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Progressive loss of SIRT1 with cell cycle withdrawal

Authors

  • Tsutomu Sasaki,

    1. Department of Neuroscience, University of Virginia School of Medicine, Charlottesville, VA 22908, USA
    2. Neuroscience Graduate Program, University of Virginia, Charlottesville, VA 22908, USA
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  • Bernhard Maier,

    1. Department of Neuroscience, University of Virginia School of Medicine, Charlottesville, VA 22908, USA
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  • Andrzej Bartke,

    1. Department of Physiology and Internal Medicine, Southern Illinois University School of Medicine, Springfield, IL 62794, USA
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  • Heidi Scrable

    1. Department of Neuroscience, University of Virginia School of Medicine, Charlottesville, VA 22908, USA
    2. Neuroscience Graduate Program, University of Virginia, Charlottesville, VA 22908, USA
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Errata

This article is corrected by:

  1. Errata: Corrigendum Volume 5, Issue 6, 585, Article first published online: 20 November 2006


Heidi Scrable, Department of Neuroscience, University of Virginia School of Medicine, PO Box 801392, Charlottesville, VA 22908, USA. Tel.: +1 434 982 1416; fax: +1 434 982 4380; e-mail: hs2n@virginia.edu

Summary

Sir2 is an NAD+-dependent deacetylase that regulates lifespan in yeast, worms and flies. The mammalian orthologs of Sir2 include SIRT1 in humans and mice. In this study, we analyzed the level of SIRT1 in human lung fibroblasts (IMR90) and mouse embryonic fibroblasts (MEFs) from mice with normal, accelerated, and delayed aging. SIRT1 protein, but not mRNA, decreased significantly with serial cell passage in both human and murine cells. Mouse SIRT1 decreased rapidly in prematurely senescent (p44 Tg) MEFs, remained high in MEFs with delayed senescence (Igf-1r–/–), and was inversely correlated with senescence-activated β-galactosidase (SA-βGal) activity. Reacquisition of mitotic capability following spontaneous immortalization of serially passaged wild-type MEFs restored the level of SIRT1 to that of early passage, highly proliferative MEFs. In mouse and human fibroblasts, we found a significant positive correlation between the levels of SIRT1 and proliferating cell nuclear antigen (PCNA), a DNA processing factor expressed during S-phase. In the animal, we found that SIRT1 decreased with age in tissues in which mitotic activity also declines, such as the thymus and testis, but not in tissues such as the brain in which there is little change in mitotic activity throughout life. Again, the decreases in SIRT1 were highly correlated with decreases in PCNA. Finally, loss of SIRT1 with age was accelerated in mice with accelerated aging but was not observed in long-lived growth hormone-receptor knockout mice. Thus, as mitotic activity ceases in mouse and human cells in the normal environment of the animal or in the culture dish, there is a concomitant decline in the level of SIRT1.

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