Brain IRS2 Signaling Coordinates Life Span and Nutrient Homeostasis

Taguchi, Akiko; Wartschow, Lynn M.; White, Morris F.

doi:10.1126/science.1142179

Cited by 484 publications

(460 citation statements)

References 24 publications

(12 reference statements)

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“…Mutation of genes in this signaling pathway confers greater resistance to oxidative stress and phenotypic characteristics consistent with delayed and slowed aging. In particular, heterozygous deletion of the IGF1R gene has been shown to causes a modest reduction in size, improves stress resistance and extends life span in mice (Hoizenberger 2003 Table 4 Allele combination effect on longevity life span and extend the life span of mice up to 20% (Taguchi et al 2007). In humans, IGF1R variants have been found associated with susceptibility to metabolic syndrome-related phenotypes, in particular with the risk of having insulin resistance and arterial hypertension (Sookoian et al 2010).…”

Section: Discussionmentioning

confidence: 99%

A/ASP/VAL allele combination of IGF1R, IRS2, and UCP2 genes is associated with better metabolic profile, preserved energy expenditure parameters, and low mortality rate in longevity

Barbieri

Boccardi

Esposito

et al. 2011

AGE

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A large array of gene involved in human longevity seems to be in relationship with insulin/ IGF1 pathway. However, if such genes interact each other, or with other genes, to reduce the age-related metabolic derangement and determine the long-lived phenotype has been poorly investigated. Thus, we tested the role of interchromosomal interactions among IGF1R, IRS2, and UCP2 genes on the probability to reach extreme old age in 722 unrelated Italian subjects (401 women and 321 men; mean age, 62.83±25.30 years) enrolled between 1998 and 1999. In particular, the G/A-IGF1R, Gly/Asp-IRS2, and Ala/ Val-UCP2 allele combination was tested for association with longevity, metabolic profile and energy expenditure parameters. The effect on all-cause and cause-specific mortality rate was also assessed after a mean follow-up of 6 years. The analysis revealed that AAV allele combination is associated with a decreased all-cause mortality risk (HR, 0.72; 95% CI, 0.63-0.91; p=0.03) and with a higher probability to reach the extreme of old age (OR, 3.185; 95% CI, 1.63-6.19; p=0.0006). The analysis also revealed lower HOMA-IR (Diff, −0.532, 95% CI, 0.886-0.17; p= 0.003), higher respiratory quotient (Diff, 0.0363, 95% CI, 0.014-0.05; p=0.001), and resting metabolic rate (Diff, 101.80693, 95% CI, p=0.038) for AAV allele combination. In conclusion, A-IGF1R/ Asp-IRS2/Val-UCP2 allele combination is associated with a decreased all-cause mortality risk and with an increased chance of longevity. Such an effect is probably due to the combined effect of IGF1R, IRS2, and UCP2 genes on energy metabolism and on the age-related metabolic remodeling capacity.

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Section: Discussionmentioning

confidence: 99%

A/ASP/VAL allele combination of IGF1R, IRS2, and UCP2 genes is associated with better metabolic profile, preserved energy expenditure parameters, and low mortality rate in longevity

Barbieri

Boccardi

Esposito

et al. 2011

AGE

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“…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).…”

Section: Other "Aging Genes" Lack Unique Network Propertiesmentioning

confidence: 99%

Genes regulated by caloric restriction have unique roles within transcriptional networks

Swindell

2008

Mechanisms of Ageing and Development

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Caloric restriction (CR) has received much interest as an intervention that delays age-related disease and increases lifespan. Whole-genome microarrays have been used to identify specific genes underlying these effects, and in mice, this has led to the identification of genes with expression responses to CR that are shared across multiple tissue types. Such CR-regulated genes represent strong candidates for future investigation, but have been understood only as a list, without regard to their broader role within transcriptional networks. In this study, co-expression and network properties of CR-regulated genes were investigated using data generated by more than 600 Affymetrix microarrays. This analysis identified groups of co-expressed genes and regulatory factors associated with the mammalian CR response, and uncovered surprising network properties of CR-regulated genes. Genes downregulated by CR were highly connected and located in dense network regions. In contrast, CR-upregulated genes were weakly connected and positioned in sparse network regions. Some network properties were mirrored by CR-regulated genes from invertebrate models, suggesting an evolutionary basis for the observed patterns. These findings contribute to a systems-level picture of how CR influences transcription within mammalian cells, and point towards a comprehensive understanding of CR in terms of its influence on biological networks.

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“…For example, IIS regulates adult life span in both Caenorhabditis elegans, e.g., (Dorman et al 1995;Lin et al 1997) and Drosophila melanogastor, e.g., (Clancy et al 2001;Tatar et al 2001;Alic et al 2011). IIS also plays a key role in mammalian aging, with global (Holzenberger et al 2003;Selman et alKappeler et al 2008;Taguchi et al 2007) deletion of IIS genes extending lifespan in mice. In addition, this lifespan extension has been shown to be associated, in some models , with a greater period of adult life free from disease (see .…”

Section: Introductionmentioning

confidence: 99%

“…Indeed, currently only one study has reported antioxidant levels in long-lived IIS mutants, and this was limited to a single antioxidant enzyme in a single tissue. Taguchi et al (2007) reported that long-lived brain-specific insulin receptor substrate 2 heterozygous (bIrs2 +/− ) and homozygous (bIrs2 −/− ) knockout mice were protected against an age-associated decrease in postprandial manganese superoxide dismutase (MnSOD) levels. However, in contrast, a large amount of data on antioxidant enzyme status and oxidative damage has been reported for long-lived GH-deficient dwarf mice.…”

Section: Introductionmentioning

confidence: 99%

Longevity of insulin receptor substrate1 null mice is not associated with increased basal antioxidant protection or reduced oxidative damage

Page

Withers

Selman

2012

AGE

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Insulin receptor substrate-1 null (Irs1 −/− ) mice are long lived and importantly they also demonstrate increased resistance to several age-related pathologies compared to wild type (WT) controls. Currently, the molecular mechanisms that underlie lifespan extension in long-lived mice are unclear although protection against oxidative damage may be important. Here, we determined both the activities of several intracellular antioxidants and levels of oxidative damage in brain, skeletal muscle, and liver of Irs1 −/− and WT mice at 80, 450, and 700 days of age, predicting that long-lived Irs1 −/− mice would be protected against oxidative damage. We measured activities of both intracellular superoxide dismutases (SOD); cytosolic (CuZnSOD) and mitochondrial (MnSOD), glutathione peroxide (GPx), glutathione reductase (GR), catalase (CAT), and reduced glutathione (GHS). Of these, only hepatic CAT was significantly altered (increased) in Irs1 −/− mice. In addition, the levels of protein oxidation (protein carbonyl content) and lipid peroxidation (4-hydroxynonenal) were unaltered in Irs1 −/− mice, although the hepatic GSH/ GSSG ratio, indicating an oxidized environment, was significantly lower in long-lived Irs1 −/− mice. Overall, our results do not support the premise that lifespan extension in Irs1 −/− mice is associated with greater tissue antioxidant protection or reduced oxidative damage.

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Brain IRS2 Signaling Coordinates Life Span and Nutrient Homeostasis

Cited by 484 publications

References 24 publications

A/ASP/VAL allele combination of IGF1R, IRS2, and UCP2 genes is associated with better metabolic profile, preserved energy expenditure parameters, and low mortality rate in longevity

A/ASP/VAL allele combination of IGF1R, IRS2, and UCP2 genes is associated with better metabolic profile, preserved energy expenditure parameters, and low mortality rate in longevity

Genes regulated by caloric restriction have unique roles within transcriptional networks

Longevity of insulin receptor substrate1 null mice is not associated with increased basal antioxidant protection or reduced oxidative damage

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