Induction of autophagy by spermidine promotes longevity.
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.
Eisenberg
Tobias
T
Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria.
Knauer
Heide
H
Schauer
Alexandra
A
Büttner
Sabrina
S
Ruckenstuhl
Christoph
C
Carmona-Gutierrez
Didac
D
Ring
Julia
J
Schroeder
Sabrina
S
Magnes
Christoph
C
Antonacci
Lucia
L
Fussi
Heike
H
Deszcz
Luiza
L
Hartl
Regina
R
Schraml
Elisabeth
E
Criollo
Alfredo
A
Megalou
Evgenia
E
Weiskopf
Daniela
D
Laun
Peter
P
Heeren
Gino
G
Breitenbach
Michael
M
Grubeck-Loebenstein
Beatrix
B
Herker
Eva
E
Fahrenkrog
Birthe
B
Fröhlich
Kai-Uwe
KU
Sinner
Frank
F
Tavernarakis
Nektarios
N
Minois
Nadege
N
Kroemer
Guido
G
Madeo
Frank
F
D000107:Acetylation; D000328:Adult; D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D017173:Caenorhabditis elegans / Q000187:drug effects / Q000276:immunology / Q000502:physiology; D004331:Drosophila melanogaster / Q000187:drug effects / Q000276:immunology / Q000502:physiology; D005260:Female; D006367:HeLa Cells; D006657:Histones / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008136:Longevity / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009336:Necrosis; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000276:immunology / Q000502:physiology; D013095:Spermidine / Q000494:pharmacology*
D006657:Histones; D013095:Spermidine