H₂O₂ Accelerates Cellular Senescence by Accumulation of Acetylated p53 via Decrease in the Function of SIRT1 by NAD⁺ Depletion

Abstract

It has been reported that p53 acetylation, which promotes cellular senescence, can be regulated by the NAD⁺-dependent deacetylase SIRT1, the human homolog of yeast Sir2, a protein that modulates lifespan. To clarify the role of SIRT1 in cellular senescence induced by oxidative stress, we treated normal human diploid fibroblast TIG-3 cells with H₂O₂ and examined DNA cleavage, depletion of intracellular NAD⁺, expression of p21, SIRT1, and acetylated p53, cell cycle arrest, and senescence-associated β-galactosidase (SA-β-gal) activity. DNA cleavage was observed immediately in TIG-3 cells treated with H₂O₂, though no cell death was observed. NAD⁺ levels in TIG-3 cells treated with H₂O₂ were also decreased significantly. Pre-incubation with the poly (ADP-ribose) polymerase (PARP) inhibitor resulted in preservation of intracellular NAD⁺ levels. The amount of acetylated p53 was increased in TIG-3 cells at 4h after H₂O₂ treatment, while there was little to no decrease in SIRT1 protein expression. The expression level of p21 was increased at 12h and continued to increase for up to 24h. Additionally, exposure of TIG-3 cells to H₂O₂ induced cell cycle arrest at 24h and increased SA-β-gal activity at 48h. This pathway likely plays an important role in the acceleration of cellular senescence by oxidative stress.

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

“…4B). These findings are compatible to the previous finding of H 2 We then examined whether ROS, as induced by toxic compounds or direct exposure of H 2 O 2 , was the cause of the increased p21 expression and cell cycle arrest in L-PDMCs, since this has been reported previously (16,22). However, we found that NAC inhibition of H 2 O 2 accumulation had no effect on cell cycle arrest (Fig.…”

Accelerated premature stress-induced senescence of young annulus fibrosus cells of rats by high glucose-induced oxidative stress

“…As additional evidence for a role of ROS in aging, increased expression of the antioxidant enzyme catalase in mitochondria of transgenic mice can extend life-span and reduce age-related changes in tissues such as that of the heart [10][11][12]. It is well known that damaged mitochondria release harmful ROS into the cytosol [25][26][27][28][29][30]. In the present study, we demonstrated an excessive generation of oxidative stress, such as ROS, through mitochondrial damage in young rat AF cells treated with high glucose concentrations with a dose-and time-dependent manner compared to normal control.…”

“…ROS are thought to play a role in various cellular processes, such as senescence, which appear to cause cellular damage and lack of physiological function. Therefore, the accumulation of ROS has been reported to be associated with a variety of diseases including neurodegenerative diseases, DM, cancer, premature aging, and inflammatory disorders [29,30]. To date, little information is available about the effect of DM on the senescence of young AF cells and premature intervertebral disc degeneration.…”

Aryl Hydrocarbon Receptor Mediates Indoxyl Sulfate-Induced Cellular Senescence in Human Umbilical Vein Endothelial Cells

“…Sirtuin 1 (Sirt1), the closest homologue of silent information regulator2 (Sir2), has been identified to be a NAD ＋ -dependent deacetylase whose activity plays a significant role in the processes of senescence, apoptosis and cell cycle modulation by regulating the acetylation of lysine groups of many transcriptional factors and proteins, such as histones, p53 and FOXO transcriptional factors [17][18][19] . In addition, oxidative stress has been shown to reduce the cellular NAD ＋ content by suppressing the activation of intracellular nicotinamide phosphoribosyltransferase (iNampt), the rate-limiting enzyme for NAD ＋ biosynthesis derived from nicotinamide (NAM), and decreasing the Sirt1 activity 10,[20][21][22] . Therefore, Sirt1 is considered to be a key player in the promotion of oxidative stress-mediated cellular senescence 23) .…”