Spermidine-induced hypusination preserves mitochondrial and cognitive function during aging

Sebastian J. Hofer a,b,c, YongTian Liangd, Andreas Zimmermann a,b,c, Sabrina Schroedera,b,c, Jörn Dengjele, Guido Kroemer f,g,h, Tobias Eisenberga,b,c, Stephan J. Sigristd, and Frank Madeoa,b,

a Institute of Molecular Biosciences, NAWI Graz, University of Graz, Graz, Austria; b BioTechMed-Graz, Graz, Austria; c Field of Excellence BioHealth, University of Graz, Graz, Austria; d Institute of Biology/Genetics, Freie Universität Berlin, Berlin, Germany; e Department of Biology, University of Fribourg, Fribourg, Switzerland; f Equipe Labellisée par la Ligue Contre le Cancer, Université de Paris Université Sorbonne Paris Cité, INSERM U1138, Centre de Recherche des Cordeliers, Paris, France; g Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, Villejuif, France; h Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France

Crohn’s disease (CD) is a chronic inflammatory disease of the gastrointestinal tract. Current medications have potentially serious side effects. Hence there is increasing interest in alternative therapies. We previously demonstrated the anti-inflammatory effects of FAHF-2 in vitro on PBMCs and mucosa from CD subjects. Here we investigated the anti-inflammatory effects of a bioactive compound isolated from Ganoderma lucidum (G. lucidum), a key herbal constituent of FAHF-2, in CD in vitro.Spermidine is a natural polyamine, central to cellular homeostasis and growth, that promotes macroautophagy/autophagy. The polyamine pathway is highly conserved from bacteria to mammals and spermidine (prominently found in some kinds of aged cheese, wheat germs, nuts, soybeans, and fermented products thereof, among others) is an intrinsic part of the human diet. Apart from nutrition, spermidine is available to mammalian organisms from intracellular biosynthesis and microbial production in the gut. Importantly, externally supplied spermidine (via drinking water or food) prolongs lifespan, activates autophagy, improves mitochondrial function, and refills polyamine pools that decline during aging in various tissues of model organisms, including mice. In two adjacent studies, we explored how dietary spermidine supplementation enhances eEF5/EIF5A hypusination, cerebral mitochondrial function and cognition in aging Drosophila melanogaster and mice.

Autophagy; Drosophila; hypusination; learning; memory; mitophagy; Pink1; polyamines; spermidine