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.
Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria.
Tobias
T
Eisenberg
Heide
H
Knauer
Alexandra
A
Schauer
Sabrina
S
Büttner
Christoph
C
Ruckenstuhl
Didac
D
Carmona-Gutierrez
Julia
J
Ring
Sabrina
S
Schroeder
Christoph
C
Magnes
Lucia
L
Antonacci
Heike
H
Fussi
Luiza
L
Deszcz
Regina
R
Hartl
Elisabeth
E
Schraml
Alfredo
A
Criollo
Evgenia
E
Megalou
Daniela
D
Weiskopf
Peter
P
Laun
Gino
G
Heeren
Michael
M
Breitenbach
Beatrix
B
Grubeck-Loebenstein
Eva
E
Herker
Birthe
B
Fahrenkrog
Kai-Uwe
KU
Fröhlich
Frank
F
Sinner
Nektarios
N
Tavernarakis
Nadege
N
Minois
Guido
G
Kroemer
Frank
F
Madeo
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