title: Life span extension by targeting a link between metabolism and histone acetylation in Drosophila.
abstract: Old age is associated with a progressive decline of mitochondrial function and changes in nuclear chromatin. However, little is known about how metabolic activity and epigenetic modifications change as organisms reach their midlife. Here, we assessed how cellular metabolism and protein acetylation change during early aging in Drosophila melanogaster. Contrary to common assumptions, we find that flies increase oxygen consumption and become less sensitive to histone deacetylase inhibitors as they reach midlife. Further, midlife flies show changes in the metabolome, elevated acetyl-CoA levels, alterations in protein-notably histone-acetylation, as well as associated transcriptome changes. Based on these observations, we decreased the activity of the acetyl-CoA-synthesizing enzyme ATP citrate lyase (ATPCL) or the levels of the histone H4 K12-specific acetyltransferase Chameau. We find that these targeted interventions both alleviate the observed aging-associated changes and promote longevity. Our findings reveal a pathway that couples changes of intermediate metabolism during aging with the chromatin-mediated regulation of transcription and changes in the activity of associated enzymes that modulate organismal life span.
authors.affiliation: Department of Physiological Chemistry, Biomedical Center and Center for Integrated Protein Science Munich, Ludwig-Maximilians University, Planegg-Martinsried, Germany Department of Molecular Biology, Biomedical Center and Center for Integrated Protein Science Munich, Ludwig-Maximilians University, Planegg-Martinsried, Germany.
authors.forename: Shahaf
authors.initials: S
authors.lastname: Peleg
authors.affiliation: Department of Molecular Biology, Biomedical Center and Center for Integrated Protein Science Munich, Ludwig-Maximilians University, Planegg-Martinsried, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Feller
authors.affiliation: Department of Molecular Biology, Biomedical Center and Center for Integrated Protein Science Munich, Ludwig-Maximilians University, Planegg-Martinsried, Germany Protein Analysis Unit, Biomedical Center, Ludwig-Maximilians University, Planegg-Martinsried, Germany.
authors.forename: Ignasi
authors.initials: I
authors.lastname: Forne
authors.affiliation: Institute of Experimental Genetics, Helmholtz Zentrum Munich, German Research Center for Environment and Health (GmbH), Neuherberg, Germany.
authors.forename: Evelyn
authors.initials: E
authors.lastname: Schiller
authors.affiliation: Institute of Molecular Systems Biology, ETH Zürich, Zürich, Switzerland PhD Program on Systems Biology, Life Science Zürich, Zürich, Switzerland.
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Sévin
authors.affiliation: Department of Molecular Biology, Biomedical Center and Center for Integrated Protein Science Munich, Ludwig-Maximilians University, Planegg-Martinsried, Germany.
authors.forename: Tamas
authors.initials: T
authors.lastname: Schauer
authors.affiliation: Department of Molecular Biology, Biomedical Center and Center for Integrated Protein Science Munich, Ludwig-Maximilians University, Planegg-Martinsried, Germany.
authors.forename: Catherine
authors.initials: C
authors.lastname: Regnard
authors.affiliation: Department of Molecular Biology, Biomedical Center and Center for Integrated Protein Science Munich, Ludwig-Maximilians University, Planegg-Martinsried, Germany Bioinformatics Unit, Biomedical Center, Ludwig-Maximilians University, Planegg-Martinsried, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Straub
authors.affiliation: Department of Molecular Biology, Biomedical Center and Center for Integrated Protein Science Munich, Ludwig-Maximilians University, Planegg-Martinsried, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Prestel
authors.affiliation: Department of Physiological Chemistry, Biomedical Center and Center for Integrated Protein Science Munich, Ludwig-Maximilians University, Planegg-Martinsried, Germany Department of Molecular Biology, Biomedical Center and Center for Integrated Protein Science Munich, Ludwig-Maximilians University, Planegg-Martinsried, Germany.
authors.forename: Caroline
authors.initials: C
authors.lastname: Klima
authors.affiliation: Department of Physiological Chemistry, Biomedical Center and Center for Integrated Protein Science Munich, Ludwig-Maximilians University, Planegg-Martinsried, Germany Department of Molecular Biology, Biomedical Center and Center for Integrated Protein Science Munich, Ludwig-Maximilians University, Planegg-Martinsried, Germany.
authors.forename: Melanie
authors.initials: M
authors.lastname: Schmitt Nogueira
authors.affiliation: Institute of Experimental Genetics, Helmholtz Zentrum Munich, German Research Center for Environment and Health (GmbH), Neuherberg, Germany.
authors.forename: Lore
authors.initials: L
authors.lastname: Becker
authors.affiliation: Friedrich-Baur-Institut, Department of Neurology, Ludwig-Maximilians University, Munich, Germany DZNE - German Center for Neurodegenerative Diseases, Munich, Germany Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Klopstock
authors.affiliation: Institute of Molecular Systems Biology, ETH Zürich, Zürich, Switzerland.
authors.forename: Uwe
authors.initials: U
authors.lastname: Sauer
authors.affiliation: Department of Molecular Biology, Biomedical Center and Center for Integrated Protein Science Munich, Ludwig-Maximilians University, Planegg-Martinsried, Germany.
authors.forename: Peter B
authors.initials: PB
authors.lastname: Becker
authors.affiliation: Department of Molecular Biology, Biomedical Center and Center for Integrated Protein Science Munich, Ludwig-Maximilians University, Planegg-Martinsried, Germany Protein Analysis Unit, Biomedical Center, Ludwig-Maximilians University, Planegg-Martinsried, Germany Munich Cluster for Systems Neurology (SyNergy), Munich, Germany imhof@lmu.de andreas.ladurner@med.lmu.de.
authors.forename: Axel
authors.initials: A
authors.lastname: Imhof
authors.affiliation: Department of Physiological Chemistry, Biomedical Center and Center for Integrated Protein Science Munich, Ludwig-Maximilians University, Planegg-Martinsried, Germany Munich Cluster for Systems Neurology (SyNergy), Munich, Germany imhof@lmu.de andreas.ladurner@med.lmu.de.
authors.forename: Andreas G
authors.initials: AG
authors.lastname: Ladurner
mesh_terms: D001275:ATP Citrate (pro-S)-Lyase / Q000235:genetics / Q000378:metabolism; D000107:Acetylation; D000123:Acetyltransferases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism; D004331:Drosophila melanogaster / Q000235:genetics / Q000254:growth & development / Q000378:metabolism*; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D008136:Longevity; D011499:Protein Processing, Post-Translational
chemical_list: D029721:Drosophila Proteins; D006657:Histones; D000123:Acetyltransferases; C467710:chm protein, Drosophila; D001275:ATP Citrate (pro-S)-Lyase
keywords: acetylation; ageing; chromatin; metabolism