Autophagy: a cytoprotective mechanism with anti-aging properties
Abstract
Autophagy has been considered for some time as a mechanism of cellular self-destruction leading to cell death. We have tackled the question whether autophagy is cytoprotective or cytotoxic in two ways.
First we have screened more than 1000 established or experimental anticancer agents for their capacity to induce autophagic LC3 puncta in human cancer cells, finding that some 100 were able to do so, but that none among these “autophagy inducers” killed tumor cells in an autophagy-dependent fashion. Rather autophagy inhibition sensitized the tumor cells to cell death induction.
Second, we determined the impact of whole-body autophagy induction in experimental animals. We found that autophagy-inducing pharmacological agents such as resveratrol and spermidine enhanced life span in an autophagy-dependent fashion. Similarly genetic manipulations that increase longevity (such as inactivation of the C. elegans p53 ortholog Cep1 or overexpression of the SIRT1 ortholog sirt2.1) induce autophagy, and inhibition of autophagy abolishes their lifespan-extending effect. We found that induction of autophagy by resveratrol requires the NAD+-dependent deacetylase sirtuin 1 (SIRT1). The acetylase inhibitor spermidine stimulates autophagy independent of SIRT1 in human and yeast cells as well as in nematodes. Although resveratrol and spermidine ignite autophagy through distinct mechanisms, these compounds stimulate convergent pathways that culminate in concordant modifications of the acetylproteome. Both agents favor convergent deacetylation and acetylation reactions in the cytosol and in the nucleus, respectively. At doses at which neither resveratrol nor spermidine did stimulate autophagy alone, these agents synergistically induced autophagy, both in vitro and in vivo. Altogether, these data underscore the importance of an autophagy-regulatory network of antagonistic deacetylases and acetylases that can be pharmacologically manipulated. Moreover, our data indicate that autophagy is mostly (always?) a cytoprotective event.
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