• Cellular physiology
• Molecular biology

• Male
• Animals
• Isoptera/genetics
• Isoptera/metabolism
• Sex Determination Processes/genetics
• Ants

• Japan Science and Technology Agency
• Japan Society for the Promotion of Science

• National Natural Science Foundation of China
• Science and Technology Commission of Shanghai Municipality
• Science and Technology Innovation Plan Of Shanghai Science and Technology Commission
• Shanghai Municipal Health and Family Planning Commission
• Guangdong Key Project
• Innovative Research Team of High-level Local University in Shanghai
• Shanghai Clinical Key Subject Construction Project

• aging
• intervention
• mechanism

• Humans
• Aging/genetics
• Aging/metabolism
• Neoplasms/genetics
• Cardiovascular Diseases

• Trypanosoma brucei (T. brucei)
• fatty acids
• host-parasite interactions
• lipids
• metabolism
• uptake

• Humans
• Cattle
• Animals
• Trypanosoma brucei brucei
• Fatty Acids
• Genomics
• Mammals

• P20 GM109094 NIGMS NIH HHS
• National Institute of General Medical Sciences

Cellular, small invertebrate and vertebrate models are a driving force in biogerontology studies. Using various models, such as yeasts, appropriate tissue culture cells, Drosophila, the nematode Caenorhabditis elegans and the mouse, has tremendously increased our knowledge around the relationship between diet, nutrient-response signaling pathways and lifespan regulation. In recent years, combinatorial drug treatments combined with mutagenesis, high-throughput screens, as well as multi-omics approaches, have provided unprecedented insights in cellular metabolism, development, differentiation, and aging. Scientists are, therefore, moving towards characterizing the fine architecture and cross-talks of growth and stress pathways towards identifying possible interventions that could lead to healthy aging and the amelioration of age-related diseases in humans. In this short review, we briefly examine recently uncovered knowledge around nutrient-response pathways, such as the Insulin Growth Factor (IGF) and the mechanistic Target of Rapamycin signaling pathways, as well as specific GWAS and some EWAS studies on lifespan and age-related disease that have enhanced our current understanding within the aging and biogerontology fields. We discuss what is learned from the rich and diverse generated data, as well as challenges and next frontiers in these scientific disciplines.

The incidence of Parkinson's disease (PD) has increased tremendously, especially in the aged population and people with metabolic dysfunction; however, its underlying molecular mechanisms remain unclear. SH2B1, an intracellular adaptor protein, contributes to the signal transduction of several receptor tyrosine kinases and exerts beneficial metabolic effects for body weight regulation; however, whether SH2B1 plays a major role in pathological neurodegeneration in PD has not yet been investigated. This study aimed to investigate the effects of SH2B1 in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)–induced PD mice with Sh2b1 deficiency or neuron-specific Sh2b1 overexpression. Cellular and molecular mechanisms were elucidated using human dopaminergic neuron SH-SY5Y cells analysed. We found that SH2B1 expression was confirmed to be downregulated in the blood samples of PD patients and in the brains of mice with MPTP-induced chronic PD. Sh2b1 deficiency caused marked exacerbation of behavioural defects and increased neuronal apoptosis in MPTP-treated mice, whereas restoration of neuron-specific Sh2b1 expression significantly reversed these effects. Similar results were observed in MPP ⁺ -treated SH-SY5Y cells. Mechanistically, upon binding to heat shock cognate 70 (HSC70), SH2B1 promotes HSC70-related recognition and PLIN4 lysosomal translocation and degradation, thus suppressing lipid peroxidation stress in the brains of PD mice. Adeno-associated virus-mediated rescue of neuronal HSC70 expression functionally alleviated the neuropathology of PD in wild-type but not in Sh2b1-deficient mice. This is the first study to examine the molecular underpinnings of SH2B1 against MPTP-induced neurodegeneration through cell autonomous promotion of neuronal survival in an in vivo PD model. Our findings reveal that SH2B1 antagonizes neurodegenerative pathology in PD via the SH2B1–HSC70–PLIN4 axis.

•

Brain tissues, especially in TH⁺ neurons, of PD mice showed low SH2B1 expression.

• Apoptosis
• Heat shock protein
• Neurodegeneration
• PLIN4
• Parkinson's disease
• SH2B1

• DNA damage repair
• aging
• genes
• genetics
• life expectancy
• signaling pathways

• Aging/genetics
• Animals
• Apoptosis
• DNA Damage
• Gene Regulatory Networks
• Humans
• Longevity
• Stress, Physiological

Nowadays, one of the biggest problems in healthcare is an obesity epidemic. Consumption of cheap and low-quality energy-rich diets, low physical activity, and sedentary work favor an increase in the number of obesity cases within many populations/nations. This is a burden on society, public health, and the economy with many deleterious consequences. Thus, studies concerning this disorder are extremely needed, including searching for new, effective, and fitting models. Obesity may be related, among other factors, to disrupting adipocytes activity, disturbance of metabolic homeostasis, dysregulation of hormonal balance, cardiovascular problems, or disorders in nutrition which may lead to death. Because of the high complexity of obesity, it is not easy to find an ideal model for its studies which will be suitable for genetic and physiological analysis including specification of different compounds’ (hormones, neuropeptides) functions, as well as for signaling pathways analysis. In recent times, in search of new models for human diseases there has been more and more attention paid to insects, especially in neuro-endocrine regulation. It seems that this group of animals might also be a new model for human obesity. There are many arguments that insects are a good, multidirectional, and complex model for this disease. For example, insect models can have similar conservative signaling pathways (e.g., JAK-STAT signaling pathway), the presence of similar hormonal axis (e.g., brain–gut axis), or occurrence of structural and functional homologues between neuropeptides (e.g., neuropeptide F and human neuropeptide Y, insulin-like peptides, and human insulin) compared to humans. Here we give a hint to use insects as a model for obesity that can be used in multiple ways: as a source of genetic and peptidomic data about etiology and development correlated with obesity occurrence as well as a model for novel hormonal-based drug activity and their impact on mechanism of disease occurrence.

• hormones
• insects
• model
• neuropeptides
• obesity
• peptides

• Drosophila
• aging
• insulin receptor
• kinase insert domain
• longevity
• reproduction

yki-induced gut tumors in Drosophila are associated with host wasting, including muscle dysfunction, lipid loss, and hyperglycemia, a condition reminiscent of human cancer cachexia. We previously used this model to identify tumor-derived ligands that contribute to host wasting. To identify additional molecular networks involved in host-tumor interactions, we develop PathON, a web-based tool analyzing the major signaling pathways in Drosophila, and uncover the Upd3/Jak/Stat axis as an important modulator. We find that yki-gut tumors secrete Upd3 to promote self-overproliferation and enhance Jak/Stat signaling in host organs to cause wasting, including muscle dysfunction, lipid loss, and hyperglycemia. We further reveal that Upd3/Jak/Stat signaling in the host organs directly triggers the expression of ImpL2, an antagonistic binding protein for insulin-like peptides, to impair insulin signaling and energy balance. Altogether, our results demonstrate that yki-gut tumors produce a Jak/Stat pathway ligand, Upd3, that regulates both self-growth and host wasting.

Ding et al. show that yki^3SA-gut tumors produce Upd3 as a cachectic ligand to simultaneously promote self-growth and host organ wasting via systemic activation of Jak/Stat signaling in Drosophila. The Upd3/Jak/Stat axis induces host ImpL2 production and perturbs insulin response, leading to muscle mitochondrial dysfunction, lipid loss, and carbohydrate elevation.

• Drosophila
• ImpL2
• Jak/Stat signaling
• Upd3
• cancer cachexia
• lipid loss
• muscle dysfunction
• tumor-induced wasting
• yki

The endoplasmic reticulum (ER)-resident transmembrane protein kinase/RNase Ire1 is a conserved sensor of the cellular unfolded protein response and has been implicated in lipid homeostasis, including lipid synthesis and transport, across species. Here we report a novel catabolic role of Ire1 in regulating lipid mobilization in Drosophila. We found that Ire1 is activated by nutrient deprivation, and, importantly, fat body-specific Ire1 deficiency leads to increased lipid mobilization and sensitizes flies to starvation, whereas fat body Ire1 overexpression results in the opposite phenotypes. Genetic interaction and biochemical analyses revealed that Ire1 regulates lipid mobilization by promoting Xbp1s-associated FoxO degradation and suppressing FoxO-dependent lipolytic programs. Our results demonstrate that Ire1 is a catabolic sensor and acts through the Xbp1s-FoxO axis to hamper the lipolytic response during chronic food deprivation. These findings offer new insights into the conserved Ire1 regulation of lipid homeostasis.

•

Food deprivation systemically activates Ire1 and increases Xbp1 splicing

• Cell biology
• Lipid
• Molecular biology

• Circadian rhythm
• High-fat diet
• Insulin resistance
• Obesity
• Type-II diabetes

• ImpL2
• PINK1
• PTEN
• Parkin
• mitochondria

• Drosophila
• IGF
• aging
• insulin
• insulin receptor
• insulin resistance
• longevity
• reproduction

• Aging
• Animals
• Binding Sites
• Caenorhabditis elegans
• Caenorhabditis elegans Proteins/metabolism
• Diapause
• Dimerization
• Drosophila Proteins/metabolism
• Drosophila melanogaster
• Female
• Insulin/metabolism
• Insulin Resistance
• Ligands
• Longevity
• Mutation
• Phenotype
• Phosphorylation
• Protein Binding
• Protein Domains
• Receptor Protein-Tyrosine Kinases/genetics
• Receptor Protein-Tyrosine Kinases/metabolism
• Receptor, IGF Type 1/genetics
• Receptor, IGF Type 1/metabolism
• Receptor, Insulin/metabolism
• Signal Transduction
• Substrate Specificity

• R37 AG024360 NIA NIH HHS
• R01 AG013662 NIA NIH HHS

Insulin signaling is critical for developmental growth and adult homeostasis, yet the downstream regulators of this signaling pathway are not completely understood. Using the model organism Drosophila melanogaster, we took a genomic approach to identify novel mediators of insulin signaling. These studies led to the identification of Meep, encoded by the gene CG32335. Expression of this gene is both insulin receptor- and diet-dependent. We found that Meep was specifically required in the developing fat body to tolerate a high-sugar diet (HSD). Meep is not essential on a control diet, but when reared on an HSD, knockdown of meep causes hyperglycemia, reduced growth, developmental delay, pupal lethality, and reduced longevity. These phenotypes stem in part from Meep’s role in promoting insulin sensitivity and protein stability. This work suggests a critical role for protein homeostasis in development during overnutrition. Because Meep is conserved and obesity-associated in mammals, future studies on Meep may help to understand the role of proteostasis in insulin-resistant type 2 diabetes.

• Diabetes
• Drosophila
• High-sugar Diet
• Insulin
• Metabolism
• Obesity

Sugar-feeding provides energy for mosquitoes. Facilitated glucose transporters (GLUTs) are responsible for the uptake of glucose in animals. However, knowledge of GLUTs function in Anopheles spp. is limited.

Phylogenetic analysis of GLUTs in Anopheles stephensi was performed by the maximum likelihood and Bayesian inference methods. The spatial and temporal expression patterns of four Asteglut genes were analyzed by qPCR. The function of Asteglut1 was examined using a dsRNA-mediated RNA interference method. Transcriptome analysis was used to investigate the global influence of Asteglut1 on mosquito physiology.

We identified 4 glut genes, Asteglut1, Asteglutx, Asteglut3 and Asteglut4 in An. stephensi. Asteglut1, Asteglut3 and Asteglut4 were mainly expressed in the midgut. Plasmodium berghei infection differentially regulated the expression of Asteglut genes with significant downregulation of Asteglut1 and Asteglut4, while upregulation of Asteglutx. Only knocking-down Asteglut1 facilitated Plasmodium berghei infection in An. stephensi. This might be due to the accumulation of glucose prior to blood-feeding in dsAsteglut1-treated mosquitoes. Our transcriptome analysis revealed that knockdown of Asteglut1 differentially regulated expression of genes associated with multiple functional clusters, especially those related to detoxification and immunity. The dysregulation of multiple pathways might contribute to the increased P. berghei infection.

Our study shows that Asteglut1 participates in defense against P. berghei in An. stephensi. The regulation of Asteglut1 on vector competence might through modulating multiple biological processes, such as detoxification and immunity.

• AMPK
• diabetes
• insulin resistance
• iron oxide nanoparticles
• nanozymes

• AMP-Activated Protein Kinases/metabolism
• Animals
• Blood Glucose/metabolism
• Diabetes Mellitus, Experimental/drug therapy
• Diabetes Mellitus, Experimental/metabolism
• Dietary Sugars/adverse effects
• Disease Models, Animal
• Drosophila melanogaster
• Enzyme Activation/drug effects
• Magnetite Nanoparticles/therapeutic use
• Nanomedicine
• Organelles/drug effects
• Organelles/metabolism

• Animals
• Cold-Shock Response/genetics
• Drosophila melanogaster/genetics
• Drosophila melanogaster/physiology
• Energy Metabolism/genetics
• Insulin/genetics
• Insulin/metabolism
• Larva/genetics
• Larva/physiology
• Memory, Long-Term/physiology
• Mushroom Bodies/metabolism
• Protein Biosynthesis/genetics
• Sensory Receptor Cells/metabolism
• Signal Transduction/genetics
• Sucrose/metabolism

• Drosophila
• disease model
• gut bacteria
• gut hormone
• metabolism and endocrinology
• nutrient sensing
• stress sensing
• tumor-induced wasting

Gomisin N (GN) is lignin derived from Schisandra chinensis that has been reported to exhibit hepato-protective, anti-cancer, and anti-inflammatory effects. However, its role in whole-body energetic homeostasis remains unclear. In this study, we employed Drosophila melanogaster as a diet-induced obese model to elucidate the effects of GN on lipid and glucose metabolism by measuring climbing activity, triglyceride levels, and lifespan under a rearing condition of a high-fat diet (HFD) containing 20% coconut oil, with or without GN. Constant exposure of flies to an HFD resulted in increased body weight and decreased climbing activity, along with a shortened life span. Importantly, the administration of GN to HFD groups lowered their body weight and induced a specific upregulation of lipid storage droplet (Lsd)-2 and hormone-sensitive lipase (Hsl), in addition to improved lifespan. Importantly, GN in HFD groups appeared to downregulate heat shock protein Hsp90 family member (dGRP94), a key regulator of the endoplasmic reticulum stress response, which may also contribute to improved life span in the presence of GN. Taken together, these in vivo findings suggest that GN could serve as a useful agent for the prevention and treatment of obesity.

• Drosophila melanogaster
• endoplasmic reticulum stress response
• gomisin N
• obesity

• fat body
• insect lipid metabolism
• lipogenesis
• lipolysis

• Animals
• Insecta/metabolism
• Lipid Metabolism

• adipokinetic hormone
• insulin
• lipid metabolism
• lipogenesis
• lipolysis
• neuropeptides
• peptide hormones

• Cancer
• Obesity
• Review
• SH2B1
• Signaling pathway

Oogenesis features an enormous increase in mitochondrial mass and mtDNA copy number, which are required to furnish mature eggs with an adequate supply of mitochondria and to curb the transmission of deleterious mtDNA variants. Quiescent in dividing germ cells, mtDNA replication initiates upon oocyte determination in the Drosophila ovary, which necessitates active mitochondrial respiration. However, the underlying mechanism for this dynamic regulation remains unclear. Here, we show that an feedforward insulin-Myc loop promotes mitochondrial respiration and biogenesis by boosting the expression of electron transport chain subunits and of factors essential for mtDNA replication and expression, and for the import of mitochondrial proteins. We further reveal that transient activation of JNK enhances the expression of the insulin receptor and initiates the insulin-Myc signaling loop. This signaling relay promotes mitochondrial biogenesis in the ovary, and thereby plays a role in limiting the transmission of deleterious mtDNA mutations. Our study demonstrates cellular mechanisms that couple mitochondrial biogenesis and inheritance with oocyte development.

• D. melanogaster
• JNK signaling
• Myc
• developmental biology
• insulin signaling
• mitochondria
• mitochondrial inheritance
• mtDNA

• Diabetes
• drosophila melanogaster
• obesity
• trehalose
• triglyceride

• Drosophila fat
• FlyBook
• lipases
• lipid transport
• lipogenesis
• lipolysis
• triacylglycerol

• AC133/prominin-1
• ecdysone
• fat body

• Cardiac hypertrophy
• Mitochondria
• SH2B1
• miR-142-3p

• Adipose
• Beta adrenergic receptor
• ERK
• Fat
• Free fatty acid
• Insulin resistance
• Lipolysis
• Obesity

• 3T3 Cells
• Adipocytes, White/metabolism
• Animals
• Drosophila melanogaster
• Humans
• Lipolysis
• MAP Kinase Signaling System
• Mice
• Mice, Inbred C57BL
• Mitogen-Activated Protein Kinase 1/metabolism
• Mitogen-Activated Protein Kinase 3/metabolism
• Obesity/metabolism
• Phosphorylation
• Receptors, Adrenergic, beta-3/chemistry
• Receptors, Adrenergic, beta-3/metabolism
• Serine/metabolism

• R01 DK107717 NIDDK NIH HHS
• Howard Hughes Medical Institute
• P01 CA120964 NCI NIH HHS
• R01 AR057352 NIAMS NIH HHS
• P30 DK034854 NIDDK NIH HHS
• K01 DK093638 NIDDK NIH HHS

• Src homology 2 B adaptor protein 1
• gastric cancer
• malignant transformation
• risk factor

• Diet
• Genetics
• Insect
• Lipid droplet
• Lipid metabolism

• Alzheimer’s disease
• SH2B1 protein
• amyloid-β accumulation
• diabetes

• ABC transporters
• glutathione
• high-throughput screen
• metal detoxification
• metal homeostasis

• Animals
• Cell Line
• Drosophila melanogaster/cytology
• Drosophila melanogaster/genetics
• Gene Expression Profiling/methods
• Gene Expression Regulation/drug effects
• Genomics/methods
• Homeostasis/genetics
• Metals/metabolism
• Metals/pharmacology
• RNA Interference
• Zinc/metabolism
• Zinc/pharmacology

• P30 CA006516 NCI NIH HHS
• R01 GM067761 NIGMS NIH HHS
• R21 ES025615 NIEHS NIH HHS
• Howard Hughes Medical Institute

• Expression genome-wide
• GWAS
• IRS
• JAK
• Locus
• SH2B1
• STAT

• Adaptor Proteins, Signal Transducing/genetics
• Adaptor Proteins, Signal Transducing/metabolism
• Adolescent
• Adult
• Animals
• Body Weight/drug effects
• Body Weight/genetics
• Cells, Cultured
• Female
• Gene Expression Regulation/drug effects
• Humans
• Hypothalamus/drug effects
• Hypothalamus/metabolism
• Insulin/metabolism
• Insulin/pharmacology
• Leptin/metabolism
• Leptin/pharmacology
• Male
• Mice
• Mice, Knockout
• Mutation
• Signal Transduction/drug effects
• Signal Transduction/genetics
• Young Adult

• Animals
• Humans
• Insulin/metabolism
• Receptor, Insulin/metabolism
• Signal Transduction/physiology
• Transcription, Genetic/physiology

• R01 DK052852 NIDDK NIH HHS
• P30 DK026687 NIDDK NIH HHS
• P01 HL087123 NHLBI NIH HHS
• P30 DK063608 NIDDK NIH HHS
• R01 HL125649 NHLBI NIH HHS
• R37 DK058282 NIDDK NIH HHS
• T32 DK007328 NIDDK NIH HHS
• R01 DK064819 NIDDK NIH HHS
• R01 DK058282 NIDDK NIH HHS
• P30 DK020541 NIDDK NIH HHS
• R01 DK057539 NIDDK NIH HHS

Trabecular meshwork (TM) plays an important role in maintaining normal intraocular pressure (IOP). Studies have shown that glaucomatous TM tissues are stiffer than those of normal tissue. The high expression of fibronectin protein (FN) and adaptor protein (LNK) may be related to high resistance to aqueous humor outflow as well as high IOP. Our concern is what factors lead to the variation of the stiffness of trabecular tissue/cells.

Atomic force microscope (AFM) and Western blot (WB) analysis were applied to test TM cells of rats cultured with different concentrations of dexamethasone (DEX) and mifepristone (MIF). Rat TM cells were randomly divided into 7 groups, marked as D1, D2, D3 and M1, M2 M3 for different concentrations of DEX and MIF, respectively, and C for blank control.

The elastic modulus of the treated cells were 2.67 ± 0.914 KPa, 2.92 ± 0.986 KPa, 4.52 ± 1.22 KPa for D1, D2, D3, 2.06 ± 0.745 KPa, 1.23 ± 0.462 KPa, 0.467 ± 0.275 KPa for M1, M2, M3, and 2.43 ± 0.713 KPa for C group, respectively. Expressions of FN and LNK increase (decrease) with the increase of the concentrations of DEX (MIF).

We focus on the relationship between the stiffness and the expressions of FN and LNK of rat TM cells. We analyzed the correlation between cell stiffness and FN, LNK expression, discussed the relationship between cell stiffness and aqueous humor outflow resistance.

The changes of TM cell stiffness and the expressions of FN and LNK are positively correlated.

• AFM
• Intraocular pressure
• Outflow resistance
• Protein expression
• TM cells stiffness

Protein phosphorylation on tyrosine (Tyr) residues has evolved as an important mechanism to coordinate cell communication in multicellular organisms. The importance of this process has been revealed by the discovery of the prominent oncogenic properties of tyrosine kinases (TK) upon deregulation of their physiological activities, often due to protein overexpression and/or somatic mutation. Recent reports suggest that TK oncogenic signaling is also under the control of small adaptor proteins. These cytosolic proteins lack intrinsic catalytic activity and signal by linking two functional members of a catalytic pathway. While most adaptors display positive regulatory functions, a small group of this family exerts negative regulatory functions by targeting several components of the TK signaling cascade. Here, we review how these less studied adaptor proteins negatively control TK activities and how their loss of function induces abnormal TK signaling, promoting tumor formation. We also discuss the therapeutic consequences of this novel regulatory mechanism in human oncology.

• adaptor proteins
• cancer therapy
• cell signaling
• human cancer
• tyrosine kinase

• Activin-β
• NF-κB/Relish
• complex I perturbation
• lipid metabolism
• mitochondrial synchrony