Cell Metabolism
Volume 2, Issue 1, July 2005, Pages 67-76
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Article
Mammalian SIRT1 limits replicative life span in response to chronic genotoxic stress

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Summary

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.

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These authors contributed equally to this work.

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Present address: Department of Medicine, Division of Endocrinology, Stanford University School of Medicine and GRECC, VA Palo Alto Health  Care System, Palo Alto, California 94304.