Foxo signaling declines with age
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ABSTRACT:
PROVIDER: PRJNA505319 | ENA |
REPOSITORIES: ENA
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Project description:We performed RNA-seq for WT and foxo mutant flies, by combining with Dr. Baihua's foxo chip-seq data, we found 101 foxo-repressed and 300 foxo-activated genes. By analyzing expression change of these genes during age, we found foxo-repressed genes became activated, while foxo-activated genes became repressed, suggesting foxo signaling declines with age.
2018-11-14 | GSE122470 | GEO
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: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:Age-related depletion of stem cells causes tissue degeneration and failure to tissue regeneration, driving aging at the organismal level. Previously we reported a cell-non-autonomous DAF-16/FOXO activity in antagonizing the age-related loss of germline stem/progenitor cells (GSPCs) in C. elegans, indicating that regulation of stem cell aging occurs at the organ system level. Here we discover the molecular effector that links the cell-non-autonomous DAF-16/FOXO activity to GSPC maintenance over time by performing a tissue-specific DAF-16/FOXO transcriptome analysis. Our data show that dos-3, which encodes a non-canonical Notch ligand, is a direct transcriptional target of DAF-16/FOXO and mediates the effect of the cell-non-autonomous DAF-16/FOXO activity on GSPC maintenance through activating Notch signaling in the germ line. Importantly, expression of a human homologous protein can functionally substitute for DOS-3 in this scenario. As Notch signaling controls the specification of many tissue stem cells, similar mechanisms may exist in other aging stem cell systems.
2024-02-29 | GSE243994 | 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
Project description:FOXO transcription factors control numerous pathways involving metabolism, stress response, and longevity. Although direct targets of FOXO have been reported in various long-lived mutants and under stress conditions, no studies have investigated how normal aging impacts the cellular activity of FOXO. In this study, we compared genome wide dFOXO-bound sites in young and aged wild-type flies kept under normal feeding conditions to evaluate the dynamics of FOXO gene targeting during aging. Our results provide a new insight into FOXO chromatin targeting under a normal aging model and highlight the diverse regulatory mechanisms for FOXO transcriptional activity that are currently less understood.
2019-04-25 | GSE121102 | GEO
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:Age-dependent changes in transcription factor FOXO targeting in Drosophila melanogaster
| PRJNA495643 | ENA
Project description:Post-embryonic development of the nematode C. elegans is governed by nutrient availability. L1-stage larvae remain in a state of developmental arrest after hatching until they feed. This “L1 arrest” (or "L1 diapause") is associated with increased stress resistance, supporting starvation survival. Loss of the transcription factor daf-16/FOXO, an effector of insulin/IGF signaling, results in arrest-defective and starvation-sensitive phenotypes. We show that daf-16/FOXO regulates L1 arrest cell-nonautonomously, suggesting that insulin/IGF signaling regulates at least one additional signaling pathway. We used mRNA-seq to identify candidate signaling molecules affected by daf-16/FOXO during L1 arrest. daf-16/FOXO had overlapping but distinct effects on gene expression in L1 arrest compared to daf-2/InsR adults. Notably, dbl-1/TGF-β, a ligand for the Sma/Mab pathway, and daf-36, which encodes an upstream component of the daf-12/NHR steroid hormone signaling pathway, were up-regulated during L1 arrest in a daf-16/FOXO mutant. Using genetic epistasis analysis, we show that dbl-1/TGF-β and daf-12/NHR steroid hormone signaling pathways are required for the daf-16/FOXO arrest-defective phenotype, suggesting that daf-16/FOXO represses dbl-1/TGF-β and daf-36. The dbl-1/TGF-β and daf-12/NHR pathways have not previously been shown to affect L1 development, but we found that disruption of these pathways delayed L1 development in fed larvae, consistent with these pathways promoting development in starved daf-16/FOXO mutants. Though the dbl-1/TGF-β and daf-12/NHR pathways are epistatic to daf-16/FOXO for the arrest-defective phenotype, disruption of these pathways does not suppress starvation sensitivity of daf-16/FOXO mutants. This observation uncouples starvation survival from developmental arrest, indicating that DAF-16/FOXO targets distinct effectors for each phenotype, and revealing that inappropriate development during starvation does not cause the early demise of daf-16/FOXO mutants. Overall, this study shows that daf-16/FOXO promotes developmental arrest cell-nonautonomously by repressing pathways that promote larval development.
2016-05-27 | GSE69329 | GEO