Progressive loss of SIRT1 with cell cycle withdrawal

Abstract

SummarySir2 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 β β β -galactosidase (SA-β β β β Gal) activity. Reacquisition of mitotic capability following spontaneous immortalization of serially passaged wildtype 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 hormonereceptor 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.

SIRT1 negatively regulates HDAC1-dependent transcriptional repression by the RBP1 family of proteins

“…The observation that inhibition of SIRT1 by either sirtinol or splitomicin induces senescence in H1299 (O Binda, unpublished observation;Ota et al, 2006), HUVEC (Ota et al, 2007) andMCF-7 (Ota et al, 2006) cells correlates with increased R2-mediated repression and RBP1-induced senescence, thereby providing indirect evidence suggesting that SIRT1 activity may antagonize the growth arrest phenotype caused by RBP1 family protein overexpression. A recent study, has reported that SIRT1 is gradually lost in aging cells (Sasaki et al, 2006). So, while SIRT1 levels fade away as the cells age, HDAC1-dependent transcriptional repression could be SIRT1 regulates HDAC1-dependent repression O Binda et al relieved from SIRT1 inhibition and lead to senescence, as observed with p53/PML (Langley et al, 2002).…”

H2O2Accumulation Mediates Differentiation Capacity Alteration, But Not Proliferative Decline, in Senescent Human Fetal Mesenchymal Stem Cells

“…1C, lower right). In addition to morphological changes and SA-b-gal positivity, the histone deacetylase sirtuin-1 (SIRT1), also a marker of cellular senescence (37), was also decreased in L-PDMCs from different donors (Fig. 1D, E).…”

Aging by epigenetics—A consequence of chromatin damage?

“…Significantly, a decreased level of expression of the closest mammalian ortholog of Sir2, SirT1, correlates with apparent premature aging of mice with increased activity of p53 family members [24]. Moreover, in aging wild type mice, SirT1 protein level decreases with age in mitotic tissues [25]. Thus, the ability of Sir2-like proteins to regulate aging appears to be conserved through evolution.…”