Long-Lived Growth Hormone Receptor Knockout Mice Show a Delay in Age-Related Changes of Body Composition and Bone Characteristics

Bonkowski, Michael S.; Pamenter, Richard W.; Rocha, Juliana S.; Masternak, Michał M.; Panici, Jacob A.; Bartke, Andrzej

doi:10.1093/gerona/61.6.562

Cited by 64 publications

(57 citation statements)

References 31 publications

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“…In addition to mutants mice of GH, knockout mice of GH receptor (GHR) had been developed for the study of ageing. Targeted disruption of GHR in mice also resulted in increased lifespan up to 65% than normal controls [5]. As expected, these mice also exhibited decreased body weights, insulin and IGF-1 level.…”

Section: Introductionsupporting

confidence: 68%

“…These results clearly demonstrate that high levels of GH could accelerate aging and low levels of GH could delay aging in mice. Reduced serum levels of the IGF-1 were observed in both GH-deficient and GH-resistant GHR (-/-) mice [3][4][5]. It strongly suggests that GH is actively involved in the control of the lifespan in mice by regulating the production of the IGF-1 and GH/IGF-1 axis is a key regulator of longevity in mice.…”

Section: Introductionmentioning

confidence: 98%

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Animal Models for the IGF-1 Signal System in Longevity

Kwak¹

2012

Journal of Life Science

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Longevity is an exciting but difficult subject to study because it is determined by complex processes that require the coordinated action of several genetic factors as well as physiological and environmental influences. Genetic approaches have been applied to animal models to identify the molecular mechanism responsible for longevity. Several experimental model organisms obtained over the last decades suggest that the complete deletion of a single gene by gene targeting has proven to be an invaluable tool for the discovery of the mechanisms underlying longevity. The first discovery of long-lived mutants came from Caenorhabditis elegans research, which identified the insulin/IGF-1 pathway as responsible for longevity in this worm. IGF-1 is a multifunctional polypeptide that has sequence similarity to insulin and is involved in normal growth and development of cells. Several factors in the IGF-1 system have since been studied by gene targeting in the control of longevity in lower species, including nematode and fruit fly. In addition, significant progress has been made using mice models to extend the lifespan by targeted mutations that interfere with growth hormone/IGF-1 and IGF-1 signaling cascades. A recent finding that IGF-1 is involved in aging in mice was achieved by using liver-specific knockout mutant mice, and this clearly demonstrated that the IGF-1 signal pathway can extend the lifespan in both invertebrates and vertebrate models. Although the underlying molecular mechanisms for the control of longevity are not fully understood, it is widely accepted that reduced IGF-1 signaling plays an important role in the control of aging and longevity. Several genes involved in the IGF-1 signaling system are reviewed in relation to longevity in genetically modified mice models.

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Section: Introductionsupporting

confidence: 68%

Section: Introductionmentioning

confidence: 98%

Animal Models for the IGF-1 Signal System in Longevity

Kwak¹

2012

Journal of Life Science

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“…Food consumption, O2 utilization, when adjusted for body mass, is higher in dwarf and GHR −/− mice, and these mice also have higher adiposity (Meyer et al ., 2004; Bonkowski et al ., 2006). It is possible that their elevations in adiponectin and leptin, or reduced body temperature, contribute to their extended longevity (Bartke et al ., 2013) and may themselves be influenced by alterations in hypothalamic status.…”

Section: Discussionmentioning

confidence: 99%

Growth hormone modulates hypothalamic inflammation in long‐lived pituitary dwarf mice

et al. 2015

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SummaryMice in which the genes for growth hormone (GH) or GH receptor (GHR −/−) are disrupted from conception are dwarfs, possess low levels of IGF‐1 and insulin, have low rates of cancer and diabetes, and are extremely long‐lived. Median longevity is also increased in mice with deletion of hypothalamic GH‐releasing hormone (GHRH), which leads to isolated GH deficiency. The remarkable extension of longevity in hypopituitary Ames dwarf mice can be reversed by a 6‐week course of GH injections started at the age of 2 weeks. Here, we demonstrate that mutations that interfere with GH production or response, in the Snell dwarf, Ames dwarf, or GHR −/− mice lead to reduced formation of both orexigenic agouti‐related peptide (AgRP) and anorexigenic proopiomelanocortin (POMC) projections to the main hypothalamic projection areas: the arcuate nucleus (ARH), paraventricular nucleus (PVH), and dorsomedial nucleus (DMH). These mutations also reduce hypothalamic inflammation in 18‐month‐old mice. GH injections, between 2 and 8 weeks of age, reversed both effects in Ames dwarf mice. Disruption of GHR specifically in liver (LiGHRKO), a mutation that reduces circulating IGF‐1 but does not lead to lifespan extension, had no effect on hypothalamic projections or inflammation, suggesting an effect of GH, rather than peripheral IGF‐1, on hypothalamic development. Hypothalamic leptin signaling, as monitored by induction of pStat3, is not impaired by GHR deficiency. Together, these results suggest that early‐life disruption of GH signaling produces long‐term hypothalamic changes that may contribute to the longevity of GH‐deficient and GH‐resistant mice.

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“…Mice with mutations that cause GHD or GH resistance live longer than their genetically normal siblings (9,(36)(37)(38)(39). In addition, adult body size, which can be considered a biological outcome marker of GH actions, was negatively correlated with longevity in other species, including rats (40), horses (41) and domestic dogs (42,43).…”

Section: Discussionmentioning

confidence: 99%

GH replacement therapy in elderly GH-deficient patients: a systematic review

Kokshoorn

Biermasz

Roelfsema

et al. 2011

European Journal of Endocrinology

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Context: Recombinant human GH (rhGH) is prescribed for the treatment of adults with GH deficiency (GHD). However, conflicting data are available on the efficacy of rhGH treatment in elderly GHD patients. Objective: To assess the efficacy of rhGH treatment in elderly GHD subjects. Methods: We searched the available literature in PubMed, Cochrane Library, Web of Science and EMBASE. Study selection: Studies on GHD patients, aged O60 years, treated with rhGH were eligible for inclusion. Data extraction was performed by two reviewers independently. Results: We found 11 eligible studies with a total of 534 patients. Only two studies had prospective, randomized, placebo-controlled study designs of rhGH treatment with a duration of 6 (nZ15) and 12 months (nZ62), respectively. Treatment with rhGH decreased total and low density lipoprotein (LDL) cholesterol levels by 4-8 and 11-16%, respectively, but did not alter high density lipoprotein or triglyceride levels. RhGH did not affect body mass index, but decreased waist circumference (by w3 cm) and waist/hip ratio. RhGh did not consistently affect blood pressure or bone mineral density. RhGH increased lean body mass by 2-5% and decreased total fat mass by 7-10% in four studies, but did not affect body composition in two other studies. RhGH consistently improved quality of life (QoL) parameters reflected in AGHDA-scores. There were no explicit data on elderly GHD patients aged O80 years. Conclusion: RhGH replacement in elderly subjects with GHD decreases LDL cholesterol levels and improves QoL, but the effects on other parameters are not unequivocal. There were no data on the efficacy and safety of rhGH treatment in octogenarians with GHD.

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Long-Lived Growth Hormone Receptor Knockout Mice Show a Delay in Age-Related Changes of Body Composition and Bone Characteristics

Cited by 64 publications

References 31 publications

Animal Models for the IGF-1 Signal System in Longevity

Animal Models for the IGF-1 Signal System in Longevity

Growth hormone modulates hypothalamic inflammation in long‐lived pituitary dwarf mice

GH replacement therapy in elderly GH-deficient patients: a systematic review

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