600E [59], p53 [60], p21 [61] and p16 [62] all resulted in elevated ROS generation. In many of the above reported instances remedy with antioxidants, such as Nacetyl cysteine, were capable to prevent the cellcycle arrest supporting a causal role for ROS inside the course of action (Figure 2b). These information indicate that elevated ROS are a consequence on the activation with the senescence programme and has led to the suggestion that ROS may possibly act as signalling molecules throughout cellular senescence [63]. Nonetheless, mechanistically it can be still unclear how these pathways contribute to mitochondrial dysfunction and ROS generation. Takahashi and colleagues, applying human fibroblasts expressing a temperaturesensitive simian virus 40 massive T antigen, connected p16 with ROS production through protein kinase C signalling [62]. Protein kinase C has been shown to activate a nonmitochondrial supply of ROS, generated by NADPHoxidase through phosphorylation of p47phox, an important component of NADPH oxidase [64]. Constant with this study, NADPH oxidases have been shown to limit the replicative lifespan of human endothelial cells in culture through ROS generation [65].Oncogeneinduced senescence has been related with mitochondrial dysfunction and ROS production, which is dependent on intact p53 and Rb tumour suppression pathways. Mitochondrial dysfunction resulted within the loss of ATP and activation of AMPK; furthermore, mitochondrialderived ROS were shown to contribute to the oxidation of DNA [66]. Within a recent study, it was shown that BRAFV600Einduced senescence was accompanied by the activation of pyruvate dehydrogenase, which resulted inside the enhanced use of pyruvate by the tricarboxylic acid cycle followed by increased respiration and ROS generation [59]. The part of p53 and p21 in ROS generation through senescence continues to be not properly understood.1107658-78-5 Price An association amongst p53 and transcriptional activation of genes involved in mitochondrial apoptosis has been demonstrated [67], as well as a stressinduced translocation of p53 to mitochondria resulting in elevated outer membrane permeabilisation [68]; however, a direct role of mitochondrial p53 in cellular senescence has not yet been demonstrated.1262412-13-4 Order In contrast, transcriptional regulation of mitochondrial genes by p53 has been reported to impact on mitochondrial function and contribute toCorreiaMelo et al.PMID:23962101 Longevity Healthspan 2014, 3:1 http://www.longevityandhealthspan.com/content/3/1/Page 5 ofageing. p53 knockout mice exhibited decreased expression of the Sco2 gene, that is required for the assembly of the mitochondrial DNAencoded COX II subunit [69]. In late generation telomerase knockout mice which have critically brief telomeres, activation of p53 has been shown to repress the promoters of PGC1 and PGC1 genes, master regulators of mitochondrial biogenesis and function, thereby contributing to decreased mitochondrial function [70]. Knockdown of each p53 and p21 by RNAmediated interference has been shown to cut down ROS generation in each telomeredependent and independent senescence [21]. Our group has found that ROS levels raise in senescent cells as a result of signalling by way of p21, and feed back into DNA harm induction as well as the DDR, generating a stable, selfsustaining feedback loop (Figure 2c). This feedback loop persists even in irreversibly deep senescence. In addition, p21 seems to become the essential mediator between the DDR and MAPK and transforming development issue (TGF) stressinduced signalling cascades, which have been shown to co.