Autophagy mediates the mitotic senescence transition (original) (raw)

  1. Andrew R.J. Young1,5,
  2. Masako Narita1,5,
  3. Manuela Ferreira1,2,
  4. Kristina Kirschner1,
  5. Mahito Sadaie1,
  6. Jeremy F.J. Darot1,3,
  7. Simon Tavaré1,
  8. Satoko Arakawa4,
  9. Shigeomi Shimizu4,
  10. Fiona M. Watt1 and
  11. Masashi Narita1,6
  12. 1Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Cambridge CB2 0RE, United Kingdom;
  13. 2Center of Neuroscience and Cell Biology, University of Coimbra, Coimbra 3004-517, Portugal;
  14. 3EMBL-EBI, Wellcome Trust Genome Campus, Cambridge CB10 1SD, United Kingdom;
  15. 4Department of Pathological Cell Biology, Medical Research Institute, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8510, Japan
  16. ↵5 These authors contributed equally to this work.

Abstract

As a stress response, senescence is a dynamic process involving multiple effector mechanisms whose combination determines the phenotypic quality. Here we identify autophagy as a new effector mechanism of senescence. Autophagy is activated during senescence and its activation is correlated with negative feedback in the PI3K–mammalian target of rapamycin (mTOR) pathway. A subset of autophagy-related genes are up-regulated during senescence: Overexpression of one of those genes, ULK3, induces autophagy and senescence. Furthermore, inhibition of autophagy delays the senescence phenotype, including senescence-associated secretion. Our data suggest that autophagy, and its consequent protein turnover, mediate the acquisition of the senescence phenotype.

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