A surge in endogenous spermidine is essential for rapamycin-induced autophagy and longevity
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.<b>Abbreviation</b>: 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.
Authors
- Ioanna Daskalaki (ORCID: https://orcid.org/0000-0002-2423-9660)
- Ulrich Stelzl (ORCID: https://orcid.org/0000-0003-2500-3585)
- Sebastian J. Hofer (ORCID: https://orcid.org/0000-0002-0756-0014)
- Nektarios Tavernarakis (ORCID: https://orcid.org/0000-0002-5253-1466)
- Guido Kroemer (ORCID: https://orcid.org/0000-0002-9334-4405)
- Frank Madeo (ORCID: https://orcid.org/0000-0002-5070-1329)
- Simon Sedej (ORCID: https://orcid.org/0000-0002-4419-6821)
- Mahmoud Abdellatif (ORCID: https://orcid.org/0000-0002-5042-9054)
Institutions
- University of Crete (GR)
- Inserm (FR)
- University of Graz (AT)
- Institut Universitaire de France (FR)
- Medical University of Graz (AT)
- Université Paris Cité (FR)
- Université Paris-Saclay (FR)
- Institut Gustave Roussy (FR)
- University of Maribor (SI)
- Sorbonne Université (FR)
- Centre de Recherche des Cordeliers (FR)
- Assistance Publique – Hôpitaux de Paris (FR)
- Hôpital Européen Georges-Pompidou (FR)
- Nawi Graz (AT)
- Hôpital Européen (FR)
- BioTechMed-Graz (AT)
- Foundation for Research and Technology Hellas (GR)
Publication Details
- Journal
- Autophagy
- Published
- 2024-08-30
- DOI
- https://doi.org/10.1080/15548627.2024.2396793
- Citations
- 16
- Primary Topic
- Polyamine Metabolism and Applications
- Type
- article
- Field-Weighted Citation Impact
- 3.74
Funders
- Association pour la Recherche sur le Cancer
- Seerave Foundation
- Equipex
- European Commission
- Agence Nationale de la Recherche
- Institut National de la Santé et de la Recherche Médicale
- Austrian Science Fund
- Fondation pour la Recherche Médicale
- Ligue Contre le Cancer
- Institut Universitaire de France
- Institut National Du Cancer
- Karl-Franzens-Universität Graz
- Direction Générale de l’offre de Soins
- Medizinische Universität Graz
- Hellenic Foundation for Research and Innovation
- Ministère des Solidarités et de la Santé
- BioTechMed-Graz
- Université de Paris
- HORIZON EUROPE Framework Programme
- Labex Immuno-Oncology