Modelling the p53/p66Shc Aging Pathway in the Shortest Living Vertebrate Nothobranchius Furzeri

Abstract

Oxidative stress induced by reactive oxygen species (ROS) increases during lifespan and is involved in aging processes. The p66Shc adaptor protein is a master regulator of oxidative stress response in mammals. Ablation of p66Shc enhances oxidative stress resistance both in vitro and in vivo. Most importantly, it has been demonstrated that its deletion retards aging in mice. Recently, new insights in the molecular mechanisms involving p66Shc and the p53 tumor suppressor genes were given: a specific p66Shc/p53 transcriptional regulation pathway was uncovered as determinant in oxidative stress response and, likely, in aging. p53, in a p66Shc-dependent manner, negatively downregulates the expression of 200 genes which are involved in the G2/M transition of mitotic cell cycle and are downregulated during physiological aging. p66Shc modulates the response of p53 by activating a p53 isoform (p44/p53, also named Delta40p53). Based on these latest results, several developments are expected in the future, as the generation of animal models to study aging and the evaluation of the use of the p53/p66Shc target genes as biomarkers in aging related diseases. The aim of this review is to investigate the conservation of the p66Shc and p53 role in oxidative stress between fish and mammals. We propose to approach this study trough a new model organism, the annual fish Nothobranchius furzeri, that has been demonstrated to develop typical signs of aging, like in mammals, including senescence, neurodegeneration, metabolic disorders and cancer.

The path from mitochondrial ROS to aging runs through the mitochondrial permeability transition pore

“…Indeed, it has been argued that oxidation of membrane phospholipids is critical for the progression of aging (Pamplona, ; possibly through activation of the mPTP). In addition, oxidative stress triggers the transfer of proteins that enhance mPTP activation such as P53, which is transported to the mitochondrial matrix, or P66Shc, which is transported to the mitochondrial intermembrane space where its cytochrome c ‐dependent ROS production, in turn, activates the mPTP (Savino et al ., ; Priami et al ., ; Di Lisa et al ., ). Moreover, oxidized pyridine nucleotides also activate the mPTP (Chernyak & Bernardi, ; Ronchi et al ., ) and oxidative stress is manifested in increased oxidation of pyridine nucleotides (Sies et al ., ).…”

The African turquoise killifish: A research organism to study vertebrate aging and diapause

“…Aging in the turquoise killifish has been extensively characterized at both the phenotypical and molecular level in both the GRZ strain and other strains such as MZM0403 and 0410 (Baumgart et al., 2012, 2014; Di Cicco, Tozzini, Rossi & Cellerino, 2011; Hartmann et al., 2009, 2011; Priami et al., 2015; Terzibasi Tozzini et al., 2014; Terzibasi et al., 2008; Tozzini, Baumgart, Battistoni & Cellerino, 2012). Indeed, despite their short lifespan compared to other vertebrates, various strains of the turquoise killifish recapitulate numerous stereotypical aging traits that have been reported in other vertebrates (Figure 5), including decline in reproduction, fertility, cognition, mobility, regeneration, and tissue homeostasis, along with increased incidence of senescence, neural and muscular degeneration, and cancerous lesions (Di Cicco et al., 2011; Terzibasi, Valenzano & Cellerino, 2007; Terzibasi et al., 2008; Valenzano, Terzibasi, Cattaneo, Domenici & Cellerino, 2006; Wendler, Hartmann, Hoppe & Englert, 2015).…”

Sirtuins and their interactions with transcription factors and poly(ADP-ribose) polymerases

“…These TFs are also capable of direct modulation of DNA repair genes and proteins [146]. Moreover, the p53 family could also be linked to ageing at the organism level [146,160]. Other emerging roles of p53 in glucose and lipid metabolism, ROS signalling and oxidative stress [64] suggest a significant functional overlap with SIRT pathways.…”