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In addition to their extended lifespans, slow-aging growth hormone receptor/binding protein gene-disrupted (knockout) (GHR-KO) mice are hypoinsulinemic and highly sensitive to the action of insulin. It has been proposed that this insulin sensitivity is important for their longevity and increased healthspan. We tested whether this insulin sensitivity of the GHR-KO mouse is necessary for its retarded aging by abrogating that sensitivity with a transgenic alteration that improves development and secretory function of pancreatic β-cells by expressing Igf-1 under the rat insulin promoter 1 (RIP::IGF-1). The RIP::IGF-1 transgene increased circulating insulin content in GHR-KO mice, and thusly fully normalized their insulin sensitivity, without affecting the proliferation of any non-β-cell cell types. Multiple (nonsurvivorship) longevity-associated physiological and endocrinological characteristics of these mice (namely beneficial blood glucose regulatory control, altered metabolism, and preservation of memory capabilities) were partially or completely normalized, thus supporting the causal role of insulin sensitivity for the decelerated senescence of GHR-KO mice. We conclude that a delayed onset and/or decreased pace of aging can be hormonally regulated., (© 2014 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.)

Mice with targeted deletion of the growth hormone receptor (GHRKO mice) are growth hormone (GH) resistant, small, obese, hypoinsulinemic, highly insulin sensitive and remarkably long-lived. To elucidate the unexpected coexistence of adiposity with improved insulin sensitivity and extended longevity, we examined effects of surgical removal of visceral (epididymal and perinephric) fat on metabolic traits related to insulin signaling and longevity. Comparison of results obtained in GHRKO mice and in normal animals from the same strain revealed disparate effects of visceral fat removal (VFR) on insulin and glucose tolerance, adiponectin levels, accumulation of ectopic fat, phosphorylation of insulin signaling intermediates, body temperature, and respiratory quotient (RQ). Overall, VFR produced the expected improvements in insulin sensitivity and reduced body temperature and RQ in normal mice and had opposite effects in GHRKO mice. Some of the examined parameters were altered by VFR in opposite directions in GHRKO and normal mice, and others were affected in only one genotype or exhibited significant genotype × treatment interactions. Functional differences between visceral fat of GHRKO and normal mice were confirmed by measurements of adipokine secretion, lipolysis, and expression of genes related to fat metabolism. We conclude that in the absence of GH signaling, the secretory activity of visceral fat is profoundly altered and unexpectedly promotes enhanced insulin sensitivity. The apparent beneficial effects of visceral fat in GHRKO mice may also explain why reducing adiposity by calorie restriction fails to improve insulin signaling or further extend longevity in these animals., (© 2011 The Authors. Aging Cell © 2011 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland.)

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.

Growth hormone receptor knockout (GHRKO) mice live about 40%-55% longer than their normal (N) littermates. Previous studies of 21-month-old GHRKO and N mice showed major alterations of the hepatic expression of genes involved in insulin signaling. Differences detected at this age may have been caused by the knockout of the growth hormone receptor (GHR) or by differences in biological age between GHRKO and N mice. To address this question, we compared GHRKO and N mice at ages corresponding to the same percentage of median life span to see if the differences of gene expression persisted. Comparison of GHRKO and N mice at approximately 50% of biological life span showed significant differences in hepatic expression of all 14 analyzed genes. We conclude that these changes are due to disruption of GHR gene and the consequent suppression of growth hormone signaling rather than to differences in "biological age" between mutant and normal animals sampled at the same chronological age.