Growth hormone-releasing hormone disruption extends lifespan and regulates response to caloric restriction in mice

Autor: Joshua A. Huber, Andrzej Bartke, Liou Y. Sun, Reyhan Westbrook, Jacob D Boehm, William R. Swindell, Roberto Salvatori, Yimin Fang, Adam Spong, Cristal M. Hill
Rok vydání: 2013
Předmět:
Pituitary gland
Mouse
medicine.medical_treatment
Mutant
Hypopituitarism
Growth Hormone-Releasing Hormone
0302 clinical medicine
Biology (General)
Receptor
Mice
Knockout
2. Zero hunger
0303 health sciences
General Neuroscience
General Medicine
Growth hormone–releasing hormone
Phenotype
medicine.anatomical_structure
Liver
Genes and Chromosomes
Knockout mouse
Medicine
caloric restriction
hormones
hormone substitutes
and hormone antagonists
Research Article
endocrine system
medicine.medical_specialty
mice
NF-E2-Related Factor 2
QH301-705.5
Science
Longevity
Biology
General Biochemistry
Genetics and Molecular Biology
Xenobiotics
03 medical and health sciences
Internal medicine
medicine
Animals
030304 developmental biology
General Immunology and Microbiology
Gene Expression Profiling
Insulin
aging
medicine.disease
Endocrinology
growth hormone
030217 neurology & neurosurgery
Hormone
Zdroj: eLife, Vol 2 (2013)
eLife
ISSN: 2050-084X
DOI: 10.7554/elife.01098
Popis: We examine the impact of targeted disruption of growth hormone-releasing hormone (GHRH) in mice on longevity and the putative mechanisms of delayed aging. GHRH knockout mice are remarkably long-lived, exhibiting major shifts in the expression of genes related to xenobiotic detoxification, stress resistance, and insulin signaling. These mutant mice also have increased adiponectin levels and alterations in glucose homeostasis consistent with the removal of the counter-insulin effects of growth hormone. While these effects overlap with those of caloric restriction, we show that the effects of caloric restriction (CR) and the GHRH mutation are additive, with lifespan of GHRH-KO mutants further increased by CR. We conclude that GHRH-KO mice feature perturbations in a network of signaling pathways related to stress resistance, metabolic control and inflammation, and therefore provide a new model that can be used to explore links between GHRH repression, downregulation of the somatotropic axis, and extended longevity. DOI: http://dx.doi.org/10.7554/eLife.01098.001
eLife digest There is increasing evidence that the hormonal systems involved in growth, the metabolism of glucose, and the processes that balance energy intake and expenditure might also be involved in the aging process. In rodents, mutations in genes involved in these hormone-signaling pathways can substantially increase lifespan, as can a diet that is low in calories but which avoids malnutrition. As well as living longer, such mice also show reductions in age-related conditions such as diabetes, memory loss and cancer. Many of these effects appear to involve the actions of growth hormone. Mice with mutations that disrupt the development of the pituitary gland, which produces growth hormone, show increased longevity, as do mice that lack the receptor for growth hormone. However, these animals also show changes in a number of other hormones, making it difficult to be sure that the reduction in growth hormone signaling is responsible for their increased lifespan. Now, Sun et al. have studied mutant mice that lack a gene called GHRH, which promotes the release of growth hormone. These mice, which have normal levels of all other pituitary hormones, lived for up to 50% longer than their wild-type littermates. They were more active than normal mice and had more body fat, and showed greatly increased sensitivity to insulin. Some of the changes in these mutant mice resembled those seen in animals with a restricted calorie intake, suggesting that the same mechanisms may be implicated in both. However, Sun et al. found that caloric restriction further increased the lifespans of their GHRH knockout mice, indicating that at least some of the effects of caloric restriction are independent of disrupted growth hormone signaling. The results of this study are an important step forward for understanding how growth hormone signaling and caloric restriction regulate aging, both individually and in combination. The GHRH knockout mice are likely to become an important model system for studying these processes and for understanding the complex interactions between diet and hormonal pathways. DOI: http://dx.doi.org/10.7554/eLife.01098.002
Databáze: OpenAIRE
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