IGF-1 receptor regulates lifespan and resistance to oxidative stress in mice

Abstract

Studies in invertebrates have led to the identification of a number of genes that regulate lifespan, some of which encode components of the insulin or insulin-like signalling pathways. Examples include the related tyrosine kinase receptors InR (Drosophila melanogaster) and DAF-2 (Caenorhabditis elegans) that are homologues of the mammalian insulin-like growth factor type 1 receptor (IGF-1R). To investigate whether IGF-1R also controls longevity in mammals, we inactivated the IGF-1R gene in mice (Igf1r). Here, using heterozygous knockout mice because null mutants are not viable, we report that Igf1r(+/-) mice live on average 26% longer than their wild-type littermates (P < 0.02). Female Igf1r(+/-) mice live 33% longer than wild-type females (P < 0.001), whereas the equivalent male mice show an increase in lifespan of 16%, which is not statistically significant. Long-lived Igf1r(+/-) mice do not develop dwarfism, their energy metabolism is normal, and their nutrient uptake, physical activity, fertility and reproduction are unaffected. The Igf1r(+/-) mice display greater resistance to oxidative stress, a known determinant of ageing. These results indicate that the IGF-1 receptor may be a central regulator of mammalian lifespan.

Central insulin‐like growth factor‐1 ( IGF ‐1) restores whole‐body insulin action in a model of age‐related insulin resistance and IGF ‐1 decline

“…Diminished growth hormone/insulin‐like growth factor‐1 (GH/IGF‐1) signaling improves longevity across nature, including mice heterozygous for the IGF‐1 receptor (IGF‐1R) (Holzenberger et al ., 2003; Barzilai et al ., 2012). Moreover, low IGF‐1 action is relevant to humans because of its link to less cancer risk (Renehan et al ., 2004), an observation that spurred the development of IGF‐1R antagonists as a clinical cancer treatment (Pollak, 2012).…”

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

“…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.…”

Developing criteria for evaluation of geroprotectors as a key stage toward translation to the clinic

“…Pathways and mechanisms linked to both stress resistance and longevity include the insulin/IGF‐1 (Longo & Fabrizio, 2002) (Holzenberger et al ., 2003), TOR (Lin et al ., 2014) and NF‐κB (Helenius et al ., 1996) signaling pathways, DNA repair (Moskalev et al ., 2013), free radicals detoxication (Cutler, 2005), molecular chaperones (Morley & Morimoto, 2004), and epigenetic control of gene expression (Saunders & Verdin, 2009). In their recent review, Epel and Lithgow (Epel & Lithgow, 2014) suggested that reduction in stress resistance is a common feature for all of the nine hallmarks of aging proposed earlier by López‐Otín et al .…”