Non-cell-autonomous regulation of germline proteostasis by insulin/IGF-1 signaling-induced dietary peptide uptake via PEPT-1.

Gametogenesis involves active protein synthesis and is proposed to rely on proteostasis. Our previous work in C. elegans indicates that germline development requires coordinated activities of insulin/IGF-1 signaling (IIS) and HSF-1, the central regulator of the heat shock response. However, the downstream mechanisms were not identified. Here, we show that depletion of HSF-1 from germ cells impairs chaperone gene expression, causing protein degradation and aggregation and, consequently, reduced fecundity and gamete quality. Conversely, reduced IIS confers germ cell resilience to HSF-1 depletion-induced protein folding defects and various proteotoxic stresses. Surprisingly, this effect was not mediated by an enhanced stress response, which underlies longevity in low IIS conditions, but by reduced ribosome biogenesis and translation rate. We found that IIS activates the expression of intestinal peptide transporter PEPT-1 by alleviating its repression by FOXO/DAF-16, allowing dietary proteins to be efficiently incorporated into an amino acid pool that fuels germline protein synthesis. Our data suggest this non-cell-autonomous pathway is critical for proteostasis regulation during gametogenesis.

Disruption of lysosomal nutrient sensing scaffold contributes to pathogenesis of a fatal neurodegenerative lysosomal storage disease.

The ceroid lipofuscinosis neuronal 1 (CLN1) disease, formerly called infantile neuronal ceroid lipofuscinosis, is a fatal hereditary neurodegenerative lysosomal storage disorder. This disease is caused by loss-of-function mutations in the CLN1 gene, encoding palmitoyl-protein thioesterase-1 (PPT1). PPT1 catalyzes depalmitoylation of S-palmitoylated proteins for degradation and clearance by lysosomal hydrolases. Numerous proteins, especially in the brain, require dynamic S-palmitoylation (palmitoylation-depalmitoylation cycles) for endosomal trafficking to their destination. While 23 palmitoyl-acyl transferases in the mammalian genome catalyze S-palmitoylation, depalmitoylation is catalyzed by thioesterases such as PPT1. Despite these discoveries, the pathogenic mechanism of CLN1 disease has remained elusive. Here, we report that in the brain of Cln1-/- mice, which mimic CLN1 disease, the mechanistic target of rapamycin complex-1 (mTORC1) kinase is hyperactivated. The activation of mTORC1 by nutrients requires its anchorage to lysosomal limiting membrane by Rag GTPases and Ragulator complex. These proteins form the lysosomal nutrient sensing scaffold to which mTORC1 must attach to activate. We found that in Cln1-/- mice, two constituent proteins of the Ragulator complex (vacuolar (H+)-ATPase and Lamtor1) require dynamic S-palmitoylation for endosomal trafficking to the lysosomal limiting membrane. Intriguingly, Ppt1 deficiency in Cln1-/- mice misrouted these proteins to the plasma membrane disrupting the lysosomal nutrient sensing scaffold. Despite this defect, mTORC1 was hyperactivated via the IGF1/PI3K/Akt-signaling pathway, which suppressed autophagy contributing to neuropathology. Importantly, pharmacological inhibition of PI3K/Akt suppressed mTORC1 activation, restored autophagy, and ameliorated neurodegeneration in Cln1-/- mice. Our findings reveal a previously unrecognized role of Cln1/Ppt1 in regulating mTORC1 activation and suggest that IGF1/PI3K/Akt may be a targetable pathway for CLN1 disease.

Kinesin light chain 1 stabilizes insulin receptor substrate 1 to regulate the IGF-1-AKT signaling pathway during myoblast differentiation.

The IGF signaling pathway plays critical role in regulating skeletal myogenesis. We have demonstrated that KIF5B, the heavy chain of kinesin-1 motor, promotes myoblast differentiation through regulating IGF-p38MAPK activation. However, the roles of the kinesin light chain (Klc) in IGF pathway and myoblast differentiation remain elusive. In this study, we found that Klc1 was upregulated during muscle regeneration and downregulated in senescence mouse muscles and dystrophic muscles from mdx (X-linked muscular dystrophic) mice. Gain- and loss-of-function experiments further displayed that Klc1 promotes AKT-mTOR activity and positively regulates myogenic differentiation. We further identified that the expression levels of IRS1, the critical node of IGF-1 signaling, are downregulated in Klc1-depleted myoblasts. Coimmunoprecipitation study revealed that IRS1 interacted with the 88-154 amino acid sequence of Klc1 via its PTB domain. Notably, the reduced Klc1 levels were found in senescence and osteoporosis skeletal muscle samples from both mice and human. Taken together, our findings suggested a crucial role of Klc1 in the regulation of IGF-AKT pathway during myogenesis through stabilizing IRS1, which might ultimately influence the development of muscle-related disorders.

Distinct signaling by insulin and IGF-1 receptors and their extra- and intracellular domains.

Insulin and insulin-like growth factor 1 (IGF-1) receptors share many downstream signaling pathways but have unique biological effects. To define the molecular signals contributing to these distinct activities, we performed global phosphoproteomics on cells expressing either insulin receptor (IR), IGF-1 receptor (IGF1R), or chimeric IR-IGF1R receptors. We show that IR preferentially stimulates phosphorylations associated with mammalian target of rapamycin complex 1 (mTORC1) and Akt pathways, whereas IGF1R preferentially stimulates phosphorylations on proteins associated with the Ras homolog family of guanosine triphosphate hydrolases (Rho GTPases), and cell cycle progression. There were also major differences in the phosphoproteome between cells expressing IR versus IGF1R in the unstimulated state, including phosphorylation of proteins involved in membrane trafficking, chromatin remodeling, and cell cycle. In cells expressing chimeric IR-IGF1R receptors, these differences in signaling could be mapped to contributions of both the extra- and intracellular domains of these receptors. Thus, despite their high homology, IR and IGF1R preferentially regulate distinct networks of phosphorylation in both the basal and stimulated states, allowing for the unique effects of these hormones on organismal function.

Prenatal stress aggravates age-dependent cognitive decline, insulin signaling dysfunction, and the pro-inflammatory response in the APPNL-F/NL-F mouse model of Alzheimer's disease.

Accumulating evidence indicates that early adverse life experiences may be involved in the pathogenesis of Alzheimer's disease (AD). Prenatal stress (PS) can affect brain maturation and neuroimmune and metabolic interactions, leading to age-dependent cognitive deficits in offspring. However, a multi-faceted cause-and-effect impact of PS on the development of cognitive deficits in the process of physiological ageing and in the APPNL-F/NL-F mouse model of Alzheimer's disease has not yet been evaluated. We have identified age-dependent cognitive learning and memory deficits using male C57BL/6 J (wild type, WT) and the knock-in APPNL-F/NL-F (KI) aged 12, 15, and 18 months. An increase in the Aß42/Aß40 ratio and mouse ApoE levels in the hippocampus and frontal cortex preceded the onset of cognitive deficits in the KI mice. Moreover, dysfunction in insulin signaling, including increased IRS-1 serine phosphorylation in both brain areas and the tyrosine phosphorylation deficit in the frontal cortex, suggested age-dependent insulin/IGF-1 resistance. Resistance was reflected by disturbances in mTOR or ERK1/2 kinase phosphorylation and excessive pro-inflammatory (TNF-α, IL-6, and IL-23) status in the KI mice. Importantly, our study has provided insights into the higher vulnerability to PS-induced exacerbation of age-dependent cognitive deficits and biochemical dysfunction in KI mice than in WT animals. We anticipate our study will lead to future investigation of a multi-faceted cause-and-effect relationship between stress during neurodevelopment and the onset of AD pathology, distinguishing it from changes in the course of dementia during normal ageing.

Multi-omics identify xanthine as a pro-survival metabolite for nematodes with mitochondrial dysfunction.

Aberrant mitochondrial function contributes to the pathogenesis of various metabolic and chronic disorders. Inhibition of insulin/IGF-1 signaling (IIS) represents a promising avenue for the treatment of mitochondrial diseases, although many of the molecular mechanisms underlying this beneficial effect remain elusive. Using an unbiased multi-omics approach, we report here that IIS inhibition reduces protein synthesis and favors catabolism in mitochondrial deficient Caenorhabditis elegans We unveil that the lifespan extension does not occur through the restoration of mitochondrial respiration, but as a consequence of an ATP-saving metabolic rewiring that is associated with an evolutionarily conserved phosphoproteome landscape. Furthermore, we identify xanthine accumulation as a prominent downstream metabolic output of IIS inhibition. We provide evidence that supplementation of FDA-approved xanthine derivatives is sufficient to promote fitness and survival of nematodes carrying mitochondrial lesions. Together, our data describe previously unknown molecular components of a metabolic network that can extend the lifespan of short-lived mitochondrial mutant animals.

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.

Polygonati Rhizoma Polysaccharide Prolongs Lifespan and Healthspan in Caenorhabditis elegans.

Polygonati Rhizoma is the dried rhizome of Polygonatum kingianum coll.et hemsl., Polygonatum sibiricum Red. or Polygonatum cyrtonema Hua, and has a long history of medication. Raw Polygonati Rhizoma (RPR) numbs the tongue and stings the throat, while prepared Polygonati Rhizoma (PPR) can remove the numbness of the tongue, and at the same time enhance its functions of invigorating the spleen, moistening the lungs and tonifying the kidneys. There are many active ingredients in Polygonati Rhizoma (PR), among which polysaccharide is one of the most important active ingredients. Therefore, we studied the effect of Polygonati Rhizoma polysaccharide (PRP) on the lifespan of Caenorhabditis elegans (C. elegans) and found that polysaccharide in PPR (PPRP) was more effective than Polysaccharide in RPR (RPRP) in prolonging the lifespan of C. elegans, reducing the accumulation of lipofuscin, and increasing the frequency of pharyngeal pumping and movement. The further mechanism study found that PRP can improve the anti-oxidative stress ability of C. elegans, reduce the accumulation of reactive oxygen species (ROS) in C. elegans, and improve the activity of antioxidant enzymes. The results of quantitative real-time PCR(q-PCR) experiments suggested that PRP may prolong the lifespan of C. elegans by down-regulating daf-2 and activating daf-16 and sod-3, and the transgenic nematode experiments were consistent with its results, so it was hypothesized that the mechanism of age delaying effect of PRP was related to daf-2, daf-16 and sod-3 of the insulin signaling pathway. In short, our research results provide a new idea for the application and development of PRP.

Caenorhabditis elegans DAF-16 regulates lifespan and immune responses to Cryptococcus neoformans and Cryptococcus gattii infections.

BACKGROUND: Cryptococcosis is a life-threatening infection is primarily caused by two sibling species Cryptococcus neoformans and Cryptococcus gattii. Several virulence-related factors of these cryptococci have been widely investigated in Caenorhabditis elegans, representing a facile in vivo model of host-pathogen interaction. While recent studies elucidated cryptococcal virulence factors, intrinsic host factors that affect susceptibility to infections by cryptococci remain unclear and poorly investigated. RESULTS: Here, we showed that defects in C. elegans insulin/insulin-like growth factor-1 (IGF-1) signaling (IIS) pathway influenced animal lifespan and mechanisms of host resistance in cryptococcal infections, which required the activation of aging regulator DAF-16/Forkhead box O transcription factor. Moreover, accumulation of lipofuscin, DAF-16 nuclear localization, and expression of superoxide dismutase (SOD-3) were elevated in C. elegans due to host defenses during cryptococcal infections. CONCLUSION: The present study demonstrated the relationship between longevity and immunity, which may provide a possibility for novel therapeutic intervention to improve host resistance against cryptococcal infections.

Exposure to fluopimomide at sublethal doses causes oxidative stress in Caenorhabditis elegans regulated by insulin/insulin-like growth factor 1-like signaling pathway.

Fluopimomide is an innovative pesticide, widely used for agricultural pest management; however, little is known about its effect on non-target organisms. This study was designed to assess the potential risk of fluopimomide and the molecular mechanisms using Caenorhabditis elegans, a common model animal. The oxidative stress-related indicators were analyzed in C. elegans after exposure to fluopimomide for 24 h at three sublethal doses (0.2, 1.0, and 5.0 mg/L). The results demonstrated that sublethal exposure to fluopimomide adversely affected the nematodes growth, locomotive behaviors, reproduction, and lifespan, accompanying with enhanced of reactive oxygen species (ROS) generation, lipid and lipofuscin accumulation, and malondialdehyde content. In addition, exposure to fluopimomide significantly inhibited antioxidant systems including superoxide dismutase, catalase, glutathione S-transferase, and glutathione in the nematodes. Moreover, the expression of oxidative stress-related genes of sod-3, hsp-16.1, gst-4, ctl-2, daf-16, and daf-2 were significantly down-regulated, while the expression of skn-1 was significantly up-regulated. Further evidence revealed that daf-16 and skn-1 mutant strains of C. elegans significantly decreased ROS production upon fluopimomide exposure compared with the wild-type nematodes. Overall, our findings indicated that exposure to fluopimomide at sublethal doses caused oxidative damage, mainly associated with insulin/IGF-1-like signaling pathway in C. elegans. This is the first report of potential toxic effects of fluopimomide even at low concentrations, providing a new insight into the mechanisms of toxicity to C. elegans by fluopimomide.

Effect of Pinoresinol and Vanillic Acid Isolated from Catalpa bignonioides on Mouse Myoblast Proliferation via the Akt/mTOR Signaling Pathway.

Growth and maintenance of skeletal muscle is essential for athletic performance and a healthy life. Stimulating the proliferation and differentiation of muscle cells may help prevent loss of muscle mass. To discover effective natural substances enabling to mitigate muscle loss without side effects, we evaluated muscle growth with several compounds extracted from Catalpa bignonioides Walt. Among these compounds, pinoresinol and vanillic acid increased C2C12, a mouse myoblast cell line, proliferation being the most without cytotoxicity. These substances activated the Akt/mammalian target of the rapamycin (mTOR) pathway, which positively regulates the proliferation of muscle cells. In addition, the results of in silico molecular docking study showed that they may bind to the active site of insulin-like growth factor 1 receptor (IGF-1R), which is an upstream of the Akt/mTOR pathway, indicating that both pinoresinol and vanillic acid stimulate myoblast proliferation through direct interaction with IGF-1R. These results suggest that pinoresinol and vanillic acid may be a natural supplement to improve the proliferation of skeletal muscle via IGF-1R/Akt/mTOR signaling and thus strengthen muscles.

Ellagic Acid Increases Stress Resistance via Insulin/IGF-1 Signaling Pathway in Caenorhabditis elegans.

Ellagic acid is a natural polyphenol found in various fruits and vegetables. Numerous studies have shown that ellagic acid has beneficial effects on human health. In this study, we investigated the stress resistant action of ellagic acid in Caenorhabditis elegans (C. elegans). Notably, 50 µM ellagic acid prolonged the lifespan of C. elegans by 36.25%, 36.22%, 155.1%, and 79.07% under ultraviolet radiation stress, heat stress, oxidative stress, and Pseudomonas aeruginosa infection stress, respectively. Furthermore, the mechanism by which ellagic acid reduces the damage caused by ultraviolet radiation in C. elegans was explored. Ellagic acid could significantly induce the nucleus translocation of DAF-16 and, thereby, activate a series of target genes to resist ultraviolet radiation stress. Moreover, ellagic acid also significantly increased the expression of SOD-3 by 3.61 times and the activity of superoxide dismutase by 3.70 times to clean out harmful reactive oxygen species in C. elegans exposed to ultraviolet radiation stress. In both daf-16 mutant and daf-2; daf-16 double-mutant worms exposed to ultraviolet radiation, ellagic acid could no longer prolong their lifespan. These results indicate that ellagic acid plays an important role in resisting ultraviolet radiation stress in C. elegans, probably in an insulin/IGF-1 signaling pathway-dependent way.

Transcriptome Analysis of Insulin Signaling-Associated Transcription Factors in C. elegans Reveal Their Genome-Wide Target Genes Specificity and Complexity.

Insulin/IGF-1-like signaling (IIS) plays a crucial, conserved role in development, growth, reproduction, stress tolerance, and longevity. In Caenorhabditis elegans, the enhanced longevity under reduced insulin signaling (rIIS) is primarily regulated by the transcription factors (TFs) DAF-16/FOXO, SKN-1/Nrf-1, and HSF1/HSF-1. The specific and coordinated regulation of gene expression by these TFs under rIIS has not been comprehensively elucidated. Here, using RNA-sequencing analysis, we report a systematic study of the complexity of TF-dependent target gene interactions during rIIS under analogous genetic and experimental conditions. We found that DAF-16 regulates only a fraction of the C. elegans transcriptome but controls a large set of genes under rIIS; SKN-1 and HSF-1 show the opposite trend. Both of the latter TFs function as activators and repressors to a similar extent, while DAF-16 is predominantly an activator. For expression of the genes commonly regulated by TFs under rIIS conditions, DAF-16 is the principal determining factor, dominating over the other two TFs, irrespective of whether they activate or repress these genes. The functional annotations and regulatory networks presented in this study provide novel insights into the complexity of the gene regulatory networks downstream of the IIS pathway that controls diverse phenotypes, including longevity.

Insulin-Like Growth Factor 1 (IGF-1) Signaling in Glucose Metabolism in Colorectal Cancer.

Colorectal cancer (CRC) is one of the most common aggressive carcinoma types worldwide, characterized by unfavorable curative effect and poor prognosis. Epidemiological data re-vealed that CRC risk is increased in patients with metabolic syndrome (MetS) and its serum components (e.g., hyperglycemia). High glycemic index diets, which chronically raise post-prandial blood glucose, may at least in part increase colon cancer risk via the insulin/insulin-like growth factor 1 (IGF-1) signaling pathway. However, the underlying mechanisms linking IGF-1 and MetS are still poorly understood. Hyperactivated glucose uptake and aerobic glycolysis (the Warburg effect) are considered as a one of six hallmarks of cancer, including CRC. However, the role of insulin/IGF-1 signaling during the acquisition of the Warburg metabolic phenotypes by CRC cells is still poorly understood. It most likely results from the interaction of multiple processes, directly or indirectly regulated by IGF-1, such as activation of PI3K/Akt/mTORC, and Raf/MAPK signaling pathways, activation of glucose transporters (e.g., GLUT1), activation of key glycolytic enzymes (e.g., LDHA, LDH5, HK II, and PFKFB3), aberrant expression of the oncogenes (e.g., MYC, and KRAS) and/or overexpression of signaling proteins (e.g., HIF-1, TGF-ß1, PI3K, ERK, Akt, and mTOR). This review describes the role of IGF-1 in glucose metabolism in physiology and colorectal carcinogenesis, including the role of the insulin/IGF system in the Warburg effect. Furthermore, current therapeutic strategies aimed at repairing impaired glucose metabolism in CRC are indicated.

Modulation of caveolae by insulin/IGF-1 signaling regulates aging of Caenorhabditis elegans.

Reducing insulin/IGF-1 signaling (IIS) extends lifespan, promotes protein homeostasis (proteostasis), and elevates stress resistance of worms, flies, and mammals. How these functions are orchestrated across the organism is only partially understood. Here, we report that in the nematode Caenorhabditis elegans, the IIS positively regulates the expression of caveolin-1 (cav-1), a gene which is primarily expressed in neurons of the adult worm and underlies the formation of caveolae, a subtype of lipid microdomains that serve as platforms for signaling complexes. Accordingly, IIS reduction lowers cav-1 expression and lessens the quantity of neuronal caveolae. Reduced cav-1 expression extends lifespan and mitigates toxic protein aggregation by modulating the expression of aging-regulating and signaling-promoting genes. Our findings define caveolae as aging-governing signaling centers and underscore the potential for cav-1 as a novel therapeutic target for the promotion of healthy aging.

Study of the Effect of Neutral Polysaccharides from Rehmannia glutinosa on Lifespan of Caenorhabditis elegans.

The problem of an aging society is becoming increasingly acute. Diseases related to aging also come with it. There are some diseases that people can't treat fundamentally. Therefore, people try to find a natural ingredient from natural medicine to treat these diseases and improve the quality of life of the elderly. With the screening of a large number of traditional Chinese medicines, we found that polysaccharides from Rehmannia glutinous (PRG) can prolong the lifespan of Caenorhabditis elegans (C. elegans). Neutral polysaccharide is the main component of PRG. In the present study, we used a C. elegans model to illustrate the stress resistance and lifespan extension effect and mechanism of two kinds of neutral polysaccharide fractions from Rehmannia glutinosa (NPRG), respectively called NPRRP and NPRR. Our data showed that two kinds of neutral polysaccharides fractions could extend the lifespan and delay senescence of wild-type worms. Moreover, the mechanism study revealed that NPRG was able to promote the nuclear localization of DAF-16 resulting in the activation of antioxidant enzymatic systems under oxidative stress. We also observed that NPRG didn't increase the lifespan of mutants with daf-16 portion loss of function, suggesting NPRG prolonging the lifespan partially required the daf-16 gene on the insulin/IGF-1 signaling pathway (IIS). NPRG was found to have no effect on Escherichia coli OP50 (E.coli OP50) growth and pharyngeal pump movement of nematodes, indicating that the anti­aging effect of NPRG is not realized by the caloric restriction. However, mRNA levels of daf-2 were remarkably decreased after NPRG treatment. Thus daf-2 lost its inhibitory effect on the expression of daf-16 and had a continuous stimulation effect on the IIS, then prolonged the life of nematodes. Overall, our results illustrated the potential utilization of NPRG as a functional pharmaceutical ingredient to increase stress resistance and extend the life of C. elegans via the IIS, which could be developed as a natural supplement agent.

Untangling Longevity, Dauer, and Healthspan in Caenorhabditis elegans Insulin/IGF-1-Signalling.

The groundbreaking discovery that lower levels of insulin/IGF-1 signaling (IIS) can induce lifespan extension was reported 24 years ago in the nematode Caenorhabditis elegans. In this organism, mutations in the insulin/IGF-1 receptor gene daf-2 or other genes in this pathway can double lifespan. Subsequent work has revealed that reduced IIS (rIIS) extends lifespan across diverse species, possibly including humans. In C. elegans, IIS also regulates development into the diapause state known as dauer, a quiescent larval form that enables C. elegans to endure harsh environments through morphological adaptation, improved cellular repair, and slowed metabolism. Considerable progress has been made uncovering mechanisms that are affected by C. elegans rIIS. However, from the beginning it has remained unclear to what extent rIIS extends C. elegans lifespan by mobilizing dauer-associated mechanisms in adults. As we discuss, recent work has shed light on this question by determining that rIIS can extend C. elegans lifespan comparably through downstream processes that are either dauer-related or -independent. Importantly, these two lifespan extension programs can be distinguished genetically. It will now be critical to tease apart these programs, because each may involve different longevity-promoting mechanisms that may be relevant to higher organisms. A recent analysis of organismal "healthspan" has questioned the value of C. elegans rIIS as a paradigm for understanding healthy aging, as opposed to simply extending life. We discuss other work that argues strongly that C. elegans rIIS is indeed an invaluable model and consider the likely possibility that dauer-related processes affect parameters associated with health under rIIS conditions. Together, these studies indicate that C. elegans and analyses of rIIS in this organism will continue to provide unexpected and exciting results, and new paradigms that will be valuable for understanding healthy aging in humans.

Regulation of Ligand and Shear Stress-induced Insulin-like Growth Factor 1 (IGF1) Signaling by the Integrin Pathway.

Mechanical loading of the skeleton, as achieved during daily movement and exercise, preserves bone mass and stimulates bone formation, whereas skeletal unloading from prolonged immobilization leads to bone loss. A functional interplay between the insulin-like growth factor 1 receptor (IGF1R), a major player in skeletal development, and integrins, mechanosensors, is thought to regulate the anabolic response of osteogenic cells to mechanical load. The mechanistic basis for this cross-talk is unclear. Here we report that integrin signaling regulates activation of IGF1R and downstream targets in response to both IGF1 and a mechanical stimulus. In addition, integrins potentiate responsiveness of IGF1R to IGF1 and mechanical forces. We demonstrate that integrin-associated kinases, Rous sarcoma oncogene (SRC) and focal adhesion kinase (FAK), display distinct actions on IGF1 signaling; FAK regulates IGF1R activation and its downstream effectors, AKT and ERK, whereas SRC controls signaling downstream of IGF1R. These findings linked to our observation that IGF1 assembles the formation of a heterocomplex between IGF1R and integrin ß3 subunit indicate that the regulation of IGF1 signaling by integrins proceeds by direct receptor-receptor interaction as a possible means to translate biomechanical forces into osteoanabolic signals.

Emodin extends lifespan of Caenorhabditis elegans through insulin/IGF-1 signaling pathway depending on DAF-16 and SIR-2.1.

The naturally occurring anthraquinone emodin has been serving primarily as an anti-bacterial and anti-inflammatory agent. However, little is known about its potential on anti-aging. This investigation examined the effect of emodin on lifespan and focused on its physiological molecular mechanisms in vivo. Using Caenorhabditis elegans (C. elegans) as an animal model, we found emodin could extend lifespan of worms and improve their antioxidant capacity. Our mechanistic studies revealed that emodin might function via insulin/IGF-1 signaling (IIS) pathway involving, specifically the core transcription factor DAF-16. Quantitative RT-PCR results illustrated that emodin up-regulated transcription of DAF-16 target genes which express antioxidants to promote antioxidant capacity and lifespan of worms. In addition, attenuated effect in sir-2.1 mutants suggests that emodin likely functioned in a SIR-2.1-dependent manner. Our study uncovers a novel role of emodin in prolonging lifespan and supports the understanding of emodin being a beneficial dietary supplement.

Omics Approaches for Identifying Physiological Adaptations to Genome Instability in Aging.

DNA damage causally contributes to aging and age-related diseases. The declining functioning of tissues and organs during aging can lead to the increased risk of succumbing to aging-associated diseases. Congenital syndromes that are caused by heritable mutations in DNA repair pathways lead to cancer susceptibility and accelerated aging, thus underlining the importance of genome maintenance for withstanding aging. High-throughput mass-spectrometry-based approaches have recently contributed to identifying signalling response networks and gaining a more comprehensive understanding of the physiological adaptations occurring upon unrepaired DNA damage. The insulin-like signalling pathway has been implicated in a DNA damage response (DDR) network that includes epidermal growth factor (EGF)-, AMP-activated protein kinases (AMPK)- and the target of rapamycin (TOR)-like signalling pathways, which are known regulators of growth, metabolism, and stress responses. The same pathways, together with the autophagy-mediated proteostatic response and the decline in energy metabolism have also been found to be similarly regulated during natural aging, suggesting striking parallels in the physiological adaptation upon persistent DNA damage due to DNA repair defects and long-term low-level DNA damage accumulation occurring during natural aging. These insights will be an important starting point to study the interplay between signalling networks involved in progeroid syndromes that are caused by DNA repair deficiencies and to gain new understanding of the consequences of DNA damage in the aging process.