Disruption of Growth Hormone Receptor Prevents Calorie Restriction from Improving Insulin Action and Longevity

Abstract

Most mutations that delay aging and prolong lifespan in the mouse are related to somatotropic and/or insulin signaling. Calorie restriction (CR) is the only intervention that reliably increases mouse longevity. There is considerable phenotypic overlap between long-lived mutant mice and normal mice on chronic CR. Therefore, we investigated the interactive effects of CR and targeted disruption or knock out of the growth hormone receptor (GHRKO) in mice on longevity and the insulin signaling cascade. Every other day feeding corresponds to a mild (i.e. 15%) CR which increased median lifespan in normal mice but not in GHRKO mice corroborating our previous findings on the effects of moderate (30%) CR on the longevity of these animals. To determine why insulin sensitivity improves in normal but not GHRKO mice in response to 30% CR, we conducted insulin stimulation experiments after one year of CR. In normal mice, CR increased the insulin stimulated activation of the insulin signaling cascade (IR/IRS/PI3K/AKT) in liver and muscle. Livers of GHRKO mice responded to insulin by increased activation of the early steps of insulin signaling, which was dissipated by altered PI3K subunit abundance which putatively inhibited AKT activation. In the muscle of GHRKO mice, there was elevated downstream activation of the insulin signaling cascade (IRS/PI3K/AKT) in the absence of elevated IR activation. Further, we found a major reduction of inhibitory Ser phosphorylation of IRS-1 seen exclusively in GHRKO muscle which may underpin their elevated insulin sensitivity. Chronic CR failed to further modify the alterations in insulin signaling in GHRKO mice as compared to normal mice, likely explaining or contributing to the absence of CR effects on insulin sensitivity and longevity in these long-lived mice.

When stem cells grow old: phenotypes and mechanisms of stem cell aging

“…A main line of evidence comes from growth hormone receptor knockout mice. These mice have low levels of circulating IGF-1 and receive no additional longevity benefit from multiple types of CR Bonkowski et al, 2006Bonkowski et al, , 2009. In support of a beneficial role for reduced levels of insulin and IGF-1, dampening of insulin-IGF signaling specifically in fly ISCs improves gut homeostasis and extends lifespan, whereas reduced IGF-1 levels are associated with improved HSC self-renewal (Biteau et al, 2010;Cheng et al, 2014).…”

Fasting vs dietary restriction in cellular protection and cancer treatment: from model organisms to patients

“…The GH/IGF-I and insulin system are also significantly altered following fasting and DR. However, differences in GH response and also in the degree of reduction in circulating IGF-I, IGFBP-3, insulin and in the increase of IGFBP-1 and insulin-sensitivity are evitable (Bartke and Turyn 2001;Bonkowski et al, 2009;Breese et al, 1991;Buschemeyer et al, 2010;Dunn et al, 1997;Escriva et al, 2007;Frystyk et al, 1999;Heijboer et al, 2005;Lee et al, 2010;Shimokawa et al, 2003;Wang et al, 2006;Zhao et al, 2010). Corticosteroids tend to increase more following fasting compared with DR (Sabatino et al, 1991;Shen et al, 2009); body temperature showed a steeper decrease following fasting compared with DR (Koizumi et al, 1992;Longo and Finch 2003a;Shen et al, 2009).…”

“…In D. melanogaster, mutations in the insulin receptor substrate (chico) extend lifespan, but its role in stress resistance is not clear (Clancy et al, 2001;Giannakou and Partridge, 2007). In mice, stress resistance and lifespan are controlled by the GH/IGF-I axis and the downstream orthologs of the genes that regulate stress resistance and/or life span in yeast and worms (BrownBorg et al, 1996;Migliaccio et al, 1999;Coschigano et al, 2000;Holzenberger et al, 2003;Yan et al, 2007;Bonkowski et al, 2009;Selman et al, 2009). In agreement with the findings in lower eukaryotes, the activities of anti-oxidant enzymes superoxide dismutases and catalase are decreased in murine hepatocytes exposed to GH or IGF-I and in transgenic mice overexpressing GH (Brown-Borg and Rakoczy, 2000;Brown-Borg et al, 2002).…”

Effect of growth hormone receptor gene disruption and PMA treatment on the expression of genes involved in primordial follicle activation in mice ovaries

“…This phenotype is accompanied by an increased lifespan of GHRKO mice when compared to littermate controls (List et al 2011). GHRKO mice are also hypoinsulinemic and have increased insulin sensitivity (Bonkowski et al 2009). Similarly to GHRKO mice, Ames dwarf (df/df) mice have a mutation that decreases pituitary GH secretion and consequently r e d u c e s s e r u m c o n c e n t r a t i o n s o f I G F -I (Chandrashekar and Bartke 1993).…”