Targeted disruption of growth hormone receptor interferes with the beneficial actions of calorie restriction

Abstract

Reduced intake of nutrients [calorie restriction (CR)] extends longevity in organisms ranging from yeast to mammals. Mutations affecting somatotropic, insulin, or homologous signaling pathways can increase life span in worms, flies, and mice, and there is considerable evidence that reduced secretion of insulin-like growth factor I and insulin are among the mechanisms that mediate the effects of CR on aging and longevity in mammals. In the present study, mice with targeted disruption of the growth hormone (GH) receptor [GH receptor͞GH-binding protein knockout (GHRKO) mice] and their normal siblings were fed ad libitum (AL) or subjected to 30% CR starting at 2 months of age. In normal females and males, CR produced the expected increases in overall, average, median, and maximal life span. Longevity of normal mice subjected to CR resembles that of GHRKO animals fed AL. In sharp contrast to its effects in normal mice, CR failed to increase overall, median, or average life span in GHRKO mice and increased maximal life span only in females. In a separate group of animals, CR for 1 year improved insulin sensitivity in normal mice but failed to further enhance the remarkable insulin sensitivity in GHRKO mutants. These data imply that somatotropic signaling is critically important not only in the control of aging and longevity under conditions of unlimited food supply but also in mediating the effects of CR on life span. The present findings also support the notion that enhanced sensitivity to insulin plays a prominent role in the actions of CR and GH resistance on longevity.insulin-like growth factor I ͉ insulin ͉ longevity ͉ aging ͉ dietary restriction M utations affecting somatotropic and͞or insulin signaling can produce a marked increase of longevity in mice. Genes related to homologous signaling pathways in the yeast Saccharomyces cerevisiae, the worm Caenorhabditis elegans, and the f ly Drosophila melanogaster play a key role in the control of aging in these species (1-3). A moderate reduction in the intake of nutrients [also known as calorie restriction (CR)] is extremely effective in delaying aging and increasing longevity in organisms ranging from yeast to mammals (3-5). We have previously reported that CR produces an additional increase in the life span of a long-lived hypopituitary mutant mouse, the Ames dwarf, and alters the slope of its survival curve similarly to the effects of CR in normal mice (6). This result was counterintuitive because both Ames dwarfs and normal animals subjected to CR have reduced insulin-like growth factor I (IGF-I) and insulin levels and share other phenotypic characteristics. Although C. elegans with a mutation in the insulin͞IGF-I homologous signaling pathway Daf 16͞FOXO lived longer when subjected to CR (7,8), CR failed to further increase longevity in D. melanogaster with a chico mutation that interferes with insulin͞IGF-I signaling and prolongs life (9). Interpretation of the findings obtained in Ames dwarf mice is complicated by the fact that in addition to growth hormone (GH...

Sterol regulatory element-binding protein-1c orchestrates metabolic remodeling of white adipose tissue by caloric restriction

“…It was previously reported that the antiaging and prolongevity actions of CR were attenuated in long‐lived GH receptor (GHR) KO mice (Bonkowski et al ., 2006). Visceral fat removal elevated the respiratory quotient in GHRKO mice, but had the opposite effect in WT mice (Masternak et al ., 2012).…”

Genes regulated by caloric restriction have unique roles within transcriptional networks

“…The extent to which these genes interact with CR-regulated pathways is unclear (Miller et al, 2002;Tsuchiya et al, 2004;Bonkowski et al, 2006;Swindell, 2007). However, some evidence suggests that such aging genes are likely to be highly connected within biological networks (Ferrarini et al, 2005;Curtis et al, 2006).…”

Evidence for only two independent pathways for decreasing senescence in Caenorhabditis elegans

“…In the field of aging research, epistatic analysis using survival curves and average lifespan has become a standard method of determining the independence of genes and pathways (Bartke et al 2001;Bonkowski et al 2006;Braeckman et al 2000;Clancy et al 2002;Kenyon et al 1993;Lakowski and Hekimi 1998;Tissenbaum and Ruvkun 1998). As such, this study uses a similar epistatic design.…”