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Hofer, SJ; Daskalaki, I; Abdellatif, M; Stelzl, U; Sedej, S; Tavernarakis, N; Kroemer, G; Madeo, F.
A surge in endogenous spermidine is essential for rapamycin-induced autophagy and longevity.
Autophagy. 2024; 20(12):2824-2826 Doi: 10.1080/15548627.2024.2396793 [OPEN ACCESS]
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Co-Autor*innen der Med Uni Graz
Abdellatif Mahmoud
Sedej Simon
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Abstract:
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.
Find related publications in this database (using NLM MeSH Indexing)
Autophagy - drug effects, physiology
Spermidine - pharmacology, metabolism
Animals - administration & dosage
Longevity - drug effects, physiology
Sirolimus - pharmacology
Mice - administration & dosage
Humans - administration & dosage
Eukaryotic Translation Initiation Factor 5A - administration & dosage
Peptide Initiation Factors - metabolism
Fasting - administration & dosage
Ornithine Decarboxylase - metabolism
Caenorhabditis elegans - metabolism, drug effects

Find related publications in this database (Keywords)
Aging
autophagy
lifespan
rapamycin
spermidine
MTOR
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