Induction of Autophagy by Spermidine Promotes Longevity

Nat Cell Biol. 2009 Nov;11(11):1305-14. doi: 10.1038/ncb1975. Epub 2009 Oct 4.

Abstract

Ageing results from complex genetically and epigenetically programmed processes that are elicited in part by noxious or stressful events that cause programmed cell death. Here, we report that administration of spermidine, a natural polyamine whose intracellular concentration declines during human ageing, markedly extended the lifespan of yeast, flies and worms, and human immune cells. In addition, spermidine administration potently inhibited oxidative stress in ageing mice. In ageing yeast, spermidine treatment triggered epigenetic deacetylation of histone H3 through inhibition of histone acetyltransferases (HAT), suppressing oxidative stress and necrosis. Conversely, depletion of endogenous polyamines led to hyperacetylation, generation of reactive oxygen species, early necrotic death and decreased lifespan. The altered acetylation status of the chromatin led to significant upregulation of various autophagy-related transcripts, triggering autophagy in yeast, flies, worms and human cells. Finally, we found that enhanced autophagy is crucial for polyamine-induced suppression of necrosis and enhanced longevity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Adult
  • Animals
  • Autophagy / drug effects*
  • Caenorhabditis elegans / drug effects
  • Caenorhabditis elegans / immunology
  • Caenorhabditis elegans / physiology
  • Drosophila melanogaster / drug effects
  • Drosophila melanogaster / immunology
  • Drosophila melanogaster / physiology
  • Female
  • HeLa Cells
  • Histones / metabolism
  • Humans
  • Hydrogen-Ion Concentration
  • Longevity / drug effects*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Necrosis
  • Saccharomyces cerevisiae / drug effects
  • Saccharomyces cerevisiae / immunology
  • Saccharomyces cerevisiae / physiology
  • Spermidine / pharmacology*

Substances

  • Histones
  • Spermidine