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Spermidine – cardioprotection and life span extension

Cardiovascular disease has reached epidemic proportions in the aging society and remains the worldwide leading cause of death. This publication shows that the natural spermidine protects the heart from age associated deteriorations and suggests a new and feasible strategy for the prevention of cardiovascular disease.

It is known that human aging is accompanied by cardiac hypertrophic remodeling and a progressive decline of left ventricular (LV) diastolic function. No treatment has yet been shown to convincingly target and prevent age-associated diastolic dysfunction or heart failure, because the understanding of the fundamental mechanisms underlying progressive deteriorations and function of the aging heart is incomplete.

Recent studies have revealed that autophagy, a major cellular quality control mechanism, may be able to minimize the functional decline of aging cardiomyocytes by degrading and recycling damaged and potentially toxic proteins. Clearance of dysfunctional mitochondria through a specific type of selective autophagy, termed mitophagy, may be beneficial for cardiac function, because mitochondria can overproduce reactive oxygen species if they are functionally impaired and trigger lethal signaling pathways. In model organisms it has been shown that autophagy, as well as autophagy induced by supplementation of spermidine, has longevity-enhancing effects.

The scientists showed that in aging mice spermidine treatment ameliorated hypertrophic remodeling of the aged heart, blocked age-related changes in cardiomyocyte composition and functionality, enhanced diastolic function independently of effects on systemic blood pressure and extended lifespan. They argue that it might be plausible that lifespan prolongation by spermidine is due to the suppression of death from cardiac-related causes; however, to what degree the effects of spermidine on the heart account for its lifespan prolonging effects is a highly challenging question and remains to be investigated. They showed further, that Spermidine treatment reduced blood pressure and delays progression to heart failure in a rat disease model of hypertension-induced hypertrophy.

As the authors explain, the cardioprotective effects of spermidine may be due to several underlying mechanisms, including both direct cardiac effects and extracardiac (systemic and renal) effects. Systemic effects by spermidine might involve anti-inflammatory processes, as well as a blood-pressure-lowering effect. Both chronic low-grade inflammation and hypertension have been reported to cause mechano-elastical impairment and mitochondrial dysfunction of cardiomyocytes. Oral supplementation of spermidine promotes basal autophagic flux in cardiac tissue, and the direct protective effects of spermidine on the heart seem to require cardiomyocyte autophagy.

In accordance with the experimental findings, epidemiological analyses also confirmed the novel concept that spermidine-rich diets are protective against cardiovascular disease and reduce the risk of cardiac death in humans.

Tobias Eisenberg, Mahmoud Abdellatif, Sabrina Schroeder, Uwe Primessnig, Slaven Stekovic, Tobias Pendl, Alexandra Harger, Julia Schipke, Andreas Zimmermann, Albrecht Schmidt, Mingming Tong, Christoph Ruckenstuhl, Christopher Dammbrueck, Angelina S Gross, Viktoria Herbst, Christoph Magnes, Gert Trausinger, Sophie Narath, Andreas Meinitzer, Zehan Hu, Alexander Kirsch, Kathrin Eller, Didac Carmona-Gutierrez, Sabrina Büttner, Federico Pietrocola, Oskar Knittelfelder, Emilie Schrepfer, Patrick Rockenfeller, Corinna Simonini, Alexandros Rahn, Marion Horsch, Kristin Moreth, Johannes Beckers, Helmut Fuchs, Valerie Gailus-Durner, Frauke Neff, Dirk Janik, Birgit Rathkolb, Jan Rozman, Martin Hrabe de Angelis, Tarek Moustafa, Guenter Haemmerle, Manuel Mayr, Peter Willeit, Marion von Frieling-Salewsky, Burkert Pieske, Luca Scorrano, Thomas Pieber, Raimund Pechlaner, Johann Willeit, Stephan J Sigrist, Wolfgang A Linke, Christian Mühlfeld, Junichi Sadoshima, Joern Dengjel, Stefan Kiechl, Guido Kroemer, Simon Sedej & Frank Madeo. Cardioprotection and lifespan extension by the natural polyamine spermidine. Nat Med. 2016 Dec;22(12):1428-1438. doi: 10.1038/nm.4222.