The Effects of Growth Hormone (GH) Treatment on GH and Insulin/IGF-1 Signaling in Long-Lived Ames Dwarf Mice

Abstract

The disruption of the growth hormone (GH) axis in mice promotes insulin sensitivity and is strongly correlated with extended longevity. Ames dwarf (Prop1(df), df/df) mice are GH, prolactin (PRL), and thyrotropin (TSH) deficient and live approximately 50% longer than their normal siblings. To investigate the effects of GH on insulin and GH signaling pathways, we subjected these dwarf mice to twice-daily GH injections (6 microg/g/d) starting at the age of 2 weeks and continuing for 6 weeks. This produced the expected activation of the GH signaling pathway and stimulated somatic growth of the Ames dwarf mice. However, concomitantly with increased growth and increased production of insulinlike growth factor-1, the GH treatment strongly inhibited the insulin signaling pathway by decreasing insulin sensitivity of the dwarf mice. This suggests that improving growth of these animals may negatively affect both their healthspan and longevity by causing insulin resistance.

Vitamin B12–dependent taurine synthesis regulates growth and bone mass

“…Consistent with the notion that perturbation in taurine metabolism underlies the GH resistance observed upon B 12 deficiency, measurement of taurine and its derivatives in Gif -/-(F2) /B 12 liver showed complete rescue of these metabolites to the levels seen in WT liver ( Figure 4E). Moreover, further suggesting a critical role of taurine in the GH/B 12 -dependent pathway, taurine deficiency has previously been shown to be associated with GH/IGF1 signaling downregulation in Ames dwarf mice (35), and methionine metabolism is significantly perturbed in patients with GH deficiency (36).…”

The somatotropic axis and longevity in mice

“…GH treatment counters not only the enhanced stress resistance exhibited in long-living mice but also the longevity benefits afforded by many of the mutations listed elsewhere in this report. Ames mice treated with GH do not live as long as those not receiving GH treatment (72,85). Moreover, GH administration abolishes the DR benefits in Ames mice (42).…”

Metabolic Effects of Abdominal Fats in Animal Models and Humans

“…In contrast, giant transgenic animals overexpressing GH have decreased levels of adiponectin and are short lived [58]. Additional studies in GH-deficient Ames dwarf mice indicated that supplementing GH decreases adiponectin levels in these long-living mice and also shortens their life span [76,77]. These data show that well-functioning adipose tissue and the efficient production of adiponectin are as crucial not only for healthy metabolism but also for a long life span.…”

“…Adiponectin levels are also shown to be negatively associated with GH levels. Studies in long-living GH-deficient Ames dwarf mice and GH-resistant Laron dwarf mice showed that these small animals are characterized by elevated levels of circulating adiponectin [16,58,[75][76][77][78][79]. In contrast, giant transgenic animals overexpressing GH have decreased levels of adiponectin and are short lived [58].…”

“…Increased inflammatory pathway activity and insulin resistance is suggested to play a major role in shortening the life span of these lean mice. In contrast, GH-deficient Ames dwarf and Laron (GHRKO) dwarf mice have a tendency to increased obesity in comparison to their normal controls as they age [17], but are characterized by 40-60% extended longevity and high insulin sensitivity [15,16,77,135]. These long-living mice also have elevated levels of adiponectin and show decreased inflammation through their life span [78].…”