Spermidine is essential for fasting-mediated autophagy and longevity

Nat Cell Biol. 2024 Sep;26(9):1571-1584. doi: 10.1038/s41556-024-01468-x. Epub 2024 Aug 8.

Abstract

Caloric restriction and intermittent fasting prolong the lifespan and healthspan of model organisms and improve human health. The natural polyamine spermidine has been similarly linked to autophagy enhancement, geroprotection and reduced incidence of cardiovascular and neurodegenerative diseases across species borders. Here, we asked whether the cellular and physiological consequences of caloric restriction and fasting depend on polyamine metabolism. We report that spermidine levels increased upon distinct regimens of fasting or caloric restriction in yeast, flies, mice and human volunteers. Genetic or pharmacological blockade of endogenous spermidine synthesis reduced fasting-induced autophagy in yeast, nematodes and human cells. Furthermore, perturbing the polyamine pathway in vivo abrogated the lifespan- and healthspan-extending effects, as well as the cardioprotective and anti-arthritic consequences of fasting. Mechanistically, spermidine mediated these effects via autophagy induction and hypusination of the translation regulator eIF5A. In summary, the polyamine-hypusination axis emerges as a phylogenetically conserved metabolic control hub for fasting-mediated autophagy enhancement and longevity.

MeSH terms

  • Animals
  • Autophagy* / drug effects
  • Caenorhabditis elegans* / metabolism
  • Caloric Restriction*
  • Drosophila melanogaster / metabolism
  • Eukaryotic Translation Initiation Factor 5A
  • Fasting*
  • Humans
  • Longevity* / drug effects
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Peptide Initiation Factors / genetics
  • Peptide Initiation Factors / metabolism
  • Saccharomyces cerevisiae / genetics
  • Saccharomyces cerevisiae / metabolism
  • Spermidine* / metabolism
  • Spermidine* / pharmacology

Substances

  • Spermidine
  • Peptide Initiation Factors
  • Eukaryotic Translation Initiation Factor 5A

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