Autophagy Impairment Induces Premature Senescence in Primary Human FibroblastsReport as inadecuate

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Recent studies have demonstrated that activation of autophagy increases the lifespan of organisms from yeast to flies. In contrast to the lifespan extension effect in lower organisms, it has been reported that overexpression of unc-51-like kinase 3 ULK3, the mammalian homolog of autophagy-specific gene 1 ATG1, induces premature senescence in human fibroblasts. Therefore, we assessed whether the activation of autophagy would genuinely induce premature senescence in human cells.

Methodology-Principal Findings

Depletion of ATG7, ATG12, or lysosomal-associated membrane protein 2 Lamp2 by transfecting siRNA or infecting cells with a virus containing gene-specific shRNA resulted in a senescence-like state in two strains of primary human fibroblasts. Prematurely senescent cells induced by autophagy impairment exhibited the senescent phenotypes, similar to the replicatively senescent cells, such as increased senescence associated β-galactosidase SA-β-gal activity, reactive oxygen species ROS generation, and accumulation of lipofuscin. In addition, expression levels of ribosomal protein S6 kinase1 S6K1, p-S6K1, p-S6, and eukaryotic translation initiation factor 4E eIF4E binding protein 1 4E-BP1 in the mammalian target of rapamycin mTOR pathway and beclin-1, ATG7, ATG12-ATG5 conjugate, and the sequestosome 1 SQSTM1-p62 monomer in the autophagy pathway were decreased in both the replicatively and the autophagy impairment-induced prematurely senescent cells. Furthermore, it was found that ROS scavenging by N-acetylcysteine NAC and inhibition of p53 activation by pifithrin-α or knockdown of p53 using siRNA, respectively, delayed autophagy impairment-induced premature senescence and restored the expression levels of components in the mTOR and autophagy pathways.


Taken together, we concluded that autophagy impairment induces premature senescence through a ROS- and p53-dependent manner in primary human fibroblasts.

Author: Hyun Tae Kang, Ki Baek Lee, Sung Young Kim, Hae Ri Choi, Sang Chul Park



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