Autophagy mediates pharmacological lifespan extension by spermidine and resveratrol.
Although autophagy has widely been conceived as a self-destructive mechanism that causes cell death, accumulating evidence suggests that autophagy usually mediates cytoprotection, thereby avoiding the apoptotic or necrotic demise of stressed cells. Recent evidence produced by our groups demonstrates that autophagy is also involved in pharmacological manipulations that increase longevity. Exogenous supply of the polyamine spermidine can prolong the lifespan of (while inducing autophagy in) yeast, nematodes and flies. Similarly, resveratrol can trigger autophagy in cells from different organisms, extend lifespan in nematodes, and ameliorate the fitness of human cells undergoing metabolic stress. These beneficial effects are lost when essential autophagy modulators are genetically or pharmacologically inactivated, indicating that autophagy is required for the cytoprotective and/or anti-aging effects of spermidine and resveratrol. Genetic and functional studies indicate that spermidine inhibits histone acetylases, while resveratrol activates the histone deacetylase Sirtuin 1 to confer cytoprotection/longevity. Although it remains elusive whether the same histones (or perhaps other nuclear or cytoplasmic proteins) act as the downstream targets of spermidine and resveratrol, these results point to an essential role of protein hypoacetylation in autophagy control and in the regulation of longevity.
Morselli
Eugenia
E
INSERM, U848, F-94805 Villejuif, France.
Galluzzi
Lorenzo
L
Kepp
Oliver
O
Criollo
Alfredo
A
Maiuri
Maria Chiara
MC
Tavernarakis
Nektarios
N
Madeo
Frank
F
Kroemer
Guido
G
D055372:AMP-Activated Protein Kinases / Q000187:drug effects; D000375:Aging / Q000378:metabolism; D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D017173:Caenorhabditis elegans / Q000187:drug effects / Q000201:enzymology; D004330:Drosophila / Q000187:drug effects / Q000201:enzymology; D051548:Histone Acetyltransferases / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D051550:I-kappa B Kinase / Q000187:drug effects; D008136:Longevity / Q000187:drug effects*; D000077185:Resveratrol; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000201:enzymology; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D013095:Spermidine / Q000494:pharmacology*; D013267:Stilbenes / Q000494:pharmacology*
D013267:Stilbenes; D051548:Histone Acetyltransferases; D051550:I-kappa B Kinase; D055372:AMP-Activated Protein Kinases; D056564:Sirtuin 1; D000077185:Resveratrol; D013095:Spermidine