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

Authors: Chua KF; Mostoslavsky R; Lombard DB; Pang WW; Saito S; Franco S; Kaushal D; Cheng HL; Fischer MR; Stokes N; Murphy MM; Appella E; Alt FW

Abstract: 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 p19(ARF) senescence regulator or its downstream target p53. However, upon acute DNA damage or oncogene expression, SIRT1-deficient cells show normal p19(ARF) 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 p19(ARF) as a downstream effector in this pathway.

Keywords: Animals; *Cell Aging/drug effects; Cell Proliferation/drug effects; Cyclin-Dependent Kinase Inhibitor p16; *DNA Damage/drug effects; Doxorubicin/pharmacology; Fibroblasts; Genes, ras/genetics; Hydrogen Peroxide/pharmacology; Mice; Mice, Knockout; NIH 3T3 Cells; Oxidative Stress/drug effects; S Phase/drug effects; Sirtuin 1; Sirtuins/deficiency/genetics/*metabolism; Tumor Suppressor Protein p14ARF/metabolism
Journal: Cell metabolism
Volume: 2
Issue: 1
Pages: 67-76
Date: Aug. 2, 2005
PMID: 16054100
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Citation:

Chua KF, Mostoslavsky R, Lombard DB, Pang WW, Saito S, Franco S, Kaushal D, Cheng HL, Fischer MR, Stokes N, Murphy MM, Appella E, Alt FW (2005) Mammalian SIRT1 limits replicative life span in response to chronic genotoxic stress. Cell metabolism 2: 67-76.


Lifespan Factors:
  • Sirt1 sirtuin 1 (silent mating type information regulation 2, homolog) 1 (S. cerevisiae)


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