Foxo signaling declines with age
Ontology highlight
ABSTRACT:
ORGANISM(S): Drosophila melanogaster
PROVIDER: GSE122470 | GEO | 2018/11/14
REPOSITORIES: GEO
Similar Datasets
Project description:Foxo signaling declines with age
| PRJNA505319 | ENA
Project description:Heart performance declines with age. Reduced protein quality control (PQC) due to decreased function of the ubiquitin/proteasome system (UPS), autophagy, and/or chaperone-mediated protein refolding is a likely contributor to age-associated cardiac performance decline. The transcription factor FOXO participates in the regulation of genes involved PQC and a host of other processes. Here, the effect of cardiac-restricted dFOXO overexpression was investigated in Drosophila, a genetically pliable and rapidly aging model. Modest dFOXO overexpression in the heart was protective, ameliorating functional decline with age. Increased expression of genes associated predominantly with UPS relative to other PQC components accompanied dFOXO-mediated cardioprotection, which was corroborated by a significant decrease in ubiquitinated myocardial proteins. In agreement, knockdown of upregulated UPS components seemingly induced premature aging. Despite these findings, excessive dFOXO overexpression or knockdown proved detrimental to heart function and overall organismal development. This study highlights Drosophila as a model of cardiac aging and FOXO as a tightly-regulated mediator of proteostasis and heart performance over time. Two replicates of 4 different samples were analyzed. Two of these samples were controls (GMH5 x yw 1 week and GMH5 x yw 5 week).
2016-07-01 | E-GEOD-73205 | biostudies-arrayexpress
Project description:Heart performance declines with age. Reduced protein quality control (PQC) due to decreased function of the ubiquitin/proteasome system (UPS), autophagy, and/or chaperone-mediated protein refolding is a likely contributor to age-associated cardiac performance decline. The transcription factor FOXO participates in the regulation of genes involved PQC and a host of other processes. Here, the effect of cardiac-restricted dFOXO overexpression was investigated in Drosophila, a genetically pliable and rapidly aging model. Modest dFOXO overexpression in the heart was protective, ameliorating functional decline with age. Increased expression of genes associated predominantly with UPS relative to other PQC components accompanied dFOXO-mediated cardioprotection, which was corroborated by a significant decrease in ubiquitinated myocardial proteins. In agreement, knockdown of upregulated UPS components seemingly induced premature aging. Despite these findings, excessive dFOXO overexpression or knockdown proved detrimental to heart function and overall organismal development. This study highlights Drosophila as a model of cardiac aging and FOXO as a tightly-regulated mediator of proteostasis and heart performance over time.
2016-07-01 | GSE73205 | GEO
Project description:Under stress conditions mammalian cells activate compensatory mechanisms to survive and maintain cellular function. During catabolic conditions, such as low nutrients, systemic inflammation, cancer or infections, protein breakdown is enhanced and aminoacids are released from muscles to sustain liver gluconeogenesis and tissues protein synthesis. Proteolysis in muscle is orchestrated by a set of genes named atrophy-related genes. A system that is activated both in short and prolonged stress conditions is the family of Forkhead Box (Fox) O transcription factors. Here, we report that muscle-specific deletion of FoxO members resulted in protection from muscle loss because FoxO family is required for induction of autophagy-lysosome and ubiquitin-proteasome systems. Importantly, FoxOs are required for Akt activity but not for mTOR signalling underlining the concept that FoxOs are upstream mTOR for the control of protein breakdown when nutrients are lacking. Moreover, FoxO family controls the induction of critical genes belonging to several fundamental stress response pathways such as unfolded protein response, ROS detoxification and translational regulation. Finally, we identify a set of novel FoxO-dependent ubiquitin ligases including the recent discovered MUSA11 and a new one, which we named Specific of Muscle Atrophy and Regulated by Transcription (SMART). Our findings identify the critical role of FoxO in regulating a variety of genes belonging to pathways important for stress-response under catabolic conditions. Gene expression in muscles of muscle-specific FoxO 1,3,4 knock-out mice that were fed normally or starved
2015-04-24 | GSE52667 | GEO
Project description:Under stress conditions mammalian cells activate compensatory mechanisms to survive and maintain cellular function. During catabolic conditions, such as low nutrients, systemic inflammation, cancer or infections, protein breakdown is enhanced and aminoacids are released from muscles to sustain liver gluconeogenesis and tissues protein synthesis. Proteolysis in muscle is orchestrated by a set of genes named atrophy-related genes. A system that is activated both in short and prolonged stress conditions is the family of Forkhead Box (Fox) O transcription factors. Here, we report that muscle-specific deletion of FoxO members resulted in protection from muscle loss because FoxO family is required for induction of autophagy-lysosome and ubiquitin-proteasome systems. Importantly, FoxOs are required for Akt activity but not for mTOR signalling underlining the concept that FoxOs are upstream mTOR for the control of protein breakdown when nutrients are lacking. Moreover, FoxO family controls the induction of critical genes belonging to several fundamental stress response pathways such as unfolded protein response, ROS detoxification and translational regulation. Finally, we identify a set of novel FoxO-dependent ubiquitin ligases including the recent discovered MUSA11 and a new one, which we named Specific of Muscle Atrophy and Regulated by Transcription (SMART). Our findings identify the critical role of FoxO in regulating a variety of genes belonging to pathways important for stress-response under catabolic conditions. Gene expression in muscles of muscle-specific FoxO 1,3,4 knock-out mice that were fed normally or starved We generated knocked-out FoxO 1,3,4 specifically in muscle by crossing FoxO1-3-4-floxed mice (FoxO1,3,4 f/f) with a transgenic line expressing Cre recombinase under the control of MLC1f promoter to generate muscle-specific FoxO1,3,4 triple knockout mice. These mice were either fed ad libitum or starved. Subsequently gene expression of the gastrocnemius muscles was analyzed. For each of the 4 conditions (FOXO1,3,4 f/f fed or starved, FOXO1,3,4-/- fed or starved), we isolated the gastrocnemius muscles of 3 mice thus yielding 6 muscles per condition. RNA was prepared from these muscles using the TRIzol method (Life Technologies) followed by cleanup with the RNeasy kit (QIAGEN). RNA concentration was determined by spectrophotometry and quality of the RNA was monitored using the Agilent 2100 Bioanalyzer (Agilent Technologies). RNA of the 6 muscles per condition was pooled equimolarly and used for further microarray analysis. cRNA was prepared, labelled and hybridised to Affymetrix Mouse Genome 430 2.0 Arrays using Affymetrix-supplied kits and according to standard Affymetrix protocols. Expression values were summarized using the Mas 5.0 algorithm. Genes that were up- or downregulated upon starvation compared to the fed condition were determined using Excel software. A threshold of 1.5 was used for the fold up-or downregulation consistent with the fold change that can be reliably detected with these type of arrays.
2015-04-24 | E-GEOD-52667 | biostudies-arrayexpress
Project description:Genome maintenance defects cause complex disease phenotypes characterized by developmental failure, cancer susceptibility and premature aging. It remains poorly understood how DNA damage responses function during organismal development and maintain tissue functionality when DNA damage accumulates with aging. Here we show that the FoxO transcription factor DAF-16 is activated in response to DNA damage during development while the DNA damage responsiveness of DAF-16 declines with aging. We find that in contrast to its established role in mediating starvation arrest, DAF-16 alleviates DNA damage induced developmental arrest and even in the absence of DNA repair promotes developmental growth and enhances somatic tissue functionality. We demonstrate that the GATA transcription factor EGL-27 co-regulates DAF-16 target genes in response to DNA damage and together with DAF-16 promotes developmental growth. We propose that EGL-27/GATA activity specifies DAF-16 mediated DNA damage responses to enable developmental progression and to prolong tissue functioning when DNA damage persists. Synchronized L1 and xpa-1 mutant larvae were UV or mock treated, or starved
2014-11-18 | E-GEOD-51161 | biostudies-arrayexpress
Project description:Skeletal muscle senescence influences whole organism aging, yet little is known on the relay of pro-longevity signals from muscles to other tissues. We performed an RNAi screen in Drosophila for muscle-released cytokines ('myokines') regulating lifespan and identified Myoglianin, the homolog of human Myostatin. Myoglianin is induced in skeletal muscles by the transcription factor Mnt and together they constitute an inter-organ signaling module that regulates lifespan, age-related muscle dysfunction, and protein synthesis across aging tissues. Both Mnt and Myoglianin activate already in young age the protective decline in protein synthesis that is typical of old age, while knock-down of Myoglianin impairs this process. Mechanistically, Mnt decreases the expression of nucleolar components in muscles while also decreasing nucleolar size in distant tissues via Myostatin/p38 MAPK signaling. Our results highlight a myokine-dependent inter-organ longevity pathway that coordinates nucleolar function and protein synthesis across aging tissues. Affymetrix microarrays were used to evaluate genome-wide expression in skeletal muscles of flies with muscle-specific overexpression of FOXO or Mnt (Affymetrix Drosophila Genome 2.0 Array). This design allowed us to identify genes and pathways induced by overexpression of FOXO and/or Mnt, and enabled us to address the degree to which FOXO-induced pathways were independent of those induced by Mnt. Three independent biological replicates from each of three groups (control, UAS-Foxo and UAS-Mnt)
2014-07-02 | E-GEOD-39877 | biostudies-arrayexpress
Project description:FoxO transcription factors promote longevity across taxa. How they do so is poorly understood. In the nematode Caenorhabditis elegans, the A- and F-isoforms of the FoxO transcription factor DAF-16 extend life span in the context of reduced DAF-2 insulin-like growth factor receptor (IGFR) signaling. To elucidate the mechanistic basis for DAF-16/FoxO-dependent life span extension, we performed an integrative analysis of isoform-specific daf-16/FoxO mutants. In contrast to previous studies suggesting that DAF-16F plays a more prominent role in life span control than DAF-16A, isoform-specific daf-16/FoxO mutant phenotypes and whole transcriptome profiling revealed a predominant role for DAF-16A over DAF-16F in life span control, stress resistance, and target gene regulation. Integration of these data sets enabled the prioritization of a subset of 92 DAF-16/FoxO target genes for functional interrogation. Among 29 genes tested, two DAF-16A-specific target genes significantly influenced longevity. Our discovery of new longevity genes underscores the efficacy of our integrative strategy while providing a general framework for identifying specific downstream gene regulatory events that contribute substantially to transcription factor functions. As FoxO transcription factors have conserved functions in promoting longevity and may be dysregulated in aging-related diseases, these findings promise to illuminate fundamental principles underlying aging in animals. Whole-transcriptome profiling of daf-16/FoxO isoform-specific deletion mutants in the long-lived daf-2(e1370) background. Included are daf-16 wild-type, daf-16 null mutation, daf-16a/f mutation, two independent daf-16a mutations, and daf-16f mutation. N2 wild-type controls are also included.
2015-08-27 | E-GEOD-72426 | biostudies-arrayexpress
Project description:We identify two quiescent stem-cell states through relative CD34 expression: CD34High, with stemness properties (genuine state), and CD34Low, more committed to myogenic differentiation (primed state). The genuine-quiescent state is preserved into later life succumbing only in extreme old age due to acquisition of primed-state traits. We identified niche-derived IGF1-dependent Akt activation as detrimental to the genuine stem-cell state by imposing primed-state features via FoxO inhibition. Interventions to neutralize Akt and promote FoxO activity drive primed-to-genuine state conversion, while FoxO inactivation deteriorates the genuine state at young age, causing muscle regenerative failure, as in geriatric mice.
2020-10-29 | GSE155642 | GEO
Project description:We identify two quiescent stem-cell states through relative CD34 expression: CD34High, with stemness properties (genuine state), and CD34Low, more committed to myogenic differentiation (primed state). The genuine-quiescent state is preserved into later life succumbing only in extreme old age due to acquisition of primed-state traits. We identified niche-derived IGF1-dependent Akt activation as detrimental to the genuine stem-cell state by imposing primed-state features via FoxO inhibition. Interventions to neutralize Akt and promote FoxO activity drive primed-to-genuine state conversion, while FoxO inactivation deteriorates the genuine state at young age, causing muscle regenerative failure, as in geriatric mice.
2020-10-29 | GSE157562 | GEO