and tau fate. Polyamines exert an array of physiological effects that support neuronal function and cognitive processing. Specific stimuli can elicit a polyamine stress response (PSR), resulting in altered central polyamine homeostasis. Evidence suggests that elevations in polyamines following a short-term stressor are beneficial; however, persistent stress and subsequent PSR activation may lead to maladaptive polyamine dysregulation, which is observed in AD, and may contribute to neuropathology and disease progression. METHODS:Male and female mice harboring tau P301L mutation (rTg4510) were examined for a tau-induced central polyamine stress response (tau-PSR). The direct effect of tau-PSR byproducts on tau fibrillization and oligomerization were measured using a thioflavin T assay and a N2a split superfolder GFP-Tau (N2a-ssGT) cell line, respectively. To therapeutically target the tau-PSR, we bilaterally injected caspase 3-cleaved tau truncated at aspartate 421 (AAV9 Tau ΔD421) into the hippocampus and cortex of spermidine/spermine-N1-acetyltransferase (SSAT), a key regulator of the tau-PSR, knock out (SSAT-/-), and wild type littermates, and the effects on tau neuropathology, polyamine dysregulation, and behavior were measured. Lastly, cellular models were employed to further examine how SSAT repression impacted tau biology. RESULTS:Tau induced a unique tau-PSR signature in rTg4510 mice, notably in the accumulation of acetylated spermidine. In vitro, higher-order polyamines prevented tau fibrillization but acetylated spermidine failed to mimic this effect and even promoted fibrillization and oligomerization. AAV9 Tau ΔD421 also elicited a unique tau-PSR in vivo, and targeted disruption of SSAT prevented the accumulation of acetylated polyamines and impacted several tau phospho-epitopes. Interestingly, SSAT knockout mice presented with altered behavior in the rotarod task, the elevated plus maze, and marble burying task, thus highlighting the impact of polyamine homeostasis within the brain. CONCLUSION:These data represent a novel paradigm linking tau pathology and polyamine dysfunction and that targeting specific arms within the polyamine pathway may serve as new targets to mitigate certain components of the tau phenotype.

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Cardioprotection and lifespan extension by the natural polyamine spermidine.

Publications

Cardioprotection and lifespan extension by the natural polyamine spermidine.

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