Редактирование: IGF1R (раздел)

==Publications==

{{medline-entry
|title=Comparison of mitochondrial transplantation by using a stamp-type multineedle injector and platelet-rich plasma therapy for hair aging in naturally aging mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32707439
|abstract=The mechanism of hair loss caused by aging is related to mitochondrial dysfunction. Pep-1-mediated mitochondrial transplantation is a potential therapeutic application for mitochondrial disorders, but its efficacy against hair aging remains unknown. This study compared platelet-rich plasma (PRP) therapy with mitochondrial transplantation for hair restoration and examined the related regulation in naturally aging mice. After dorsal hair removal, 100-week-old mice received weekly unilateral injections of 200 μg of allogeneic mitochondria-labeled 5-bromo-2'-deoxyuridine with (P-Mito) or without Pep-1 conjugation (Mito) or human PRP with a stamp-type electric injector for 1 month. The contralateral sides were used as corresponding sham controls. Compared with the control and corresponding sham groups, all treatments stimulated hair regrowth, and the effectiveness of P-Mito was equal to that of PRP. However, histology revealed that only P-Mito maintained hair length until day 28 and yielded more anagen follicles with abundant dermal collagen equivalent to that of the PRP group. Mitochondrial transplantation increased the thickness of subcutaneous fat compared with the control and PRP groups, and only P-Mito consistently increased mitochondria in the subcutaneous muscle and mitochondrial DNA copies in the skin layer. Therefore, P-Mito had a higher penetrating capacity than Mito did. Moreover, P-Mito treatment was as effective as PRP treatment in comprehensively reducing the expression of aging-associated gene markers, such as [[IGF1R]] and [[MRPS5]], and increasing antiaging Klotho gene expression. This study validated the efficacy of mitochondrial therapy in the restoration of aging-related hair loss and demonstrated the distinct effects of PRP treatment.

|keywords=* Aging mice
* Hair growth
* Mitochondrial transplantation
* Pep-1
* Platelet-rich plasma
|full-text-url=https://sci-hub.do/10.1016/j.biopha.2020.110520
}}
{{medline-entry
|title=Alcohol drinking exacerbates neural and behavioral pathology in the 3xTg-AD mouse model of Alzheimer's disease.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31733664
|abstract=Alzheimer's disease (AD) is a progressive neurodegenerative disorder that represents the most common cause of dementia in the United States. Although the link between alcohol use and AD has been studied, preclinical research has potential to elucidate neurobiological mechanisms that underlie this interaction. This study was designed to test the hypothesis that nondependent alcohol drinking exacerbates the onset and magnitude of AD-like neural and behavioral pathology. We first evaluated the impact of voluntary 24-h, two-bottle choice home-cage alcohol drinking on the prefrontal cortex and amygdala neuroproteome in C57BL/6J mice and found a striking association between alcohol drinking and AD-like pathology. Bioinformatics identified the AD-associated proteins [[MAPT]] (Tau), amyloid beta precursor protein ([[APP]]), and presenilin-1 (PSEN-1) as the main modulators of alcohol-sensitive protein networks that included AD-related proteins that regulate energy metabolism (ATP5D, [[HK1]], [[AK1]], [[PGAM1]], CKB), cytoskeletal development (BASP1, [[CAP1]], [[DPYSL2]] [CRMP2], [[ALDOA]], [[TUBA1A]], [[CFL2]], ACTG1), cellular/oxidative stress (HSPA5, [[HSPA8]], [[ENO1]], ENO2), and DNA regulation (PURA, YWHAZ). To address the impact of alcohol drinking on AD, studies were conducted using 3xTg-AD mice that express human [[MAPT]], [[APP]], and PSEN-1 transgenes and develop AD-like brain and behavioral pathology. 3xTg-AD and wild-type mice consumed alcohol or saccharin for 4 months. Behavioral tests were administered during a 1-month alcohol-free period. Alcohol intake induced AD-like behavioral pathologies in 3xTg-AD mice including impaired spatial memory in the Morris Water Maze, diminished sensorimotor gating as measured by prepulse inhibition, and exacerbated conditioned fear. Multiplex immunoassay conducted on brain lysates showed that alcohol drinking upregulated primary markers of AD pathology in 3xTg-AD mice: Aβ 42/40 ratio in the lateral entorhinal and prefrontal cortex and total Tau expression in the lateral entorhinal cortex, medial prefrontal cortex, and amygdala at 1-month post alcohol exposure. Immunocytochemistry showed that alcohol use upregulated expression of pTau (Ser199/Ser202) in the hippocampus, which is consistent with late-stage AD. According to the NIA-AA Research Framework, these results suggest that alcohol use is associated with Alzheimer's pathology. Results also showed that alcohol use was associated with a general reduction in Akt/mTOR signaling via several phosphoproteins (IR, [[IRS1]], [[IGF1R]], [[PTEN]], ERK, mTOR, p70S6K, RPS6) in multiple brain regions including hippocampus and entorhinal cortex. Dysregulation of Akt/mTOR phosphoproteins suggests alcohol may target this pathway in AD progression. These results suggest that nondependent alcohol drinking increases the onset and magnitude of AD-like neural and behavioral pathology in 3xTg-AD mice.
|mesh-terms=* Alcohol Drinking
* Alzheimer Disease
* Amyloid beta-Protein Precursor
* Animals
* Behavior, Animal
* Brain
* Disease Models, Animal
* Mice, Transgenic
* tau Proteins
|keywords=* Aging
* Amyloid beta
* Ethanol
* GSK
* Immunohistochemistry
* Morris Water Maze
* Prepulse inhibition
* Self-administration
* Tau pathology
* Transgenic mouse model
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6939615
}}
{{medline-entry
|title=Integration of Biochemical, Cellular, and Genetic Indicators for Understanding the Aging Process in a Bivalve Mollusk Chlamys farreri.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31392593
|abstract=The major causal factors for the irreversible decline in physical vitality during organismal aging are postulated to be a chronic state of cellular redox imbalance, metabolic toxicity, and impaired energy homeostasis. We assessed whether the relevant enzyme activity, oxidative stress, and intracellular ATP might be causally involved in the aging of short-lived Chlamys farreri (life span 4~5 years). A total of eight related biochemical and cellular indicators were chosen for the subsequent analysis. All the indicators were measured in seven different tissues from scallops aged one to four years, and our data support that the aging of C. farreri is associated with attenuated tissue enzyme activity as well as a decreased metabolic rate. Through principal component analysis, we developed an integrated vigor index for each tissue for comprehensive age-related fitness evaluation. Remarkably, all tissue-integrated vigor indexes significantly declined with age, and the kidney was observed to be the most representative tissue. Further transcriptional profiling of the enzymatic genes provided additional detail on the molecular responses that may underlie the corresponding biochemical results. Moreover, these critical molecular responses may be attributed to the conserved hierarchical regulators, e.g., FOXO, AMPKs, mTOR, and [[IGF1R]], which were identified as potentially novel markers for chronic fitness decline with age in bivalves. The present study provides a systematic approach that could potentially benefit the global assessment of the aging process in C. farreri and provide detailed evaluation of the biochemical, cellular, and genetic indicators that might be involved. This information may assist in a better understanding of bivalve adaptability and life span.
|mesh-terms=* AMP-Activated Protein Kinases
* Adenosine Triphosphate
* Aging
* Animals
* Bivalvia
* Energy Metabolism
* Forkhead Box Protein O1
* Gene Expression Profiling
* Gene Expression Regulation, Developmental
* Gills
* Gonads
* Hepatopancreas
* Homeostasis
* Kidney
* Organ Specificity
* Oxidation-Reduction
* Oxidative Stress
* Principal Component Analysis
* Receptor, IGF Type 1
* TOR Serine-Threonine Kinases
* Transcriptome
|keywords=* Adaptation
* Aging
* Evolution
* Physiological vitality
* Scallop
|full-text-url=https://sci-hub.do/10.1007/s10126-019-09917-7
}}
{{medline-entry
|title=In mice transgenic for [[IGF1]] under keratin-14 promoter, lifespan is decreased and the rates of aging and thymus involution are accelerated.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30981207
|abstract=[[IGF1]] signaling is supposedly a key lifespan determinant in metazoans. However, controversial lifespan data were obtained with different means used to modify [[IGF1]] or its receptor ([[IGF1]]R) expression in mice. The emerging puzzle lacks pieces of evidence needed to construct a coherent picture. We add to the available evidence by using the Gompertz model (GM), with account for the artifactual component of the Strehler-Mildvan correlation between its parameters, to compare the survival patterns of female FVB/N and FVB/N-derived K14/m[[IGF1]] mice. In K14/m[[IGF1]] vs. FVB/N mice, the rate of aging ([i]γ[/i]) is markedly increased without concomitant changes in the initial mortality ([i]μ[/i] ). In published cases where [[IGF1]] signaling was altered by modifying liver or muscle [[IGF1]] or whole body [[IGF1]]R expression, lifespan changes are attributable to [i]μ[/i] . The accelerated aging and associated tumor yield in K14/m[[IGF1]] mice are consistent with the finding that the age-associated decreases in thymus weight and serum thymulin are accelerated in K14/m[[IGF1]] mice. Our results underscore the importance of accounting for the mathematical artifacts of data fitting to GM in attempts to resolve discrepancies in survival data and to differentiate the contributions of the initial mortality and the rate of aging to changes in lifespan.
|mesh-terms=* Aging
* Animals
* Female
* Insulin-Like Growth Factor I
* Keratin-14
* Longevity
* Mice
* Mice, Transgenic
* Promoter Regions, Genetic
* Receptor, IGF Type 1
* Signal Transduction
* Thymic Factor, Circulating
* Thymus Gland
|keywords=* Gompertz model
* IGF1
* Strehler-Mildvan correlation
* age-related-diseases
* aging
* cancer
* papilloma
* parametric analysis
* survival pattern
* thymulin
* thymus
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6503882
}}
{{medline-entry
|title=Insulin/IGF-1 signaling and aging.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30557473
|abstract=Insulin and IGF-1 have a high similarity in structure and play pivotal roles in regulation of aging and longevity. Insulin is bound to insulin receptor on cell surface, whereas IGF-1 is bound to [[IGF1R]], but the molecules to transduce intracellular signals are almost identical, including Akt and FoxO. Akt is a kinase to regulate growth and metabolism in various tissues, and among the substrates, FoxO is one of the key transcription factors to regulate expression of a number or genes, including anti-oxidative enzymes. Akt phosphorylates FoxO and sup- presses its activity by promoting translocation to cytoplasm. In yeast, worms and flies, it is known that various mutations to impair insulin/IGF-1 signaling prolong longevity, potentially via activation of FoxO. In mice, however, longevity was prolonged in some models with disrup- tion of insulin/IGF-1 signaling-related genes, whereas it was shortened in others. Moreover, in many cases, prolonged longevity was accompanied by growth retardation or metabolic disorders, which means that they did not live a 'long and healthy' life. It is still controversial whether suppression of insulin/IGF-1 signaling is beneficial in terms of aging also in mammalians.
|mesh-terms=* Aging
* Animals
* Humans
* Insulin
* Insulin-Like Growth Factor I
* Longevity
* Signal Transduction


}}
{{medline-entry
|title=Effect of young exosomes injected in aged mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30254438
|abstract=Exosomes, nanosized extracellular vesicles, are known to circulate through the blood stream to transfer molecular signals from tissue to tissue. To determine whether exosomes affect aging in animals, we primarily identified the changes in exosomal miRNA contents during the aging process. In exosomes from 12-month-old mice, mmu-miR-126-5p and mmu-miR-466c-5p levels were decreased and mmu-miR-184-3p and mmu-miR-200b-5p levels were increased significantly compared with those of 3-month-old mice. Their levels in exosomes were partially correlated with those in tissues: levels of only mmu-miR-126-5p and mmu-miR-466c-5p in lungs and/or liver were decreased, but those of mmu-miR-184-3p and mmu-miR-200b-5p in tissues did not coincide with those of exosomes. In the aged tissues injected with young exosomes isolated from serum, mmu-miR-126b-5p levels were reversed in the lungs and liver. Expression changes in aging-associated molecules in young exosome-injected mice were obvious: p16 , [[MTOR]], and [[IGF1R]] were significantly downregulated in the lungs and/or liver of old mice. In addition, telomerase-related genes such as [i]Men1[/i], [i]Mre11a[/i], [i]Tep1[/i], [i]Terf2[/i], [i]Tert[/i], and [i]Tnks[/i] were significantly upregulated in the liver of old mice after injection of young exosomes. These results indicate that exosomes from young mice could reverse the expression pattern of aging-associated molecules in aged mice. Eventually, exosomes may be used as a novel approach for the treatment and diagnosis of aging animals.
|mesh-terms=* Aging
* Animals
* Down-Regulation
* Exosomes
* Gene Expression Profiling
* Injections
* Liver
* Lung
* Male
* Mice, Inbred C57BL
* MicroRNAs
* Telomerase
|keywords=* biomarker
* exosome
* injection
* molecular therapy
* reverse aging
* telomerase
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6141108
}}
{{medline-entry
|title=The genetic component of human longevity: New insights from the analysis of pathway-based SNP-SNP interactions.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29577582
|abstract=In human longevity studies, single nucleotide polymorphism (SNP) analysis identified a large number of genetic variants with small effects, yet not easily replicable in different populations. New insights may come from the combined analysis of different SNPs, especially when grouped by metabolic pathway. We applied this approach to study the joint effect on longevity of SNPs belonging to three candidate pathways, the insulin/insulin-like growth factor signalling (IIS), DNA repair and pro/antioxidant. We analysed data from 1,058 tagging SNPs in 140 genes, collected in 1825 subjects (1,089 unrelated nonagenarians from the Danish 1905 Birth Cohort Study and 736 Danish controls aged 46-55 years) for evaluating synergic interactions by SNPsyn. Synergies were further tested by the multidimensional reduction (MDR) approach, both intra- and interpathways. The best combinations (FDR<0.0001) resulted those encompassing [[IGF1R]]-rs12437963 and [[PTPN1]]-rs6067484, [[TP53]]-rs2078486 and [[ERCC2]]-rs50871, [[TXNRD1]]-rs17202060 and [[TP53]]-rs2078486, the latter two supporting a central role of [[TP53]] in mediating the concerted activation of the DNA repair and pro-antioxidant pathways in human longevity. Results were consistently replicated with both approaches, as well as a significant effect on longevity was found for the [[GHSR]] gene, which also interacts with partners belonging to both IIS and DNA repair pathways (PAPPA, [[PTPN1]], [[PARK7]], MRE11A). The combination [[GHSR]]-MREA11, positively associated with longevity by MDR, was further found influencing longitudinal survival in nonagenarian females (p = .026). Results here presented highlight the validity of SNP-SNP interactions analyses for investigating the genetics of human longevity, confirming previously identified markers but also pointing to novel genes as central nodes of additional networks involved in human longevity.
|mesh-terms=* Aging
* Female
* Humans
* Longevity
* Male
* Polymorphism, Single Nucleotide
* Survival Analysis
|keywords=* 
SNP

* aging
* epistasis
* genetic component of human longevity
* pathway-based analysis
* synergic interaction
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5946073
}}
{{medline-entry
|title=The Alzheimer's disease transcriptome mimics the neuroprotective signature of IGF-1 receptor-deficient neurons.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/28595357
|abstract=Seminal studies using post-mortem brains of patients with Alzheimer's disease evidenced aberrant insulin-like growth factor 1 receptor ([[IGF1R]]) signalling. Addressing causality, work in animal models recently demonstrated that long-term suppression of [[IGF1R]] signalling alleviates Alzheimer's disease progression and promotes neuroprotection. However, the underlying mechanisms remain largely elusive. Here, we showed that genetically ablating [[IGF1R]] in neurons of the ageing brain efficiently protects from neuroinflammation, anxiety and memory impairments induced by intracerebroventricular injection of amyloid-β oligomers. In our mutant mice, the suppression of [[IGF1R]] signalling also invariably led to small neuronal soma size, indicative of profound changes in cellular homeodynamics. To gain insight into transcriptional signatures leading to Alzheimer's disease-relevant neuronal defence, we performed genome-wide microarray analysis on laser-dissected hippocampal [[CA1]] after neuronal [[IGF1R]] knockout, in the presence or absence of APP/PS1 transgenes. Functional analysis comparing neurons in early-stage Alzheimer's disease with [[IGF1R]] knockout neurons revealed strongly convergent transcriptomic signatures, notably involving neurite growth, cytoskeleton organization, cellular stress response and neurotransmission. Moreover, in Alzheimer's disease neurons, a high proportion of genes responding to Alzheimer's disease showed a reversed differential expression when [[IGF1R]] was deleted. One of the genes consistently highlighted in genome-wide comparison was the neurofilament medium polypeptide Nefm. We found that [[NEFM]] accumulated in hippocampus in the presence of amyloid pathology, and decreased to control levels under [[IGF1R]] deletion, suggesting that reorganized cytoskeleton likely plays a role in neuroprotection. These findings demonstrated that significant resistance of the brain to amyloid-β can be achieved lifelong by suppressing neuronal [[IGF1R]] and identified IGF-dependent molecular pathways that coordinate an intrinsic program for neuroprotection against proteotoxicity. Our data also indicate that neuronal defences against Alzheimer's disease rely on an endogenous gene expression profile similar to the neuroprotective response activated by genetic disruption of [[IGF1R]] signalling. This study highlights neuronal [[IGF1R]] signalling as a relevant target for developing Alzheimer's disease prevention strategies.
|mesh-terms=* Aging
* Alzheimer Disease
* Amyloid beta-Peptides
* Animals
* Anxiety
* CA1 Region, Hippocampal
* Encephalitis
* Female
* Infusions, Intraventricular
* Male
* Memory Disorders
* Mice
* Mice, Knockout
* Mice, Transgenic
* Neurons
* Neuroprotective Agents
* Receptor, IGF Type 1
* Transcriptome
|keywords=* Alzheimer’s disease
* amyloid-β oligomers
* hippocampus CA1
* insulin-like growth factor receptor
* transcriptome
|full-text-url=https://sci-hub.do/10.1093/brain/awx132
}}
{{medline-entry
|title=β Cell Aging Markers Have Heterogeneous Distribution and Are Induced by Insulin Resistance.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/28380379
|abstract=We hypothesized that the known heterogeneity of pancreatic β cells was due to subpopulations of β cells at different stages of their life cycle with different functional capacities and that further changes occur with metabolic stress and aging. We identified new markers of aging in β cells, including [[IGF1R]]. In β cells [[IGF1R]] expression correlated with age, dysfunction, and expression of known age markers p16 , p53BP1, and senescence-associated β-galactosidase. The new markers showed striking heterogeneity both within and between islets in both mouse and human pancreas. Acute induction of insulin resistance with an insulin receptor antagonist or chronic ER stress resulted in increased expression of aging markers, providing insight into how metabolic stress might accelerate dysfunction and decline of β cells. These novel findings about β cell and islet heterogeneity, and how they change with age, open up an entirely new set of questions about the pathogenesis of type 2 diabetes.
|mesh-terms=* Adolescent
* Adult
* Aged
* Aging
* Animals
* Biomarkers
* Cellular Senescence
* Diabetes Mellitus, Type 2
* Female
* Flow Cytometry
* Gene Expression Regulation, Developmental
* Glucose
* Green Fluorescent Proteins
* Hemolytic Plaque Technique
* Humans
* Insulin
* Insulin Resistance
* Insulin-Secreting Cells
* Male
* Mice, Inbred C57BL
* Middle Aged
* RNA, Messenger
* Receptor, IGF Type 1
* Stress, Physiological
* Tumor Suppressor p53-Binding Protein 1
* Young Adult
|keywords=* aging markers
* beta-cell heterogeneity
* islets
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5471618
}}
{{medline-entry
|title=30 YEARS OF THE MINERALOCORTICOID RECEPTOR: Nongenomic effects via the mineralocorticoid receptor.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/28348113
|abstract=The mineralocorticoid receptor (MR) belongs to the steroid hormone receptor family and classically functions as a ligand-dependent transcription factor. It is involved in water-electrolyte homeostasis and blood pressure regulation but independent from these effects also furthers inflammation, fibrosis, hypertrophy and remodeling in cardiovascular tissues. Next to genomic effects, aldosterone elicits very rapid actions within minutes that do not require transcription or translation and that occur not only in classical MR epithelial target organs like kidney and colon but also in nonepithelial tissues like heart, vasculature and adipose tissue. Most of these effects can be mediated by classical MR and its crosstalk with different signaling cascades. Near the plasma membrane, the MR seems to be associated with caveolin and striatin as well as with receptor tyrosine kinases like [[EGFR]], PDGFR and [[IGF1R]] and G protein-coupled receptors like AT1 and [[GPER1]], which then mediate nongenomic aldosterone effects. [[GPER1]] has also been named a putative novel MR. There is a close interaction and functional synergism between the genomic and the nongenomic signaling so that nongenomic signaling can lead to long-term effects and support genomic actions. Therefore, understanding nongenomic aldosterone/MR effects is of potential relevance for modulating genomic aldosterone effects and may provide additional targets for intervention.
|mesh-terms=* Aldosterone
* Animals
* Gene Expression Regulation
* Genomics
* Humans
* Receptors, Mineralocorticoid
* Signal Transduction
|keywords=* aging
* cardiovascular
* corticosteroids
* growth factor receptors
* renin–angiotensin system
|full-text-url=https://sci-hub.do/10.1530/JOE-16-0659
}}
{{medline-entry
|title=A serum miRNA profile of human longevity: findings from the Baltimore Longitudinal Study of Aging (BLSA).
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/27824314
|abstract=In [i]C. elegans[/i], miRNAs are genetic biomarkers of aging. Similarly, multiple miRNAs are differentially expressed between younger and older persons, suggesting that miRNA-regulated biological mechanisms affecting aging are evolutionarily conserved. Previous human studies have not considered participants' lifespans, a key factor in identifying biomarkers of aging. Using PCR arrays, we measured miRNA levels from serum samples obtained longitudinally at ages 50, 55, and 60 from 16 non-Hispanic males who had documented lifespans from 58 to 92. Numerous miRNAs showed significant changes in expression levels. At age 50, 24 miRNAs were significantly upregulated, and 73 were significantly downregulated in the long-lived subgroup (76-92 years) as compared with the short-lived subgroup (58-75 years). In long-lived participants, the most upregulated was miR-373-5p, while the most downregulated was miR-15b-5p. Longitudinally, significant Pearson correlations were observed between lifespan and expression of nine miRNAs (p value<0.05). Six of these nine miRNAs (miR-211-5p, 374a-5p, 340-3p, 376c-3p, 5095, 1225-3p) were also significantly up- or downregulated when comparing long-lived and short-lived participants. Twenty-four validated targets of these miRNAs encoded aging-associated proteins, including [[PARP1]], [[IGF1R]], and [[IGF2R]]. We propose that the expression profiles of the six miRNAs (miR-211-5p, 374a-5p, 340-3p, 376c-3p, 5095, and 1225-3p) may be useful biomarkers of aging.
|mesh-terms=* Aged
* Aged, 80 and over
* Aging
* Animals
* Biomarkers
* Caenorhabditis elegans
* Down-Regulation
* Gene Expression Profiling
* Humans
* Longevity
* Longitudinal Studies
* Male
* MicroRNAs
* Middle Aged
* Pilot Projects
* Polymerase Chain Reaction
* Up-Regulation
|keywords=* aging
* biomarker
* long-lived
* longitudinal study
* miRNA
* short-lived
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5191881
}}
{{medline-entry
|title=Differential Regulation of Hippocampal IGF-1-Associated Signaling Proteins by Dietary Restriction in Aging Mouse.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/27718093
|abstract=Time-dependent alterations in several biological processes of an organism may be characterized as aging. One of the effects of aging is the decline in cognitive functions. Dietary restriction (DR), an intervention where the consumption of food is lessened but without malnutrition, is a well-established mechanism that has a wide range of important outcomes including improved health span, delayed aging, and extension of lifespan of various species. It also plays a beneficial role in protecting against age-dependent deterioration of cognitive functions, and has neuroprotective properties against neurodegenerative diseases. Insulin-like growth factor (IGF)-1 plays an important role in the regulation of cellular and tissue functions, and relating to the aging process the most important pathway of IGF-1 is the phosphatidylinositol 3-kinase (PI3K) and protein kinase B (Akt/PKB) signaling cascade. Although many have studied the changes in the level of IGF-1 and its effect on neural proliferation, the downstream signaling proteins have not been fully elucidated. Hence in the present investigation, the IGF-1 gene expression and the normal endogenous levels of [[IGF1R]] (IGF-1 receptor), PI3K, Akt, pAkt, and pFoxO in the hippocampus of young, adult, and old mice were determined using real-time PCR and Western blot analyses. The effects of DR on these protein levels were also studied. Results showed a decrease in the levels of IGF-1, [[IGF1R]], PI3K, and pAkt, while pFoxO level increased with respect to age. Under DR, these protein levels are maintained in adult mice, but old mice displayed diminished expression levels of these proteins as compared to ad libitum-fed mice. Maintenance of PI3K/Akt pathway results in the phosphorylation of FoxOs, necessary for the enhancement of neural proliferation and survival in adult mice. The down-regulation of IGF-I signaling, as observed in old mice, leads to increasing the activity of FoxO factors that may be important for the neuroprotective effects seen with DR.
|mesh-terms=* Aging
* Animals
* Body Weight
* Caloric Restriction
* Densitometry
* Female
* Hippocampus
* Insulin-Like Growth Factor I
* Liver
* Mice, Inbred BALB C
* RNA, Messenger
* Signal Transduction
|keywords=* Aging
* DR
* Hippocampus
* IGF-1
* Mouse
|full-text-url=https://sci-hub.do/10.1007/s10571-016-0431-7
}}
{{medline-entry
|title=Lidocaine Impairs Proliferative and Biosynthetic Functions of Aged Human Dermal Fibroblasts.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/27537755
|abstract=The aged are at increased risk of postoperative wound healing complications. Because local anesthetics are infiltrated commonly into the dermis of surgical wounds, we sought to determine whether local anesthetics adversely affect proliferative and biosynthetic functions of dermal fibroblasts. We also evaluated the effect of local anesthetics on insulin-like growth factor-1 (IGF-1) and transforming growth factor-β1 (TGF-β1), growth factors that are important regulators of wound healing. Human dermal fibroblasts (HFB) from aged and young donors were exposed to local anesthetic agents at clinically relevant concentrations. We screened the effects of lidocaine, bupivacaine, mepivacaine, and ropivacaine on proliferation of HFB. Lidocaine was most detrimental to proliferation in HFB. We then evaluated the effect of lidocaine on expression and function of the growth factors, IGF-1 and TGF-β1. Lastly, concurrent exposure to lidocaine and IGF-1 or TGF-β1 was evaluated for their effects on proliferation and expression of dermal collagens, respectively. Lidocaine and mepivacaine inhibited proliferation in aged HFB (for lidocaine 88% of control, 95% confidence interval [CI], 80%-98%, P = .009 and for mepivacaine 90% of control, 95% CI, 81%-99%, P = .032) but not in young HFB. Ropivacaine and bupivacaine did not inhibit proliferation. Because of the clinical utility of lidocaine relative to mepivacaine, we focused on lidocaine. Lidocaine decreased proliferation in aged HFB, which was abrogated by IGF-1. Lidocaine inhibited transcripts for IGF-1 and insulin-like growth factor-1 receptor ([[IGF1R]]) in fibroblasts from aged donors (IGF-1, log2 fold-change -1.25 [42% of control, 95% CI, 19%-92%, P = .035] and [[IGF1R]], log2 fold-change -1.00 [50% of control, 95% CI, 31%-81%, P = .014]). In contrast, lidocaine did not affect the expression of IGF-1 or [[IGF1R]] transcripts in the young HFB. Transcripts for collagen III were decreased after lidocaine exposure in aged and young HFB (log2 fold-change -1.28 [41% of control, 95% CI, 20%-83%, P = .022] in aged HFB and log2 fold-change -1.60 [33% of control, 95% CI, 15%-73%, P = .019] in young HFB). Transcripts for collagen I were decreased in aged HFB (log2 fold-change -1.82 [28% of control, 95% CI, 14%-58%, P = .006]) but not in the young HFB. Similar to the transcripts, lidocaine also inhibited the protein expression of collagen III in young and aged HFB (log2 fold-change -1.79 [29% of control, 95% CI, 18%-47%, P = .003] in young HFB and log2 fold-change -1.76 [30% of control, 95% CI, 9%-93%, P = .043] in aged HFB). The effect of lidocaine on the expression of collagen III protein was obviated by TGF-β1 in both young and aged HFB. Our results show that lidocaine inhibits processes relevant to dermal repair in aged HFB. The detrimental responses to lidocaine are due, in part, to interactions with IGF-1 and TGF-β1.
|mesh-terms=* Adult
* Aged, 80 and over
* Aging
* Anesthetics, Local
* Cell Proliferation
* Cells, Cultured
* Dermis
* Fibroblasts
* Humans
* Lidocaine
* Male
* Protein Biosynthesis

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4991565
}}
{{medline-entry
|title=Growth Hormone Receptor Deficiency Protects against Age-Related [[NLRP3]] Inflammasome Activation and Immune Senescence.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/26876170
|abstract=The hallmarks of age-related immune senescence are chronic inflammation, aberrant expansion of effector memory, and loss of naive T lymphocytes due in part to systemic activation of innate immune sensor [[NLRP3]] inflammasome in myeloid lineage cells. The endogenous mechanisms that regulate inflammasome activation during aging are unknown. Here, we present evidence that growth hormone receptor (GH-R)-dependent downregulation of [[NLRP3]] inflammasome in macrophages is linked to pro-longevity effects that maintain immune system homeostasis in aging. Deletion of GH-R prevented the macrophage-driven age-related activation of inflammasome in response to [[NLRP3]] ligands and also increased the preservation of naive T cells, even in advanced age and with higher IFNγ secretion from effector cells. The mechanism of inflammasome inhibition is linked to autocrine somatotropic axis as ablation of [[IGF1R]] in macrophages lowered the [[NLRP3]] inflammasome activation. Together, our findings show that functional somatotropic axis in macrophages controls inflammation, thus linking [[NLRP3]]-mediated innate immune signaling to health span and longevity. 
|mesh-terms=* Aging
* Animals
* Autocrine Communication
* Bone Marrow Cells
* Carrier Proteins
* Gene Expression Regulation
* Homeostasis
* Immunity, Innate
* Immunologic Memory
* Inflammasomes
* Interferon-gamma
* Longevity
* Macrophages
* Mice
* Mice, Knockout
* NLR Family, Pyrin Domain-Containing 3 Protein
* Receptor, IGF Type 1
* Receptors, Somatotropin
* Signal Transduction
* Spleen
* T-Lymphocytes

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5992590
}}
{{medline-entry
|title=Gene transcripts associated with muscle strength: a CHARGE meta-analysis of 7,781 persons.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/26487704
|abstract=Lower muscle strength in midlife predicts disability and mortality in later life. Blood-borne factors, including growth differentiation factor 11 (GDF11), have been linked to muscle regeneration in animal models. We aimed to identify gene transcripts associated with muscle strength in adults. Meta-analysis of whole blood gene expression (overall 17,534 unique genes measured by microarray) and hand-grip strength in four independent cohorts (n = 7,781, ages: 20-104 yr, weighted mean = 56), adjusted for age, sex, height, weight, and leukocyte subtypes. Separate analyses were performed in subsets (older/younger than 60, men/women). Expression levels of 221 genes were associated with strength after adjustment for cofactors and for multiple statistical testing, including [[ALAS2]] (rate-limiting enzyme in heme synthesis), [[PRF1]] (perforin, a cytotoxic protein associated with inflammation), [[IGF1R]], and [[IGF2BP2]] (both insulin like growth factor related). We identified statistical enrichment for hemoglobin biosynthesis, innate immune activation, and the stress response. Ten genes were associated only in younger individuals, four in men only and one in women only. For example, [[PIK3R2]] (a negative regulator of PI3K/AKT growth pathway) was negatively associated with muscle strength in younger (<60 yr) individuals but not older (≥ 60 yr). We also show that 115 genes (52%) have not previously been linked to muscle in NCBI PubMed abstracts. This first large-scale transcriptome study of muscle strength in human adults confirmed associations with known pathways and provides new evidence for over half of the genes identified. There may be age- and sex-specific gene expression signatures in blood for muscle strength.
|mesh-terms=* Adult
* Age Factors
* Aged
* Aged, 80 and over
* Aging
* Cohort Studies
* Female
* Gene Ontology
* Heart
* Humans
* Knee
* Male
* Middle Aged
* Muscle Strength
* RNA, Messenger
* Reproducibility of Results
* Sex Characteristics
* Young Adult
|keywords=* blood
* gene-expression
* human
* leukocyte
* muscle
* strength
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4757025
}}
{{medline-entry
|title=The Heart Protection Effect of Alcalase Potato Protein Hydrolysate Is through [[IGF1R]]-PI3K-Akt Compensatory Reactivation in Aging Rats on High Fat Diets.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/25950762
|abstract=The prevalence of obesity is high in older adults. Alcalase potato protein hydrolysate (APPH), a nutraceutical food, might have greater benefits and be more economical than hypolipidemic drugs. In this study, serum lipid profiles and heart protective effects were evaluated in high fat diet (HFD) induced hyperlipidemia in aging rats treated with APPH (15, 45 and 75 mg/kg/day) and probucol (500 mg/kg/day). APPH treatments reduced serum triacylglycerol (TG), total cholesterol (TC), and low density lipoprotein (LDL) levels to the normal levels expressed in the control group. Additionally, the [[IGF1R]]-PI3K-Akt survival pathway was reactivated, and Fas-[[FADD]] (Fas-associated death domain) induced apoptosis was inhibited by APPH treatments (15 and 45 mg/kg/day) in HFD aging rat hearts. APPH (75 mg/kg/day) rather than probucol (500 mg/kg/day) treatment could reduce serum lipids without affecting HDL expression. The heart protective effect of APPH in aging rats with hyperlipidemia was through lowering serum lipids and enhancing the activation of the compensatory [[IGF1R]]-PI3K-Akt survival pathway. 
|mesh-terms=* Aging
* Animals
* Anticholesteremic Agents
* Apoptosis
* Cardiotonic Agents
* Cholesterol
* Diet, High-Fat
* Dietary Supplements
* Fas-Associated Death Domain Protein
* Hyperlipidemias
* Lipoproteins, LDL
* Phosphatidylinositol 3-Kinases
* Plant Proteins
* Probucol
* Protein Hydrolysates
* Proto-Oncogene Proteins c-akt
* Rats
* Rats, Sprague-Dawley
* Receptor, IGF Type 1
* Signal Transduction
* Solanum tuberosum
* Subtilisins
* Triglycerides

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4463638
}}
{{medline-entry
|title=Clinical significance of proliferation, apoptosis and senescence of nasopharyngeal cells by the simultaneously blocking [[EGF]], IGF-1 receptors and Bcl-xl genes.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/24055032
|abstract=In previous work, we constructed short hairpin RNA (shRNA) expression plasmids that targeted human [[EGF]] and IGF-1 receptors messenger RNA, respectively, and demonstrated that these vectors could induce apoptosis of human nasopharyngeal cell lines (CNE2) and inhibit ligand-induced pAkt and pErk activation. We have constructed multiple shRNA expression vectors of targeting [[EGF]]R, [[IGF1R]] and Bcl-xl, which were transfected to the CNE2 cells. The mRNA expression was assessed by RT-PCR. The growth of the cells, cell cycle progression, apoptosis of the cells, senescent tumor cells and the proteins of [[EGF]]R, [[IGF1R]] and Bcl-xl were analyzed by MTT, flow cytometry, cytochemical therapy or Western blot. In group of simultaneously blocking [[EGF]]R, [[IGF1R]] and Bcl-xl genes, the mRNA of [[EGF]]R, [[IGF1R]] and Bcl-xl expression was decreased by (66.66±3.42)%, (73.97±2.83)% and (64.79±2.83)%, and the protein expressions was diminished to (67.69±4.02)%, (74.32±2.30)%, and (60.00±3.34)%, respectively. Meanwhile, the cell apoptosis increased by 65.32±0.18%, 65.16±0.25% and 55.47±0.45%, and senescent cells increased by 1.42±0.15%, 2.26±0.15% and 3.22±0.15% in the second, third and fourth day cultures, respectively. Simultaneously blocking [[EGF]]R, [[IGF1R]] and Bcl-xl genes is capable of altering the balance between proliferating versus apoptotic and senescent cells in the favor of both of apoptosis and senescence and, therefore, the tumor cells regression.
|mesh-terms=* Apoptosis
* Cell Line, Tumor
* Cell Proliferation
* Cellular Senescence
* ErbB Receptors
* Humans
* Nasopharyngeal Neoplasms
* RNA Interference
* Receptor, IGF Type 1
* bcl-X Protein
|keywords=* Bcl-xl
* Epidermal growth factor receptor
* Insulin-like growth factor-1 receptor
* Nasopharyngeal cancer
* Senescence
* Short hairpin RNA
|full-text-url=https://sci-hub.do/10.1016/j.bbrc.2013.08.070
}}