A surge in endogenous spermidine is essential for rapamycin-induced autophagy and longevity.

Autor:	Hofer SJ; Institute of Molecular Biosciences, NAWI Graz, University of Graz, Graz, Austria.; BioTechMed-Graz, Graz, Austria.; Field of Excellence BioHealth, University of Graz, Graz, Austria., Daskalaki I; Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology - Hellas, Heraklion, Greece.; Department of Biology, School of Sciences and Engineering, University of Crete, Heraklion, Greece., Abdellatif M; BioTechMed-Graz, Graz, Austria.; Division of Cardiology, Medical University of Graz, Graz, Austria., Stelzl U; BioTechMed-Graz, Graz, Austria.; Field of Excellence BioHealth, University of Graz, Graz, Austria.; Institute of Pharmaceutical Sciences, Pharmaceutical Chemistry, University of Graz, Graz, Austria., Sedej S; BioTechMed-Graz, Graz, Austria.; Division of Cardiology, Medical University of Graz, Graz, Austria.; Institute of Physiology, Faculty of Medicine, University of Maribor, Maribor, Slovenia., Tavernarakis N; Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology - Hellas, Heraklion, Greece.; Division of Basic Sciences, School of Medicine, University of Crete, Heraklion, Greece., Kroemer G; Centre de Recherche des Cordeliers, Équipe Labellisée par la Ligue Contre le Cancer, Université de Paris Cité, Sorbonne Université, Inserm U1138, Institut Universitaire de France, Paris, France.; Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Center, Université Paris Saclay, Villejuif, France.; Institut du Cancer Paris CARPEM, Department of Biology, Hôpital Européen Georges Pompidou, AP-HP, Paris, France., Madeo F; Institute of Molecular Biosciences, NAWI Graz, University of Graz, Graz, Austria.; BioTechMed-Graz, Graz, Austria.; Field of Excellence BioHealth, University of Graz, Graz, Austria.
Jazyk:	angličtina
Zdroj:	Autophagy [Autophagy] 2024 Sep 12, pp. 1-3. Date of Electronic Publication: 2024 Sep 12.
DOI:	10.1080/15548627.2024.2396793
Abstrakt:	Acute nutrient deprivation (fasting) causes an immediate increase in spermidine biosynthesis in yeast, flies, mice and humans, as corroborated in four independent clinical studies. This fasting-induced surge in spermidine constitutes the critical first step of a phylogenetically conserved biochemical cascade that leads to spermidine-dependent hypusination of EIF5A (eukaryotic translation initiation factor 5A), which favors the translation of the pro-macroautophagic/autophagic TFEB (transcription factor EB), and hence an increase in autophagic flux. We observed that genetic or pharmacological inhibition of the spermidine increase by inhibition of ODC1 (ornithine decarboxylase 1) prevents the pro-autophagic and antiaging effects of fasting in yeast, nematodes, flies and mice. Moreover, knockout or knockdown of the enzymes required for EIF5A hypusination abolish fasting-mediated autophagy enhancement and longevity extension in these organisms. Of note, autophagy and longevity induced by rapamycin obey the same rule, meaning that they are tied to an increase in spermidine synthesis. These findings indicate that spermidine is not only a "caloric restriction mimetic" in the sense that its supplementation mimics the beneficial effects of nutrient deprivation on organismal health but that it is also an obligatory downstream effector of the antiaging effects of fasting and rapamycin. Abbreviation : EIF5A: eukaryotic translation initiation factor 5A; IGF1: insulin like growth factor 1; MTOR: mechanistic target of rapamycin kinase; ODC1: ornithine decarboxylase 1; TFEB: transcription factor EB.
Databáze:	MEDLINE
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