The p66shc adaptor protein controls oxidative stress response and life span in mammals

Abstract

Gene mutations in invertebrates have been identified that extend life span and enhance resistance to environmental stresses such as ultraviolet light or reactive oxygen species. In mammals, the mechanisms that regulate stress response are poorly understood and no genes are known to increase individual life span. Here we report that targeted mutation of the mouse p66shc gene induces stress resistance and prolongs life span. p66shc is a splice variant of p52shc/p46shc (ref. 2), a cytoplasmic signal transducer involved in the transmission of mitogenic signals from activated receptors to Ras. We show that: (1) p66shc is serine phosphorylated upon treatment with hydrogen peroxide (H2O2) or irradiation with ultraviolet light; (2) ablation of p66shc enhances cellular resistance to apoptosis induced by H2O2 or ultraviolet light; (3) a serine-phosphorylation defective mutant of p66shc cannot restore the normal stress response in p66shc-/- cells; (4) the p53 and p21 stress response is impaired in p66shc-/- cells; (5) p66shc-/- mice have increased resistance to paraquat and a 30% increase in life span. We propose that p66shc is part of a signal transduction pathway that regulates stress apoptotic responses and life span in mammals.

Role of dietary amino acid balance in diet restriction‐mediated lifespan extension, renoprotection, and muscle weakness in aged mice

“…For study 2, a DR group that was supplemented with EAAs, without methionine ( n  = 20), was also established, and its phenotype was compared with those of simple DR ( n  = 25) and DR plus EAAs ( n  = 30) groups. Based on previous reports (Bluher, Kahn, & Kahn, 2003; Forster et al., 2003; Migliaccio et al., 1999; Mitchell et al., 2016; Weindruch & Walford, 1982), the survival rate of male C57BL/6 mice is approximately 50%–60% at 24 months old. Thus, we decided to use 24 months as the end‐point of this study, which enabled us to analyze the effect of each dietary regimen on survival, cardiac function, glucose metabolism, muscle function, histology, and serum parameters in living middle aged and older mice, but not in very old mice.…”

Mitochondria and aging: A role for the mitochondrial transition pore?

“…The beneficial effects of mitochondria‐targeted drugs such as plastoquinone derivatives (Anisimov et al., 2008, 2011) or MitoTEMPO (Miura et al., 2017; Owada et al., 2017) and of endogenous indoleamine melatonine (Escames et al., 2010; Paradies, Paradies, Ruggiero, & Petrosillo, 2017) reinforce this theory. Similarly, mice deleted for the gene of the p66shc adaptor protein have reduced ROS generation and delayed aging (Migliaccio et al., 1999; Napoli et al., 2003). However, new recent data challenged this hypothesis as they show that ROS can be beneficial and extend lifespan at least in lower organisms such as flies and worms (Sanz, 2016; Sena & Chandel, 2012).…”

Genes regulated by caloric restriction have unique roles within transcriptional networks

“…A number of "aging genes" have been identified for which mutations significantly increase mouse lifespan and delay the onset of age-related disease (Prop1, Pit1, Ghr,Ghrhr,Irs1,Irs2,PappA,Clk1,Shc1,Igf1r,Kl,Adcy5,Surf1,Insr,Ucp2,Gpx4) (Brown-Borg et al, 1996;Kopchick and Laron, 1999;Migliaccio et al, 1999;Flurkey et al, 2001;Bluher et al, 2003;Holzenberger et al, 2003;Kurosu et al, 2005;Liu et al, 2005;Conti et al, 2006;Conover and Bale, 2007;Dell'Agnello et al, 2007;Ran et al, 2007;Taguchi et al, 2007;Yan et al, 2007;Selman et al, 2008). The extent to which these genes interact with CR-regulated pathways is unclear (Miller et al, 2002;Tsuchiya et al, 2004;Bonkowski et al, 2006;Swindell, 2007).…”