Dietary spermidine improves cognitive function

Sabrina Schroeder¹, Sebastian J Hofer², Andreas Zimmermann³, Raimund Pechlaner⁴, Christopher Dammbrueck⁵, Tobias Pendl⁵, G Mark Marcello⁶, Viktoria Pogatschnigg⁵, Martina Bergmann⁵, Melanie Müller⁵, Verena Gschiel⁵, Selena Ristic⁵, Jelena Tadic³, Keiko Iwata⁷, Gesa Richter⁸, Aitak Farzi⁹, Muammer Üçal¹⁰, Ute Schäfer¹⁰, Michael Poglitsch⁵, Philipp Royer⁵, Ronald Mekis⁵, Marlene Agreiter⁵, Regine C Tölle¹¹, Péter Sótonyi⁶, Johann Willeit⁴, Barbara Mairhofer¹², Helga Niederkofler¹², Irmgard Pallhuber¹², Gregorio Rungger¹³, Herbert Tilg¹⁴, Michaela Defrancesco¹⁵, Josef Marksteiner¹⁶, Frank Sinner¹⁷, Christoph Magnes¹⁸, Thomas R Pieber¹⁹, Peter Holzer⁹, Guido Kroemer²⁰, Didac Carmona-Gutierrez⁵, Luca Scorrano²¹, Jörn Dengjel¹¹, Tobias Madl²², Simon Sedej²³, Stephan J Sigrist²⁴, Bence Rácz⁶, Stefan Kiechl²⁵, Tobias Eisenberg²⁶, Frank Madeo²⁷

Affiliations

¹ Institute of Molecular Biosciences, NAWI Graz, University of Graz, 8010 Graz, Austria; BioTechMed-Graz, 8010 Graz, Austria.
² Institute of Molecular Biosciences, NAWI Graz, University of Graz, 8010 Graz, Austria; BioTechMed-Graz, 8010 Graz, Austria; Field of Excellence BioHealth, University of Graz, 8010 Graz, Austria.
³ Institute of Molecular Biosciences, NAWI Graz, University of Graz, 8010 Graz, Austria; Field of Excellence BioHealth, University of Graz, 8010 Graz, Austria.
⁴ Department of Neurology, Medical University of Innsbruck, 6020 Innsbruck, Austria.
⁵ Institute of Molecular Biosciences, NAWI Graz, University of Graz, 8010 Graz, Austria.
⁶ Department of Anatomy and Histology, University of Veterinary Medicine Budapest, 1078 Budapest, Hungary.
⁷ Veneto Institute of Molecular Medicine, 35129 Padova, Italy; Research Center for Child Mental Development, University of Fukui, 910-1193 Fukui, Japan; Department of Biology, University of Padova, 35121 Padova, Italy.
⁸ Gottfried Schatz Research Center for Cell Signaling, Metabolism and Aging Molecular Biology and Biochemistry Medical University of Graz, 8010 Graz, Austria.
⁹ Otto Loewi Research Center (for Vascular Biology, Immunology and Inflammation), Division of Pharmacology, Medical University of Graz (MUG), 8010 Graz, Austria.
¹⁰ Department of Neurosurgery, RU Experimental Neurotraumatology, Medical University Graz, 8036 Graz, Austria.
¹¹ Department of Biology, University of Fribourg, Chemin du Musée 10, 1700 Fribourg, Switzerland.
¹² Department of Psychiatry, Bruneck Hospital, 39031 Bruneck, Italy.
¹³ Department of Neurology, Bruneck Hospital, 39031 Bruneck, Italy.
¹⁴ Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology and Metabolism, Medical University of Innsbruck, 6020 Innsbruck, Austria.
¹⁵ Department of Psychiatry, Psychotherapy and Psychosomatics, Medical University of Innsbruck, 6020 Innsbruck, Austria.
¹⁶ Department of Psychiatry and Psychotherapy A, Hall State Hospital, 6060 Hall in Tirol, Austria.
¹⁷ HEALTH-Institute for Biomedicine and Health Sciences, Joanneum Research Forschungsgesellschaft mbH, 8010 Graz, Austria; Division of Endocrinology and Diabetology, Department of Internal Medicine, Medical University of Graz, 8036 Graz, Austria.
¹⁸ HEALTH-Institute for Biomedicine and Health Sciences, Joanneum Research Forschungsgesellschaft mbH, 8010 Graz, Austria.
¹⁹ BioTechMed-Graz, 8010 Graz, Austria; HEALTH-Institute for Biomedicine and Health Sciences, Joanneum Research Forschungsgesellschaft mbH, 8010 Graz, Austria; Division of Endocrinology and Diabetology, Department of Internal Medicine, Medical University of Graz, 8036 Graz, Austria.
²⁰ Equipe Labellisée par la Ligue Contre le Cancer, Université Paris Descartes, Université Paris Diderot, Université Sorbonne Paris Cité, INSERM U1138, Centre de Recherche des Cordeliers, 75006 Paris, France; Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, 94 805 Villejuif, France; Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, 75015 Paris, France; Suzhou Institute for Systems Biology, Chinese Academy of Sciences, 215123 Suzhou, China; Department of Women's and Children's Health, Karolinska University Hospital, 171 77 Stockholm, Sweden.
²¹ Veneto Institute of Molecular Medicine, 35129 Padova, Italy; Department of Biology, University of Padova, 35121 Padova, Italy.
²² BioTechMed-Graz, 8010 Graz, Austria; Gottfried Schatz Research Center for Cell Signaling, Metabolism and Aging Molecular Biology and Biochemistry Medical University of Graz, 8010 Graz, Austria.
²³ BioTechMed-Graz, 8010 Graz, Austria; Department of Cardiology, Medical University of Graz, 8036 Graz, Austria; Faculty of Medicine, University of Maribor, 2000 Maribor, Slovenia.
²⁴ Institute of Biology/Genetics, Freie Universität Berlin, 14195 Berlin, Germany.
²⁵ Department of Neurology, Medical University of Innsbruck, 6020 Innsbruck, Austria; VASCage, Research Centre on Vascular Ageing and Stroke, 6020 Innsbruck, Austria. Electronic address: stefan.kiechl@i-med.ac.at.
²⁶ Institute of Molecular Biosciences, NAWI Graz, University of Graz, 8010 Graz, Austria; BioTechMed-Graz, 8010 Graz, Austria; Field of Excellence BioHealth, University of Graz, 8010 Graz, Austria. Electronic address: tobias.eisenberg@uni-graz.at.
²⁷ Institute of Molecular Biosciences, NAWI Graz, University of Graz, 8010 Graz, Austria; BioTechMed-Graz, 8010 Graz, Austria; Field of Excellence BioHealth, University of Graz, 8010 Graz, Austria. Electronic address: frank.madeo@uni-graz.at.

PMID: 33852843
DOI: 10.1016/j.celrep.2021.108985

Free article

Dietary spermidine improves cognitive function

Sabrina Schroeder et al. Cell Rep. 2021.

Free article

. 2021 Apr 13;35(2):108985.

doi: 10.1016/j.celrep.2021.108985.

Authors

Affiliations

¹ Institute of Molecular Biosciences, NAWI Graz, University of Graz, 8010 Graz, Austria; BioTechMed-Graz, 8010 Graz, Austria.
² Institute of Molecular Biosciences, NAWI Graz, University of Graz, 8010 Graz, Austria; BioTechMed-Graz, 8010 Graz, Austria; Field of Excellence BioHealth, University of Graz, 8010 Graz, Austria.
³ Institute of Molecular Biosciences, NAWI Graz, University of Graz, 8010 Graz, Austria; Field of Excellence BioHealth, University of Graz, 8010 Graz, Austria.
⁴ Department of Neurology, Medical University of Innsbruck, 6020 Innsbruck, Austria.
⁵ Institute of Molecular Biosciences, NAWI Graz, University of Graz, 8010 Graz, Austria.
⁶ Department of Anatomy and Histology, University of Veterinary Medicine Budapest, 1078 Budapest, Hungary.
⁷ Veneto Institute of Molecular Medicine, 35129 Padova, Italy; Research Center for Child Mental Development, University of Fukui, 910-1193 Fukui, Japan; Department of Biology, University of Padova, 35121 Padova, Italy.
⁸ Gottfried Schatz Research Center for Cell Signaling, Metabolism and Aging Molecular Biology and Biochemistry Medical University of Graz, 8010 Graz, Austria.
⁹ Otto Loewi Research Center (for Vascular Biology, Immunology and Inflammation), Division of Pharmacology, Medical University of Graz (MUG), 8010 Graz, Austria.
¹⁰ Department of Neurosurgery, RU Experimental Neurotraumatology, Medical University Graz, 8036 Graz, Austria.
¹¹ Department of Biology, University of Fribourg, Chemin du Musée 10, 1700 Fribourg, Switzerland.
¹² Department of Psychiatry, Bruneck Hospital, 39031 Bruneck, Italy.
¹³ Department of Neurology, Bruneck Hospital, 39031 Bruneck, Italy.
¹⁴ Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology and Metabolism, Medical University of Innsbruck, 6020 Innsbruck, Austria.
¹⁵ Department of Psychiatry, Psychotherapy and Psychosomatics, Medical University of Innsbruck, 6020 Innsbruck, Austria.
¹⁶ Department of Psychiatry and Psychotherapy A, Hall State Hospital, 6060 Hall in Tirol, Austria.
¹⁷ HEALTH-Institute for Biomedicine and Health Sciences, Joanneum Research Forschungsgesellschaft mbH, 8010 Graz, Austria; Division of Endocrinology and Diabetology, Department of Internal Medicine, Medical University of Graz, 8036 Graz, Austria.
¹⁸ HEALTH-Institute for Biomedicine and Health Sciences, Joanneum Research Forschungsgesellschaft mbH, 8010 Graz, Austria.
¹⁹ BioTechMed-Graz, 8010 Graz, Austria; HEALTH-Institute for Biomedicine and Health Sciences, Joanneum Research Forschungsgesellschaft mbH, 8010 Graz, Austria; Division of Endocrinology and Diabetology, Department of Internal Medicine, Medical University of Graz, 8036 Graz, Austria.
²⁰ Equipe Labellisée par la Ligue Contre le Cancer, Université Paris Descartes, Université Paris Diderot, Université Sorbonne Paris Cité, INSERM U1138, Centre de Recherche des Cordeliers, 75006 Paris, France; Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, 94 805 Villejuif, France; Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, 75015 Paris, France; Suzhou Institute for Systems Biology, Chinese Academy of Sciences, 215123 Suzhou, China; Department of Women's and Children's Health, Karolinska University Hospital, 171 77 Stockholm, Sweden.
²¹ Veneto Institute of Molecular Medicine, 35129 Padova, Italy; Department of Biology, University of Padova, 35121 Padova, Italy.
²² BioTechMed-Graz, 8010 Graz, Austria; Gottfried Schatz Research Center for Cell Signaling, Metabolism and Aging Molecular Biology and Biochemistry Medical University of Graz, 8010 Graz, Austria.
²³ BioTechMed-Graz, 8010 Graz, Austria; Department of Cardiology, Medical University of Graz, 8036 Graz, Austria; Faculty of Medicine, University of Maribor, 2000 Maribor, Slovenia.
²⁴ Institute of Biology/Genetics, Freie Universität Berlin, 14195 Berlin, Germany.
²⁵ Department of Neurology, Medical University of Innsbruck, 6020 Innsbruck, Austria; VASCage, Research Centre on Vascular Ageing and Stroke, 6020 Innsbruck, Austria. Electronic address: stefan.kiechl@i-med.ac.at.
²⁶ Institute of Molecular Biosciences, NAWI Graz, University of Graz, 8010 Graz, Austria; BioTechMed-Graz, 8010 Graz, Austria; Field of Excellence BioHealth, University of Graz, 8010 Graz, Austria. Electronic address: tobias.eisenberg@uni-graz.at.
²⁷ Institute of Molecular Biosciences, NAWI Graz, University of Graz, 8010 Graz, Austria; BioTechMed-Graz, 8010 Graz, Austria; Field of Excellence BioHealth, University of Graz, 8010 Graz, Austria. Electronic address: frank.madeo@uni-graz.at.

PMID: 33852843
DOI: 10.1016/j.celrep.2021.108985

Abstract

Decreased cognitive performance is a hallmark of brain aging, but the underlying mechanisms and potential therapeutic avenues remain poorly understood. Recent studies have revealed health-protective and lifespan-extending effects of dietary spermidine, a natural autophagy-promoting polyamine. Here, we show that dietary spermidine passes the blood-brain barrier in mice and increases hippocampal eIF5A hypusination and mitochondrial function. Spermidine feeding in aged mice affects behavior in homecage environment tasks, improves spatial learning, and increases hippocampal respiratory competence. In a Drosophila aging model, spermidine boosts mitochondrial respiratory capacity, an effect that requires the autophagy regulator Atg7 and the mitophagy mediators Parkin and Pink1. Neuron-specific Pink1 knockdown abolishes spermidine-induced improvement of olfactory associative learning. This suggests that the maintenance of mitochondrial and autophagic function is essential for enhanced cognition by spermidine feeding. Finally, we show large-scale prospective data linking higher dietary spermidine intake with a reduced risk for cognitive impairment in humans.

Keywords: Pink1; aging; autophagy; cognitive function; dietary spermidine; memory; mitochondria; mitophagy.

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Conflict of interest statement

Declaration of interests F.M., S.J.S., and D.C.-G. have equity interests in The Longevity Labs (TLL), a company founded in 2016 that develops natural food extracts. T.E. has equity interests in and conducts paid consultancies for TLL. G.K. holds research contracts with Bayer Healthcare, Genentech, GlaxoSmithKline, Institut Mérieux, Kaleido Biosciences, Lytix Biopharma, NuCana, Oncolinx, PharmaMar, Samsara Therapeutics, SOTIO, and Tioma Therapeutics. G.K. is on the Board of Directors of the Bristol Myers Squibb Foundation France. G.K. is a scientific cofounder of everImmune, a biotech company that develops immunostimulatory bacteria, and Therafast Bio. F.M. and T.E. are inventors on a pending patent application related to this work.

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Dietary spermidine improves cognitive function

Affiliations

Dietary spermidine improves cognitive function

Authors

Affiliations

Abstract

Conflict of interest statement

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Molecular Biology Databases