Dietary spermidine improves cognitive function.

Sabrina Schroeder,Helga Niederkofler,Tobias Madl,Muammer Üçal,Ute Schäfer,Irmgard Pallhuber,Tobias Eisenberg,Péter Sótonyi,Bence Rácz,Verena Gschiel,Herbert Tilg,Gesa Richter,Viktoria Pogatschnigg,Melanie Müller,G Mark Marcello,Aitak Farzi,Johann Willeit,Tobias Pendl,Christopher Dammbrueck,Frank Sinner,Frank Madeo,Jörn Dengjel,Ronald Mekis,Sebastian J Hofer,Thomas R Pieber,Michael Poglitsch,Simon Sedej,Marlene Agreiter,Christoph Magnes,Peter Holzer,Luca Scorrano,Josef Marksteiner,Barbara Mairhofer,Selena Ristic,Raimund Pechlaner,Guido Kroemer,Gregorio Rungger,Stephan J Sigrist,Stefan Kiechl,Martina Bergmann,Andreas Zimmermann,Michaela Defrancesco,Didac Carmona-Gutiérrez ,P Royer ,Koichi Iwata ,Regine C Tölle ,Jelena Tadić

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 Atg7and 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.

Highlights

Aging is accompanied by a progressive decline in brain function (Murman, 2015), which often manifests in hippocampus-associated cognitive impairments (Todorova and Blokland, 2017)
We first determined if orally supplemented SPD can pass the blood-brain barrier (BBB)
We found that orally supplied SPD was detectable in brain tissue of aged mice after 1 week and increased in a time-dependent manner after 4 and 8 weeks of feeding to a level of up to 30% of circulating levels (Figure 1A)

Summary

Introduction

Aging is accompanied by a progressive decline in brain function (Murman, 2015), which often manifests in hippocampus-associated cognitive impairments (Todorova and Blokland, 2017). Ageassociated alterations in memory formation have been linked to mitochondrial dysfunction (Todorova and Blokland, 2017). At the molecular level, aging reduces the function of respiratory complexes and oxidative phosphorylation (OXPHOS) capacity (Navarro and Boveris, 2007; Shetty et al, 2011).

Methods

Results

Conclusion