Gluconeogenesis and PEPCK are critical components of healthy aging and dietary restriction life extension.

Abstract:

:High glucose diets are unhealthy, although the mechanisms by which elevated glucose is harmful to whole animal physiology are not well understood. In Caenorhabditis elegans, high glucose shortens lifespan, while chemically inflicted glucose restriction promotes longevity. We investigated the impact of glucose metabolism on aging quality (maintained locomotory capacity and median lifespan) and found that, in addition to shortening lifespan, excess glucose negatively impacts locomotory healthspan. Conversely, disrupting glucose utilization by knockdown of glycolysis-specific genes results in large mid-age physical improvements via a mechanism that requires the FOXO transcription factor DAF-16. Adult locomotory capacity is extended by glycolysis disruption, but maximum lifespan is not, indicating that limiting glycolysis can increase the proportion of life spent in mobility health. We also considered the largely ignored role of glucose biosynthesis (gluconeogenesis) in adult health. Directed perturbations of gluconeogenic genes that specify single direction enzymatic reactions for glucose synthesis decrease locomotory healthspan, suggesting that gluconeogenesis is needed for healthy aging. Consistent with this idea, overexpression of the central gluconeogenic gene pck-2 (encoding PEPCK) increases health measures via a mechanism that requires DAF-16 to promote pck-2 expression in specific intestinal cells. Dietary restriction also features DAF-16-dependent pck-2 expression in the intestine, and the healthspan benefits conferred by dietary restriction require pck-2. Together, our results describe a new paradigm in which nutritional signals engage gluconeogenesis to influence aging quality via DAF-16. These data underscore the idea that promotion of gluconeogenesis might be an unappreciated goal for healthy aging and could constitute a novel target for pharmacological interventions that counter high glucose consequences, including diabetes.

journal_name

PLoS Genet

journal_title

PLoS genetics

authors

Onken B,Kalinava N,Driscoll M

doi

10.1371/journal.pgen.1008982

subject

Has Abstract

pub_date

2020-08-25 00:00:00

pages

e1008982

issue

8

eissn

1553-7390

issn

1553-7404

pii

PGENETICS-D-19-01625

journal_volume

16

pub_type

杂志文章
  • Liver-Enriched Gene 1, a Glycosylated Secretory Protein, Binds to FGFR and Mediates an Anti-stress Pathway to Protect Liver Development in Zebrafish.

    abstract::Unlike mammals and birds, teleost fish undergo external embryogenesis, and therefore their embryos are constantly challenged by stresses from their living environment. These stresses, when becoming too harsh, will cause arrest of cell proliferation, abnormal cell death or senescence. Such organisms have to evolve a so...

    journal_title:PLoS genetics

    pub_type: 杂志文章

    doi:10.1371/journal.pgen.1005881

    authors: Hu M,Bai Y,Zhang C,Liu F,Cui Z,Chen J,Peng J

    更新日期:2016-02-22 00:00:00

  • Insight into Genotype-Phenotype Associations through eQTL Mapping in Multiple Cell Types in Health and Immune-Mediated Disease.

    abstract::Genome-wide association studies (GWAS) have transformed our understanding of the genetics of complex traits such as autoimmune diseases, but how risk variants contribute to pathogenesis remains largely unknown. Identifying genetic variants that affect gene expression (expression quantitative trait loci, or eQTLs) is c...

    journal_title:PLoS genetics

    pub_type: 杂志文章

    doi:10.1371/journal.pgen.1005908

    authors: Peters JE,Lyons PA,Lee JC,Richard AC,Fortune MD,Newcombe PJ,Richardson S,Smith KG

    更新日期:2016-03-25 00:00:00

  • DNA methylation dynamics in human induced pluripotent stem cells over time.

    abstract::Epigenetic reprogramming is a critical event in the generation of induced pluripotent stem cells (iPSCs). Here, we determined the DNA methylation profiles of 22 human iPSC lines derived from five different cell types (human endometrium, placental artery endothelium, amnion, fetal lung fibroblast, and menstrual blood c...

    journal_title:PLoS genetics

    pub_type: 杂志文章

    doi:10.1371/journal.pgen.1002085

    authors: Nishino K,Toyoda M,Yamazaki-Inoue M,Fukawatase Y,Chikazawa E,Sakaguchi H,Akutsu H,Umezawa A

    更新日期:2011-05-01 00:00:00

  • A single Ho-induced double-strand break at the MAT locus is lethal in Candida glabrata.

    abstract::Mating-type switching is a complex mechanism that promotes sexual reproduction in Saccharomycotina. In the model species Saccharomyces cerevisiae, mating-type switching is initiated by the Ho endonuclease that performs a site-specific double-strand break (DSB) at MAT, repaired by homologous recombination (HR) using on...

    journal_title:PLoS genetics

    pub_type: 杂志文章

    doi:10.1371/journal.pgen.1008627

    authors: Maroc L,Zhou-Li Y,Boisnard S,Fairhead C

    更新日期:2020-10-15 00:00:00

  • The (p)ppGpp-binding GTPase Era promotes rRNA processing and cold adaptation in Staphylococcus aureus.

    abstract::Ribosome assembly cofactors are widely conserved across all domains of life. One such group, the ribosome-associated GTPases (RA-GTPase), act as molecular switches to coordinate ribosome assembly. We previously identified the Staphylococcus aureus RA-GTPase Era as a target for the stringent response alarmone (p)ppGpp,...

    journal_title:PLoS genetics

    pub_type: 杂志文章

    doi:10.1371/journal.pgen.1008346

    authors: Wood A,Irving SE,Bennison DJ,Corrigan RM

    更新日期:2019-08-29 00:00:00

  • Convergent evolution of linked mating-type loci in basidiomycete fungi.

    abstract::Sexual development is a key evolutionary innovation of eukaryotes. In many species, mating involves interaction between compatible mating partners that can undergo cell and nuclear fusion and subsequent steps of development including meiosis. Mating compatibility in fungi is governed by the mating type (MAT) loci. In ...

    journal_title:PLoS genetics

    pub_type: 杂志文章

    doi:10.1371/journal.pgen.1008365

    authors: Sun S,Coelho MA,Heitman J,Nowrousian M

    更新日期:2019-09-06 00:00:00

  • Cellular variability of RpoS expression underlies subpopulation activation of an integrative and conjugative element.

    abstract::Conjugative transfer of the integrative and conjugative element ICEclc in the bacterium Pseudomonas knackmussii is the consequence of a bistable decision taken in some 3% of cells in a population during stationary phase. Here we study the possible control exerted by the stationary phase sigma factor RpoS on the bistab...

    journal_title:PLoS genetics

    pub_type: 杂志文章

    doi:10.1371/journal.pgen.1002818

    authors: Miyazaki R,Minoia M,Pradervand N,Sulser S,Reinhard F,van der Meer JR

    更新日期:2012-01-01 00:00:00

  • The Hippo pathway regulates homeostatic growth of stem cell niche precursors in the Drosophila ovary.

    abstract::The Hippo pathway regulates organ size, stem cell proliferation and tumorigenesis in adult organs. Whether the Hippo pathway influences establishment of stem cell niche size to accommodate changes in organ size, however, has received little attention. Here, we ask whether Hippo signaling influences the number of stem ...

    journal_title:PLoS genetics

    pub_type: 杂志文章

    doi:10.1371/journal.pgen.1004962

    authors: Sarikaya DP,Extavour CG

    更新日期:2015-02-02 00:00:00

  • Endothelin receptor Aa regulates proliferation and differentiation of Erb-dependent pigment progenitors in zebrafish.

    abstract::Skin pigment patterns are important, being under strong selection for multiple roles including camouflage and UV protection. Pigment cells underlying these patterns form from adult pigment stem cells (APSCs). In zebrafish, APSCs derive from embryonic neural crest cells, but sit dormant until activated to produce pigme...

    journal_title:PLoS genetics

    pub_type: 杂志文章

    doi:10.1371/journal.pgen.1007941

    authors: Camargo-Sosa K,Colanesi S,Müller J,Schulte-Merker S,Stemple D,Patton EE,Kelsh RN

    更新日期:2019-02-27 00:00:00

  • Inflammation-mediated genetic and epigenetic alterations drive cancer development in the neighboring epithelium upon stromal abrogation of TGF-β signaling.

    abstract::Deletion of tumor suppressor genes in stromal fibroblasts induces epithelial cancer development, suggesting an important role of stroma in epithelial homoeostasis. However, the underlying mechanisms remain to be elucidated. Here we report that deletion of the gene encoding TGFβ receptor 2 (Tgfbr2) in the stromal fibro...

    journal_title:PLoS genetics

    pub_type: 杂志文章

    doi:10.1371/journal.pgen.1003251

    authors: Achyut BR,Bader DA,Robles AI,Wangsa D,Harris CC,Ried T,Yang L

    更新日期:2013-01-01 00:00:00

  • A combinatorial amino acid code for RNA recognition by pentatricopeptide repeat proteins.

    abstract::The pentatricopeptide repeat (PPR) is a helical repeat motif found in an exceptionally large family of RNA-binding proteins that functions in mitochondrial and chloroplast gene expression. PPR proteins harbor between 2 and 30 repeats and typically bind single-stranded RNA in a sequence-specific fashion. However, the b...

    journal_title:PLoS genetics

    pub_type: 杂志文章

    doi:10.1371/journal.pgen.1002910

    authors: Barkan A,Rojas M,Fujii S,Yap A,Chong YS,Bond CS,Small I

    更新日期:2012-01-01 00:00:00

  • Coronary heart disease-associated variation in TCF21 disrupts a miR-224 binding site and miRNA-mediated regulation.

    abstract::Genome-wide association studies (GWAS) have identified chromosomal loci that affect risk of coronary heart disease (CHD) independent of classical risk factors. One such association signal has been identified at 6q23.2 in both Caucasians and East Asians. The lead CHD-associated polymorphism in this region, rs12190287, ...

    journal_title:PLoS genetics

    pub_type: 杂志文章

    doi:10.1371/journal.pgen.1004263

    authors: Miller CL,Haas U,Diaz R,Leeper NJ,Kundu RK,Patlolla B,Assimes TL,Kaiser FJ,Perisic L,Hedin U,Maegdefessel L,Schunkert H,Erdmann J,Quertermous T,Sczakiel G

    更新日期:2014-03-27 00:00:00

  • Trappc9 deficiency causes parent-of-origin dependent microcephaly and obesity.

    abstract::Some imprinted genes exhibit parental origin specific expression bias rather than being transcribed exclusively from one copy. The physiological relevance of this remains poorly understood. In an analysis of brain-specific allele-biased expression, we identified that Trappc9, a cellular trafficking factor, was express...

    journal_title:PLoS genetics

    pub_type: 杂志文章

    doi:10.1371/journal.pgen.1008916

    authors: Liang ZS,Cimino I,Yalcin B,Raghupathy N,Vancollie VE,Ibarra-Soria X,Firth HV,Rimmington D,Farooqi IS,Lelliott CJ,Munger SC,O'Rahilly S,Ferguson-Smith AC,Coll AP,Logan DW

    更新日期:2020-09-02 00:00:00

  • Cyclin G and the Polycomb Repressive complexes PRC1 and PR-DUB cooperate for developmental stability.

    abstract::In Drosophila, ubiquitous expression of a short Cyclin G isoform generates extreme developmental noise estimated by fluctuating asymmetry (FA), providing a model to tackle developmental stability. This transcriptional cyclin interacts with chromatin regulators of the Enhancer of Trithorax and Polycomb (ETP) and Polyco...

    journal_title:PLoS genetics

    pub_type: 杂志文章

    doi:10.1371/journal.pgen.1007498

    authors: Dardalhon-Cuménal D,Deraze J,Dupont CA,Ribeiro V,Coléno-Costes A,Pouch J,Le Crom S,Thomassin H,Debat V,Randsholt NB,Peronnet F

    更新日期:2018-07-11 00:00:00

  • The meiotic nuclear lamina regulates chromosome dynamics and promotes efficient homologous recombination in the mouse.

    abstract::The nuclear lamina is the structural scaffold of the nuclear envelope and is well known for its central role in nuclear organization and maintaining nuclear stability and shape. In the past, a number of severe human disorders have been identified to be associated with mutations in lamins. Extensive research on this to...

    journal_title:PLoS genetics

    pub_type: 杂志文章

    doi:10.1371/journal.pgen.1003261

    authors: Link J,Jahn D,Schmitt J,Göb E,Baar J,Ortega S,Benavente R,Alsheimer M

    更新日期:2013-01-01 00:00:00

  • Mutation in MRPS34 compromises protein synthesis and causes mitochondrial dysfunction.

    abstract::The evolutionary divergence of mitochondrial ribosomes from their bacterial and cytoplasmic ancestors has resulted in reduced RNA content and the acquisition of mitochondria-specific proteins. The mitochondrial ribosomal protein of the small subunit 34 (MRPS34) is a mitochondria-specific ribosomal protein found only i...

    journal_title:PLoS genetics

    pub_type: 杂志文章

    doi:10.1371/journal.pgen.1005089

    authors: Richman TR,Ermer JA,Davies SM,Perks KL,Viola HM,Shearwood AM,Hool LC,Rackham O,Filipovska A

    更新日期:2015-03-27 00:00:00

  • Reproductive Aging Drives Protein Accumulation in the Uterus and Limits Lifespan in C. elegans.

    abstract::Aging in Caenorhabditis elegans is characterized by widespread physiological and molecular changes, but the mechanisms that determine the rate at which these changes occur are not well understood. In this study, we identify a novel link between reproductive aging and somatic aging in C. elegans. By measuring global ag...

    journal_title:PLoS genetics

    pub_type: 杂志文章

    doi:10.1371/journal.pgen.1005725

    authors: Zimmerman SM,Hinkson IV,Elias JE,Kim SK

    更新日期:2015-12-11 00:00:00

  • E3 ubiquitin ligase CHIP and NBR1-mediated selective autophagy protect additively against proteotoxicity in plant stress responses.

    abstract::Plant stress responses require both protective measures that reduce or restore stress-inflicted damage to cellular structures and mechanisms that efficiently remove damaged and toxic macromolecules, such as misfolded and damaged proteins. We have recently reported that NBR1, the first identified plant autophagy adapto...

    journal_title:PLoS genetics

    pub_type: 杂志文章

    doi:10.1371/journal.pgen.1004116

    authors: Zhou J,Zhang Y,Qi J,Chi Y,Fan B,Yu JQ,Chen Z

    更新日期:2014-01-30 00:00:00

  • Transcription facilitated genome-wide recruitment of topoisomerase I and DNA gyrase.

    abstract::Movement of the transcription machinery along a template alters DNA topology resulting in the accumulation of supercoils in DNA. The positive supercoils generated ahead of transcribing RNA polymerase (RNAP) and the negative supercoils accumulating behind impose severe topological constraints impeding transcription pro...

    journal_title:PLoS genetics

    pub_type: 杂志文章

    doi:10.1371/journal.pgen.1006754

    authors: Ahmed W,Sala C,Hegde SR,Jha RK,Cole ST,Nagaraja V

    更新日期:2017-05-02 00:00:00

  • The monothiol glutaredoxin GrxD is essential for sensing iron starvation in Aspergillus fumigatus.

    abstract::Efficient adaptation to iron starvation is an essential virulence determinant of the most common human mold pathogen, Aspergillus fumigatus. Here, we demonstrate that the cytosolic monothiol glutaredoxin GrxD plays an essential role in iron sensing in this fungus. Our studies revealed that (i) GrxD is essential for gr...

    journal_title:PLoS genetics

    pub_type: 杂志文章

    doi:10.1371/journal.pgen.1008379

    authors: Misslinger M,Scheven MT,Hortschansky P,López-Berges MS,Heiss K,Beckmann N,Heigl T,Hermann M,Krüger T,Kniemeyer O,Brakhage AA,Haas H

    更新日期:2019-09-16 00:00:00

  • A natural system of chromosome transfer in Yersinia pseudotuberculosis.

    abstract::The High Pathogenicity Island of Yersinia pseudotuberculosis IP32637 was previously shown to be horizontally transferable as part of a large chromosomal segment. We demonstrate here that at low temperature other chromosomal loci, as well as a non-mobilizable plasmid (pUC4K), are also transferable. This transfer, desig...

    journal_title:PLoS genetics

    pub_type: 杂志文章

    doi:10.1371/journal.pgen.1002529

    authors: Lesic B,Zouine M,Ducos-Galand M,Huon C,Rosso ML,Prévost MC,Mazel D,Carniel E

    更新日期:2012-01-01 00:00:00

  • DNA dynamics during early double-strand break processing revealed by non-intrusive imaging of living cells.

    abstract::Chromosome breakage is a major threat to genome integrity. The most accurate way to repair DNA double strand breaks (DSB) is homologous recombination (HR) with an intact copy of the broken locus. Mobility of the broken DNA has been seen to increase during the search for a donor copy. Observing chromosome dynamics duri...

    journal_title:PLoS genetics

    pub_type: 杂志文章

    doi:10.1371/journal.pgen.1004187

    authors: Saad H,Gallardo F,Dalvai M,Tanguy-le-Gac N,Lane D,Bystricky K

    更新日期:2014-03-13 00:00:00

  • Unraveling the genetics of human obesity.

    abstract::The use of modern molecular biology tools in deciphering the perturbed biochemistry and physiology underlying the obese state has proven invaluable. Identifying the hypothalamic leptin/melanocortin pathway as critical in many cases of monogenic obesity has permitted targeted, hypothesis-driven experiments to be perfor...

    journal_title:PLoS genetics

    pub_type: 杂志文章,评审

    doi:10.1371/journal.pgen.0020188

    authors: Mutch DM,Clément K

    更新日期:2006-12-29 00:00:00

  • Genetic diversity in the interference selection limit.

    abstract::Pervasive natural selection can strongly influence observed patterns of genetic variation, but these effects remain poorly understood when multiple selected variants segregate in nearby regions of the genome. Classical population genetics fails to account for interference between linked mutations, which grows increasi...

    journal_title:PLoS genetics

    pub_type: 杂志文章

    doi:10.1371/journal.pgen.1004222

    authors: Good BH,Walczak AM,Neher RA,Desai MM

    更新日期:2014-03-27 00:00:00

  • ------Widespread conservation and lineage-specific diversification of genome-wide DNA methylation patterns across arthropods.

    abstract::Cytosine methylation is an ancient epigenetic modification yet its function and extent within genomes is highly variable across eukaryotes. In mammals, methylation controls transposable elements and regulates the promoters of genes. In insects, DNA methylation is generally restricted to a small subset of transcribed g...

    journal_title:PLoS genetics

    pub_type: 杂志文章

    doi:10.1371/journal.pgen.1008864

    authors: Lewis SH,Ross L,Bain SA,Pahita E,Smith SA,Cordaux R,Miska EA,Lenhard B,Jiggins FM,Sarkies P

    更新日期:2020-06-25 00:00:00

  • The Caenorhabditis elegans synthetic multivulva genes prevent ras pathway activation by tightly repressing global ectopic expression of lin-3 EGF.

    abstract::The Caenorhabditis elegans class A and B synthetic multivulva (synMuv) genes redundantly antagonize an EGF/Ras pathway to prevent ectopic vulval induction. We identify a class A synMuv mutation in the promoter of the lin-3 EGF gene, establishing that lin-3 is the key biological target of the class A synMuv genes in vu...

    journal_title:PLoS genetics

    pub_type: 杂志文章

    doi:10.1371/journal.pgen.1002418

    authors: Saffer AM,Kim DH,van Oudenaarden A,Horvitz HR

    更新日期:2011-12-01 00:00:00

  • Meta-analysis of genome-wide scans for total body BMD in children and adults reveals allelic heterogeneity and age-specific effects at the WNT16 locus.

    abstract::To identify genetic loci influencing bone accrual, we performed a genome-wide association scan for total-body bone mineral density (TB-BMD) variation in 2,660 children of different ethnicities. We discovered variants in 7q31.31 associated with BMD measurements, with the lowest P = 4.1 × 10(-11) observed for rs917727 w...

    journal_title:PLoS genetics

    pub_type: 杂志文章,meta分析

    doi:10.1371/journal.pgen.1002718

    authors: Medina-Gomez C,Kemp JP,Estrada K,Eriksson J,Liu J,Reppe S,Evans DM,Heppe DH,Vandenput L,Herrera L,Ring SM,Kruithof CJ,Timpson NJ,Zillikens MC,Olstad OK,Zheng HF,Richards JB,St Pourcain B,Hofman A,Jaddoe VW,Smith G

    更新日期:2012-07-01 00:00:00

  • Genetic analysis of floral symmetry in Van Gogh's sunflowers reveals independent recruitment of CYCLOIDEA genes in the Asteraceae.

    abstract::The genetic basis of floral symmetry is a topic of great interest because of its effect on pollinator behavior and, consequently, plant diversification. The Asteraceae, which is the largest family of flowering plants, is an ideal system in which to study this trait, as many species within the family exhibit a compound...

    journal_title:PLoS genetics

    pub_type: 杂志文章

    doi:10.1371/journal.pgen.1002628

    authors: Chapman MA,Tang S,Draeger D,Nambeesan S,Shaffer H,Barb JG,Knapp SJ,Burke JM

    更新日期:2012-01-01 00:00:00

  • Adaptive Protein Evolution in Animals and the Effective Population Size Hypothesis.

    abstract::The rate at which genomes adapt to environmental changes and the prevalence of adaptive processes in molecular evolution are two controversial issues in current evolutionary genetics. Previous attempts to quantify the genome-wide rate of adaptation through amino-acid substitution have revealed a surprising diversity o...

    journal_title:PLoS genetics

    pub_type: 杂志文章

    doi:10.1371/journal.pgen.1005774

    authors: Galtier N

    更新日期:2016-01-11 00:00:00

  • Genetic mechanism of human neutrophil antigen 2 deficiency and expression variations.

    abstract::Human neutrophil antigen 2 (HNA-2) deficiency is a common phenotype as 3-5% humans do not express HNA-2. HNA-2 is coded by CD177 gene that associates with human myeloproliferative disorders. HNA-2 deficient individuals are prone to produce HNA-2 alloantibodies that cause a number of disorders including transfusion-rel...

    journal_title:PLoS genetics

    pub_type: 杂志文章

    doi:10.1371/journal.pgen.1005255

    authors: Li Y,Mair DC,Schuller RM,Li L,Wu J

    更新日期:2015-05-29 00:00:00