The Influence of Shc Proteins on Life Span in Mice

Ramsey, Jon J.; Tran, Dianna; Giorgio, Marco; Griffey, Stephen M.; Koehne, Amanda; Laing, Steven T.; Taylor, Sandra L.; Kim, Kyoungmi; Cortopassi, Gino A; Lloyd, Kent; Hagopian, Kevork; Tomilov, Alexey; Migliaccio, Enrica; Pelicci, Pier Giuseppe; McDonald, Roger B.

doi:10.1093/gerona/glt198

Cited by 38 publications

(29 citation statements)

References 27 publications

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“…Indeed, lung emphysema and fibrosis are frequent in both G3 and later generations of TERC −/− independently by the p66SHC deletion, although we could not establish that lung dysfunction is the cause of death of these mice. Histiocytic sarcoma was reported to be the most frequent tumor lesion in C57Bl/6 mice, including p66SHC −/− (Ramsey et al ., 2014) and TERC −/− (Khoo et al ., 2007) models. In any case, the early mortality of TERC −/− mice is not determined by p66SHC suggesting that oxidative stress and telomere attrition do not cooperate to determine lifespan.…”

Section: Discussionmentioning

confidence: 99%

P66SHC deletion improves fertility and progeric phenotype of late-generation TERC-deficient mice but not their short lifespan

2016

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SummaryOxidative stress and telomere attrition are considered the driving factors of aging. As oxidative damage to telomeric DNA favors the erosion of chromosome ends and, in turn, telomere shortening increases the sensitivity to pro‐oxidants, these two factors may trigger a detrimental vicious cycle. To check whether limiting oxidative stress slows down telomere shortening and related progeria, we have investigated the effect of p66SHC deletion, which has been shown to reduce oxidative stress and mitochondrial apoptosis, on late‐generation TERC (telomerase RNA component)‐deficient mice having short telomeres and reduced lifespan. Double mutant (TERC −/− p66SHC −/−) mice were generated, and their telomere length, fertility, and lifespan investigated in different generations. Results revealed that p66SHC deletion partially rescues sterility and weight loss, as well as organ atrophy, of TERC‐deficient mice, but not their short lifespan and telomere erosion.Therefore, our data suggest that p66SHC‐mediated oxidative stress and telomere shortening synergize in some tissues (including testes) to accelerate aging; however, early mortality of late‐generation mice seems to be independent of any link between p66SHC‐mediated oxidative stress and telomere attrition.

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Section: Discussionmentioning

confidence: 99%

P66SHC deletion improves fertility and progeric phenotype of late-generation TERC-deficient mice but not their short lifespan

2016

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“…4), and Shc mice developed by the Pelicci group (ShcP or ShcPelicci, also known as p66Shc(Ϫ/Ϫ, Refs. 3,4,8,9). Names in literature for these two models can be described by these definitions: ShcL, ShcProlla; ShcKO, ShcP ϭ ShcPelicci ϭ p66Shc(Ϫ/Ϫ).…”

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p46Shc Inhibits Thiolase and Lipid Oxidation in Mitochondria

Tomilov

Tomilova

Shan

et al. 2016

Journal of Biological Chemistry

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Although the p46Shc isoform has been known to be mitochondrially localized for 11 years, its function in mitochondria has been a mystery. We confirmed p46Shc to be mitochondrially localized and showed that the major mitochondrial partner of p46Shc is the lipid oxidation enzyme 3-ketoacylCoA thiolase ACAA2, to which p46Shc binds directly and with a strong affinity. Increasing p46Shc expression inhibits, and decreasing p46Shc stimulates enzymatic activity of thiolase in vitro. Thus, we suggest p46Shc to be a negative mitochondrial thiolase activity regulator, and reduction of p46Shc expression activates thiolase. This is the first demonstration of a protein that directly binds and controls thiolase activity. Thiolase was thought previously only to be regulated by metabolite balance and steadystate flux control. Thiolase is the last enzyme of the mitochondrial fatty acid beta-oxidation spiral, and thus is important for energy metabolism. Mice with reduction of p46Shc are lean, resist obesity, have higher lipid oxidation capacity, and increased thiolase activity. The thiolase-p46Shc connection shown here in vitro and in organello may be an important underlying mechanism explaining the metabolic phenotype of Shcdepleted mice in vivo.Shc proteins have three isoforms: p46, p52, and p66, and have major effects on metabolism (1-4). p52Shc contacts the insulin receptor and regulates the signaling between the IRS1 and Ras pathway (5). In 2004, it was demonstrated that the major mitochondrial Shc isoform is p46Shc (6), but since that time the mitochondrial partner and physiological function of p46Shc has been a mystery. Here we show the mitochondrial partner and function of p46Shc, and suggest how this could contribute to the obesity-resistance observed in ShcKO mice.There are three isoforms at the mammalian Shc locus, the highly expressed isoforms p46Shc and p52Shc, and the minor p66Shc. All three Shc isoforms are derived from a single DNA locus. First, two mRNA are produced: p66Shc and p52/46Shc by means of trans-splicing. The p66Shc mRNA has start codons for all three Shc isoforms. The p52/46Shc-mRNA does not have a start codon for p66Shc and only produces p52Shc and p46Shc (7). For this reason, knockdowns of either p66Shc, or all three Shc isoforms together have been achieved to date. There are two mouse models of Shc depletion produced to date: ShcL, also known as p66ShcKO developed by the Tom Prolla group (ShcProlla, Ref. 4), and Shc mice developed by the Pelicci group (ShcP or ShcPelicci, also known as p66Shc (Ϫ/Ϫ, Refs. 3,4,8,9). Names in literature for these two models can be described by these definitions: ShcL, ShcProlla; ShcKO, ShcP ϭ ShcPelicci ϭ p66Shc(Ϫ/Ϫ).Briefly, ShcL or ShcProlla mice have a deletion of only the minor p66Shc isoform and have no health benefits: ShcL mice are not lean, do not resist weight gain on high fat diets (HFD), 2 and are not longer-lived on HFD, and do not have improved insulin sensitivity (4). Thus p66Shc deletion by itself does not result in health benefits.By contrast, ShcKO have...

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“…This is not the first time a study was unable to replicate the increase in lifespan shown in an original study. For example, knockout mouse models for the signaling molecule p66Shc (p66shc −/− mice) (Migliaccio et al., 1999), insulin receptor substrate 2 (Irs2) (Irs2 +/− mice) (Taguchi, Wartschow & White, 2007), and the IGF1 receptor ( Igf1r +/− mice) (Holzenberger et al., 2003) all showed substantial lifespan extension in initial reports that was not confirmed in follow‐up studies (Bokov et al., 2011; Ladiges et al., 2009; Liang et al., 2003 ; Ramsey et al., 2014; Selman, Lingard, Gems, Partridge & Withers, 2008; Selman et al., 2007; Unnikrishnan, Deepa, Herd & Richardson, 2017). Differences in genetic background can potentially modulate lifespan results.…”

Section: Discussionmentioning

confidence: 99%

Lifelong reduction in complex IV induces tissue‐specific metabolic effects but does not reduce lifespan or healthspan in mice

et al. 2018

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SummaryLoss of SURF1, a Complex IV assembly protein, was reported to increase lifespan in mice despite dramatically lower cytochrome oxidase (COX) activity. Consistent with this, our previous studies found advantageous changes in metabolism (reduced adiposity, increased insulin sensitivity, and mitochondrial biogenesis) in Surf1 −/− mice. The lack of deleterious phenotypes in Surf1 −/− mice is contrary to the hypothesis that mitochondrial dysfunction contributes to aging. We found only a modest (nonsignificant) extension of lifespan (7% median, 16% maximum) and no change in healthspan indices in Surf1 −/− vs. Surf1 +/+ mice despite substantial decreases in COX activity (22%–87% across tissues). Dietary restriction (DR) increased median lifespan in both Surf1 +/+ and Surf1 −/− mice (36% and 19%, respectively). We measured gene expression, metabolites, and targeted expression of key metabolic proteins in adipose tissue, liver, and brain in Surf1 +/+ and Surf1 −/− mice. Gene expression was differentially regulated in a tissue‐specific manner. Many proteins and metabolites are downregulated in Surf1 −/− adipose tissue and reversed by DR, while in brain, most metabolites that changed were elevated in Surf1 −/− mice. Finally, mitochondrial unfolded protein response (UPRmt)‐associated proteins were not uniformly altered by age or genotype, suggesting the UPRmt is not a key player in aging or in response to reduced COX activity. While the changes in gene expression and metabolism may represent compensatory responses to mitochondrial stress, the important outcome of this study is that lifespan and healthspan are not compromised in Surf1 −/− mice, suggesting that not all mitochondrial deficiencies are a critical determinant of lifespan.

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The Influence of Shc Proteins on Life Span in Mice

Cited by 38 publications

References 27 publications

P66SHC deletion improves fertility and progeric phenotype of late-generation TERC-deficient mice but not their short lifespan

P66SHC deletion improves fertility and progeric phenotype of late-generation TERC-deficient mice but not their short lifespan

p46Shc Inhibits Thiolase and Lipid Oxidation in Mitochondria

Lifelong reduction in complex IV induces tissue‐specific metabolic effects but does not reduce lifespan or healthspan in mice

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