Does Reduced IGF-1R Signaling in Igf1r+/− Mice Alter Aging?

Abstract

Mutations in insulin/IGF-1 signaling pathway have been shown to lead to increased longevity in various invertebrate models. Therefore, the effect of the haplo- insufficiency of the IGF-1 receptor (Igf1r+/−) on longevity/aging was evaluated in C57Bl/6 mice using rigorous criteria where lifespan and end-of-life pathology were measured under optimal husbandry conditions using large sample sizes. Igf1r+/− mice exhibited reductions in IGF-1 receptor levels and the activation of Akt by IGF-1, with no compensatory increases in serum IGF-1 or tissue IGF-1 mRNA levels, indicating that the Igf1r+/− mice show reduced IGF-1 signaling. Aged male, but not female Igf1r+/− mice were glucose intolerant, and both genders developed insulin resistance as they aged. Female, but not male Igf1r+/− mice survived longer than wild type mice after lethal paraquat and diquat exposure, and female Igf1r+/− mice also exhibited less diquat-induced liver damage. However, no significant difference between the lifespans of the male Igf1r+/− and wild type mice was observed; and the mean lifespan of the Igf1r+/− females was increased only slightly (less than 5%) compared to wild type mice. A comprehensive pathological analysis showed no significant difference in end-of-life pathological lesions between the Igf1r+/− and wild type mice. These data show that the Igf1r+/− mouse is not a model of increased longevity and delayed aging as predicted by invertebrate models with mutations in the insulin/IGF-1 signaling pathway.

IGF-1 has sexually dimorphic, pleiotropic, and time-dependent effects on healthspan, pathology, and lifespan

“…The Interventions Testing Program, designed to test the reproducibility of lifespan studies at multiple testing sites, has validated eight treatments that extend lifespan; seven are unique to one sex. Our lifespan extension in the IGF-1-deficient female mice mirrors the haploinsufficiency of igfr study performed by the Richardson laboratory, where females showed a modest increase in lifespan that was not evident in males (Bokov et al 2011). The mechanism(s) underlying the sexual dimorphism of lifespan studies, including those with IGF-1 deficiency, are still largely unknown.…”

“…Although this study has been routinely cited in the literature as evidence that IGF-1 signaling in mammals is detrimental to both healthspan and lifespan, the short lifespan of the control animals in this study (∼750 days) compromise interpretation. Follow-up studies where control animals exhibited a normal lifespan did not result in a dramatic extension of lifespan and females exhibited a modest 5-10% increase in lifespan whereas no increase was observed in response to IGF-1 deficiency in males (Bokov et al 2011;Xu et al 2014). The studies detailed here clearly demonstrate that deficiencies in circulating IGF-1 beginning at or before 5 months of age result in a 15% increase in lifespan in females and that decreases in IGF-1 occurring later in life have little effect.…”

Altered metabolism and resistance to obesity in long-lived mice producing reduced levels of IGF-I

“…In addition, brain-specific overexpression of IGFBP-6 causes glucose intolerance and insulin resistance both on a control diet and on a high-fat diet and promotes increased weight gain (3). As mentioned above, reduction of IGF-I signaling by reducing levels of IGF-I receptors has also been associated with impairments in glucose metabolism under both normal and high-fatfed conditions (4,19,21). Conversely, mice lacking IGFBP-3, -4, and -5, and thus displaying increased levels of IGF-I, show significant enhancement in several measurements of glucose metabolism, including glucose tolerance (31).…”

“…However, this relationship has been less clearly defined in models in which IGF-I signaling has been targeted directly. In independent studies, reduction of the cellular receptor of IGF-I (IGF-IR) in mice has been reported to extend lifespan in female but not male mice (4,21). Interestingly, both studies also reported a significant impairment in glucose metabolism in male mice that was not generally found in female mice.…”

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.…”