Abstract
The correlation of physiological sensitivity to insulin (vis-à-vis glycemic regulation) and longevity is extensively established, creating a justifiable gerontological interest on whether insulin sensitivity is causative, or even predictive, of some or all phenotypes of slowed senescence (including longevity). The growth hormone receptor/ binding protein gene-disrupted (GHR-KO) mouse is the most extensively investigated insulin-sensitive, attenuated aging model. It was reported that, in a manner divergent from similar mutants, GHR-KO mice fail to respond to caloric restriction (CR) by altering their insulin sensitivity. We hypothesized that maximized insulin responsiveness is what causes GHR-KO mice to exhibit a suppressed survivorship response to dietary (including caloric) restriction; and attempted to refute this hypothesis by assessing the effects of CR on GHR-KO mice for varied slow-aging-associated phenotypes. In contrast to previous reports, we found GHR-KO mice on CR to be less responsive than their ad libitum (A.L.) counterparts to the hypoglycemia-inducing effects of insulin. Further, CR had negligible effects on the metabolism or cognition of GHR-KO mice. Therefore, our data suggest that the effects of CR on the insulin sensitivity of GHR-KO mice do not concur with the effects of CR on the aging of GHR-KO mice.
Highlights
This was based on the hypothesis that it is the maximization of the response to caloric restriction (CR) in the insulin sensitivity test that acts as a “ceiling/floor” effect limiting the survivorship response to CR [Bonkowski et al, 2006]
Our insulin sensitivity results in GHR-KO mice on 30% CR differed from those obtained in a previous study, showing that caloric restriction promotes euglycemia in GHR-KO mice (Figure 2C)
Those caveats emptor notwithstanding, that blood insulin content is increased by CR in GHR-KO mice (Figure 2E) dovetails with the improved performance in glucose bolus assimilation (Figure 2A), decreased insulin sensitivity (Figure 2C), and decreased gluconeogenic capability (Figure 2D) of GHR-KO mice on CR relative to their A.L. counterparts
Summary
Improvements in insulin sensitivity or blood glucose homeostatic management are hallmarks of many slow-aging mutant and dietarily restricted animals, supporting the conjectures that these endocrine and metabolic phenomena may be positive regulators of (or indicators of interventions that might promote) longevity [Arum et al, 2009; Bartke, 2008; Bonkowski et al, 2006; Lawler et al, 2008; Longo & Finch, 2003; Masoro, 2003; Masoro, 2005; Mattison et al, 2007; Piper & Bartke, 2008]. It is of high gerontological interest to study causal associations between longevity and physiological correlates that might result in anti-aging healthspan therapies based on engendering those physiological correlates, or that might serve as useful biomarkers for pharmacological or lifestyle interventions to delay the onset and/or decelerate the rate of senescence. The growth hormone receptor/binding protein (Ghr/bp) gene-disrupted (knockout) (GHR-KO) mouse is homozygous for a targeted disruption (knock-out, KO) of the growth hormone (GH) receptor (GHR)/binding protein gene, and is GH-resistant, resulting in decreased GH hormonal signaling. GHR-KO mice were generated by insertional mutagenesis that disrupted the Ghr/bp gene; this results in decreased hepatic production of insulin-like growth factor 1 (IGF-1), which leads to markedly reduced levels of circulating IGF-1, a reduced growth rate, an approximately 20% reduction in adulthood length, and an approximately 40% reduction in adult body weight [Zhou et al, 1997].
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