Crotamiton derivative JM03 extends lifespan and improves 1 oxidative and hypertonic stress resistance in Caenorhabditis 2 elegans via inhibiting OSM-9
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PROVIDER: PRJNA763103 | ENA |
REPOSITORIES: ENA
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Project description:While screening our in-house 1,072 marketed drugs for their ability to extend the lifespan using Caenorhabditis elegans (C. elegans) as an animal model, crotamiton (N-ethyl-o-crotonotoluidide) showed anti-aging activity and was selected for further structural optimization. After replacing the ortho-methyl of crotamiton with ortho-fluoro, crotamiton derivative JM03 was obtained and showed better activity in terms of lifespan-extension and stress resistance than crotamiton. It was further explored that JM03 extended the lifespan of C. elegans through osmotic avoidance abnormal-9 (OSM-9). Besides, JM03 improves the ability of nematode to resist oxidative stress and hypertonic stress through OSM-9, but not osm-9/capsaicin receptor related-2 (OCR-2). Then the inhibition of OSM-9 by JM03 reduces the aggregation of Q35 in C. elegans via upregulating the genes associated with proteostasis. SKN-1 signaling was also found to be activated after JM03 treatment, which might contribute to proteostasis, stress resistance and lifespan extension. In summary, this study explored a new small molecule derived from crotamiton, which has efficient anti-oxidative, anti-hypertonic and anti-aging effects, and could further lead to promising application prospects.
2022-04-10 | GSE200459 | GEO
Project description:While screening our in-house 1,072 marketed drugs for their ability to extend the lifespan using Caenorhabditis elegans (C. elegans) as an animal model, crotamiton (N-ethyl-o-crotonotoluidide) showed anti-aging activity and was selected for further structural optimization. After replacing the ortho-methyl of crotamiton with ortho-fluoro, crotamiton derivative JM03 was obtained and showed better activity in terms of lifespan-extension and stress resistance than crotamiton. It was further explored that JM03 extended the lifespan of C. elegans through osmotic avoidance abnormal-9 (OSM-9). Besides, JM03 improves the ability of nematode to resist oxidative stress and hypertonic stress through OSM-9, but not osm-9/capsaicin receptor related-2 (OCR-2). Then the inhibition of OSM-9 by JM03 reduces the aggregation of Q35 in C. elegans via upregulating the genes associated with proteostasis. SKN-1 signaling was also found to be activated after JM03 treatment, which might contribute to proteostasis, stress resistance and lifespan extension. In summary, this study explored a new small molecule derived from crotamiton, which has efficient anti-oxidative, anti-hypertonic and anti-aging effects, and could further lead to promising application prospects.
2021-09-17 | GSE184076 | GEO
Project description:Crotamiton derivative JM03 extends lifespan and improves oxidative and hypertonic stress resistance in Caenorhabditis elegans via inhibiting OSM-9
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Project description:Activation of Sirt1, the mammalian homolog of an NAD+-dependent deacetylase known to modulate lifespan in lower organisms, is thought to hold promise as a strategy for delaying aging in mammals. SRT1720, a novel compound developed as a specific and potent activator of Sirt1, has shown promising effects to glucose homeostasis in short-term studies of rats and mice. Here we show SRT1720 extends both mean and maximum lifespan of mice fed a high-fat diet and has concrete benefits to health including reduced liver steatosis and increased insulin sensitivity and locomotor activity. Gene expression profiles and markers of inflammation and apoptosis were also restored to levels more reflective of standard diet controls. Furthermore, the benefits incurred by SRT1720 occurred in the absence of any observable toxicity. The current findings provide hope that safe and effective treatments may be developed to mitigate age-related diseases and enhance lifespan in humans.
2011-08-18 | GSE19102 | GEO
Project description:Activation of Sirt1, the mammalian homolog of an NAD+-dependent deacetylase known to modulate lifespan in lower organisms, is thought to hold promise as a strategy for delaying aging in mammals. SRT1720, a novel compound developed as a specific and potent activator of Sirt1, has shown promising effects to glucose homeostasis in short-term studies of rats and mice. Here we show SRT1720 extends both mean and maximum lifespan of mice fed a high-fat diet and has concrete benefits to health including reduced liver steatosis and increased insulin sensitivity and locomotor activity. Gene expression profiles and markers of inflammation and apoptosis were also restored to levels more reflective of standard diet controls. Furthermore, the benefits incurred by SRT1720 occurred in the absence of any observable toxicity. The current findings provide hope that safe and effective treatments may be developed to mitigate age-related diseases and enhance lifespan in humans. Male C57BL/6J mice obtained at 12 weeks of age were maintained on a standard purified mouse diet (AIN-93G) until 56 weeks of age prior to the start of the experiment. Beginning at 56 weeks of age, the SD group was fed a standard AIN-93G diet for the duration of the study. Three separate groups were placed on a high-fat diet (HFD) (AIN-93G modified by the addition of hydrogenated coconut oil to provide 60% of calories from fat) or HFD + 30mg/kg body weight SRT1720 (HFD-L) or 100mg/kg body weight SRT1720 (HFD-H) and remained on those diets throughout the study. All mice were fed ad libitum. Food intake and body weight were measured biweekly for the duration of the study.
2011-08-17 | E-GEOD-19102 | biostudies-arrayexpress
Project description:Transcriptional regulation plays an important role in the control of gene expression during aging. However, translation efficiency likely plays an equally important role in determining protein abundance, but has been relatively under studied in this context. Here we used RNA-seq and ribosome profiling to investigate the role of translational regulation in lifespan extension by CAN1 gene deletion in yeast. Through comparison of the transcriptional and translational changes in cells lacking CAN1 with other long-lived mutants, we were able to identify critical regulatory factors, including transcription factors and mRNA-binding proteins, that coordinate transcriptional and translational responses. Together, our data support a model in which deletion of CAN1 extends replicative lifespan through increased translation of proteins that facilitate cellular response to stress. This study extends our understanding of the importance of translational control in regulating stress resistance and longevity.
2017-02-20 | GSE85198 | GEO
Project description:The mitochondrial unfolded protein response (UPRmt) has been associated with long lifespan across metazoans. In Caenorhabditis elegans, mild developmental mitochondrial stress activates UPRmt reporters and extends lifespan. We show that similar developmental stress is necessary and sufficient to extend Drosophila lifespan, and identify Phosphoglycerate Mutase 5 (PGAM5) as a mediator of this response. Developmental mitochondrial stress leads to activation of FoxO, via Apoptosis Signal-regulating Kinase 1 (ASK1) and Jun-N-terminal Kinase (JNK). This activation persists into adulthood and induces a select set of chaperones, many of which have been implicated in lifespan extension in flies. Persistent FoxO activation can be reversed by a high- protein diet in adulthood, through mTORC1 and GCN-2 activity. Accordingly, the observed lifespan extension is prevented on a high-protein diet and in FoxO-null flies. The diet-sensitivity of this pathway has important implications for interventions that seek to engage the UPRmt to improve metabolic health and longevity.
2017-10-25 | GSE106105 | GEO
Project description:Adaptation of C. elegans to hypertonic environments involves the accumulation of the organic osmolyte glycerol via transcriptional upregulation of the glycerol biosynthestic enzyme gpdh-1. A number of mutants, termed osmotic stress resistant (osr) mutants, have been identified. osr mutants cause constitutive upregulation of gpdh-1 and confer extreme resistance to hypertonicity. We tested the hypothesis that osr mutants broadly activate a gene expression program normally activated by osmotic stress in wild type animals using Affymterix microarray analysis of the hypertonic stress response in wild type animals and of constituitive gene expression changes in five osr mutants. Experiment Overall Design: Young adult C. elegans were exposed to hypertonic growth plates for varying times prior to RNA extraction and hybridization on Affymetrix microarrays. Since we wished to separate direct response from secondary responses to osmotic stress, we collected worms following short term exposures to hypertonic conditions (15 minutes and 1 hour) and after long term exposure to hypertonic conditions (6 hours or a full generation of growth under hypertonic conditions). We also collected young adults from the osr mutants osm-7, osm-8, osm-11, dpy-9, and dpy-10 for microarray analysis. These mutants were grown under isotonic conditions to determine whether that constitutively activate genes normally regulated by hypertonic stress in wild type animals.
2009-12-14 | E-GEOD-19310 | biostudies-arrayexpress