Редактирование: IGFBP3

Insulin-like growth factor-binding protein 3 precursor (IBP-3) (IGF-binding protein 3) (IGFBP-3) [IBP3]

==Publications==

{{medline-entry
|title=Cellular and Molecular Biomarkers Indicate Premature Aging in Pseudoxanthoma Elasticum Patients.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32489700
|abstract=The molecular processes of aging are very heterogenic and not fully understood. Studies on rare progeria syndromes, which display an accelerated progression of physiological aging, can help to get a better understanding. Pseudoxanthoma elasticum (PXE) caused by mutations in the [i]ATP-binding cassette sub-family C member 6[/i] ([i][[ABCC6]][/i]) gene shares some molecular characteristics with such premature aging diseases. Thus, this is the first study trying to broaden the knowledge of aging processes in PXE patients. In this study, we investigated aging associated biomarkers in primary human dermal fibroblasts and sera from PXE patients compared to healthy controls. Determination of serum concentrations of the aging biomarkers eotaxin-1 (CCL11), growth differentiation factor 11 ([[GDF11]]) and insulin-like growth factor 1 (IGF1) showed no significant differences between PXE patients and healthy controls. Insulin-like growth factor binding protein 3 ([[IGFBP3]]) showed a significant increase in serum concentrations of PXE patients older than 45 years compared to the appropriate control group. Tissue specific gene expression of [[GDF11]] and [[IGFBP3]] were significantly decreased in fibroblasts from PXE patients compared to normal human dermal fibroblasts (NHDF). [[IGFBP3]] protein concentration in supernatants of fibroblasts from PXE patients were decreased compared to NHDF but did not reach statistical significance due to potential gender specific variations. The minor changes in concentration of circulating aging biomarkers in sera of PXE patients and the significant aberrant tissue specific expression seen for selected factors in PXE fibroblasts, suggests a link between [[ABCC6]] deficiency and accelerated aging processes in affected peripheral tissues of PXE patients.

|keywords=* CCL11
* GDF11
* IGF1
* IGFBP
* aging
* pseudoxanthoma elasticum
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7220280
}}
{{medline-entry
|title=Elevated circulating HtrA4 in preeclampsia may alter endothelial expression of senescence genes.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32056555
|abstract=Preeclampsia (PE) is a serious complication of human pregnancy. Women who have had PE, especially early-onset PE (EPE), have an increased risk of cardiovascular disease (CVD) later in life. However, how PE is linked to CVD is not well understood. We previously reported that HtrA4, a placenta-specific protease, is significantly elevated in EPE, and inhibits the proliferation of endothelial cells as well as endothelial progenitor cells (EPCs). This can potentially impair endothelial repair and regeneration, leading to endothelial aging, which is a major risk factor of CVD. In this study, we examined whether HtrA4 can alter endothelial expression of senescence genes. Human umbilical vein endothelial cells (HUVECs) and primary EPCs isolated from cord blood of healthy pregnancies were used as in vitro models. Firstly, HUVECs were treated with HtrA4 at the highest levels detected in EPE for 48h and screened with a senescence PCR array. The results were then validated by RT-PCR and ELISA in HUVECs and EPCs treated with HtrA4 for 24 and 48h. We observed that HtrA4 significantly up-regulated [[IGFBP3]], [[SERPINE1]] and [[SERPINB2]], which all promote senescence. IGFBP-3 protein was also significantly elevated in the media of HtrA4-treated HUVECs. Conversely, a number of genes including [[CDKN2C]], [[PCNA]], [[CALR]], [[CHEK2]] and [[NOX4]] were downregulated by HtrA4. Many of these genes also showed a similar trend of change in EPCs following HtrA4 treatment. Elevation of placenta-derived HtrA4 in PE alters the expression of endothelial genes to promote cellular senescence and may contribute to premature endothelial aging.

|keywords=* Endothelial aging
* Endothelial cells
* HtrA4
* Preeclampsia
* Senescence
|full-text-url=https://sci-hub.do/10.1016/j.placenta.2019.12.012
}}
{{medline-entry
|title=Paracrine senescence of human endometrial mesenchymal stem cells: a role for the insulin-like growth factor binding protein 3.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31951594
|abstract=Stress-induced premature cell senescence is well recognized to be accompanied by emerging the senescence-associated secretory phenotype (SASP). Secreted SASP factors can promote the senescence of normal neighboring cells through autocrine/paracrine pathways and regulate the senescence response, as well. Regarding human endometrium-derived mesenchymal stem cells (MESCs), the SASP regulation mechanisms as well as paracrine activity of senescent cells have not been studied yet. Here, we examined the role of insulin-like growth factor binding protein 3 ([[IGFBP3]]) in the paracrine senescence induction in young MESCs. The H O -induced premature senescence of MESCs led to increased [[IGFBP3]] in conditioned media (CM). The inhibitory analysis of both MAPK and PI3K signaling pathways showed that [[IGFBP3]] releasing from senescent cells is mainly regulated by PI3K/Akt pathway activity. [[IGFBP3]] appears to be an important senescence-mediating factor as its immunodepletion from the senescent CM weakened the pro-senescent effect of CM on young MESCs and promoted their growth. In contrast, young MESCs acquired the senescence phenotype in response to simultaneous addition of recombinant [[IGFBP3]] (r[[IGFBP3]]). The mechanism of extracellular [[IGFBP3]] internalization was also revealed. The present study is the first to demonstrate a significant role of extracellular [[IGFBP3]] in paracrine senescence induction of young MESCs.

|keywords=* IGFBP3
* endocytosis
* endometrial stem cells
* paracrine senescence
* secretome
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7053595
}}
{{medline-entry
|title=Are There Common Mechanisms Between the Hutchinson-Gilford Progeria Syndrome and Natural Aging?
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31156709
|abstract=The Hutchinson-Gilford progeria syndrome (HGPS) is a premature aging disease caused by mutations of the [i]LMNA[/i] gene leading to increased production of a partially processed form of the nuclear fibrillar protein lamin A - progerin. Progerin acts as a dominant factor that leads to multiple morphological anomalies of cell nuclei and disturbances in heterochromatin organization, mitosis, DNA replication and repair, and gene transcription. Progerin-positive cells are present in primary fibroblast cultures obtained from the skin of normal donors at advanced ages. These cells display HGPS-like defects in nuclear morphology, decreased H3K9me3 and HP1, and increased histone [[H2AX]] phosphorylation marks of the DNA damage loci. Inhibition of progerin production in cells of aged non-HGPS donors [i]in vivo[/i] increases the proliferative activity, H3K9me3, and HP1, and decreases the senescence markers p21, [[IGFBP3]], and [[GADD45B]] to the levels of young donor cells. Thus, progerin-dependent mechanisms act in natural aging. Excessive activity of the same mechanisms may well be the cause of premature aging in HGPS. Telomere attrition is widely regarded to be one of the primary hallmarks of aging. Progerin expression in normal human fibroblasts accelerates the loss of telomeres. Changes in lamina organization may directly affect telomere attrition resulting in accelerated replicative senescence and progeroid phenotypes. The chronological aging in normal individuals and the premature aging in HGPS patients are mediated by similar changes in the activity of signaling pathways, including downregulation of DNA repair and chromatin organization, and upregulation of ERK, mTOR, GH-[[IGF1]], MAPK, TGFβ, and mitochondrial dysfunction. Multiple epigenetic changes are common to premature aging in HGPS and natural aging. Recent studies showed that epigenetic systems could play an active role as drivers of both forms of aging. It may be suggested that these systems translate the effects of various internal and external factors into universal molecular hallmarks, largely common between natural and accelerated forms of aging. Drugs acting at both natural aging and HGPS are likely to exist. For example, vitamin D3 reduces the progerin production and alleviates most HGPS features, and also slows down epigenetic aging in overweight and obese non-HGPS individuals with suboptimal vitamin D status.

|keywords=* aging
* epigenetics
* lamin
* progerin
* rejuvenation
* reprogramming
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6529819
}}
{{medline-entry
|title=Blunted satellite cell response is associated with dysregulated IGF-1 expression after exercise with age.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30062517
|abstract=Insulin-like growth factor-1 (IGF-1) regulates protein synthesis and cell cycle kinetics. Given that aging is associated with anabolic resistance, we sought to determine if the attenuated exercise-induced satellite cell (SC) expression in older muscle is associated with a blunted IGF-1 response. SC expression (Pax7  cells) and protein (Western blot) and mRNA (RT-PCR) expression of IGF-1 splice variants and ubiquitous (IGFBP4) and muscle-specific ([[IGFBP3]] and -5) IGF-1 binding proteins were measured in skeletal muscle of young (Y: 22 ± 2, n = 7) and older (O: 70 ± 2, n = 7) adults up to 48 h after an acute bout of resistance exercise. SC expression was greater in Y compared to O (age; P < 0.01) and increased (interaction; P < 0.05) by 24 h after exercise in Y only. IGF-1Ea and IGF-1Eb mRNA tended to be greater in O (age; P < 0.06-0.09). IGF-1Eb mRNA increased at 48 h (time; P < 0.05), whereas IGF-1Ec mRNA increased (interaction; P < 0.05) at 24 and 48 h in O only. IGF binding protein (IGFBP)4 mRNA was greater (age; P < 0.01) in O with the increase at 24 h and 48 h (time; P < 0.01) primarily driven by changes in O (interaction; P < 0.01). Despite [[IGFBP3]] mRNA being greater in O (age; P < 0.01) and increasing at 48 h (time; P < 0.01), there was no effect of age or exercise on [[IGFBP3]] protein expression. In contrast, [[IGFBP5]] mRNA was greater (age; P < 0.01) despite [[IGFBP5]] protein expression being lower (age; P < 0.01) in O compared to Y. The greater muscle-specific expression of IGF-1 family members with a blunted post-exercise SC expression may be a compensatory attempt to rescue age-related anabolic resistance.
|mesh-terms=* Aged
* Aging
* Exercise
* Humans
* Insulin-Like Growth Factor Binding Proteins
* Insulin-Like Growth Factor I
* Male
* Satellite Cells, Skeletal Muscle
* Young Adult
|keywords=* Exercise
* Hypertrophy
* Muscle protein synthesis
* Sarcopenia
* Satellite cells
|full-text-url=https://sci-hub.do/10.1007/s00421-018-3954-4
}}
{{medline-entry
|title=Systemic analysis of gene expression profiles in porcine granulosa cells during aging.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29228554
|abstract=Current studies have revealed that aging is a negative factor that suppresses granulosa cell functions and causes low fertility in women. However, the difference in gene expression between normal and aging granulosa cells remains undefined. Therefore, the aim of this study was to investigate the gene expression profiles of granulosa cells during aging. Granulosa cells from young healthy porcine ovaries were aged [i]in vitro[/i] by prolonging the culture time (for 48h). First, the extracellular ultrastructure was observed by scanning electron microscopy followed by RNA-seq and KEGG pathway analysis. The results showed that the extracellular ultrastructure was significantly altered by aging; cell membranes were rough, and cavitations were found. Moreover, the formations of filopodia were greatly reduced. RNA-seq data revealed that 3411 genes were differentially expressed during aging, of which 2193 genes were up-regulated and 1218 genes were down-regulated. KEGG pathway analysis revealed that 25 pathways including pathway in cancer, PI3K-Akt signaling pathway, focal adhesion, proteoglycans in cancer, and cAMP signaling pathway were the most changed. Moreover, several high differentially expressed genes (CEBPB, [[CXCL12]], [[ANGPT2]], [[IGFBP3]], and BBOX1) were identified in aging granulosa cells, The expressions of these genes and genes associated with extracellular matrix remodeling associated genes (TIMP3, [[MMP2]], [[MMP3]], and CTGF), energy metabolism associated genes (SLC2A1, PPARγ) and steroidogenesis associated genes (StAR, [[CYP11A1]] and LHCGR) were confirmed by quantitative PCR. This study identifies the differently changed pathways and their related genes, contributes to the understanding of aging in granulosa cells, and provides an important foundation for further studies.

|keywords=* Gerotarget
* RNA-seq
* aging
* gene expression
* granulosa cell
* porcine
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5722506
}}
{{medline-entry
|title=G protein-coupled receptor kinase 4-induced cellular senescence and its senescence-associated gene expression profiling.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/28912086
|abstract=Senescent cells have lost their capacity for proliferation and manifest as irreversibly in cell cycle arrest. Many membrane receptors, including G protein-coupled receptors (GPCRs), initiate a variety of intracellular signaling cascades modulating cell division and potentially play roles in triggering cellular senescence response. GPCR kinases (GRKs) belong to a family of serine/threonine kinases. Although their role in homologous desensitization of activated GPCRs is well established, the involvement of the kinases in cell proliferation is still largely unknown. In this study, we isolated [[GRK4]]-GFP expressing HEK293 cells by fluorescence-activated cell sorting (FACS) and found that the ectopic expression of [[GRK4]] halted cell proliferation. Cells expressing [[GRK4]] ([[GRK4]]( )) demonstrated cell cycle G1/G0 phase arrest, accompanied with significant increase of senescence-associated-β-galactosidase (SA-β-Gal) activity. Expression profiling analysis of 78 senescence-related genes by qRT-PCR showed a total of 17 genes significantly changed in [[GRK4]]( ) cells (≥ 2 fold, p < 0.05). Among these, 9 genes - [[AKT1]], p16 , p27 , p19 , [[IGFBP3]], [[MAPK14]], [[PLAU]], [[THBS1]], [[TP73]] - were up-regulated, while 8 genes, Cyclin A2, Cyclin D1, [[CDK2]], [[CDK6]], [[ETS1]], [[NBN]], [[RB1]], [[SIRT1]], were down-regulated. The increase in cyclin-dependent kinase inhibitors (p16, p27) and p38 MAPK proteins ([[MAPK14]]) was validated by immunoblotting. Neither p53 nor p21  protein was detectable, suggesting no p53 activation in the HEK293 cells. These results unveil a novel function of [[GRK4]] on triggering a p53-independent cellular senescence, which involves an intricate signaling network.
|mesh-terms=* Cell Division
* Cell Line, Tumor
* Cell Proliferation
* Cellular Senescence
* Flow Cytometry
* G-Protein-Coupled Receptor Kinase 4
* Gene Expression Profiling
* Gene Expression Regulation
* HEK293 Cells
* Humans
* MCF-7 Cells
* Transcriptome
* Tumor Suppressor Protein p53
|keywords=* Cellular senescence
* G protein-coupled receptor kinase 4
* Gene expression profiling
* p53-independent senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5944352
}}
{{medline-entry
|title=A small molecule inhibitor of PAI-1 protects against doxorubicin-induced cellular senescence.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/27736799
|abstract=Doxorubicin, an anthracycline antibiotic, is a commonly used anticancer drug. In spite of its widespread usage, its therapeutic effect is limited by its cardiotoxicity. On the cellular level, Doxorubicin-induced cardiotoxicity manifests as stress induced premature senescence. Previously, we demonstrated that plasminogen activator inhibitor-1 (PAI-1), a potent inhibitor of serine proteases, is an important biomarker and regulator of cellular senescence and aging. Here, we tested the hypothesis that pharmacological inhibition of cellular PAI-1 protects against stress- and aging-induced cellular senescence and delineated the molecular basis of protective action of PAI-1 inhibition. Results show that TM5441, a potent small molecule inhibitor of PAI-1, effectively prevents Doxorubicin-induced senescence in cardiomyocytes, fibroblasts and endothelial cells. TM5441 exerts its inhibitory effect on Doxorubicin-induced cellular senescence by decreasing reactive oxygen species generation, induction of antioxidants like catalase and suppression of stress-induced senescence cadre p53, p21, p16, PAI-1 and [[IGFBP3]]. Importantly, TM5441 also reduces replicative senescence of fibroblasts. Together these results for the first time demonstrate the efficacy of PAI-1 inhibitor in prevention of Doxorubicin-induced and replicative senescence in normal cells. Thus PAI-1 inhibitor may form an important adjuvant component of chemotherapy regimens, limiting not only Doxorubicin-induced cardiac senescence but also ameliorating the prothrombotic profile.
|mesh-terms=* Animals
* Antibiotics, Antineoplastic
* Cardiotoxicity
* Cells, Cultured
* Cellular Senescence
* Doxorubicin
* Fibroblasts
* Humans
* Mice
* Myocytes, Cardiac
* Piperazines
* Rats
* Serpin E2
* para-Aminobenzoates
|keywords=* Doxorubicin
* cardiomyocytes
* cellular senescence
* endothelial cells
* fibroblasts
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5341920
}}
{{medline-entry
|title=Growth hormone secretion is diminished and tightly controlled in humans enriched for familial longevity.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/27605408
|abstract=Reduced growth hormone (GH) signaling has been consistently associated with increased health and lifespan in various mouse models. Here, we assessed GH secretion and its control in relation with human familial longevity. We frequently sampled blood over 24 h in 19 middle-aged offspring of long-living families from the Leiden Longevity Study together with 18 of their partners as controls. Circulating GH concentrations were measured every 10 min and insulin-like growth factor 1 (IGF-1) and insulin-like growth factor binding protein 3 ([[IGFBP3]]) every 4 h. Using deconvolution analysis, we found that 24-h total GH secretion was 28% lower (P = 0.04) in offspring [172 (128-216) mU L  ] compared with controls [238 (193-284) mU L  ]. We used approximate entropy (ApEn) to quantify the strength of feedback/feedforward control of GH secretion. ApEn was lower (P = 0.001) in offspring [0.45 (0.39-0.53)] compared with controls [0.66 (0.56-0.77)], indicating tighter control of GH secretion. No significant differences were observed in circulating levels of IGF-1 and [[IGFBP3]] between offspring and controls. In conclusion, GH secretion in human familial longevity is characterized by diminished secretion rate and more tight control. These data imply that the highly conserved GH signaling pathway, which has been linked to longevity in animal models, is also associated with human longevity.

|keywords=* IGF-1
* approximate entropy
* familial longevity
* growth hormone
* hormone secretion
* human
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6398524
}}
{{medline-entry
|title=Genomewide meta-analysis identifies loci associated with IGF-I and IGFBP-3 levels with impact on age-related traits.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/27329260
|abstract=The growth hormone/insulin-like growth factor (IGF) axis can be manipulated in animal models to promote longevity, and IGF-related proteins including IGF-I and IGF-binding protein-3 (IGFBP-3) have also been implicated in risk of human diseases including cardiovascular diseases, diabetes, and cancer. Through genomewide association study of up to 30 884 adults of European ancestry from 21 studies, we confirmed and extended the list of previously identified loci associated with circulating IGF-I and IGFBP-3 concentrations (IGF1, [[IGFBP3]], [[GCKR]], [[TNS3]], [[GHSR]], [[FOXO3]], [[ASXL2]], [[NUBP2]]/IGFALS, [[SORCS2]], and [[CELSR2]]). Significant sex interactions, which were characterized by different genotype-phenotype associations between men and women, were found only for associations of IGFBP-3 concentrations with SNPs at the loci [[IGFBP3]] and [[SORCS2]]. Analyses of SNPs, gene expression, and protein levels suggested that interplay between [[IGFBP3]] and genes within the [[NUBP2]] locus (IGFALS and HAGH) may affect circulating IGF-I and IGFBP-3 concentrations. The IGF-I-decreasing allele of SNP rs934073, which is an eQTL of [[ASXL2]], was associated with lower adiposity and higher likelihood of survival beyond 90 years. The known longevity-associated variant rs2153960 ([[FOXO3]]) was observed to be a genomewide significant SNP for IGF-I concentrations. Bioinformatics analysis suggested enrichment of putative regulatory elements among these IGF-I- and IGFBP-3-associated loci, particularly of rs646776 at [[CELSR2]]. In conclusion, this study identified several loci associated with circulating IGF-I and IGFBP-3 concentrations and provides clues to the potential role of the IGF axis in mediating effects of known ([[FOXO3]]) and novel ([[ASXL2]]) longevity-associated loci. 
|mesh-terms=* Adult
* Aging
* Female
* Gene Expression Regulation
* Genome-Wide Association Study
* Humans
* Insulin-Like Growth Factor Binding Protein 3
* Insulin-Like Growth Factor I
* Male
* Metabolome
* Quantitative Trait Loci
* Quantitative Trait, Heritable
* Regulatory Sequences, Nucleic Acid
|keywords=* IGF-I
* IGFBP-3
* aging
* genomewide association study
* growth hormone axis
* longevity
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5013013
}}
{{medline-entry
|title=Unbiased analysis of senescence associated secretory phenotype (SASP) to identify common components following different genotoxic stresses.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/27288264
|abstract=Senescent cells secrete senescence-associated secretory phenotype (SASP) proteins to carry out several functions, such as sensitizing surrounding cells to senesce; immunomodulation; impairing or fostering cancer growth; and promoting tissue development. Identifying secreted factors that achieve such tasks is a challenging issue since the profile of secreted proteins depends on genotoxic stress and cell type. Currently, researchers are trying to identify common markers for SASP. The present investigation compared the secretome composition of five different senescent phenotypes in two different cell types: bone marrow and adipose mesenchymal stromal cells ([[MSC]]). We induced [[MSC]] senescence by oxidative stress, doxorubicin treatment, X-ray irradiation, and replicative exhaustion. We took advantage of LC-MS/MS proteome identification and subsequent gene ontology (GO) evaluation to perform an unbiased analysis (hypothesis free manner) of senescent secretomes. GO analysis allowed us to distribute SASP components into four classes: extracellular matrix/cytoskeleton/cell junctions; metabolic processes; ox-redox factors; and regulators of gene expression. We used Ingenuity Pathway Analysis (IPA) to determine common pathways among the different senescent phenotypes. This investigation, along with identification of eleven proteins that were exclusively expressed in all the analyzed senescent phenotypes, permitted the identification of three key signaling paths: [[MMP2]] - TIMP2; [[IGFBP3]] - PAI-1; and Peroxiredoxin 6 - ERP46 - [[PARK7]] - Cathepsin D - Major vault protein. We suggest that these paths could be involved in the paracrine circuit that induces senescence in neighboring cells and may confer apoptosis resistance to senescent cells.
|mesh-terms=* Adipocytes
* Bone Marrow Cells
* Cellular Senescence
* DNA Damage
* Humans
* Mesenchymal Stem Cells
* Oxidation-Reduction
* Phenotype
|keywords=* mesenchymal stem cells
* secretome
* senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4993333
}}
{{medline-entry
|title=Telomerase activity promotes osteoblast differentiation by modulating IGF-signaling pathway.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/26260615
|abstract=The contribution of deficient telomerase activity to age-related decline in osteoblast functions and bone formation is poorly studied. We have previously demonstrated that telomerase over-expression led to enhanced osteoblast differentiation of human bone marrow skeletal (stromal) stem cells (h[[MSC]]) in vitro and in vivo. Here, we investigated the signaling pathways underlying the regulatory functions of telomerase in osteoblastic cells. Comparative microarray analysis and Western blot analysis of telomerase-over expressing h[[MSC]] (h[[MSC]]-[[TERT]]) versus primary h[[MSC]] revealed significant up-regulation of several components of insulin-like growth factor (IGF) signaling. Specifically, a significant increase in IGF-induced AKT phosphorylation and alkaline phosphatase (ALP) activity were observed in h[[MSC]]-[[TERT]]. Enhanced ALP activity was reduced in presence of [[IGF1]] receptor inhibitor: picropodophyllin. In addition, telomerase deficiency caused significant reduction in IGF signaling proteins in osteoblastic cells cultured from telomerase deficient mice (Terc(-/-)). The low bone mass exhibited by Terc(-/-) mice was associated with significant reduction in serum levels of [[IGF1]] and [[IGFBP3]] as well as reduced skeletal mRNA expression of Igf1, Igf2, Igf2r, Igfbp5 and Igfbp6. [[IGF1]]-induced osteoblast differentiation was also impaired in Terc(-/-) [[MSC]]. In conclusion, our data demonstrate that impaired IGF/AKT signaling contributes to the observed decreased bone mass and bone formation exhibited by telomerase deficient osteoblastic cells.
|mesh-terms=* Animals
* Cell Differentiation
* Cells, Cultured
* Cellular Senescence
* Enzyme Activation
* Humans
* Insulin-Like Growth Factor Binding Proteins
* Mesenchymal Stem Cells
* Mice
* Mice, Knockout
* Osteoblasts
* Phosphatidylinositol 3-Kinases
* Phosphorylation
* Proto-Oncogene Proteins c-akt
* RNA
* Signal Transduction
* Somatomedins
* Telomerase
|keywords=* Aging
* Bone
* Bone marrow stromal stem cells
* IGF
* Osteoblasts
* Telomerase
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4602053
}}
{{medline-entry
|title=Reference values of IGF1, [[IGFBP3]] and IGF1/[[IGFBP3]] ratio in adult population in the Czech Republic.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/25744488
|abstract=IGF1 is responsible for regulation of growth, metabolism and differentiation of human cells. [[IGFBP3]] is the most abundant of the carrier proteins for IGF1 in the blood. IGF1/[[IGFBP3]] molar ratio is an indicator of IGF1 bioavailability. We decided to create a file of reference ranges of IGF1, [[IGFBP3]] and IGF1/IGFBPP3 ratio for the adult Czech population across the age spectrum. We selected a group of 1022 subjects, 467 males and 555 females (ages 20-98 years), from several regions in the Czech Republic. The group consisted of blood donors and patients undergoing regular preventive examinations. Serum levels of IGF1 and [[IGFBP3]] were measured using the following radioimmunoassay kits: IRMA IGF1 (Immunotech, Marseille, France) and IRMA [[IGFBP3]] (Immunotech, Prague, Czech Republic). The IGF1/[[IGFBP3]] ratio was also calculated. The following groups of patients were excluded: patients with diabetes, high blood glucose, high insulin levels, post-surgery patients, polymorbid patients, and subjects with oncological diseases. Subjects were divided into seven age-groups. Changes in the levels of observed analytes in each decade across the age spectrum were evaluated. All statistical analyses were performed by SAS 9.3 (Statistical Analysis Software release 9.3; SAS Institute Inc., Cary, NC, USA). All three parameters IGF1, [[IGFBP3]] and IGF1/[[IGFBP3]] decreased in parallel with decrease in age: p<0.0001, r=-0.64, -0.35 and -0.54, respectively. The dynamics of the decline was different between males and females. Linear regression models with age as independent variable fitted by gender are displayed in Fig. 1. Non-parametric reference interval curves (medians and 2.5th-97.5th percentiles) for IGF1, [[IGFBP3]] and IGF1/[[IGFBP3]] ratio as function of age by gender are displayed in Fig. 2(a,b,c). All medians and 2.5th-97.5th percentiles were plotted by cubic spline. For males, linear regression models were as follows: IGF1=291.34619-2.41211 × age, [[IGFBP3]]=2931.62778-6.11659 × age, IGF1/[[IGFBP3]]=0.02897-0.00021213 × age. For females, we plotted the following: IGF1=241.67406-1.98466 × age, [[IGFBP3]]=3688.60561-16.39560 × age, IGF1/[[IGFBP3]]=0.02029-0.00013233 × age. IGF1 was statistically significantly higher in males with p<0.0001 (Wilcoxon test) but decreased faster (p=0.0121). [[IGFBP3]] was statistically significantly higher in females with p=0.0004 (Wilcoxon test) but decreased faster (p<0.0001). IGF1/[[IGFBP3]] was statistically significantly higher in males with p<0.0001 (Wilcoxon test) but decreased faster (p<0.0001). Authors recommend using of a linear regression model based reference ranges for IGF1, [[IGFBP3]] and IGF1/[[IGFBP3]] ratio and using different reference ranges for genders.
|mesh-terms=* Adult
* Aged
* Aged, 80 and over
* Aging
* Czech Republic
* Female
* Humans
* Insulin-Like Growth Factor Binding Protein 3
* Insulin-Like Growth Factor I
* Linear Models
* Male
* Middle Aged
* Radioimmunoassay
* Reference Values
* Sex Characteristics
* Young Adult
|keywords=* Adult population
* IGF1
* IGF1/IGFBP3 ratio
* IGFBP3
* Reference values
|full-text-url=https://sci-hub.do/10.1016/j.cca.2015.02.036
}}
{{medline-entry
|title=Serum levels of bioactive [[IGF1]] and physiological markers of ageing in healthy adults.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/24179101
|abstract=Senescent changes in body composition and muscle strength are accompanied by reduced production of GH and [[IGF1]], but the causal relationship remains elusive. We speculate that serum bioactive [[IGF1]], measured by the [[IGF1]] kinase receptor activation assay, is closer related to human physiological ageing than total [[IGF1]] measured by immunoassay. We conducted a cross-sectional study in 150 adult males and females, between 20 and 70 years. After an overnight fasting, serum levels of bioactive [[IGF1]], total [[IGF1]] and IGF-binding protein 1 ([[IGFBP1]]) and [[IGFBP3]] were assessed. Furthermore, body composition and muscle strength was measured. Total [[IGF1]] levels were higher in females (P=0.048). Bioactive [[IGF1]] were identical in males and females (P=0.31), decreasing with age. Total [[IGF1]] tended to decrease more with age compared with bioactive [[IGF1]] (-1.48 vs -0.89 percent/year, P=0.052). Total body fat (TBF) was lower and BMI was higher in males (P<0.001 and P=0.005), and both increased with age. Knee extension and elbow flexion force were higher in males (P=0.001 and P=0.001), but decreased with age in both genders.  Total but not bioactive [[IGF1]] was positively correlated to TBF, knee extension and muscle function in males. In multiple linear regression, only age predicted total [[IGF1]], whereas age and [[IGFBP1]] predicted bioactive [[IGF1]]. Bioactive [[IGF1]] tends to decrease to a lesser extent than total [[IGF1]] with age and was not correlated with measures of body composition or muscle strength. Therefore, levels of circulating bioactive [[IGF1]] does not appear to be a better biomarker of physiological ageing than total [[IGF1]].
|mesh-terms=* Adult
* Aged
* Aging
* Body Composition
* Body Mass Index
* Cross-Sectional Studies
* Female
* Humans
* Insulin-Like Growth Factor Binding Protein 1
* Insulin-Like Growth Factor Binding Protein 3
* Insulin-Like Growth Factor I
* Male
* Middle Aged
* Muscle Strength
* Sex Factors

|full-text-url=https://sci-hub.do/10.1530/EJE-13-0661
}}
{{medline-entry
|title=Reduced expression level of the cyclic adenosine monophosphate response element-binding protein contributes to lung aging.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/23991634
|abstract=Lung aging is associated with morphological and physiological changes in which alterations in transcription factors, including the cyclic adenosine monophosphate response element-binding protein (CREB), could play a role. We studied CREB in lung tissue from mice at different ages and in response to known age-related factors (e.g., cellular senescence and matrix modifications with advanced glycation end-products [AGEs]). Our study shows that protein but not mRNA levels of CREB are reduced in the lungs of old mice. CREB reduction was also observed in senescent human lung fibroblasts (WI-38, LuFi) and human lung epithelial cells (A549) cultured on AGE-modified collagen matrix. Reduction of CREB protein is partially based on pre- and posttranslational modifications as exhibited by an increase in the CREB-regulating microRNA 34b and CREB ubiquitination. Permanent down-regulation of CREB in lung cells impaired cell proliferation and viability and increased the number of cells with senescence-associated β-galactosidase activity. CREB down-regulation was accompanied by the reduced expression of 165 genes in WI-38 fibroblasts and A549 epithelial cells, of which 15 genes showed a reduced expression in lung tissues of old mice. The CREB-dependent reduction in [[RAB27A]] coding for the Ras-related protein Rab27A and [[IGFBP3]] coding for the insulin-like growth factor-binding protein 3 has been confirmed for aged lung tissue, senescent fibroblasts, and lung epithelial cells on AGE-modified collagen. Our data demonstrate that the reduced protein expression of CREB might play a significant role in lung aging by modifying the transcription of [[RAB27A]], [[IGFBP3]], and other target genes. 
|mesh-terms=* Aging
* Animals
* Cell Line, Tumor
* Cell Proliferation
* Cell Survival
* Cellular Senescence
* Cyclic AMP
* Cyclic AMP Response Element-Binding Protein
* Down-Regulation
* Epithelial Cells
* Fibroblasts
* Humans
* Insulin-Like Growth Factor Binding Protein 3
* Lung
* Mice
* Mice, Inbred C57BL
* MicroRNAs
* Protein Modification, Translational
* RNA Processing, Post-Transcriptional
* Ubiquitination
* beta-Galactosidase
* rab GTP-Binding Proteins

|full-text-url=https://sci-hub.do/10.1165/rcmb.2013-0057OC
}}
{{medline-entry
|title=Depletion of HPV16 early genes induces autophagy and senescence in a cervical carcinogenesis model, regardless of viral physical state.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/23913724
|abstract=In cervical carcinomas, high-risk human papillomavirus ([[HR]]-HPV) may be integrated into host chromosomes or remain extra-chromosomal (episomal). We used the W12 cervical keratinocyte model to investigate the effects of HPV16 early gene depletion on in vitro cervical carcinogenesis pathways, particularly effects shared by cells with episomal versus integrated HPV16 DNA. Importantly, we were able to study the specific cellular consequences of viral gene depletion by using short interfering RNAs known not to cause phenotypic or transcriptional off-target effects in keratinocytes. We found that while cervical neoplastic progression in vitro was characterized by dynamic changes in HPV16 transcript levels, viral early gene expression was required for cell survival at all stages of carcinogenesis, regardless of viral physical state, levels of early gene expression or histology in organotypic tissue culture. Moreover, HPV16 early gene depletion induced changes in host gene expression that were common to both episome-containing and integrant-containing cells. In particular, we observed up-regulation of autophagy genes, associated with enrichment of senescence and innate immune-response pathways, including the senescence-associated secretory phenotype (SASP). In keeping with these observations, HPV16 early gene depletion induced autophagy in both episome-containing and integrant-containing W12 cells, as evidenced by the appearance of autophagosomes, punctate expression of the autophagy marker LC3, conversion of LC3B-I to LC3B-II, and reduced levels of the autophagy substrate p62. Consistent with the reported association between autophagy and senescence pathways, HPV16 early gene depletion induced expression of the senescence marker beta-galactosidase and increased secretion of the SASP-related protein [[IGFBP3]]. Together, these data indicate that depleting [[HR]]-HPV early genes would be of potential therapeutic benefit in all cervical carcinogenesis pathways, regardless of viral physical state. In addition, the senescence/SASP response associated with autophagy induction may promote beneficial immune effects in bystander cells.
|mesh-terms=* Autophagy
* Cell Line, Tumor
* Cell Transformation, Viral
* Cellular Senescence
* Female
* Gene Expression Regulation, Neoplastic
* Gene Expression Regulation, Viral
* Human papillomavirus 16
* Humans
* Oncogene Proteins, Viral
* Papillomavirus E7 Proteins
* Papillomavirus Infections
* Phenotype
* Plasmids
* RNA Interference
* RNA, Messenger
* RNA, Viral
* Repressor Proteins
* Time Factors
* Transfection
* Uterine Cervical Neoplasms
* Virus Integration
|keywords=* HPV16
* autophagy
* cervix
* senescence
* squamous cell carcinoma
|full-text-url=https://sci-hub.do/10.1002/path.4244
}}