Molecular Insights into SIRT1 Protection Against UVB-Induced Skin Fibroblast Senescence by Suppression of Oxidative Stress and p53 Acetylation

Abstract

Stresses, such as exposure to ultraviolet radiation and those associated with aging, are known to cause premature cellular senescence that is characterized by growth arrest and morphological and gene expression changes. This study was designed to investigate the protective effect of Sirtuin1 (SIRT1) on the UVB-induced premature senescence. Under in vitro experimental conditions, exposure to a subcytotoxic dose of UVB enhanced human skin fibroblasts senescence, as characterized by increased β-galactosidase activity and increased levels of senescence-associated proteins. However, adenovirus-mediated SIRT1 overexpression significantly protected fibroblasts from UVB-induced cellular deterioration. Exposure to UVB-induced cell senescence was associated with oxidative stress and p38 mitogen-activated protein kinase activation. Molecular analysis demonstrated that deacetylation of Forkhead box O3α (FOXO3α) by SIRT1 changed the transcriptional activity of FOXO3α and increased resistance to the oxidative stress. In addition, SIRT1 suppressed UVB-induced p53 acetylation and its transcriptional activity, which directly affected the cell cycle arrest induced by UVB. Further study demonstrated that SIRT1 activation inhibited cell senescence in the skin of the HR1 hairless mouse exposed to UVB. The study identifies a new role for SIRT1 in the UVB-induced senescence of skin fibroblats and provides a potential target for skin protection through molecuar insights into the mechanisms responsible for UVB-induced photoaging.

MicroRNA-34a affects chondrocyte apoptosis and proliferation by targeting the SIRT1/p53 signaling pathway during the pathogenesis of osteoarthritis

“…Thus, SIRT1 may regulate p53 function by deacetylating p53. Chung et al reported that the overexpression of SIRT1 significantly protects fibroblasts from UVB-induced cellular senescence by suppressing UVB-induced p53 acetylation and its transcriptional activity (35). …”

Exogenous nicotinamide supplementation and moderate physical exercise can attenuate the aging process in skeletal muscle of rats

“…Because p53 is deacetylated by SIRT1 the Acp53/p53 ratio was used to assess the activity of SIRT1 (Chung et al 2015;Feng et al 2015;Kim et al 2016;Li et al 2015;Song et al 2015;Weidele et al 2017) and the results showed that exercise and NAM treatment as well as the combined effects of these increased the activity of SIRT1 in old muscle. In terms of exercise training this is similar to our earlier results (Koltai et al 2010(Koltai et al , 2012 however, the intensity of training was much less than that used in those studies.…”

Melatonin regulates the aging mouse hippocampal homeostasis via the sirtuin1-FOXO1 pathway

“…The mouse double minute 2 homolog ( Mdm2 ) and the E3 ubiquitin-protein ligase are important negative autoregulators of p53. MDM2 binds to FOXO1 and FOXO3A and promotes their ubiquitination and subsequent degradation (Chung et al, 2015[13]; Fu et al, 2009[21]; Huang and Tindall, 2011[25]). The Wnt/β-catenin pathway regulates FOXO1 activities.…”