Progressive loss of SIRT1 with cell cycle withdrawal

Tsutomu Sasaki, Bernhard Maier, Andrzej Bartke, Heidi Scrable

Research output: Contribution to journalArticle

143 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)413-422
Number of pages10
JournalAging Cell
Volume5
Issue number5
DOIs
StatePublished - Oct 2006
Externally publishedYes

Fingerprint

Cell Cycle
Fibroblasts
Proliferating Cell Nuclear Antigen
Galactosidases
Serial Passage
Somatotropin Receptors
S Phase
Knockout Mice
Diptera
NAD
Thymus Gland
Testis
Yeasts
Lung
Messenger RNA
DNA
Brain

Keywords

  • Aging
  • GHRKO
  • Igf-1r-/-
  • p44
  • Senescence
  • Sir2

ASJC Scopus subject areas

  • Cell Biology

Cite this

Progressive loss of SIRT1 with cell cycle withdrawal. / Sasaki, Tsutomu; Maier, Bernhard; Bartke, Andrzej; Scrable, Heidi.

In: Aging Cell, Vol. 5, No. 5, 10.2006, p. 413-422.

Research output: Contribution to journalArticle

Sasaki, Tsutomu ; Maier, Bernhard ; Bartke, Andrzej ; Scrable, Heidi. / Progressive loss of SIRT1 with cell cycle withdrawal. In: Aging Cell. 2006 ; Vol. 5, No. 5. pp. 413-422.
@article{9e48b9400acf4aa6a362e6cc0888b50c,
title = "Progressive loss of SIRT1 with cell cycle withdrawal",
abstract = "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.",
keywords = "Aging, GHRKO, Igf-1r-/-, p44, Senescence, Sir2",
author = "Tsutomu Sasaki and Bernhard Maier and Andrzej Bartke and Heidi Scrable",
year = "2006",
month = "10",
doi = "10.1111/j.1474-9726.2006.00235.x",
language = "English (US)",
volume = "5",
pages = "413--422",
journal = "Aging Cell",
issn = "1474-9718",
publisher = "Wiley-Blackwell",
number = "5",

}

TY - JOUR

T1 - Progressive loss of SIRT1 with cell cycle withdrawal

AU - Sasaki, Tsutomu

AU - Maier, Bernhard

AU - Bartke, Andrzej

AU - Scrable, Heidi

PY - 2006/10

Y1 - 2006/10

N2 - 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.

AB - 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.

KW - Aging

KW - GHRKO

KW - Igf-1r-/-

KW - p44

KW - Senescence

KW - Sir2

UR - http://www.scopus.com/inward/record.url?scp=33748331132&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33748331132&partnerID=8YFLogxK

U2 - 10.1111/j.1474-9726.2006.00235.x

DO - 10.1111/j.1474-9726.2006.00235.x

M3 - Article

VL - 5

SP - 413

EP - 422

JO - Aging Cell

JF - Aging Cell

SN - 1474-9718

IS - 5

ER -