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Brain IGF-1 receptors control mammalian growth and lifespan through a neuroendocrine mechanism.

ABSTRACT: Mutations that decrease insulin-like growth factor (IGF) and growth hormone signaling limit body size and prolong lifespan in mice. In vertebrates, these somatotropic hormones are controlled by the neuroendocrine brain. Hormone-like regulations discovered in nematodes and flies suggest that IGF signals in the nervous system can determine lifespan, but it is unknown whether this applies to higher organisms. Using conditional mutagenesis in the mouse, we show that brain IGF receptors (IGF-1R) efficiently regulate somatotropic development. Partial inactivation of IGF-1R in the embryonic brain selectively inhibited GH and IGF-I pathways after birth. This caused growth retardation, smaller adult size, and metabolic alterations, and led to delayed mortality and longer mean lifespan. Thus, early changes in neuroendocrine development can durably modify the life trajectory in mammals. The underlying mechanism appears to be an adaptive plasticity of somatotropic functions allowing individuals to decelerate growth and preserve resources, and thereby improve fitness in challenging environments. Our results also suggest that tonic somatotropic signaling entails the risk of shortened lifespan.

SUBMITTER: Kappeler L

PROVIDER: S-EPMC2573928 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Siglec receptors impact mammalian lifespan by modulating oxidative stress.

Project description:Aging is a multifactorial process that includes the lifelong accumulation of molecular damage, leading to age-related frailty, disability and disease, and eventually death. In this study, we report evidence of a significant correlation between the number of genes encoding the immunomodulatory CD33-related sialic acid-binding immunoglobulin-like receptors (CD33rSiglecs) and maximum lifespan in mammals. In keeping with this, we show that mice lacking Siglec-E, the main member of the CD33rSiglec family, exhibit reduced survival. Removal of Siglec-E causes the development of exaggerated signs of aging at the molecular, structural, and cognitive level. We found that accelerated aging was related both to an unbalanced ROS metabolism, and to a secondary impairment in detoxification of reactive molecules, ultimately leading to increased damage to cellular DNA, proteins, and lipids. Taken together, our data suggest that CD33rSiglecs co-evolved in mammals to achieve a better management of oxidative stress during inflammation, which in turn reduces molecular damage and extends lifespan.

| S-EPMC4384638 | biostudies-literature

Control of lifespan and survival by <i>Drosophila</i> NF-κB signaling through neuroendocrine cells and neuroblasts.

Project description:We report a comparative analysis of the effects of immune activation in the fly nervous system using genetic activation models to target Drosophila NF-κB within Toll versus Imd pathways. Genetic gain-of-function models for either pathway pan-neuronally as well as in discrete subsets of neural cells including neuroendocrine insulin-producing cells (IPCs) or neuroblasts reduce fly lifespan, however, these phenotypes in IPCs and neuroblasts are stronger with Toll activation than Imd activation. Of note, while aging is influenced more by Toll/NF-κB activation in IPCs during adulthood, neuroblasts influence aging more substantially during development. The study then focused on Toll/NF-κB inhibition, revealing that IPCs or neuroblasts are important for the effects of lifespan and healthspan extension but in a life stage-dependent manner while some of these effects display sexual dimorphism. Importantly, co-inhibition of Toll/NF-κB pathway in IPCs and neuroblasts increased fly lifespan greater than either cell population, suggesting that independent mechanisms might exist. Toll/NF-κB inhibition in IPCs was also sufficient to enhance survival under various fatal stresses, supporting the additional benefits to fly healthspan. In conclusion, IPCs and neuroblasts are important for Drosophila NF-κB for controlling lifespan.

| S-EPMC7803524 | biostudies-literature

Extension of Drosophila lifespan by Korean red ginseng through a mechanism dependent on dSir2 and insulin/IGF-1 signaling.

Project description:Many studies have indicated that Korean red ginseng (KRG) has anti-inflammatory and anti-oxidative effects, thereby inducing many health benefits in humans. Studies into the longevity effects of KRG are limited and have provided contradictory results, and the molecular mechanism of lifespan extension by KRG is not elucidated yet. Herein, the longevity effect of KRG was investigated in Drosophila melanogaster by feeding KRG extracts, and the molecular mechanism of lifespan extension was elucidated by using longevity-related mutant flies. KRG extended the lifespan of Drosophila when administrated at 10 and 25 ?g/mL, and the longevity benefit of KRG was not due to reduced feeding, reproduction, and/or climbing ability in fruit flies, indicating that the longevity benefit of KRG is a direct effect of KRG, not of a secondary artifact. Diet supplementation with KRG increased the lifespan of flies on a full-fed diet but not of those on a restricted diet, and the longevity effect of KRG was diminished by the mutation of dSir2, a deacetylase known to mediate the benefits of dietary restriction. Similarly, the longevity effect of KRG was mediated by the reduction of insulin/IGF-1 signaling. In conclusion, KRG extends the lifespan of Drosophila through Sir2 and insulin/IGF-1 signaling and has potential as an anti-aging dietary-restriction mimetic and prolongevity supplement.

| S-EPMC6874434 | biostudies-literature

AMPA receptors control fear extinction through an Arc-dependent mechanism.

Project description:Activity-regulated cytoskeleton-associated protein (Arc) supports fear memory through synaptic plasticity events requiring actin cytoskeleton rearrangements. We have previously shown that reducing hippocampal Arc levels through antisense knockdown leads to the premature extinction of contextual fear. Here we show that the AMPA receptor antagonist CNQX elevates hippocampal Arc levels during extinction and blocks extinction that can be rescued by reducing Arc. Increasing Arc levels with CNQX also overcomes the actin-destabilizing properties of cytochalasin D and promotes extinction. Therefore, extinction is dependent on AMPA-mediated reductions of Arc via a mechanism consistent with a role for Arc in stabilizing the actin cytoskeleton to constrain extinction.

| S-EPMC5516687 | biostudies-literature

Retinoic acid actions through mammalian nuclear receptors.

Project description: Not available

| S-EPMC3931982 | biostudies-literature

Gene expression in primate postnatal brain through lifespan

Project description:This SuperSeries is composed of the following subset Series: GSE22521: Gene expression in primate postnatal brain through lifespan - prefrontal cortex GSE22569: Gene expression in primate postnatal brain through lifespan - cerebellar cortex Refer to individual Series

2011-12-09 | E-GEOD-22570 | biostudies-arrayexpress

MicroRNA expression in primate postnatal brain through lifespan

Project description:While multiple studies have reported the accelerated evolution of brain gene expression in the human lineage, the mechanisms underlying such change remain poorly understood. Here we address this issue from a developmental perspective, by analyzing mRNA and microRNA (miRNA) expression in two brain regions within macaques, chimpanzees and humans throughout their lifespan. We find that developmental profiles of trans-regulators, such as miRNA, as well as their target genes, show the fastest rates of human-specific evolutionary change. Changes in expression of a few key regulators may be a major driving force behind human brain evolution. Human, chimpanzee and rhesus macaque post-mortem brain samples from the prefrontal cortex and cerebellar cortex were collected. The age ranges of the individuals in all three species covered the respective species' postnatal maturation period from infancy to old adulthood. RNA extracted from the dissected tissue was hybridized to B72.

2011-12-09 | E-GEOD-29356 | biostudies-arrayexpress

Disp1 regulates growth of mammalian long bones through the control of Ihh distribution.

Project description:Dispatched1 (Disp1) is required for the release of cholesterol modified hedgehog (Hh) proteins from producing cells. We investigated the role of Disp1 in Indian hedgehog (Ihh) signaling in the developing bone bypassing the lethality of the Disp1(C829F) allele at early somite stages through the supply of non-cholesterol modified Sonic hedgehog (N-Shh). The long bones that develop in the absence of wild-type Disp1, while clearly shorter, have a juxtaposition of proliferating and non-proliferating hypertrophic chondrocytes that is markedly more normal in organization than those of ihh null mutants. Direct analysis of Ihh trafficking in the target field demonstrates that Ihh is distributed well beyond Ihh expressing cells though the range of movement and signaling action is more restricted than in wild-type long bones. Consequently, a PTHrP-Ihh feedback loop is established, but over a shorter distance, reflecting the reduced range of Ihh movement. These analyses of the Disp1(C829F) mutation demonstrate that Disp1 is not absolutely required for the paracrine signaling role of Ihh in the skeleton. However, Disp1 is critical for the full extent of signaling within the chondrocyte target field and consequently the establishment of a normal skeletal growth plate.

| S-EPMC2430380 | biostudies-literature

Neuroendocrine-derived peptides promote prostate cancer cell survival through activation of IGF-1R signaling.

Project description:Neuroendocrine (NE) cells promote the progression of prostate cancer to a castration-resistant state through the production of paracrine growth factors. We have demonstrated this principle using in vitro and in vivo proliferative endpoints; however, the contributions of NE-derived pro-survival factors and anti-apoptosis to this phenomenon have not been thoroughly investigated.Here, we utilized conditioned-medium (CM) from LNCaP cells, engineered to undergo NE differentiation, and examined its effects on PC3 and LNCaP cell survival.Statistically significant changes in clonogenic survival, Annexin V staining, PARP cleavage and trypan blue positivity of approximately twofold were observed in the presence of NE-derived CM relative to control-CM for both LNCaP and PC3 cells. These changes were partially abrogated by antagonists of the neuropeptides neurotensin, bombesin, and PTHrP. Selective inhibitors of IGF-1R, EGFR or Src caused significant and nearly complete blockade of prostate cancer cell survival due to NE secretions. Similar increases in cell survival were observed for LNCaP or PC3 cells treated with NE-derived medium in the presence of docetaxel. Increased phosphorylation of IGF-1R, following treatment with NE-derived medium, was accompanied by decreased protein tyrosine phosphatase, receptor type F (PTPRF) mRNA, and protein levels. Overexpression of PTPRF decreased cell survival, the amplitude and duration of IGF-1R phosphorylation, and enhanced PARP cleavage in the presence of NE-derived medium.These data support the hypothesis that NE-derived factors act upon prostate cancer cells to stimulate pro-survival signaling and describe a novel mechanism of cross-talk between NE-derived factors and IGF-1R, mediated in part by PTPRF.

| S-EPMC4085781 | biostudies-literature

Understanding the mechanism of insulin and insulin-like growth factor (IGF) receptor activation by IGF-II.

Project description:BackgroundInsulin-like growth factor-II (IGF-II) promotes cell proliferation and survival and plays an important role in normal fetal development and placental function. IGF-II binds both the insulin-like growth factor receptor (IGF-1R) and insulin receptor isoform A (IR-A) with high affinity. Interestingly both IGF-II and the IR-A are often upregulated in cancer and IGF-II acts via both receptors to promote cancer proliferation. There is relatively little known about the mechanism of ligand induced activation of the insulin (IR) and IGF-1R. The recently solved IR structure reveals a folded over dimer with two potential ligand binding pockets arising from residues on each receptor half. Site-directed mutagenesis has mapped receptor residues important for ligand binding to two separate sites within the ligand binding pocket and we have recently shown that the IGFs have two separate binding surfaces which interact with the receptor sites 1 and 2.Methodology/principal findingsIn this study we describe a series of partial IGF-1R and IR agonists generated by mutating Glu12 of IGF-II. By comparing receptor binding affinities, abilities to induce negative cooperativity and potencies in receptor activation, we provide evidence that residue Glu12 bridges the two receptor halves leading to receptor activation.Conclusions/significanceThis study provides novel insight into the mechanism of receptor binding and activation by IGF-II, which may be important for the future development of inhibitors of its action for the treatment of cancer.

| S-EPMC3227035 | biostudies-literature

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