Stat1 activation, through systemic interferon signaling, and upregulation of innate immune system receptors drives inflammaging, that is ameliorated by dietary restriction intervention
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE162803 | GEO | 2022/08/25
REPOSITORIES: GEO
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Project description:Aging is the result of an accumulation of molecular damages, driven by multiple factors like metabolic and oxidative stress, (epi)genetic alterations, and microbiome dysbiosis. In addition, aging is characterized by a chronic, low-grade inflammation known as inflammaging that represents a high significant risk factor for most, if not all, age-related diseases. Dietary restriction (DR) is the best-known non-invasive method to ameliorate the aging phenotype in many organisms. While it has been shown that DR reduces the inflammation in some tissues, the molecular mechanisms in old individuals are still largely unknown. Here we identify a multi-tissue gene network which regulates the inflammaging and that is ameliorated by DR. Using transcriptional profiling (RNA-seq), we found that aging upregulates the innate immune system receptor together with the activation of a systemic interferon (IFN) signaling through the Interferon Regulatory Factors (Irf), inflammatory cytokines and finally Stat1 transcription factor. Our results suggest that DR is able to ameliorate inflammaging by downregulating the expression and the activity of almost all the components of this gene network. In addition, chromatin accessibility genome-wide analysis showed that the binding site of Irf and Stat1 in the promoter of their target genes are more open in aging and become closer upon DR treatment indicating a transcriptional control of the inflammaging phenotype involving epigenetic modifications. Our results provide a comprehensive understanding of the molecular network regulating the inflammation in aging and DR and present novel anti-inflammaging therapeutic targets.
2022-08-25 | GSE162802 | GEO
Project description:Aging is the result of an accumulation of molecular damages, driven by multiple factors like metabolic and oxidative stress, (epi)genetic alterations, and microbiome dysbiosis. In addition, aging is characterized by a chronic, low-grade inflammation known as inflammaging that represents a high significant risk factor for most, if not all, age-related diseases. Dietary restriction (DR) is the best-known non-invasive method to ameliorate the aging phenotype in many organisms. While it has been shown that DR reduces the inflammation in some tissues, the molecular mechanisms in old individuals are still largely unknown. Here we identify a multi-tissue gene network which regulates the inflammaging and that is ameliorated by DR. Using transcriptional profiling (RNA-seq), we found that aging upregulates the innate immune system receptor together with the activation of a systemic interferon (IFN) signaling through the Interferon Regulatory Factors (Irf), inflammatory cytokines and finally Stat1 transcription factor. Our results suggest that DR is able to ameliorate inflammaging by downregulating the expression and the activity of almost all the components of this gene network. In addition, chromatin accessibility genome-wide analysis showed that the binding site of Irf and Stat1 in the promoter of their target genes are more open in aging and become closer upon DR treatment indicating a transcriptional control of the inflammaging phenotype involving epigenetic modifications. Our results provide a comprehensive understanding of the molecular network regulating the inflammation in aging and DR and present novel anti-inflammaging therapeutic targets.
2022-08-25 | GSE162728 | GEO
Project description:Chronic inflammation predisposes to aging-associated disease, but it is unknown whether immunity regulation might be important for extending healthy lifespan. Here we show that in C. elegans, dietary restriction (DR) extends lifespan by modulating a conserved innate immunity pathway that is regulated by p38 signaling and the transcription factor ATF-7. Longevity from DR depends upon p38-ATF-7 immunity being intact but downregulated to a basal level. p38-ATF-7 immunity accelerates aging when hyperactive, influences lifespan independently of pathogen exposure, and is activated by nutrients independently of mTORC1, a major DR mediator. Longevity from reduced insulin/IGF-1 signaling (rIIS) also involves p38-ATF-7 downregulation, with signals from DAF-16/FOXO reducing food intake. We conclude that p38-ATF-7 is an immunometabolic pathway that senses bacterial and nutrient signals, that immunity modulation is critical for DR, and that DAF-16/FOXO couples appetite to growth regulation. These conserved mechanisms may influence aging in more complex organisms.
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Project description:Calorie restriction (CR) has been shown to extend lifespan and retard aging-related functional decline in animals. Previously, we found that the anti-neoplastic and lifespan-extending effects of CR in mice are regulated by forkhead box O transcription factors (FoxO1 and FoxO3), located downstream of growth hormone (GH)-insulin-like growth factor (IGF)-1 signaling, in an isoform-specific manner. Inflammaging is a term coined to represent that persistent low-level of inflammation underlies the progression of aging and related diseases. Attenuation of inflammaging in the body may underlie the effects of CR. Recent studies have also identified cellular senescence and activation of the nucleotide-binding domain, leucine-rich-containing family, pyrin-domain-containing-3 (NLRP3) inflammasome as causative factors of inflammaging. In this paper, we reviewed the current knowledge of the molecular mechanisms linking the effects of CR with the formation of inflammasomes, particularly focusing on possible relations with FoxO3. Inflammation in the brain that affects adult neurogenesis and lifespan was also reviewed as evidence of inflammaging. A recent progress of microRNA research was described as regulatory circuits of initiation and propagation of inflammaging. Finally, we briefly introduced our preliminary results obtained from the mouse models, in which Foxo1 and Foxo3 genes were conditionally knocked out in the myeloid cell lineage.
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Project description:Despite regulation, brain iron increases with aging and may enhance aging processes including neuroinflammation. Increases in magnetic resonance imaging transverse relaxation rates, R2 and R2*, in the brain have been observed during aging. We show R2 and R2* correlate well with iron content via direct correlation to semi-quantitative synchrotron-based X-ray fluorescence iron mapping, with age-associated R2 and R2* increases reflecting iron accumulation. Iron accumulation was concomitant with increased ferritin immunoreactivity in basal ganglia regions except in the substantia nigra (SN). The unexpected dissociation of iron accumulation from ferritin-upregulation in the SN suggests iron dyshomeostasis in the SN. Occurring alongside microgliosis and astrogliosis, iron dyshomeotasis may contribute to the particular vulnerability of the SN. Dietary restriction (DR) has long been touted to ameliorate brain aging and we show DR attenuated age-related in vivo R2 increases in the SN over ages 7 - 19 months, concomitant with normal iron-induction of ferritin expression and decreased microgliosis. Iron is known to induce microgliosis and conversely, microgliosis can induce iron accumulation, which of these may be the initial pathological aging event warrants further investigation. We suggest iron chelation therapies and anti-inflammatory treatments may be putative 'anti-brain aging' therapies and combining these strategies may be synergistic.
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Project description:Dietary protein dilution (DPD) promotes metabolic remodelling and health but the precise nutritional components driving this response remain elusive. Here we demonstrate that dietary amino acids (AA) are sufficient and necessary to drive the response to DPD. In particular, the restriction of dietary essential AA (EAA) supply, but not non-EAA, drives the systemic metabolic response to total AA deprivation. Furthermore, systemic deprivation of Thr and Trp, independent of total AA supply, are both adequate and necessary to confer the systemic metabolic response to both diet, and genetic AA-transport loss, driven AA restriction. Thr is also potentially limiting in low-protein diet fed humans, and dietary Thr restriction (DTR) retarded the development of obesity-associated metabolic dysfunction in mice. Liver-derived fibroblast growth factor 21 was required for the metabolic remodelling with DTR. Strikingly, hepatocyte-selective establishment of Thr biosynthetic capacity reversed the systemic response to DTR. Taken together, our studies demonstrate that the restriction of EAA are sufficient and necessary to confer the systemic metabolic effects of DPD.
2020-06-15 | PXD018205 | Pride
Project description:Dietary protein dilution (DPD) promotes metabolic-remodelling and -health but the precise nutritional components driving this response remain elusive. Here, by mimicking amino acid (AA) supply from a casein-based diet, we demonstrate that restriction of dietary essential AA (EAA), but not non-EAA, drives the systemic metabolic response to total AA deprivation; independent from dietary carbohydrate supply. Furthermore, systemic deprivation of threonine and tryptophan, independent of total AA supply, are both adequate and necessary to confer the systemic metabolic response to both diet, and genetic AA-transport loss, driven AA restriction. Dietary threonine restriction (DTR) retards the development of obesity-associated metabolic dysfunction. Liver-derived fibroblast growth factor 21 is required for the metabolic remodelling with DTR. Strikingly, hepatocyte-selective establishment of threonine biosynthetic capacity reverses the systemic metabolic response to DTR. Taken together, our studies of mice demonstrate that the restriction of EAA are sufficient and necessary to confer the systemic metabolic effects of DPD.
| S-EPMC7283339 | biostudies-literature
Project description:Compared to low-fat diets, low-carbohydrate (CHO) diets cause weight loss (WL) over a faster time frame; however, it is unknown how changes in food cravings and eating behavior contribute to this more rapid WL in the early phases of dieting. We hypothesized that reductions in food cravings and improved eating behaviors would be evident even after a relatively short (4-week) duration of CHO-restriction, and that these changes would be associated with WL. Adult participants (n = 19, 53% males, mean ± SD: BMI = 34.1 ± 0.8 kg/m2; age 40.6 ± 1.9 years) consumed a CHO-restricted diet (14% CHO, 58% fat, 28% protein) for 4 weeks. Before and after the intervention, specific and total cravings were measured with the Food Craving Inventory (FCI) and eating behaviors assessed with the Three-Factor Eating questionnaire. Food cravings were significantly reduced at week 4, while women had significantly greater reductions in sweet cravings than men. Dietary restraint was significantly increased by 102%, while disinhibiton and hunger scores were reduced (17% and 22%, respectively, p < 0.05). Changes in cravings were unrelated to changes in body weight except for the change in high-fat cravings where those who lost the most weight experienced the least reductions in fat cravings (r = -0.458, p = 0.049). Changes in dietary restraint were inversely related to several FCI subscales. A short-term, low-CHO diet was effective in reducing food cravings. These data suggest that in subjects that have successfully lost weight on a low-CHO diet, those who craved high-fat foods at the onset were able to satisfy their cravings-potentially due to the high-fat nature of this restricted diet.
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