Insulin/insulin-like Growth Factor Research Articles

Association of cigarette smoking with cerebrospinal fluid biomarkers of insulin sensitivity and neurodegeneration.

Cigarette smoking increases both the risk for insulin resistance and amyloid-β (Aβ) aggregation, and impaired brain insulin/insulin-like growth factor 1 (IGF1) signaling might increase risk factors for Alzheimer's disease (AD). We aimed to investigate the association among cerebrospinal fluid (CSF) insulin sensitivity/IGF1, glucose/lactate, and Aβ42 and further explore whether insulin sensitivity contributed to the risk for AD in active smokers. In this cross-sectional study, levels of insulin, IGF1, and lactate/glucose of 75 active smokers and 78 nonsmokers in CSF were measured. Three polymorphisms regulating IGF1 were genotyped. Analysis of variance was used to compare differences of variables between groups. Partial correlation was performed to test the relationship between CSF biomarkers and smoking status. General linear models were applied to test the interaction of the effect of single nucleotide polymorphisms and cigarette smoking on CSF IGF1 levels. In the CSF from active smokers, IGF1 and lactate levels were significantly lower (p=.016 and p=.010, respectively), whereas Aβ42 (derived from our earlier research) and insulin levels were significantly higher (p<.001 and p=.022, respectively) as compared to the CSF from nonsmokers. The AG+GG genotype of rs6218 in active smokers had a significant effect on lower CSF IGF1 levels (p=.004) and lower CSF insulin levels in nonsmokers (p=.016). Cigarette smoking as the "at-risk" factor for AD might be due to lower cerebral insulin sensitivity in CSF, and the subjects with rs6218G allele seem to be more susceptible to the neurodegenerative risks for cigarette smoking.

Piwi expressed in Drosophila adipose tissues regulates systemic IGF signaling and growth via IGF-binding protein

Piwi and its partner, Piwi-interacting RNA (piRNA), are pivotal in suppressing the harmful effects of transposable elements (TEs) linked to genomic insertional mutagenesis. While primarily active in Drosophila's adult gonadal tissues, causing sterility in its absence, Piwi's role in post-embryonic development remains unclear. Our study reveals Piwi's functional presence in the larval fat body, where it governs developmental growth through systemic insulin/insulin-like growth factor (IGF) signaling (IIS). Piwi knockdown in the fat body resulted in dysregulated TE expression, reduced developmental rate and body growth, and diminished systemic IIS activity. Notably, Piwi knockdown increased Imaginal Morphogenic Protein Late 2 (Imp-L2) expression, akin to insulin-like growth factor-binding protein 7 (IGFBP7), reducing systemic IIS and inhibiting body growth. This unveils a novel role for Piwi in larval adipose tissues, emphasizing its importance in regulating systemic IIS and overall organismal growth.

The Role of mRNA Quality Control in the Aging of Caenorhabditis elegans.

The proper maintenance of mRNA quality that is regulated by diverse surveillance pathways is essential for cellular homeostasis and is highly conserved among eukaryotes. Here, we review findings regarding the role of mRNA quality control in the aging and longevity of Caenorhabditis elegans, an outstanding model for aging research. We discuss the recently discovered functions of the proper regulation of nonsense-mediated mRNA decay, ribosome-associated quality control, and mRNA splicing in the aging of C. elegans. We describe how mRNA quality control contributes to longevity conferred by various regimens, including inhibition of insulin/insulin-like growth factor 1 (IGF-1) signaling, dietary restriction, and reduced mechanistic target of rapamycin signaling. This review provides valuable information regarding the relationship between the mRNA quality control and aging in C. elegans, which may lead to insights into healthy longevity in complex organisms, including humans.

APPA Increases Lifespan and Stress Resistance via Lipid Metabolism and Insulin/IGF-1 Signal Pathway in Caenorhabditis elegans.

Animal studies have proven that 1-acetyl-5-phenyl-1H-pyrrol-3-yl acetate (APPA) is a powerful antioxidant as a novel aldose reductase inhibitor independently synthesized by our laboratory; however, there is no current information on APPA's anti-aging mechanism. Therefore, this study examined the impact and mechanism of APPA's anti-aging and anti-oxidation capacity using the Caenorhabditis elegans model. The results demonstrated that APPA increases C. elegans' longevity without affecting the typical metabolism of Escherichia coli OP50 (OP50). APPA also had a non-toxic effect on C. elegans, increased locomotor ability, decreased the levels of reactive oxygen species, lipofuscin, and fat, and increased anti-stress capacity. QRT-PCR analysis further revealed that APPA upregulated the expression of antioxidant genes, including sod-3, gst-4, and hsp-16.2, and the critical downstream transcription factors, daf-16, skn-1, and hsf-1 of the insulin/insulin-like growth factor (IGF) receptor, daf-2. In addition, fat-6 and nhr-80 were upregulated. However, the APPA's life-prolonging effects were absent on the daf-2, daf-16, skn-1, and hsf-1 mutants implying that the APPA's life-prolonging mechanism depends on the insulin/IGF-1 signaling system. The transcriptome sequencing also revealed that the mitochondrial route was also strongly associated with the APPA life extension, consistent with mev-1 and isp-1 mutant life assays. These findings aid in the investigation of APPA's longevity extension mechanism.

Glucose-lowering effects of a synbiotic combination containing Pediococcus acidilactici in C. elegans and mice

Aims/hypothesisModulation of gut microbiota has emerged as a promising strategy to treat or prevent the development of different metabolic diseases, including type 2 diabetes and obesity. Previous data from our group suggest that the strain Pediococcus acidilactici CECT9879 (pA1c) could be an effective probiotic for regulating glucose metabolism. Hence, the objectives of this study were to verify the effectiveness of pA1c on glycaemic regulation in diet-induced obese mice and to evaluate whether the combination of pA1c with other normoglycaemic ingredients, such as chromium picolinate (PC) and oat β-glucans (BGC), could increase the efficacy of this probiotic on the regulation of glucose and lipid metabolism.MethodsCaenorhabditis elegans was used as a screening model to describe the potential synbiotic activities, together with the underlying mechanisms of action. In addition, 4-week-old male C57BL/6J mice were fed with a high-fat/high-sucrose diet (HFS) for 6 weeks to induce hyperglycaemia and obesity. Mice were then divided into eight groups (n=12 mice/group) according to dietary supplementation: control-diet group; HFS group; pA1c group (1010 colony-forming units/day); PC; BGC; pA1c+PC+BGC; pA1c+PC; and pA1c+BGC. Supplementations were maintained for 10 weeks. Fasting blood glucose was determined and an IPGTT was performed prior to euthanasia. Fat depots, liver and other organs were weighed, and serum biochemical variables were analysed. Gene expression analyses were conducted by real-time quantitative PCR. Sequencing of the V3–V4 region of the 16S rRNA gene from faecal samples of each group was performed, and differential abundance for family, genera and species was analysed by ALDEx2R package.ResultsSupplementation with the synbiotic (pA1c+PC+BGC) counteracted the effect of the high glucose by modulating the insulin–IGF-1 signalling pathway in C. elegans, through the reversal of the glucose nuclear localisation of daf-16. In diet-induced obese mice, all groups supplemented with the probiotic significantly ameliorated glucose tolerance after an IPGTT, demonstrating the glycaemia-regulating effect of pA1c. Further, mice supplemented with pA1c+PC+BGC exhibited lower fasting blood glucose, a reduced proportion of visceral adiposity and a higher proportion of muscle tissue, together with an improvement in the brown adipose tissue in comparison with the HFS group. Besides, the effect of the HFS diet on steatosis and liver damage was normalised by the synbiotic. Gene expression analyses demonstrated that the synbiotic activity was mediated not only by modulation of the insulin–IGF-1 signalling pathway, through the overexpression of GLUT-1 and GLUT-4 mediators, but also by a decreased expression of proinflammatory cytokines such as monocyte chemotactic protein-1. 16S metagenomics demonstrated that the synbiotic combinations allowed an increase in the concentration of P. acidilactici, together with improvements in the intestinal microbiota such as a reduction in Prevotella and an increase in Akkermansia muciniphila.Conclusions/interpretationOur data suggest that the combination of pA1c with PC and BGC could be a potential synbiotic for blood glucose regulation and may help to fight insulin resistance, diabetes and obesity.Graphical

Repositioning of Anti-Diabetic Drugs against Dementia: Insight from Molecular Perspectives to Clinical Trials.

Insulin resistance as a hallmark of type 2 DM (T2DM) plays a role in dementia by promoting pathological lesions or enhancing the vulnerability of the brain. Numerous studies related to insulin/insulin-like growth factor 1 (IGF-1) signaling are linked with various types of dementia. Brain insulin resistance in dementia is linked to disturbances in Aβ production and clearance, Tau hyperphosphorylation, microglial activation causing increased neuroinflammation, and the breakdown of tight junctions in the blood-brain barrier (BBB). These mechanisms have been studied primarily in Alzheimer's disease (AD), but research on other forms of dementia like vascular dementia (VaD), Lewy body dementia (LBD), and frontotemporal dementia (FTD) has also explored overlapping mechanisms. Researchers are currently trying to repurpose anti-diabetic drugs to treat dementia, which are dominated by insulin sensitizers and insulin substrates. Although it seems promising and feasible, none of the trials have succeeded in ameliorating cognitive decline in late-onset dementia. We highlight the possibility of repositioning anti-diabetic drugs as a strategy for dementia therapy by reflecting on current and previous clinical trials. We also describe the molecular perspectives of various types of dementia through the insulin/IGF-1 signaling pathway.

Ethyl caffeate attefnuates Aβ-induced toxicity in Caenorhabditis elegans AD models via the insulin/insulin-like growth factor-1 signaling pathway

The pathogenesis of Alzheimer's disease (AD), a multifactorial progressive neurodegenerative disease associated with aging, is unclear. Ethyl caffeate is a plant polyphenol that has been reported to have neuroprotective effects, but the mechanisms by which it acts are unclear. In this study, for the first time, we investigated the molecular mechanism of its anti-AD properties using the Caernorhabditis elegans model. The results of our experiments showed that ethyl caffeate delayed the paralysis symptoms of CL4176 to a different extent and reduced the exogenous 5-hydroxytryptophan-induced paralysis phenotype. Further studies revealed that ethyl caffeate lowered Aβ plaques and depressed the expression of Aβ monomers and oligomers, but did not influence the mRNA levels of Aβ. Moreover, it was able to bring paraquat-induced ROS levels down to near-standard conditions. Real-time quantitative PCR experiment showed a significant upregulation of the transcript abundance of daf-16, skn-1 and hsf-1, key factors associated with the insulin/insulin-like growth factor 1 (IGF-1) signaling pathway (IIS), and their downstream genes sod-3, gst-4 and hsp-16.2. It was further shown that ethyl caffeate activated the translocation of DAF-16 and SKN-1 from the cytoplasm to the nucleus and enhanced the expression of sod-3::GFP, gst-4::GFP and hsp-16.2::GFP in transgenic nematodes. This meant that the protection against Aβ toxicity by ethyl caffeate may be partly through the IIS signaling pathway. In addition, ethyl caffeate suppressed the aggregation of polyglutamine proteins in AM141, which indicated a potential protective effect against neurodegenerative diseases based on abnormal folding and aggregation of amyloid proteins. Taken together, ethyl caffeate is expected to develop as a potential drug for the management of AD.

Starvation-induced changes in somatic insulin/IGF-1R signaling drive metabolic programming across generations

Exposure to adverse nutritional and metabolic environments during critical periods of development can exert long-lasting effects on health outcomes of an individual and its descendants. Although such metabolic programming has been observed in multiple species and in response to distinct nutritional stressors, conclusive insights into signaling pathways and mechanisms responsible for initiating, mediating, and manifesting changes to metabolism and behavior across generations remain scarce. By using a starvation paradigm in Caenorhabditis elegans, we show that starvation-induced changes in dauer formation-16/forkhead box transcription factor class O (DAF-16/FoxO) activity, the main downstream target of insulin/insulin-like growth factor 1 (IGF-1) receptor signaling, are responsible for metabolic programming phenotypes. Tissue-specific depletion of DAF-16/FoxO during distinct developmental time points demonstrates that DAF-16/FoxO acts in somatic tissues, but not directly in the germline, to both initiate and manifest metabolic programming. In conclusion, our study deciphers multifaceted and critical roles of highly conserved insulin/IGF-1 receptor signaling in determining health outcomes and behavior across generations.

Inceptor correlates with markers of prostate cancer progression and modulates insulin/IGF1 signaling and cancer cell migration

ObjectiveThe insulin/insulin-like growth factor 1 (IGF1) pathway is emerging as a crucial component of prostate cancer progression. Therefore, we investigated the role of the novel insulin/IGF1 signaling modulator inceptor in prostate cancer. MethodsWe analyzed the expression of inceptor in human samples of benign prostate epithelium and prostate cancer. Further, we performed signaling and functional assays using prostate cancer cell lines. ResultsWe found that inceptor was expressed in human benign and malignant prostate tissue and its expression positively correlated with various genes of interest, including genes involved in androgen signaling. In vitro, total levels of inceptor were increased upon androgen deprivation and correlated with high levels of androgen receptor in the nucleus. Inceptor overexpression was associated with increased cell migration, altered IGF1R trafficking and higher IGF1R activation. ConclusionsOur in vitro results showed that inceptor expression was associated with androgen status, increased migration, and IGF1R signaling. In human samples, inceptor expression was significantly correlated with markers of prostate cancer progression. Taken together, these data provide a basis for investigation of inceptor in the context of prostate cancer.

Regulation of germline proteostasis by HSF1 and insulin/IGF-1 signaling.

Protein homeostasis (proteostasis) is essential for cellular function and organismal health and requires the concerted actions of protein synthesis, folding, transport, and turnover. In sexually reproducing organisms, the immortal germline lineage passes genetic information across generations. Accumulating evidence indicates the importance of proteome integrity for germ cells as genome stability. As gametogenesis involves very active protein synthesis and is highly energy-demanding, it has unique requirements for proteostasis regulation and is sensitive to stress and nutrient availability. The heat shock factor 1 (HSF1), a key transcriptional regulator of cellular response to cytosolic and nuclear protein misfolding has evolutionarily conserved roles in germline development. Similarly, insulin/insulin-like growth factor-1 (IGF-1) signaling, a major nutrient-sensing pathway, impacts many aspects of gametogenesis. Here, we focus on HSF1 and IIS to review insights into their roles in germline proteostasis and discuss the implications on gamete quality control during stress and aging.

Isolation of a novel missense mutation in insulin receptor as a spontaneous revertant in ImpL2 mutants in Drosophila.

Evolutionarily conserved insulin/insulin-like growth factor (IGF) signaling (IIS) correlates nutrient levels to metabolism and growth, thereby playing crucial roles in development and adult fitness. In the fruit fly Drosophila, ImpL2, an ortholog of IGFBP7, binds to and inhibits the function of Drosophila insulin-like peptides. In this study, we isolated a temperature-sensitive mutation in the insulin receptor (InR) gene as a spontaneous revertant in ImpL2 null mutants. The p.Y902C missense mutation is located at the functionally conserved amino acid residue of the first fibronectin type III domain of InR. The hypomorphic InR mutant animals showed a temperature-dependent reduction in IIS and body size. The mutant animals also exhibited metabolic defects, such as increased triglyceride and carbohydrate levels. Metabolomic analysis further revealed that defects in InR caused dysregulation of amino acid and ribonucleotide metabolism. We also observed that InR mutant females produced tiny irregular-shaped embryos with reduced fecundity. In summary, this novel allele of InR is a valuable tool for the Drosophila genetic model of insulin resistance and type 2 diabetes.

Cremastra appendiculata polysaccharides improve stress resistance and prolong the lifespan of Caenorhabditis elegans via daf-16 in the insulin signaling pathway

Cremastra appendiculata polysaccharide (CAP) exhibits potential anti-aging and stress resistance effects. In this study, we investigated the structure, antioxidant properties, and mechanism of action of CAP in Caenorhabditis elegans. The results showed that CAP primarily comprises mannose and glucose and exerts antioxidant activity in vitro. In vivo, CAP prolonged the lifespan of C. elegans in a concentration-dependent manner, with 2.0 mg/mL CAP prolonging the lifespan by 39.97 %. Compared with the control, the activities of superoxide dismutase (SOD) and catalase (CAT) antioxidant enzymes increased by 46 % and 57 %, respectively. However, the reactive oxygen species (ROS) and malondialdehyde (MDA) contents decreased by 38 % and 19.92 %, respectively, at the same CAP concentration, oxidative and heat stress resistance increased. The target genes of the insulin/insulin-like growth factor (IGF) signaling pathway, daf-16, sod-3, ctl-1, and hsp-16.2, were activated by CAP; their mRNA expression levels were upregulated by 7.23 %, 69.78 %, 43.62 %, and 58.62 %, respectively. A transgenic worm assay indicated that CAP regulates the lifespan of C. elegans through daf-16. These results suggest that CAP improves stress resistance and prolongs the lifespan of C. elegans through daf-16 in the insulin/IGF signaling pathway.

The insulin and IGF signaling pathway sustains breast cancer stem cells by IRS2/PI3K-mediated regulation of MYC.

Despite the strong association of the insulin/insulin-like growth factor (IGF) signaling (IIS) pathway with tumor initiation, recurrence, and metastasis, the mechanism by which this pathway regulates cancer progression is not well understood. Here, we report that IIS supports breast cancer stem cell (CSC) self-renewal in an IRS2-phosphatidylinositol 3-kinase (PI3K)-dependent manner that involves the activation and stabilization of MYC. IRS2-PI3K signaling enhances MYC expression through the inhibition of GSK3β activity and suppression of MYC phosphorylation on threonine 58, thus reducing proteasome-mediated degradation of MYC and sustaining active pS62-MYC function. A stable T58A-Myc mutant rescues CSC function in Irs2-/- cells, supporting the role of this MYC stabilization in IRS2-dependent CSC regulation. These findings establish a mechanistic connection between the IIS pathway and MYC and highlight a role for IRS2-dependent signaling in breast cancer progression.

Insulin/IGF-dependent Wnt signaling promotes formation of germline tumors and other developmental abnormalities following early-life starvation in Caenorhabditis elegans.

The Developmental Origins of Health and Disease hypothesis postulates that early-life stressors can predispose people to disease later in life. In the roundworm Caenorhabditis elegans, prolonged early-life starvation causes germline tumors, uterine masses, and other gonad abnormalities to develop in well-fed adults. Reduction of insulin/insulin-like growth factor (IGF) signaling (IIS) during larval development suppresses these starvation-induced abnormalities. However, molecular mechanisms at play in formation and suppression of starvation-induced abnormalities are unclear. Here we describe mechanisms through which early-life starvation and reduced IIS affect starvation-induced abnormalities. Transcriptome sequencing revealed that expression of genes in the Wnt signaling pathway is upregulated in adults starved as young larvae, and that knockdown of the insulin/IGF receptor daf-2/InsR decreases their expression. Reduction of Wnt signaling through RNAi or mutation reduced starvation-induced abnormalities, and hyperactivation of Wnt signaling produced gonad abnormalities in worms that had not been starved. Genetic and reporter-gene analyses suggest that Wnt signaling acts downstream of IIS in the soma to cell-nonautonomously promote germline hyperproliferation. In summary, this work reveals that IIS-dependent transcriptional regulation of Wnt signaling promotes starvation-induced gonad abnormalities, illuminating signaling mechanisms that contribute to adult pathology following early-life starvation.

Further Extension of Lifespan by Unc-43/CaMKII and Egl-8/PLCβ Mutations in Germline-Deficient Caenorhabditis elegans.

Reduction of insulin/insulin-like growth factor 1 (IGF1) signaling (IIS) promotes longevity across species. In the nematode Caenorhabditis elegans, ablation of germline stem cells (GSCs) and activity changes of the conserved signaling mediators unc-43/CaMKII (calcium/calmodulin-dependent kinase type II) and egl-8/PLCβ (phospholipase Cβ) also increase lifespan. Like IIS, these pathways depend on the conserved transcription factor daf-16/FOXO for lifespan extension, but how they functionally interact is unknown. Here, we show that altered unc-43/egl-8 activity further increases the lifespan of long-lived GSC-deficient worms, but not of worms that are long-lived due to a strong reduction-of-function mutation in the insulin/IGF1-like receptor daf-2. Additionally, we provide evidence for unc-43 and, to a lesser extent, egl-8 modulating the expression of certain collagen genes, which were reported to be dispensable for longevity of these particular daf-2 mutant worms, but not for other forms of longevity. Together, these results provide new insights into the conditions and potential mechanisms by which CaMKII- and PLCβ-signals modulate C. elegans lifespan.

Insulin/IGF signaling regulates presynaptic glutamate release in aversive olfactory learning.

Insulin/insulin-like growth factor (IGF) receptor signaling (IIS) supports context-dependent learning in vertebrates and invertebrates. Here, we identify cell-specific mechanisms of IIS that integrate sensory information with food context to drive synaptic plasticity and learning. In the nematode Caenorhabditis elegans, pairing food deprivation with an odor such as butanone suppresses attraction to that odor. We find that aversive olfactory learning requires the insulin receptor substrate (IRS) protein IST-1 and atypical signaling through the insulin/IGF-1 receptor DAF-2. Cell-specific knockout and rescue demonstrate that DAF-2 acts in the AWCON sensory neuron, which detects butanone, and that learning preferentially depends upon the axonally localized DAF-2c isoform. Acute food deprivation increases DAF-2 levels in AWCON post-transcriptionally through an insulin- and insulin receptor substrate-1 (ist-1)-dependent process. Aversive learning alters the synaptic output of AWCON by suppressing odor-regulated glutamate release in wild-type animals, but not in ist-1 mutants, suggesting that axonal insulin signaling regulates synaptic transmission to support aversive memory.

Astaxanthin Induces Transcriptomic Responses Associated with Lifespan Extension in Caenorhabditis elegans

Astaxanthin is a marine xanthophyll carotenoid which effectively prevents intracellular oxidative stress and has beneficial effects against various human diseases. It has been shown that astaxanthin protects Caenorhabditis elegans (C. elegans) from oxidative damages and extends the lifespan of C. elegans possibly by modulating genes involved in insulin/insulin-like growth factor (IGF) signaling (IIS) and the oxidoreductase system, although the exact mechanisms remain elusive. In this study, RNA sequencing analyses were employed to identify the differentially expressed genes in C. elegans in response to astaxanthin treatment. A total of 190 mRNAs and 6 microRNAs (miRNAs) were significantly changed by astaxanthin treatment in C. elegans. Gene ontology (GO) term and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses indicated that the mRNAs and miRNAs significantly altered by astaxanthin mainly function in innate immunity, lipid metabolism and stress responses, a significant portion of which are related to lifespan regulation in C. elegans. The study revealed novel mRNA and miRNA targets of astaxanthin, providing new insights for understanding the anti-aging mechanisms and the biological function of astaxanthin.

Stage-Dependent Activity and Pro-Chondrogenic Function of PI3K/AKT during Cartilage Neogenesis from Mesenchymal Stromal Cells

Differentiating mesenchymal stromal cells (MSCs) into articular chondrocytes (ACs) for application in clinical cartilage regeneration requires a profound understanding of signaling pathways regulating stem cell chondrogenesis and hypertrophic degeneration. Classifying endochondral signals into drivers of chondrogenic speed versus hypertrophy, we here focused on insulin/insulin-like growth factor 1 (IGF1)-induced phosphoinositide 3-kinase (PI3K)/AKT signaling. Aware of its proliferative function during early but not late MSC chondrogenesis, we aimed to unravel the late pro-chondrogenic versus pro-hypertrophic PI3K/AKT role. PI3K/AKT activity in human MSC and AC chondrogenic 3D cultures was assessed via Western blot detection of phosphorylated AKT. The effects of PI3K inhibition with LY294002 on chondrogenesis and hypertrophy were assessed via histology, qPCR, the quantification of proteoglycans, and alkaline phosphatase activity. Being repressed by ACs, PI3K/AKT activity transiently rose in differentiating MSCs independent of TGFβ or endogenous BMP/WNT activity and climaxed around day 21. PI3K/AKT inhibition from day 21 on equally reduced chondrocyte and hypertrophy markers. Proving important for TGFβ-induced SMAD2 phosphorylation and SOX9 accumulation, PI3K/AKT activity was here identified as a required stage-dependent driver of chondrogenic speed but not of hypertrophy. Thus, future attempts to improve MSC chondrogenesis will depend on the adequate stimulation and upregulation of PI3K/AKT activity to generate high-quality cartilage from human MSCs.

Control of aging by the renin–angiotensin system: a review of C. elegans, Drosophila, and mammals

The free-living, non-parasitic nematode Caenorhabditis elegans is a premier model organism for the study of aging and longevity due to its short lifespan, powerful genetic tools, and conservation of fundamental mechanisms with mammals. Approximately 70 percent of human genes have homologs in C. elegans, including many that encode proteins in pathways that influence aging. Numerous genetic pathways have been identified in C. elegans that affect lifespan, including the dietary restriction pathway, the insulin/insulin-like growth factor (IGF) signaling pathway, and the disruption of components of the mitochondrial electron transport chain. C. elegans is also a powerful system for performing drug screens, and many lifespan-extending compounds have been reported; notably, several FDA-approved medications extend the lifespan in C. elegans, raising the possibility that they can also extend the lifespan in humans. The renin–angiotensin system (RAS) in mammals is an endocrine system that regulates blood pressure and a paracrine system that acts in a wide range of tissues to control physiological processes; it is a popular target for drugs that reduce blood pressure, including angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs). Emerging evidence indicates that this system influences aging. In C. elegans, decreasing the activity of the ACE homolog acn-1 or treatment with the ACE-inhibitor Captopril significantly extends the lifespan. In Drosophila, treatment with ACE inhibitors extends the lifespan. In rodents, manipulating the RAS with genetic or pharmacological interventions can extend the lifespan. In humans, polymorphisms in the ACE gene are associated with extreme longevity. These results suggest the RAS plays a conserved role in controlling longevity. Here, we review studies of the RAS and aging, emphasizing the potential of C. elegans as a model for understanding the mechanism of lifespan control.

Examination of the potential roles of insulin-like peptide receptor in regulating the growth of Manila clam Ruditapes philippinarum

The role of insulin/insulin-like growth factor (IGF) signaling pathway in the growth regulation of marine invertebrates has not been fully studied. In this study, the economically important species Ruditapes philippinarum was sacrificed to clarify the role of IGF system in the growth regulation of R. philippinarum by real-time quantitative PCR. Systematic bioinformatics analysis can identify the major genes of IGF signaling pathway and insulin-like peptide receptor (ILPR) - mediated signaling pathway in R. philippinarum. The expression levels of IGF and its downstream signaling pathway genes in larger clams were significantly higher than those in small clams, indicating that they were involved in the growth regulation of R. philippinarum. These results suggest that IGF signaling pathway and ILPR mediated signaling pathway to regulate the growth of R. philippinarum.