In vivo cells from liver and brain from mice treated with control and keto diet collected in different ages - 12 and 26 months
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE253612 | GEO | 2024/01/31
REPOSITORIES: GEO
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Project description:Beta-hydroxybutyrate (BHB) is a ketone body synthesized during fasting or strenuous exercise. Our previous study demonstrated that a cyclic ketogenic diet (KD), which induces BHB levels similar to fasting every other week, reduces midlife mortality and improves memory in aging mice. BHB actively regulates gene expression and inflammatory activation through non-energetic signaling pathways. Neither of these activities has been well-characterized in the brain and they may represent mechanisms by which BHB affects brain function during aging. First, we analyzed hepatic gene expression in an aging KD-treated mouse cohort using bulk RNA-seq. In addition to the downregulation of TOR pathway activity, cyclic KD reduces inflammatory gene expression in the liver. We observed via flow cytometry that KD also modulates age-related systemic T cell functions. Next, we investigated whether BHB affects brain cells transcriptionallyin vitro. Gene expression analysis in primary human brain cells (microglia, astrocytes, neurons) using RNA-seq shows that BHB causes a mild level of inflammation in all three cell types. However, BHB inhibits the more pronounced LPS-induced inflammatory gene activation in microglia. Furthermore, we confirmed that BHB similarly reduces LPS-induced inflammation in primary mouse microglia and bone marrow-derived macrophages (BMDMs). BHB is recognized as an inhibitor of histone deacetylase (HDAC), an inhibitor of NLRP3 inflammasome, and an agonist of the GPCR Hcar2. Nevertheless, in microglia, BHB's anti-inflammatory effects are independent of these known mechanisms. Finally, we examined the brain gene expression of 12-month-old male mice fed with one-week and one-year cyclic KD. While a one-week KD increases inflammatory signaling, a one-year cyclic KD reduces neuroinflammation induced by aging. In summary, our findings demonstrate that BHB mitigates the microglial response to inflammatory stimuli, like LPS, possibly leading to decreased chronic inflammation in the brain after long-term KD treatment in aging mice.
2024-01-31 | GSE252513 | GEO
Project description:The ketone body β-hydroxybutyrate (BHB) is produced during dietary restriction, fasting, and exercise. A ketogenic diet (KD) results in long-term production of BHB outside of these contexts. We sought to determine a protein-matched, non-obese ketogenic diet (KD) would affect the longevity and healthspan of C57BL/6 male mice. We find that feeding KD every-other-week to prevent obesity (cyclic KD) reduces mid-life mortality but does not affect maximum lifespan. Similar feeding of a non-ketogenic high-fat/low-carbohydrate (HF) diet may have an intermediate effect on mortality. Cyclic KD improves memory performance in old age, while modestly improving composite measures of healthspan. RNAseq gene expression analysis identifies down-regulation of insulin, TOR, and fatty acid synthesis pathways as possible longevity mechanisms common to KD and HF. However, up-regulation of fasting-related PPARα target genes is unique to KD, consistent across tissues, and preserved in old age, suggesting a mechanism for an incremental benefit from KD. In all, we show that a non-obese ketogenic diet improves survival, memory, and healthspan into old age. These gene expression studies were carried out on 12 month-old male C56BL/6 mice from the NIA Aged Rodent Colony, habituated to AIN-93M control diet and then either maintained on this diet or switched for one week to a 75% kcal fat non-ketogenic high-fat diet or a 90% kcal fat ketogenic diet (all diets with 10% kcal from carbohydrates). Tissues were harvested in the middle of the nighttime feeding period (MN-3am).
2017-09-05 | GSE101657 | GEO
Project description:The Ketogenic Diet (KD) has been shown by two groups to improve cognition, memory and longevity in aged C57BL6 mice. We tested the impact of 7 months feeding the isocaloric Ketogenic Diet (KD) vs. the isocaloric standard carbohydrate-rich control diet (CD) in a mouse model of Alzheimer’s disease, APP/PS1. The KD vs. CD diets produced no significant changes in fat mass, lean Mass, or total body mass, or A-beta levels in brain. While the CD-fed APP/PS1 mice demonstrated the expected loss of Long-Term-Potentiation (LTP), LTP was completely preserved in KD-fed APP/PS1 mice to wild-type levels. RNAseq was carried out from these CD and KD-fed mouse brains, in the resulting Ingenuity Pathway Analysis the top 6 pathways induced in APP/PS1 brains on KD related to Synaptic Plasticity. Multiple biochemical elements of this pathway were evaluated in CD and KD hippocampi. Significant elevations of phospho-Erk and phospho-CREB were observed in KD vs. CD, and significant elevations of BDNF were observed in KD vs. CD females. The major effector of KD’s benefit is considered to be beta-hydroxybutyrate (BHB). BHB levels were significantly elevated in KD vs. CD mice, and fasting BHB levels were higher in females than male. We suggest that KD may rescue LTP not by reducing A-beta amyloid levels, but through higher BHB that may support greater synaptic plasticity in the face of A-beta amyloid synaptic challenge.
2023-12-31 | GSE230469 | GEO
Project description:Anorexia and fasting are host adaptations to acute infection, inducing a metabolic switch towards ketogenesis and the production of ketone bodies, including β-hydroxybutyrate (BHB). However, whether ketogenesis metabolically influences the immune response in pulmonary infections remains unclear. Here we report impaired production of BHB in humans with SARS-CoV-2-induced but not influenza-induced acute respiratory distress syndrome (ARDS). BHB promotes the survival and the production of Interferon-g from CD4+ T cells. Using metabolic tracing analysis, we uncovered that BHB provides an alternative carbon source to fuel oxidative phosphorylation (OXPHOS) and the production of bioenergetic amino acids and glutathione, which is important for maintaining the redox balance. T cells from patients with SARS-CoV-2-induced ARDS were exhausted and skewed towards glycolysis, but can be metabolically reprogrammed by BHB to perform OXPHOS, thereby increasing their functionality. Finally, we find that ketogenic diet (KD) reduced pulmonary fibrosis, a feature particular pronounced in COVID-19 ARDS and delivery of BHB as ketone ester drink reduces the mortality of SARS-CoV-2 infected mice. Altogether, our data suggest that impaired ketogenesis in patients with SARS-CoV-2 infection accounts, at least partially for disease progression and that supplementation ketone ester might represent an easy-to-implement treatment to improve the clinical outcome of COVID-19 patients.
2022-07-01 | GSE207077 | GEO
Project description:Aging is a complex biological process that compromises brain function and neuronal network activity, leading to cognitive decline and synaptic dysregulation. In recent years, a cyclic Ketogenic Diet (KD) has emerged as a potential treatment to ameliorate cognitive decline by improving memory in aged mice after long-term administration. However, whether short-term cyclic KD administration later in life preserves memory has not been addressed in detail. Accordingly, here we investigated how a short-term cyclic KD starting at 20-23 months-old regulates brain function of aged mice. Behavioral testing and long-term potentiation (LTP) recordings revealed that a cyclic KD improves working memory and hippocampal LTP in 24-27 months-old mice after 16 weeks of treatment. Moreover, the diet also promotes higher dendritic arborization complexity and dendritic spine density in the prefrontal cortex. Furthermore, to elucidate the molecular mechanisms underlying the memory improvements elicited by a cyclic KD, cortical synaptosomes of aged mice fed with this diet for 1 year were analyzed by mass spectrometry. Bioinformatics analysis revealed that long-term cyclic KD administration predominantly modulates the presynaptic compartment by inducing changes in the cAMP/PKA signaling pathway, the synaptic vesicle cycle and the actin/microtubule cytoskeleton. To test these findings in vivo, synaptic proteins from cortices of 24-27 month-old mice fed with control or cyclic KD for 16 weeks were analyzed by western blot. Interestingly, increased Brain Derived Neurotrophic Factor abundance, MAP2 phosphorylation and PKA activity were observed. Overall, we show that a cyclic KD regulates brain function and memory even when it is administered at late mid-life and significantly triggers several molecular features of long-term administration, including the PKA signaling pathway and cytoskeleton dynamics, thus promoting synaptic plasticity at advanced age.
2023-08-08 | MSV000092626 | MassIVE
Project description:Caveolae are plasma membrane invaginations found in most cells of mammals. Caveolin-1 (Cav1) encodes a major protein of the lipid rafts of these membrane structures. Cav1-null mice, though viable, show various phenotypic defects. At an early adult age, these mice show brain aging that resemble brain of one and half year old wildtype mice, and exhibit symptoms that are hallmarks of Alzheimer’s disease. It is not known if the ablation of Cav1 in these mice impacts the brain at the fetal stage that then influences brain function later in life. RNA-seq was performed to profile gene expression of fetal brain (gestation day 15) and aging brain (week 70) of Cav1 knockout mice. The data was comapred with genes expression data of fetal brain (gestation day 15) and aging brain (week 70) of wildtype mice from our earlier study.
2023-09-20 | GSE215139 | GEO
Project description:Intermittent fasting (IF) reduces cardiovascular risk factors in animals and humans, and can protect the heart against ischemic injury in models of myocardial infarction, but the underlying molecular mechanisms are unknown. To delineate molecular perturbations in response to IF, we carried out comprehensive analyses of molecular pathways and biological processes using proteomic and phosphoproteomic data followed by functional analysis of hearts from mice maintained for 6 months on either daily 12- or 16-hour fasting, every-other-day fasting or ad libitum control feeding regimens. IF regimens significantly affected pathways that regulate cyclic GMP signaling, lipid and amino acid metabolism, cell adhesion, cell death and inflammation. Comparison of differentially expressed proteome and transcriptome upon IF showed higher correlation of pathway alternation in early IF regimen, but inverse correlation of metabolic processes such as fatty acid oxidation and immune processes in later IF regimens. Echocardiographic analyses demonstrated that IF enhances stress-induced cardiac performance. In addition to providing a valuable resource, our systemic analyses reveal molecular framework for understanding how IF impacts the function of the heart and its vulnerability to injury and disease.
2023-09-27 | PXD015452 | Pride
Project description:Purpose: To test the role of Myc in adaptive expansion of beta cells Methods: Islets were isolated from 8 week old or one year old male C57BL6 mice fed a standard or high fat diet. RNAseq and DNA mehtylseq was performed. Results: RNAseq showed that Myc target genes are upregulted in young, but not old mice after a short term high fat diet. DNA methylation analysis shows hypomethylation of cell cycle genes that are Myc targets in islets from young mice fed with a HFD. Importantly, DNA hypomethylation of Myc response elements does not occur in islets from one-year-old mice fed short-term HFD Conclusions: We conclude that Myc is required for metabolic stress-mediated beta cell expansion in young mice, but with aging Myc upregulation in beta cells is not sufficient to induce beta cell replication by, at least partly, an epigenetically-mediated resistance to Myc action.
2020-09-29 | GSE131941 | GEO
Project description:Objective Obesity is a multidimensional condition that is treatable by the restoration of a lean phenotype; however, some obesity-related outcomes may persist after weight normalization. Among the organs of the human body, the brain possesses a relatively low regenerative capacity and could retain perturbations established as a result of developmental obesity. Calorie restriction (CR) or a restricted ketogenic diet (KD) are successfully used as weight loss approaches, but their impact on obesity-related effects in the brain have not been previously evaluated. Methods We performed a series of experiments in a rat model of developmental obesity induced by a 12-week cafeteria diet, followed by CR to implement weight loss. First, we assessed the impact of obesity on neurogenesis (BrdU incorporation into the hippocampus), cognitive function (water maze), and concomitant changes in hippocampal protein expression (GC/MS-MS, western blot). Next, we repeated these experiments in a rat model of weight loss induced by CR. We also measured mitochondrial enzyme activity in rats after weight loss during the fed or fasting state. By using a modified version of the water maze we evaluated cognitive abilities in rats subjected to weight loss by CR or a restricted KD. Results In this study, obesity affected metabolic processes, upregulated hippocampal NF-κB, and induced proteomic differences which were associated with impaired cognition and neurogenesis. Weight loss improved neurogenesis and enhanced cognition. While the expression pattern of some proteins persisted after weight loss, most of the changes appeared de novo revealing metabolic adjustment by overactivation of citrate synthase and downregulation of ATP synthase. As a consequence of fasting, the activity of these enzymes indicated hippocampal adaptation to negative energy balance during the weight loss phase of CR. Moreover, the effects on cognitive abilities measured after weight loss were negatively correlated with the obesity level and were alleviated by KD, which improved cognition when used as a weight loss approach. Conclusions The study shows that cognition and mitochondrial metabolism in the hippocampus are affected by CR- or KD-induced weight loss.
2021-07-01 | PXD023070 | Pride
Project description:Aging is a common risk factor in neurodegenerative disorders and the ability to investigate aging of neurons in an isogenic background would facilitate discovering the interplay between neuronal aging and onset of neurodegeneration. Here, we perform direct neuronal reprogramming of longitudinally collected human fibroblasts to reveal genetic pathways altered at different ages. Comparative transcriptome analysis of longitudinally aged striatal medium spiny neurons (MSNs), a primary neuronal subtype affected in Huntington's disease (HD), identified pathways associated with RCAN1, a negative regulator of calcineurin. Notably, RCAN1 undergoes age-dependent increase at the protein level detected in reprogrammed MSNs as well as in human postmortem striatum. In patient-derived MSNs of adult-onset HD (HD-MSNs), counteracting RCAN1 by gene knockdown (KD) rescued HD-MSNs from degeneration. The protective effect of RCAN1 KD was associated with enhanced chromatin accessibility of genes involved in longevity and autophagy, mediated through enhanced calcineurin activity, which in turn dephosphorylates and promotes nuclear localization of TFEB transcription factor. Furthermore, we reveal that G2-115 compound, an analog of glibenclamide with autophagy-enhancing activities, reduces the RCAN1-Calcineurin interaction, phenocopying the effect of RCAN1 KD. Our results demonstrate that RCAN1 is a potential genetic or pharmacological target whose reduction-of-function increases neuronal resilience to neurodegeneration in HD through chromatin reconfiguration.
2023-10-10 | GSE241430 | GEO