2007
DOI: 10.1096/fj.07-9261com
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Abstract: Recent evidence suggests that alterations in insulin/insulin-like growth factor 1 (IGF1) signaling (IIS) can increase mammalian life span. For example, in several mouse mutants, impairment of the growth hormone (GH)/IGF1 axis increases life span and also insulin sensitivity. However, the intracellular signaling route to altered mammalian aging remains unclear. We therefore measured the life span of mice lacking either insulin receptor substrate (IRS) 1 or 2, the major intracellular effectors of the IIS recepto… Show more

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Cited by 483 publications
(502 citation statements)
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“…However, in view of the well-documented role of hormones homologous to IGF-1 and insulin in the control of ageing in worms and insects, it was of great interest to determine whether a more direct targeting of IGF-1 signalling can affect longevity in mammals. While homozygous deletion of genes encoding IGF-1 receptor or IGF-1 is lethal or produces severe developmental defects, extended longevity was reported in mice heterozygous for the deletion of IGF-1 receptor [37], expressing a hypomorphic IGF-1 allele that leads to a reduction in circulating IGF-1 levels [38] as well as in mice homozygous for the deletion of insulin receptor substrate (IRS)-1 [39] or heterozygous for the deletion of IRS2 [40]. Activation of IRS1 and IRS2 mediates cellular transmission of IGF-1 as well as insulin signals.…”
Section: Mutations Affecting Insulin-like Growth Factor Signallingmentioning
confidence: 99%
“…However, in view of the well-documented role of hormones homologous to IGF-1 and insulin in the control of ageing in worms and insects, it was of great interest to determine whether a more direct targeting of IGF-1 signalling can affect longevity in mammals. While homozygous deletion of genes encoding IGF-1 receptor or IGF-1 is lethal or produces severe developmental defects, extended longevity was reported in mice heterozygous for the deletion of IGF-1 receptor [37], expressing a hypomorphic IGF-1 allele that leads to a reduction in circulating IGF-1 levels [38] as well as in mice homozygous for the deletion of insulin receptor substrate (IRS)-1 [39] or heterozygous for the deletion of IRS2 [40]. Activation of IRS1 and IRS2 mediates cellular transmission of IGF-1 as well as insulin signals.…”
Section: Mutations Affecting Insulin-like Growth Factor Signallingmentioning
confidence: 99%
“…The most extensively studied include the growth hormone (GH),the insulin/insulin-like growth factor (IGF-I) (IIS) pathway [28,29], the sirtuins, [30] but also the isoform p66 of the locus encoding for the proto-oncogene Shc p66 shc [31] and the type 5 adenylil cyclase [32.]. The relevance of the role of IIS in regulating longevity in mammals is mounting, including the demonstration of life extension in mice with heterozygote null mutation of the IGF-I Receptor (Igf1r +/− ) as well as of the insulin receptor substrate 1 (Irs1 +/− ) and mice lacking insulin receptors exclusively in the adipose tissue (FIRKO mice) [33][34][35]. These findings demonstrated that longevity can be regulated by specific pathways and suggested that targeting them may become a possible means to effectively increase lifespan and possibly retard the aging process.…”
Section: Thermodynamic Effects and Specific Pathwaysmentioning
confidence: 99%
“…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%