Ontology highlight
ABSTRACT:
PROVIDER: PRJNA939262 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Inhibition of the nutrient-responsive mTOR (mammalian target of rapamycin) signalling pathway including the key downstream S6 kinase 1 (S6K1) extends lifespan and improves healthspan in mice. However, the underlying mechanisms contributing to the profound age-related benefits observed with loss of S6K1 signalling are unclear. Cellular senescence is a stable growth arrest accompanied by an inflammatory phenotype (termed the senescence-associated secretory phenotype, or SASP). Whileboth cellular senescence and SASP-mediated chronic inflammation contribute to age-related pathology the specific role of S6K1 signalling in these process have not been determined . Here, focussing on mouse liver a key target tissue for the beneficial health effects of loss of S6K1 signalling, we show that S6K1 deletion does not reduce senescence but ameliorates inflammation and immune cell infiltration in aged livers. Using human and mouse models of senescence, we demonstrated that reduced inflammation is a liver intrinsic effect associated with S6K deletion. Furthermore, gene expression analysis suggested that downregulated cGAS/STING and IRF3 activation might mediate the impaired SASP observed upon S6K deletion. Using a hepatic oncogene induced senescence model, we showed in vivo that S6K1 deletion results in reduced IRF3 activation, impaired production of cytokines such as IL1 and reduced immune infiltration. Overall, deletion of S6K reduces inflammation in the liver suggesting that suppression of the inflammatory SASP by S6K could contribute to explain the beneficial effects of inhibiting these pathways on healthspan and lifespan.
2024-07-09 | GSE218684 | GEO
Project description:Inhibition of the nutrient-responsive mTOR (mammalian target of rapamycin) signalling pathway including the key downstream S6 kinase 1 (S6K1) extends lifespan and improves healthspan in mice. However, the underlying mechanisms contributing to the profound age-related benefits observed with loss of S6K1 signalling are unclear. Cellular senescence is a stable growth arrest accompanied by an inflammatory phenotype (termed the senescence-associated secretory phenotype, or SASP). Whileboth cellular senescence and SASP-mediated chronic inflammation contribute to age-related pathology the specific role of S6K1 signalling in these process have not been determined . Here, focussing on mouse liver a key target tissue for the beneficial health effects of loss of S6K1 signalling, we show that S6K1 deletion does not reduce senescence but ameliorates inflammation and immune cell infiltration in aged livers. Using human and mouse models of senescence, we demonstrated that reduced inflammation is a liver intrinsic effect associated with S6K deletion. Furthermore, gene expression analysis suggested that downregulated cGAS/STING and IRF3 activation might mediate the impaired SASP observed upon S6K deletion. Using a hepatic oncogene induced senescence model, we showed in vivo that S6K1 deletion results in reduced IRF3 activation, impaired production of cytokines such as IL1 and reduced immune infiltration. Overall, deletion of S6K reduces inflammation in the liver suggesting that suppression of the inflammatory SASP by S6K could contribute to explain the beneficial effects of inhibiting these pathways on healthspan and lifespan.
2024-07-09 | GSE218683 | GEO
Project description:Inhibition of the nutrient-responsive mTOR (mammalian target of rapamycin) signalling pathway including the key downstream S6 kinase 1 (S6K1) extends lifespan and improves healthspan in mice. However, the underlying mechanisms contributing to the profound age-related benefits observed with loss of S6K1 signalling are unclear. Cellular senescence is a stable growth arrest accompanied by an inflammatory phenotype (termed the senescence-associated secretory phenotype, or SASP). Whileboth cellular senescence and SASP-mediated chronic inflammation contribute to age-related pathology the specific role of S6K1 signalling in these process have not been determined . Here, focussing on mouse liver a key target tissue for the beneficial health effects of loss of S6K1 signalling, we show that S6K1 deletion does not reduce senescence but ameliorates inflammation and immune cell infiltration in aged livers. Using human and mouse models of senescence, we demonstrated that reduced inflammation is a liver intrinsic effect associated with S6K deletion. Furthermore, gene expression analysis suggested that downregulated cGAS/STING and IRF3 activation might mediate the impaired SASP observed upon S6K deletion. Using a hepatic oncogene induced senescence model, we showed in vivo that S6K1 deletion results in reduced IRF3 activation, impaired production of cytokines such as IL1 and reduced immune infiltration. Overall, deletion of S6K reduces inflammation in the liver suggesting that suppression of the inflammatory SASP by S6K could contribute to explain the beneficial effects of inhibiting these pathways on healthspan and lifespan.
2024-07-09 | GSE218682 | GEO
Project description:Transcriptome-based drug screening is emerging as a powerful tool to identify geroprotective compounds to intervene in age-related disease. We hypothesized that, by mimicking the transcriptional signature of the highly conserved longevity intervention of FOXO3 (daf-16 in worms) overexpression, we could identify and repurpose compounds with similar downstream effects to increase longevity. Our in silico screen, utilizing the LINCS transcriptome database of genetic and compound interventions, identified several FDA-approved compounds that activate FOXO downstream targets in mammalian cells. These included the neuromuscular blocker atracurium, which also robustly extends both lifespan and healthspan in C. elegans. This longevity is dependent on both daf-16 signaling and inhibition of the neuromuscular acetylcholine receptor. Other neuromuscular blockers tubocurarine and pancuronium caused similar healthspan benefits. Together, these data demonstrate the capacity to mimic genetic lifespan interventions with drugs, and in doing so, reveal that the neuromuscular acetylcholine receptor regulates the highly conserved FOXO/DAF-16 longevity pathway.
2021-07-06 | GSE149944 | GEO
Project description:The quest to extend healthspan via pharmacological means is becoming increasingly urgent, both from a health and economic perspective. Here we show that lithium, a drug approved for human use, promotes longevity and healthspan. We demonstrate that lithium extends lifespan in female and male Drosophila, when administered throughout adulthood or only later in life. The life-extending mechanism involves the inhibition of glycogen synthase kinase-3 (GSK-3) and activation of the transcription factor nuclear factor erythroid 2-related factor (NRF-2). Combining genetic loss of the NRF-2 repressor Kelch-like ECH-associated protein 1 (Keap1) with lithium treatment revealed that high levels of NRF-2 activation conferred stress resistance, while low levels additionally promoted longevity. The discovery of GSK-3 as a new therapeutic target for aging will likely lead to more effective treatments that can modulate mammalian aging and further improve health in later life. The microarray experiment examines the transcriptional profiles of wild-type (w1118) vs. wild-type (w1118) + Lithium (LiCl, 10mM). Heads and thoraces from once mated females treated with vehicle or 10mM Li were snap frozen after 10d of treatment. RNA was Dnase treated and checked for quality by Biorad Experion. RNA was processed to cRNA, labeled and used for microarray analysis (GeneChip Drosophila Genome 2.0 Array), following manufacturer's protocol.
2016-04-07 | E-MTAB-3809 | biostudies-arrayexpress
Project description:SRT1720 extends healthspan and lifespan in diet-induced obese mice
| PRJNA120447 | ENA
Project description:The root of Vicatia thibetica de Boiss is a Chinese herb medicine with homology of medicine and food. We first report that HLB01 (the extract of Vicatia thibetica de Boiss root) extends lifespan and promotes healthy parameters in Caenorhabditis elegans (C. elegans). In doxorubicin-induced senescent mice, HLB01 counteracts senescence associated biomarkers significantly, including AST, ALT, p21 and γH2AX. Interestingly, HLB01 promotes the level of collagen in C. elegans and mammalian cell systemically, which might be one of the essential factors to exert anti-aging effects of HLB01. In addition, HLB01 can scavenge free radical to perform antioxidant ability. Lifespan extension of HLB01 also dependent on DAF-16 and HSF-1 to perform oxidative stress resistance and heat stress resistance. Taken together, these data indicate that HLB01 extends lifespan and healthspan of C. elegans, resists doxorubicin‐induced senescence in mice via collagen promoting, antioxidant and stress resistance.
2021-03-06 | GSE168322 | GEO
Project description:Increased expression of SIRT1 extends the lifespan of lower organisms and delays the onset of age-related diseases in mammals. Here, we show that SRT2104, a synthetic small molecule activator of SIRT1, extends both mean and maximal lifespan of mice fed a standard diet. This is accompanied by improvements in health, including enhanced motor coordination, performance, bone mineral density and insulin sensitivity associated with higher mitochondrial content and decreased inflammation. Short-term SRT2104 treatment preserves bone and muscle mass in an experimental model of atrophy. These results demonstrate it is possible to design a small molecule that can slow aging and delay multiple age-related diseases in mammals, supporting the therapeutic potential of SIRT1 activators in humans. Key words: Sirtuins, lifespan, healthspan, osteoporosis, muscle wasting, inflammation
2014-09-22 | GSE49000 | GEO
Project description:Dietary intervention constitutes a feasible approach for modulating metabolism and improving healthspan and lifespan. Methionine restriction (MR) delays the appearance of age-related diseases and increases longevity in normal mice. However, the effect of MR on premature aging remains to be elucidated. Here, we describe that MR extends lifespan in two different mouse models of Hutchinson-Gilford progeria syndrome (HGPS) by reversing the transcriptome alterations in inflammation and DNA-damage response genes present in this condition. Further, MR improves the lipid profile and alters the levels of bile acids, both in wild-type and in progeroid mice. Notably, treatment with the bile acid cholic acid improves healthspan and lifespan in vivo. These results suggest the existence of a metabolic pathway involved in the longevity extension achieved by MR and support the possibility of dietary interventions for treating progeria.
2018-08-27 | GSE117188 | GEO
Project description:The nutrient-sensing Target of Rapamycin complex 1 (TORC1) is an evolutionarily conserved regulator of longevity. S6 kinase (S6K) is an essential downstream mediator for the effect of TORC1 on longevity. However, mechanistic insights on how TORC1-S6K signalling promotes lifespan and healthspan are still limited. Here we show that activity of S6K in the Drosophila fat body is essential for rapamycin-mediated longevity. Fat-body-specific activation of S6K blocked lifespan extension upon rapamycin feeding and induced accumulation of multilamellar lysosomal enlargements. Besides, fat body-specific S6K knockdown extended lifespan in files. We performed proteomics for Drosophila fat body to explore the fat body-specific regulation of protein expression by two separate datasets: fat body-specific S6K activation (Lsp2GS>S6KCA) with rapamycin treatment; and fat body-specific S6K inhibition (Lsp2GS>S6KRNAi). To assess if the age-prolonging mechanisms of TORC1-S6K signalling are conserved between flies and mammals, we assessed the impact of rapamycin treatment in the proteome of liver from C3B6F1 mice (F1 hybrids of C3H/HeOuJ females and C57Bl/6N males).
2024-01-12 | PXD035293 | Pride