The GH/IGF-1 axis in ageing and longevity

Junnila, Riia K.; List, Edward O.; Berryman, Darlene E.; Murrey, John W.; Kopchick, John J.

doi:10.1038/nrendo.2013.67

Cited by 434 publications

(340 citation statements)

References 120 publications

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“…These remarkably long‐lived animals are characterized by reduced postnatal growth rate, delayed development, and reduced adult body size (Junnila et al ., 2013). Mice lacking Ghrh, or Ghrhr (Flurkey et al ., 2001; Sun et al ., 2013), are also long‐lived, as are mice lacking PAPP‐A, a protease specific for IGF‐1‐binding proteins (Conover & Bale, 2007), further implicating GH and/or IGF‐1 tonicity in the regulation of mammalian aging rate and lifespan.…”

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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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confidence: 99%

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

et al. 2015

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“…Whether the RGD‐motif present in IGFBP‐2 is relevant for growth, reproductive development and lifespan were considered. In particular, the strength of correlation between impaired somatic growth and improved long‐term survival observed was assessed in a number of mouse models characterized by growth inhibition (Junnila et al ., 2013). …”

Section: Discussionmentioning

confidence: 99%

“…Growth inhibition in females but not in males correlated with improved long‐term survival in D‐mice. A sexually dimorphic effect on lifespan has also been described in heterozygous Igf1r knockout mice (Holzenberger et al ., 2003) and fits with the concept that reduced IGF1 signaling affects lifespan, particularly in female mice, whereas impaired GH signaling increases lifespan in both sexes (Bartke, 2011; Junnila et al ., 2013). In this study, antagonistic pleiotropy (Bartke, 2011), which describes beneficial and adverse effects of a hormone during ontogeny, was only observed in female D‐mice.…”

Section: Discussionmentioning

confidence: 99%

“…In fact, female Ghr knockout mice in a C57BL/6 background have been demonstrated to have a 21% increased lifespan in comparison with wild‐type mice (Coschigano et al ., 2003). In a different genetic background, Ghr −/− mice were able to reach an age of almost 5 years, which represents a quantum leap of lifespan extension and is unmatched by other long‐lived mouse models (Junnila et al ., 2013). Owing to mutations of the GHR in Laron dwarfs and corresponding mouse mutants being associated with a drastic reduction of growth, it was investigated whether moderate growth impairment, for example, caused by overabundance of IGF1 inhibitory binding proteins (Hoeflich et al ., 2004), may still have significant consequences for life expectancy and sexual development.…”

Section: Introductionmentioning

confidence: 99%

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Dissociation of somatic growth, time of sexual maturity, and life expectancy by overexpression of an RGD ‐deficient IGFBP ‐2 variant in female transgenic mice

et al. 2015

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SummaryImpaired growth is often associated with an extension of lifespan. However, the negative correlation between somatic growth and life expectancy is only true within, but not between, species. This can be observed because smaller species have, as a rule, a shorter lifespan than larger species. In insects and worms, reduced reproductive development and increased fat storage are associated with prolonged lifespan. However, in mammals the relationship between the dynamics of reproductive development, fat metabolism, growth rate, and lifespan are less clear. To address this point, female transgenic mice that were overexpressing similar levels of either intact (D‐mice) or mutant insulin‐like growth factor‐binding protein‐2 (IGFBP‐2) lacking the Arg‐Gly‐Asp (RGD) motif (E‐ mice) were investigated. Both lines of transgenic mice exhibited a similar degree of growth impairment (−9% and −10%) in comparison with wild‐type controls (C‐mice). While in D‐mice, sexual maturation was found to be delayed and life expectancy was significantly increased in comparison with C‐mice, these parameters were unaltered in E‐mice in spite of their reduced growth rate. These observations indicate that the RGD‐domain has a major influence on the pleiotropic effects of IGFBP‐2 and suggest that somatic growth and time of sexual maturity or somatic growth and life expectancy are less closely related than thought previously.

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“…Pappalysin-1 is a metalloproteinase encoded by the Pappa gene, responsible for the cleavage of IGFBP4 bound to IGF-I. In Pappa−/− mice, an abundance of IGFBP-4 and decreased bioavailability of IGF-I have been associated with a lower incidence of tumours and degenerative lesions, with an approximate six-month delay in ageing-related pathologies compared with WT mice [29,30]. …”

Section: Prace Poglądowementioning

confidence: 99%

Growth hormone, insulin-like growth factor system and carcinogenesis

Boguszewski

Kopchick

2015

Endokrynologia Polska

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The growth hormone (GH) and insulin-like growth factor (IGF) system plays an important role in the regulation of cell proliferation, differentiation, apoptosis, and angiogenesis. In terms of cell cycle regulation, the GH-IGF system induces signalling pathways for cell growth that compete with other signalling systems that result in cell death; thus the final effect of these opposed forces is critical for normal and abnormal cell growth. The association of the GH-IGF system with carcinogenesis has long been hypothesised, mainly based on in vitro studies and the use of a variety of animal models of human cancer, and also on epidemiological and clinical evidence in humans. While ample experimental evidence supports a role of the GH-IGF system in tumour promotion and progression, with several of its components being currently tested as central targets for cancer therapy, the strength of evidence from patients with acromegaly, GH deficiency, or treated with GH is much weaker. In this review, we will attempt to consolidate this data. StreszczenieOś hormon wzrostu (GH)-insulinopodobny czynnik wzrostu (IGF) odgrywa istotną rolę w regulacji proliferacji i różnicowania komórek, apoptozy i angiogenezy. Oś GH-IGF wpływa na regulację cyklu komórkowego przez pobudzenie szlaku wzrostu komórki w stosunku do szlaków sygnałowych prowadzących do śmierci komórki, a ostateczny efekt oddziaływania tych dwóch sił ma podstawowe znaczenie dla prawidłowego lub nieprawidłowego wzrostu komórki. Hipotezy na temat powiązań osi GH-IGF z karcynogenezą pojawiły się wiele lat temu, głównie w oparciu o wyniki badań in vitro oraz badań z wykorzystaniem różnych zwierzęcych modeli raka występującego u ludzi. Chociaż liczne dane doświadczalne potwierdzają rolę osi GH-IGF sprzyjającą rozwojowi i progresji nowotworów, a nad kilkoma składowymi tej osi trwają obecnie badania oceniające ich przydatność jako główne cele terapii przeciwnowotworowej, to jednak siła dowodów uzyskanych u chorych z akromegalią, niedoborem GH lub osób leczonych GH jest znacznie słabsza. W niniejszej pracy przeglądowej spróbowano zebrać wszystkie te dane.

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The GH/IGF-1 axis in ageing and longevity

Cited by 434 publications

References 120 publications

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

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

Dissociation of somatic growth, time of sexual maturity, and life expectancy by overexpression of an RGD ‐deficient IGFBP ‐2 variant in female transgenic mice

Growth hormone, insulin-like growth factor system and carcinogenesis

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