H2O2 accelerates cellular senescence by accumulation of acetylated p53 via decrease in the function of SIRT1 by NAD+...

Area of Science:

• Cellular senescence
• Oxidative stress biology
• Molecular mechanisms of aging

Background:

• Cellular senescence, a state of irreversible growth arrest, is linked to aging and can be induced by oxidative stress.
• Sirtuin 1 (SIRT1), a NAD(+)-dependent deacetylase, regulates p53 acetylation and influences lifespan.
• The precise role of SIRT1 in oxidative stress-induced senescence requires further elucidation.

Purpose of the Study:

• To investigate the role of SIRT1 in cellular senescence induced by hydrogen peroxide (H(2)O(2)) in human diploid fibroblasts.
• To examine the molecular events, including NAD(+) levels, p53 acetylation, and p21 expression, during oxidative stress-induced senescence.

Main Methods:

• Normal human diploid fibroblast TIG-3 cells were treated with H(2)O(2).
• Measurements included DNA cleavage, intracellular NAD(+) levels, p21, SIRT1, and acetylated p53 expression.
• Cell cycle arrest and senescence-associated beta-galactosidase (SA-beta-gal) activity were assessed.
• Poly (ADP-ribose) polymerase (PARP) inhibitor was used to assess NAD(+) preservation.

Main Results:

• H(2)O(2) treatment caused immediate DNA cleavage and significant depletion of intracellular NAD(+).
• Acetylated p53 levels increased, while SIRT1 protein expression remained largely unchanged.
• p21 expression increased, leading to cell cycle arrest and elevated SA-beta-gal activity.
• PARP inhibition preserved NAD(+) levels.

Conclusions:

• Oxidative stress accelerates cellular senescence through a pathway involving p53 acetylation and p21 upregulation.
• NAD(+) depletion and SIRT1 activity are key components in this senescence-inducing pathway.
• This study highlights the critical role of SIRT1 in mediating the cellular response to oxidative stress and promoting senescence.