Mammalian SIRT1 limits replicative life span in response to chronic genotoxic stress

Katrin F. Chua, Raul Mostoslavsky, David B. Lombard, Wendy W. Pang, Shin'ichi Saito, Sonia Franco, Dhruv Kaushal, Hwei Ling Cheng, Miriam R. Fischer, Nicole Stokes, Michael M. Murphy, Ettore Appella, Frederick W. Alt

Research output: Contribution to journalArticlepeer-review

214 Scopus citations


The Saccharomyces cerevisiae chromatin silencing factor Sir2 suppresses genomic instability and extends replicative life span. In contrast, we find that mouse embryonic fibroblasts (MEFs) deficient for SIRT1, a mammalian Sir2 homolog, have dramatically increased resistance to replicative senescence. Extended replicative life span of SIRT1-deficient MEFs correlates with enhanced proliferative capacity under conditions of chronic, sublethal oxidative stress. In this context, SIRT1-deficient cells fail to normally upregulate either the p19ARF senescence regulator or its downstream target p53. However, upon acute DNA damage or oncogene expression, SIRT1-deficient cells show normal p19ARF induction and cell cycle arrest. Together, our findings demonstrate an unexpected SIRT1 function in promoting replicative senescence in response to chronic cellular stress and implicate p19ARF as a downstream effector in this pathway.

Original languageEnglish (US)
Pages (from-to)67-76
Number of pages10
JournalCell Metabolism
Issue number1
StatePublished - Jul 2005
Externally publishedYes

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology


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