Insulin-Like Signaling, Nutrient Homeostasis, and Life Span

Taguchi, Akiko; White, Morris F.

doi:10.1146/annurev.physiol.70.113006.100533

Cited by 285 publications

(264 citation statements)

References 138 publications

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“…IGF-1 and its receptor alleles have been linked both directly and indirectly to body size and skeletal structure (Eigenmann et al 1984;Sutter et al 2007), as well as to life span in several mammals, including dogs (Suh et al 2008;Taguchi and White 2008;Bartke et al 2003;Samaras et al 2003;Miller et al 2002). The longitudinal data currently being collected from animals intermediate of mice and men will certainly prove beneficial in determining definitive correlation of longevity potential and circulating IGF-1.…”

Section: Discussionmentioning

confidence: 99%

Connecting serum IGF-1, body size, and age in the domestic dog

Greer

Hughes

Masternak

2010

AGE

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Many investigations in recent years have targeted understanding the genetic and biochemical basis of aging. Collectively, genetic factors and biological mechanisms appear to influence longevity in general and specifically; reduction of the insulin/IGF-1 signaling cascade has extended life span in diverse species. Genetic alteration of mammals for life extension indicates correlation to serum IGF-1 levels in mice, and IGF-1 levels have been demonstrated as a physiological predictor of frailty with aging in man. Longevity and aging data in the dog offer a close measure of the natural multifactorial longevity interactions of genetic influence, IGF-1 signaling, and environmental factors such as exposure, exercise, and lifestyle. The absence of genetic alteration more closely represents the human longevity status, and the unique species structure of the canine facilitates analyses not possible in other species. These investigations aimed to measure serum IGF-1 in numerous purebred and mixed-breed dogs of variable size and longevity in comparison to age, gender, and spay/neuter differences. The primary objective of this investigation was to determine plasma IGF-1 levels in the adult dog, including a wide range of breeds and adult body weight. The sample set includes animals ranging from just a few months of age through 204 months and ranging in size from 5 to 160 lb. Four groups were evaluated for serum IGF-1 levels, including intact and neutered males, and intact and spayed females. IGF-1 loss over time, as a function of age, decreases in all groups with significant differences between males and females. The relationship between IGF-1 and weight differs depending upon spay/neuter status, but there is an overall increase in IGF-1 levels with increasing weight. The data, currently being interrogated further for delineation of IGF-1 receptor variants and sex differences, are being collected longitudinally and explored for longevity associations previously unavailable in non-genetically modified mammals.

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Section: Discussionmentioning

confidence: 99%

Connecting serum IGF-1, body size, and age in the domestic dog

Greer

Hughes

Masternak

2010

AGE

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“…It has been established for several decades now that the insulin/insulin-like growth factor-1 (IGF1) signaling (IIS) pathway induces pleiotropic effects on development, growth, reproduction, and metabolism of multicellular animals (Taguchi and White 2008). However, it has only been more recently that this pathway has also been shown to play a conserved role in lifespan determination (reviewed in Taguchi and White 2008;Broughton and Partridge 2009)).…”

Section: Introductionmentioning

confidence: 99%

“…However, it has only been more recently that this pathway has also been shown to play a conserved role in lifespan determination (reviewed in Taguchi and White 2008;Broughton and Partridge 2009)). 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).…”

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

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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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“…Several experimental evidences suggest that caloric restriction exerts its beneficial effects on longevity through the modulation of the insulin IGF1 signaling pathway (Fontana et al 2010;Heilbronn and Ravussin 2003;Taguchi and White 2008) and recent association studies on long-lived people have demonstrated that a large array of gene involved in human longevity are in relationship with insulin/IGF1 pathway (van Heemst et al 2005;Bonafè and Olivieri 2009;Pawlikowska et al 2009). To this regard, we have previously demonstrated that the G to A transition in exon 16 of IGF1R gene is associated with longevity in an Italian population ) and more recently an overrepresentation of heterozygotes for mutation in IGF1R gene has been found among Jewish female centenarians (Suh et al 2008).…”

Section: Introductionmentioning

confidence: 99%

“…A further hypothesis to explain the anti-aging effects of calorie restriction is reduced energy expenditure with a consequent reduction in the production of reactive oxygen species (ROS; Fontana et al 2010, Leonie et al 2003Taguchi and White 2008). Interestingly, both fast and caloric restriction increase the activity of UCP2 an inner mitochondrial membrane protein involved in the regulation of energy metabolism (Andrews 2010;Zhang et al 2001), mitochondrial biogenesis, fatty acid oxidation, substrate utilization and ROS elimination, providing neuroprotective and anti-aging effects (Conti et al 2006;Bechmann et al 2002).…”

Section: Introductionmentioning

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

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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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Insulin-Like Signaling, Nutrient Homeostasis, and Life Span

Cited by 285 publications

References 138 publications

Connecting serum IGF-1, body size, and age in the domestic dog

Connecting serum IGF-1, body size, and age in the domestic dog

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

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

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