Overexpression of CYB5R3 and NQO1, two NAD+ producing enzymes, mimics aspects of caloric restriction
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PROVIDER: PRJNA425944 | ENA |
REPOSITORIES: ENA
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Project description:Calorie restriction (CR) is one of the most robust means to improve health and survival in model organisms. CR imposes a metabolic program that leads to increased stress resistance and delayed onset of chronic diseases, including cancer. In rodents, CR induces the upregulation of two NADH-dehydrogenases, namely NAD(P)H:quinone oxidoreductase 1 (Nqo1) and cytochrome b5 reductase 3 (Cyb5r3), which provide electrons for energy metabolism. It has been proposed that this upregulation may be responsible for some of the beneficial effects of CR, and defects in their activity are linked to aging and several age-associated diseases. However, it is unclear whether changes in metabolic homeostasis solely through up-regulation of these NADH-dehydrogenases have a positive impact on health and survival. We generated a mouse that overexpresses both metabolic enzymes leading to phenotypes that resemble aspects of CR including a modest increase in lifespan, greater physical performance, a decrease in chronic inflammation, and importantly, protection against carcinogenesis, one of the main hallmarks of CR. Furthermore, these animals showed an enhancement of metabolic flexibility and a significant upregulation of the NAD+/sirtuin pathway. The results highlight the importance of these NAD+ producers for the promotion of health and extended lifespan.
2018-07-31 | GSE108379 | GEO
Project description:Calorie restriction (CR) is one of the most robust means to improve health and survival in model organisms. CR imposes a metabolic program that leads to increased stress resistance and delayed onset of chronic diseases, including cancer. In rodents, CR induces the upregulation of two NADH-dehydrogenases, namely NAD(P)H:quinone oxidoreductase 1 (Nqo1) and cytochrome b5 reductase 3 (Cyb5r3), which provide electrons for energy metabolism. It has been proposed that this upregulation may be responsible for some of the beneficial effects of CR, and defects in their activity are linked to aging and several age-associated diseases. However, it is unclear whether changes in metabolic homeostasis solely through upregulation of these NADH-dehydrogenases have a positive impact on health and survival. We generated a mouse that overexpresses both metabolic enzymes leading to phenotypes that resemble aspects of CR including a modest increase in lifespan, greater physical performance, a decrease in chronic inflammation, and, importantly, protection against carcinogenesis, one of the main hallmarks of CR. Furthermore, these animals showed an enhancement of metabolic flexibility and a significant upregulation of the NAD+ /sirtuin pathway. The results highlight the importance of these NAD+ producers for the promotion of health and extended lifespan.
| S-EPMC6052403 | biostudies-literature
Project description:Therapeutic strategies to treat acute kidney injury (AKI) are lacking. Preconditioning by hypoxia (HP) and caloric restriction (CR) is highly protective in rodent AKI models. The underlying molecular mechanisms are unknown. A comparative transcriptome analysis after HP and CR identified Kynureninase (KYNU) as a common downstream target. Using a newly generated KYNU-deficient mouse line, we show that KYNU contributes to the protective effect of preconditioning. Metabolome, transcriptome and proteome analyses reveal KYNU as necessary for CR-associated maintenance of nicotinamide adenine dinucleotide (NAD+) levels. Importantly, the impact of CR on the de novo NAD+ biosynthesis pathway can be recapitulated in humans.
2023-02-13 | PXD038328 | Pride
Project description:The 5’ end of a eukaryotic mRNA generally has a methyl guanosine cap (m7G cap) that not only protects the mRNA from degradation but also mediates almost all other aspects of gene expression. Some RNAs in E. coli, yeast, and mammals were recently found to contain an NAD+ cap at their 5’ ends. Here we report development of a new method – NAD tagSeq – for transcriptome-wide identification and quantification of NAD+-capped RNAs (NAD-RNAs). The method uses first an enzymatic reaction and then a click chemistry reaction to label NAD-RNAs with a synthetic RNA tag. The tagged RNA molecules can be enriched and directly sequenced using the Oxford Nanopore sequencing technology. NAD tagSeq not only allows more accurate identification and quantification of NAD-RNAs but can also reveal sequences of whole NAD-RNA transcripts. Using NAD tagSeq, we found that NAD-RNAs in Arabidopsis are mostly produced from a few thousand protein-coding genes, with over 60% of them from fewer than 200 genes. The top 2,000 genes that were found to produce the highest numbers of NAD-RNAs were enriched in the gene ontology terms of responses to oxidative stress and other stresses, photosynthesis, and protein synthesis. For some Arabidopsis genes, over 10% of their transcripts could be NAD-capped. The NAD-RNAs in Arabidopsis have similar overall sequence structures to their canonical m7G-capped mRNAs. The identification and quantification of NAD-RNAs and revealing their sequence features provide essential steps toward understanding functions of NAD-RNAs.
2019-07-01 | GSE127755 | GEO
Project description:We developed a Copper-free, strain-promoted azide-alkyne cycloaddition reaction (SPAAC) to capture NAD-RNAs without RNA degradation. We examined the specificity of CuAAC and SPAAC reactions towards NAD+ vs. m7G, and found that both prefer NAD+ but also act on m7G. We show that m7G-capped RNA can be immuno-depleted, allowing for the specific identification of NAD-RNA via the SPAAC reaction and sequencing, which we name SPAAC-NAD-seq. Subjecting Arabidopsis RNA to both the original NAD captureSeq and SPAAC-NAD-seq, we found that more NAD+-capped RNA was identified by the latter, particularly those with low abundance. This led to the discovery of new gene ontology terms such as starch biosynthsis, intracellular protein transport and response to cadmium stress associated with genes that produce NAD-RNA. Furthermore, reads were uniformly distributed along gene bodies, which suggested that SPAAC-NAD-seq retained full-length sequence information. SPAAC-NAD-seq enables specific and efficient discovery of NAD-RNA in prokaryotes, and when combined with m7G-RNA depletion, in eukaryotes.
2021-04-14 | GSE162114 | GEO
Project description:To gain deeper insights into antibacterial mechanisms of NAD+ and bacterial adaptation, we generated and sequenced NAD+ resistant clones of Spn. For this purpose, Spn was cultivated in liquid medium with increasing concentrations (50 µM to 5 mM) of NAD+. After six passages, bacteria were plated on blood agar supplemented with 500 µM NAD+ and three clones were picked
2023-06-11 | E-MTAB-12644 | biostudies-arrayexpress
Project description:NAD+ supplementation has been shown to impart significant benefits in compromised settings, acting largely through improved mitochondrial function and DNA repair. Elevated NAD+ has been shown to improve the function of some adult stem cells, with implications that these changes could lead to sustained improvement of the tissue or system. We examined the effect of elevating NAD+ levels in models with reduced hematopoietic stem cell (HSC) potential (ATM-deficient and aged mice) and show that supplementation of NR, a NAD+ precursor, leads to improved lymphoid lineage potential and long-term cell-autonomous benefits. Transcriptional profiles from HSCs show changes driven by NR repress myeloid gene signatures, which may lead to the increased lymphoid output. Our work characterizes the improved lymphoid-potential from short-term NR treatment in functionally compromised HSCs and highlights potentially detrimental aspects of supplementing NAD+ to proficient systems.
2021-09-14 | GSE147662 | GEO
Project description:Microbiota of caloric restricted mice by WMGS
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Project description:Cockayne syndrome (CS) is an accelerated aging disorder characterized by progressive neurodegeneration caused by mutations in the genes encoding the DNA repair proteins CSA or CSB. Csbm/m mice were given a high-fat, caloric-restricted or resveratrol-supplemented diet. The high-fat diet rescued the phenotype of Csbm/m mice at the metabolic, transcriptomic and behavioral levels. Additional analysis suggests that the premature aging seen in CS mice, nematodes and human cells results from aberrant PARP activation due to deficient DNA repair leading to decreased SIRT1 activity and mitochondrial dysfunction. Notably, β-hydroxybutyrate levels are increased by the high-fat diet; and β-hydroxybutyrate, PARP inhibition, or NAD+ supplementation can activate SIRT1 and rescue CS-associated phenotypes. Mechanistically, CSB is able to displace activated PARP1 from damaged DNA to limit its activity. This study connects two emerging longevity metabolites, β-hydroxybutyrate and NAD+, through the deacetylase SIRT1 and suggests possible interventions for CS.
2014-12-22 | GSE62194 | GEO