Epigenetic alterations in longevity regulators, reduced life span, and exacerbated aging-related pathology in old father offspring mice.
Identifieur interne : 000609 ( Main/Exploration ); précédent : 000608; suivant : 000610Epigenetic alterations in longevity regulators, reduced life span, and exacerbated aging-related pathology in old father offspring mice.
Auteurs : Kan Xie [Allemagne] ; Devon P. Ryan [Allemagne] ; Brandon L. Pearson [Allemagne] ; Kristin S. Henzel [Allemagne] ; Frauke Neff [Allemagne] ; Ramon O. Vidal [Allemagne] ; Magali Hennion [Allemagne] ; Isabelle Lehmann [Allemagne] ; Melvin Schleif [Allemagne] ; Susanne Schröder [Allemagne] ; Thure Adler [Allemagne] ; Birgit Rathkolb [Allemagne] ; Jan Rozman [Allemagne] ; Anna-Lena Schütz [Allemagne] ; Cornelia Prehn [Allemagne] ; Michel E. Mickael [Allemagne] ; Marco Weiergr Ber [Allemagne] ; Jerzy Adamski [Allemagne] ; Dirk H. Busch [Allemagne] ; Gerhard Ehninger [Allemagne] ; Anna Matynia [États-Unis] ; Walker S. Jackson [Allemagne] ; Eckhard Wolf [Allemagne] ; Helmut Fuchs [Allemagne] ; Valerie Gailus-Durner [Allemagne] ; Stefan Bonn [Allemagne] ; Martin Hrab De Angelis [Allemagne] ; Dan Ehninger [Allemagne]Source :
- Proceedings of the National Academy of Sciences of the United States of America [ 1091-6490 ] ; 2018.
Descripteurs français
- KwdFr :
- Animaux (MeSH), Complexe-1 cible mécanistique de la rapamycine (génétique), Complexe-1 cible mécanistique de la rapamycine (métabolisme), Espérance de vie (MeSH), Facteurs âges (MeSH), Femelle (MeSH), Humains (MeSH), Longévité (MeSH), Mâle (MeSH), Méthylation de l'ADN (MeSH), Pedigree (MeSH), Pères (MeSH), Régions promotrices (génétique) (MeSH), Souris (MeSH), Spermatozoïdes (métabolisme), Vieillissement (génétique), Vieillissement (physiologie), Épigenèse génétique (MeSH).
- MESH :
- génétique : Complexe-1 cible mécanistique de la rapamycine, Vieillissement.
- métabolisme : Complexe-1 cible mécanistique de la rapamycine, Spermatozoïdes.
- physiologie : Vieillissement.
- Animaux, Espérance de vie, Facteurs âges, Femelle, Humains, Longévité, Mâle, Méthylation de l'ADN, Pedigree, Pères, Régions promotrices (génétique), Souris, Épigenèse génétique.
English descriptors
- KwdEn :
- Age Factors (MeSH), Aging (genetics), Aging (physiology), Animals (MeSH), DNA Methylation (MeSH), Epigenesis, Genetic (MeSH), Fathers (MeSH), Female (MeSH), Humans (MeSH), Life Expectancy (MeSH), Longevity (MeSH), Male (MeSH), Mechanistic Target of Rapamycin Complex 1 (genetics), Mechanistic Target of Rapamycin Complex 1 (metabolism), Mice (MeSH), Pedigree (MeSH), Promoter Regions, Genetic (MeSH), Spermatozoa (metabolism).
- MESH :
- chemical , genetics : Mechanistic Target of Rapamycin Complex 1.
- genetics : Aging.
- chemical , metabolism : Mechanistic Target of Rapamycin Complex 1, Spermatozoa.
- physiology : Aging.
- Age Factors, Animals, DNA Methylation, Epigenesis, Genetic, Fathers, Female, Humans, Life Expectancy, Longevity, Male, Mice, Pedigree, Promoter Regions, Genetic.
Abstract
Advanced age is not only a major risk factor for a range of disorders within an aging individual but may also enhance susceptibility for disease in the next generation. In humans, advanced paternal age has been associated with increased risk for a number of diseases. Experiments in rodent models have provided initial evidence that paternal age can influence behavioral traits in offspring animals, but the overall scope and extent of paternal age effects on health and disease across the life span remain underexplored. Here, we report that old father offspring mice showed a reduced life span and an exacerbated development of aging traits compared with young father offspring mice. Genome-wide epigenetic analyses of sperm from aging males and old father offspring tissue identified differentially methylated promoters, enriched for genes involved in the regulation of evolutionarily conserved longevity pathways. Gene expression analyses, biochemical experiments, and functional studies revealed evidence for an overactive mTORC1 signaling pathway in old father offspring mice. Pharmacological mTOR inhibition during the course of normal aging ameliorated many of the aging traits that were exacerbated in old father offspring mice. These findings raise the possibility that inherited alterations in longevity pathways contribute to intergenerational effects of aging in old father offspring mice.
DOI: 10.1073/pnas.1707337115
PubMed: 29467291
PubMed Central: PMC5877957
Affiliations:
- Allemagne, États-Unis
- Bade-Wurtemberg, Basse-Saxe, Bavière, Californie, District de Cologne, District de Dresde, District de Haute-Bavière, District de Tübingen, Hambourg, Rhénanie-du-Nord-Westphalie, Saxe (Land)
- Bonn, Dresde, Göttingen, Hambourg, Munich, Tübingen
- Université Louis-et-Maximilien de Munich, Université technique de Munich
Links toward previous steps (curation, corpus...)
Le document en format XML
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Munich</orgName></affiliation></author><author><name sortKey="Rozman, Jan" sort="Rozman, Jan" uniqKey="Rozman J" first="Jan" last="Rozman">Jan Rozman</name><affiliation wicri:level="1"><nlm:affiliation>German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, 85764 Neuherberg</wicri:regionArea><wicri:noRegion>85764 Neuherberg</wicri:noRegion><wicri:noRegion>85764 Neuherberg</wicri:noRegion><wicri:noRegion>85764 Neuherberg</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:affiliation>German Center for Diabetes Research (DZD), 85764 München-Neuherberg, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>German Center for Diabetes Research (DZD), 85764 München-Neuherberg</wicri:regionArea><wicri:noRegion>85764 München-Neuherberg</wicri:noRegion><wicri:noRegion>85764 München-Neuherberg</wicri:noRegion><wicri:noRegion>85764 München-Neuherberg</wicri:noRegion></affiliation></author><author><name sortKey="Schutz, Anna Lena" sort="Schutz, Anna Lena" uniqKey="Schutz A" first="Anna-Lena" last="Schütz">Anna-Lena Schütz</name><affiliation wicri:level="3"><nlm:affiliation>Computational Systems Biology Lab, German Center for Neurodegenerative Diseases (DZNE), 37077 Göttingen, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Computational Systems Biology Lab, German Center for Neurodegenerative Diseases (DZNE), 37077 Göttingen</wicri:regionArea><placeName><region type="land" nuts="2">Basse-Saxe</region><settlement type="city">Göttingen</settlement></placeName></affiliation></author><author><name sortKey="Prehn, Cornelia" sort="Prehn, Cornelia" uniqKey="Prehn C" first="Cornelia" last="Prehn">Cornelia Prehn</name><affiliation wicri:level="1"><nlm:affiliation>German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, 85764 Neuherberg</wicri:regionArea><wicri:noRegion>85764 Neuherberg</wicri:noRegion><wicri:noRegion>85764 Neuherberg</wicri:noRegion><wicri:noRegion>85764 Neuherberg</wicri:noRegion></affiliation></author><author><name sortKey="Mickael, Michel E" sort="Mickael, Michel E" uniqKey="Mickael M" first="Michel E" last="Mickael">Michel E. Mickael</name><affiliation wicri:level="3"><nlm:affiliation>Computational Systems Biology Lab, German Center for Neurodegenerative Diseases (DZNE), 37077 Göttingen, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Computational Systems Biology Lab, German Center for Neurodegenerative Diseases (DZNE), 37077 Göttingen</wicri:regionArea><placeName><region type="land" nuts="2">Basse-Saxe</region><settlement type="city">Göttingen</settlement></placeName></affiliation></author><author><name sortKey="Weiergr Ber, Marco" sort="Weiergr Ber, Marco" uniqKey="Weiergr Ber M" first="Marco" last="Weiergr Ber">Marco Weiergr Ber</name><affiliation wicri:level="3"><nlm:affiliation>Research Group Experimental Neuropsychopharmacology, Federal Institute for Drugs and Medical Devices, 53175 Bonn, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Research Group Experimental Neuropsychopharmacology, Federal Institute for Drugs and Medical Devices, 53175 Bonn</wicri:regionArea><placeName><region type="land" nuts="1">Rhénanie-du-Nord-Westphalie</region><region type="district" nuts="2">District de Cologne</region><settlement type="city">Bonn</settlement></placeName></affiliation></author><author><name sortKey="Adamski, Jerzy" sort="Adamski, Jerzy" uniqKey="Adamski J" first="Jerzy" last="Adamski">Jerzy Adamski</name><affiliation wicri:level="1"><nlm:affiliation>German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, 85764 Neuherberg</wicri:regionArea><wicri:noRegion>85764 Neuherberg</wicri:noRegion><wicri:noRegion>85764 Neuherberg</wicri:noRegion><wicri:noRegion>85764 Neuherberg</wicri:noRegion></affiliation><affiliation wicri:level="4"><nlm:affiliation>Chair of Experimental Genetics, Center of Life and Food Sciences Weihenstephan, Technische Universität München, 85350 Freising-Weihenstephan, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Chair of Experimental Genetics, Center of Life and Food Sciences Weihenstephan, Technische Universität München, 85350 Freising-Weihenstephan</wicri:regionArea><wicri:noRegion>85350 Freising-Weihenstephan</wicri:noRegion><orgName type="university">Université technique de Munich</orgName><placeName><settlement type="city">Munich</settlement><region type="land" nuts="1">Bavière</region><region type="district" nuts="2">District de Haute-Bavière</region></placeName></affiliation></author><author><name sortKey="Busch, Dirk H" sort="Busch, Dirk H" uniqKey="Busch D" first="Dirk H" last="Busch">Dirk H. Busch</name><affiliation wicri:level="4"><nlm:affiliation>Institute for Medical Microbiology, Immunology and Hygiene, Technische Universität München, 81675 Munich, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute for Medical Microbiology, Immunology and Hygiene, Technische Universität München, 81675 Munich</wicri:regionArea><placeName><region type="land" nuts="1">Bavière</region><region type="district" nuts="2">District de Haute-Bavière</region><settlement type="city">Munich</settlement></placeName><orgName type="university">Université technique de Munich</orgName></affiliation></author><author><name sortKey="Ehninger, Gerhard" sort="Ehninger, Gerhard" uniqKey="Ehninger G" first="Gerhard" last="Ehninger">Gerhard Ehninger</name><affiliation wicri:level="3"><nlm:affiliation>Department of Internal Medicine I, University Hospital Carl Gustav Carus, Technical University Dresden, 01307 Dresden, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Internal Medicine I, University Hospital Carl Gustav Carus, Technical University Dresden, 01307 Dresden</wicri:regionArea><placeName><region type="land" nuts="1">Saxe (Land)</region><region type="district" nuts="2">District de Dresde</region><settlement type="city">Dresde</settlement></placeName></affiliation></author><author><name sortKey="Matynia, Anna" sort="Matynia, Anna" uniqKey="Matynia A" first="Anna" last="Matynia">Anna Matynia</name><affiliation wicri:level="2"><nlm:affiliation>Jules Stein Eye Institute, University of California, Los Angeles, CA 90095.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Californie</region></placeName><wicri:cityArea>Jules Stein Eye Institute, University of California, Los Angeles</wicri:cityArea></affiliation></author><author><name sortKey="Jackson, Walker S" sort="Jackson, Walker S" uniqKey="Jackson W" first="Walker S" last="Jackson">Walker S. Jackson</name><affiliation wicri:level="3"><nlm:affiliation>Selective Vulnerability of Neurodegenerative Diseases Lab, German Center for Neurodegenerative Diseases (DZNE), 53127 Bonn, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Selective Vulnerability of Neurodegenerative Diseases Lab, German Center for Neurodegenerative Diseases (DZNE), 53127 Bonn</wicri:regionArea><placeName><region type="land" nuts="1">Rhénanie-du-Nord-Westphalie</region><region type="district" nuts="2">District de Cologne</region><settlement type="city">Bonn</settlement></placeName></affiliation></author><author><name sortKey="Wolf, Eckhard" sort="Wolf, Eckhard" uniqKey="Wolf E" first="Eckhard" last="Wolf">Eckhard Wolf</name><affiliation wicri:level="4"><nlm:affiliation>Chair of Molecular Animal Breeding and Biotechnology, Gene Center, Ludwig-Maximilians-Universität München, 81377 Munich, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Chair of Molecular Animal Breeding and Biotechnology, Gene Center, Ludwig-Maximilians-Universität München, 81377 Munich</wicri:regionArea><placeName><region type="land" nuts="1">Bavière</region><region type="district" nuts="2">District de Haute-Bavière</region><settlement type="city">Munich</settlement></placeName><orgName type="university">Université Louis-et-Maximilien de Munich</orgName></affiliation></author><author><name sortKey="Fuchs, Helmut" sort="Fuchs, Helmut" uniqKey="Fuchs H" first="Helmut" last="Fuchs">Helmut Fuchs</name><affiliation wicri:level="1"><nlm:affiliation>German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, 85764 Neuherberg</wicri:regionArea><wicri:noRegion>85764 Neuherberg</wicri:noRegion><wicri:noRegion>85764 Neuherberg</wicri:noRegion><wicri:noRegion>85764 Neuherberg</wicri:noRegion></affiliation></author><author><name sortKey="Gailus Durner, Valerie" sort="Gailus Durner, Valerie" uniqKey="Gailus Durner V" first="Valerie" last="Gailus-Durner">Valerie Gailus-Durner</name><affiliation wicri:level="1"><nlm:affiliation>German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, 85764 Neuherberg</wicri:regionArea><wicri:noRegion>85764 Neuherberg</wicri:noRegion><wicri:noRegion>85764 Neuherberg</wicri:noRegion><wicri:noRegion>85764 Neuherberg</wicri:noRegion></affiliation></author><author><name sortKey="Bonn, Stefan" sort="Bonn, Stefan" uniqKey="Bonn S" first="Stefan" last="Bonn">Stefan Bonn</name><affiliation wicri:level="3"><nlm:affiliation>Computational Systems Biology Lab, German Center for Neurodegenerative Diseases (DZNE), 37077 Göttingen, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Computational Systems Biology Lab, German Center for Neurodegenerative Diseases (DZNE), 37077 Göttingen</wicri:regionArea><placeName><region type="land" nuts="2">Basse-Saxe</region><settlement type="city">Göttingen</settlement></placeName></affiliation><affiliation wicri:level="3"><nlm:affiliation>German Center for Neurodegenerative Diseases (DZNE), 72076 Tübingen, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>German Center for Neurodegenerative Diseases (DZNE), 72076 Tübingen</wicri:regionArea><placeName><region type="land" nuts="1">Bade-Wurtemberg</region><region type="district" nuts="2">District de Tübingen</region><settlement type="city">Tübingen</settlement></placeName></affiliation><affiliation wicri:level="1"><nlm:affiliation>Center for Molecular Neurobiology, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Center for Molecular Neurobiology, University Medical Center Hamburg-Eppendorf, 20251 Hamburg</wicri:regionArea><wicri:noRegion>20251 Hamburg</wicri:noRegion><placeName><settlement type="city">Hambourg</settlement><region type="land" nuts="2">Hambourg</region></placeName></affiliation></author><author><name sortKey="Hrab De Angelis, Martin" sort="Hrab De Angelis, Martin" uniqKey="Hrab De Angelis M" first="Martin" last="Hrab De Angelis">Martin Hrab De Angelis</name><affiliation wicri:level="1"><nlm:affiliation>German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, 85764 Neuherberg</wicri:regionArea><wicri:noRegion>85764 Neuherberg</wicri:noRegion><wicri:noRegion>85764 Neuherberg</wicri:noRegion><wicri:noRegion>85764 Neuherberg</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:affiliation>German Center for Diabetes Research (DZD), 85764 München-Neuherberg, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>German Center for Diabetes Research (DZD), 85764 München-Neuherberg</wicri:regionArea><wicri:noRegion>85764 München-Neuherberg</wicri:noRegion><wicri:noRegion>85764 München-Neuherberg</wicri:noRegion><wicri:noRegion>85764 München-Neuherberg</wicri:noRegion></affiliation><affiliation wicri:level="4"><nlm:affiliation>Chair of Experimental Genetics, Center of Life and Food Sciences Weihenstephan, Technische Universität München, 85350 Freising-Weihenstephan, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Chair of Experimental Genetics, Center of Life and Food Sciences Weihenstephan, Technische Universität München, 85350 Freising-Weihenstephan</wicri:regionArea><wicri:noRegion>85350 Freising-Weihenstephan</wicri:noRegion><orgName type="university">Université technique de Munich</orgName><placeName><settlement type="city">Munich</settlement><region type="land" nuts="1">Bavière</region><region type="district" nuts="2">District de Haute-Bavière</region></placeName></affiliation></author><author><name sortKey="Ehninger, Dan" sort="Ehninger, Dan" uniqKey="Ehninger D" first="Dan" last="Ehninger">Dan Ehninger</name><affiliation wicri:level="3"><nlm:affiliation>Molecular and Cellular Cognition Lab, German Center for Neurodegenerative Diseases (DZNE), 53127 Bonn, Germany; dan.ehninger@dzne.de.</nlm:affiliation><country wicri:rule="url">Allemagne</country><wicri:regionArea>Molecular and Cellular Cognition Lab, German Center for Neurodegenerative Diseases (DZNE), 53127 Bonn</wicri:regionArea><placeName><region type="land" nuts="1">Rhénanie-du-Nord-Westphalie</region><region type="district" nuts="2">District de Cologne</region><settlement type="city">Bonn</settlement></placeName></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2018">2018</date><idno type="RBID">pubmed:29467291</idno><idno type="pmid">29467291</idno><idno type="doi">10.1073/pnas.1707337115</idno><idno type="pmc">PMC5877957</idno><idno type="wicri:Area/Main/Corpus">000609</idno><idno type="wicri:explorRef" wicri:stream="Main" wicri:step="Corpus" wicri:corpus="PubMed">000609</idno><idno type="wicri:Area/Main/Curation">000609</idno><idno type="wicri:explorRef" wicri:stream="Main" wicri:step="Curation">000609</idno><idno type="wicri:Area/Main/Exploration">000609</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">Epigenetic alterations in longevity regulators, reduced life span, and exacerbated aging-related pathology in old father offspring mice.</title><author><name sortKey="Xie, Kan" sort="Xie, Kan" uniqKey="Xie K" first="Kan" last="Xie">Kan Xie</name><affiliation wicri:level="3"><nlm:affiliation>Molecular and Cellular Cognition Lab, German Center for Neurodegenerative Diseases (DZNE), 53127 Bonn, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Molecular and Cellular Cognition Lab, German Center for Neurodegenerative Diseases (DZNE), 53127 Bonn</wicri:regionArea><placeName><region type="land" nuts="1">Rhénanie-du-Nord-Westphalie</region><region type="district" nuts="2">District de Cologne</region><settlement type="city">Bonn</settlement></placeName></affiliation></author><author><name sortKey="Ryan, Devon P" sort="Ryan, Devon P" uniqKey="Ryan D" first="Devon P" last="Ryan">Devon P. Ryan</name><affiliation wicri:level="3"><nlm:affiliation>Molecular and Cellular Cognition Lab, German Center for Neurodegenerative Diseases (DZNE), 53127 Bonn, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Molecular and Cellular Cognition Lab, German Center for Neurodegenerative Diseases (DZNE), 53127 Bonn</wicri:regionArea><placeName><region type="land" nuts="1">Rhénanie-du-Nord-Westphalie</region><region type="district" nuts="2">District de Cologne</region><settlement type="city">Bonn</settlement></placeName></affiliation></author><author><name sortKey="Pearson, Brandon L" sort="Pearson, Brandon L" uniqKey="Pearson B" first="Brandon L" last="Pearson">Brandon L. Pearson</name><affiliation wicri:level="3"><nlm:affiliation>Molecular and Cellular Cognition Lab, German Center for Neurodegenerative Diseases (DZNE), 53127 Bonn, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Molecular and Cellular Cognition Lab, German Center for Neurodegenerative Diseases (DZNE), 53127 Bonn</wicri:regionArea><placeName><region type="land" nuts="1">Rhénanie-du-Nord-Westphalie</region><region type="district" nuts="2">District de Cologne</region><settlement type="city">Bonn</settlement></placeName></affiliation></author><author><name sortKey="Henzel, Kristin S" sort="Henzel, Kristin S" uniqKey="Henzel K" first="Kristin S" last="Henzel">Kristin S. Henzel</name><affiliation wicri:level="3"><nlm:affiliation>Molecular and Cellular Cognition Lab, German Center for Neurodegenerative Diseases (DZNE), 53127 Bonn, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Molecular and Cellular Cognition Lab, German Center for Neurodegenerative Diseases (DZNE), 53127 Bonn</wicri:regionArea><placeName><region type="land" nuts="1">Rhénanie-du-Nord-Westphalie</region><region type="district" nuts="2">District de Cologne</region><settlement type="city">Bonn</settlement></placeName></affiliation></author><author><name sortKey="Neff, Frauke" sort="Neff, Frauke" uniqKey="Neff F" first="Frauke" last="Neff">Frauke Neff</name><affiliation wicri:level="1"><nlm:affiliation>Institute of Pathology, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Pathology, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg</wicri:regionArea><wicri:noRegion>85764 Neuherberg</wicri:noRegion><wicri:noRegion>85764 Neuherberg</wicri:noRegion><wicri:noRegion>85764 Neuherberg</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:affiliation>German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, 85764 Neuherberg</wicri:regionArea><wicri:noRegion>85764 Neuherberg</wicri:noRegion><wicri:noRegion>85764 Neuherberg</wicri:noRegion><wicri:noRegion>85764 Neuherberg</wicri:noRegion></affiliation></author><author><name sortKey="Vidal, Ramon O" sort="Vidal, Ramon O" uniqKey="Vidal R" first="Ramon O" last="Vidal">Ramon O. Vidal</name><affiliation wicri:level="3"><nlm:affiliation>Computational Systems Biology Lab, German Center for Neurodegenerative Diseases (DZNE), 37077 Göttingen, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Computational Systems Biology Lab, German Center for Neurodegenerative Diseases (DZNE), 37077 Göttingen</wicri:regionArea><placeName><region type="land" nuts="2">Basse-Saxe</region><settlement type="city">Göttingen</settlement></placeName></affiliation></author><author><name sortKey="Hennion, Magali" sort="Hennion, Magali" uniqKey="Hennion M" first="Magali" last="Hennion">Magali Hennion</name><affiliation wicri:level="3"><nlm:affiliation>Computational Systems Biology Lab, German Center for Neurodegenerative Diseases (DZNE), 37077 Göttingen, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Computational Systems Biology Lab, German Center for Neurodegenerative Diseases (DZNE), 37077 Göttingen</wicri:regionArea><placeName><region type="land" nuts="2">Basse-Saxe</region><settlement type="city">Göttingen</settlement></placeName></affiliation></author><author><name sortKey="Lehmann, Isabelle" sort="Lehmann, Isabelle" uniqKey="Lehmann I" first="Isabelle" last="Lehmann">Isabelle Lehmann</name><affiliation wicri:level="3"><nlm:affiliation>Molecular and Cellular Cognition Lab, German Center for Neurodegenerative Diseases (DZNE), 53127 Bonn, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Molecular and Cellular Cognition Lab, German Center for Neurodegenerative Diseases (DZNE), 53127 Bonn</wicri:regionArea><placeName><region type="land" nuts="1">Rhénanie-du-Nord-Westphalie</region><region type="district" nuts="2">District de Cologne</region><settlement type="city">Bonn</settlement></placeName></affiliation></author><author><name sortKey="Schleif, Melvin" sort="Schleif, Melvin" uniqKey="Schleif M" first="Melvin" last="Schleif">Melvin Schleif</name><affiliation wicri:level="3"><nlm:affiliation>Selective Vulnerability of Neurodegenerative Diseases Lab, German Center for Neurodegenerative Diseases (DZNE), 53127 Bonn, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Selective Vulnerability of Neurodegenerative Diseases Lab, German Center for Neurodegenerative Diseases (DZNE), 53127 Bonn</wicri:regionArea><placeName><region type="land" nuts="1">Rhénanie-du-Nord-Westphalie</region><region type="district" nuts="2">District de Cologne</region><settlement type="city">Bonn</settlement></placeName></affiliation></author><author><name sortKey="Schroder, Susanne" sort="Schroder, Susanne" uniqKey="Schroder S" first="Susanne" last="Schröder">Susanne Schröder</name><affiliation wicri:level="3"><nlm:affiliation>Molecular and Cellular Cognition Lab, German Center for Neurodegenerative Diseases (DZNE), 53127 Bonn, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Molecular and Cellular Cognition Lab, German Center for Neurodegenerative Diseases (DZNE), 53127 Bonn</wicri:regionArea><placeName><region type="land" nuts="1">Rhénanie-du-Nord-Westphalie</region><region type="district" nuts="2">District de Cologne</region><settlement type="city">Bonn</settlement></placeName></affiliation></author><author><name sortKey="Adler, Thure" sort="Adler, Thure" uniqKey="Adler T" first="Thure" last="Adler">Thure Adler</name><affiliation wicri:level="1"><nlm:affiliation>German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, 85764 Neuherberg</wicri:regionArea><wicri:noRegion>85764 Neuherberg</wicri:noRegion><wicri:noRegion>85764 Neuherberg</wicri:noRegion><wicri:noRegion>85764 Neuherberg</wicri:noRegion></affiliation><affiliation wicri:level="4"><nlm:affiliation>Institute for Medical Microbiology, Immunology and Hygiene, Technische Universität München, 81675 Munich, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute for Medical Microbiology, Immunology and Hygiene, Technische Universität München, 81675 Munich</wicri:regionArea><placeName><region type="land" nuts="1">Bavière</region><region type="district" nuts="2">District de Haute-Bavière</region><settlement type="city">Munich</settlement></placeName><orgName type="university">Université technique de Munich</orgName></affiliation></author><author><name sortKey="Rathkolb, Birgit" sort="Rathkolb, Birgit" uniqKey="Rathkolb B" first="Birgit" last="Rathkolb">Birgit Rathkolb</name><affiliation wicri:level="1"><nlm:affiliation>German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, 85764 Neuherberg</wicri:regionArea><wicri:noRegion>85764 Neuherberg</wicri:noRegion><wicri:noRegion>85764 Neuherberg</wicri:noRegion><wicri:noRegion>85764 Neuherberg</wicri:noRegion></affiliation><affiliation wicri:level="4"><nlm:affiliation>Chair of Molecular Animal Breeding and Biotechnology, Gene Center, Ludwig-Maximilians-Universität München, 81377 Munich, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Chair of Molecular Animal Breeding and Biotechnology, Gene Center, Ludwig-Maximilians-Universität München, 81377 Munich</wicri:regionArea><placeName><region type="land" nuts="1">Bavière</region><region type="district" nuts="2">District de Haute-Bavière</region><settlement type="city">Munich</settlement></placeName><orgName type="university">Université Louis-et-Maximilien de Munich</orgName></affiliation></author><author><name sortKey="Rozman, Jan" sort="Rozman, Jan" uniqKey="Rozman J" first="Jan" last="Rozman">Jan Rozman</name><affiliation wicri:level="1"><nlm:affiliation>German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, 85764 Neuherberg</wicri:regionArea><wicri:noRegion>85764 Neuherberg</wicri:noRegion><wicri:noRegion>85764 Neuherberg</wicri:noRegion><wicri:noRegion>85764 Neuherberg</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:affiliation>German Center for Diabetes Research (DZD), 85764 München-Neuherberg, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>German Center for Diabetes Research (DZD), 85764 München-Neuherberg</wicri:regionArea><wicri:noRegion>85764 München-Neuherberg</wicri:noRegion><wicri:noRegion>85764 München-Neuherberg</wicri:noRegion><wicri:noRegion>85764 München-Neuherberg</wicri:noRegion></affiliation></author><author><name sortKey="Schutz, Anna Lena" sort="Schutz, Anna Lena" uniqKey="Schutz A" first="Anna-Lena" last="Schütz">Anna-Lena Schütz</name><affiliation wicri:level="3"><nlm:affiliation>Computational Systems Biology Lab, German Center for Neurodegenerative Diseases (DZNE), 37077 Göttingen, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Computational Systems Biology Lab, German Center for Neurodegenerative Diseases (DZNE), 37077 Göttingen</wicri:regionArea><placeName><region type="land" nuts="2">Basse-Saxe</region><settlement type="city">Göttingen</settlement></placeName></affiliation></author><author><name sortKey="Prehn, Cornelia" sort="Prehn, Cornelia" uniqKey="Prehn C" first="Cornelia" last="Prehn">Cornelia Prehn</name><affiliation wicri:level="1"><nlm:affiliation>German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, 85764 Neuherberg</wicri:regionArea><wicri:noRegion>85764 Neuherberg</wicri:noRegion><wicri:noRegion>85764 Neuherberg</wicri:noRegion><wicri:noRegion>85764 Neuherberg</wicri:noRegion></affiliation></author><author><name sortKey="Mickael, Michel E" sort="Mickael, Michel E" uniqKey="Mickael M" first="Michel E" last="Mickael">Michel E. Mickael</name><affiliation wicri:level="3"><nlm:affiliation>Computational Systems Biology Lab, German Center for Neurodegenerative Diseases (DZNE), 37077 Göttingen, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Computational Systems Biology Lab, German Center for Neurodegenerative Diseases (DZNE), 37077 Göttingen</wicri:regionArea><placeName><region type="land" nuts="2">Basse-Saxe</region><settlement type="city">Göttingen</settlement></placeName></affiliation></author><author><name sortKey="Weiergr Ber, Marco" sort="Weiergr Ber, Marco" uniqKey="Weiergr Ber M" first="Marco" last="Weiergr Ber">Marco Weiergr Ber</name><affiliation wicri:level="3"><nlm:affiliation>Research Group Experimental Neuropsychopharmacology, Federal Institute for Drugs and Medical Devices, 53175 Bonn, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Research Group Experimental Neuropsychopharmacology, Federal Institute for Drugs and Medical Devices, 53175 Bonn</wicri:regionArea><placeName><region type="land" nuts="1">Rhénanie-du-Nord-Westphalie</region><region type="district" nuts="2">District de Cologne</region><settlement type="city">Bonn</settlement></placeName></affiliation></author><author><name sortKey="Adamski, Jerzy" sort="Adamski, Jerzy" uniqKey="Adamski J" first="Jerzy" last="Adamski">Jerzy Adamski</name><affiliation wicri:level="1"><nlm:affiliation>German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, 85764 Neuherberg</wicri:regionArea><wicri:noRegion>85764 Neuherberg</wicri:noRegion><wicri:noRegion>85764 Neuherberg</wicri:noRegion><wicri:noRegion>85764 Neuherberg</wicri:noRegion></affiliation><affiliation wicri:level="4"><nlm:affiliation>Chair of Experimental Genetics, Center of Life and Food Sciences Weihenstephan, Technische Universität München, 85350 Freising-Weihenstephan, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Chair of Experimental Genetics, Center of Life and Food Sciences Weihenstephan, Technische Universität München, 85350 Freising-Weihenstephan</wicri:regionArea><wicri:noRegion>85350 Freising-Weihenstephan</wicri:noRegion><orgName type="university">Université technique de Munich</orgName><placeName><settlement type="city">Munich</settlement><region type="land" nuts="1">Bavière</region><region type="district" nuts="2">District de Haute-Bavière</region></placeName></affiliation></author><author><name sortKey="Busch, Dirk H" sort="Busch, Dirk H" uniqKey="Busch D" first="Dirk H" last="Busch">Dirk H. Busch</name><affiliation wicri:level="4"><nlm:affiliation>Institute for Medical Microbiology, Immunology and Hygiene, Technische Universität München, 81675 Munich, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute for Medical Microbiology, Immunology and Hygiene, Technische Universität München, 81675 Munich</wicri:regionArea><placeName><region type="land" nuts="1">Bavière</region><region type="district" nuts="2">District de Haute-Bavière</region><settlement type="city">Munich</settlement></placeName><orgName type="university">Université technique de Munich</orgName></affiliation></author><author><name sortKey="Ehninger, Gerhard" sort="Ehninger, Gerhard" uniqKey="Ehninger G" first="Gerhard" last="Ehninger">Gerhard Ehninger</name><affiliation wicri:level="3"><nlm:affiliation>Department of Internal Medicine I, University Hospital Carl Gustav Carus, Technical University Dresden, 01307 Dresden, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Internal Medicine I, University Hospital Carl Gustav Carus, Technical University Dresden, 01307 Dresden</wicri:regionArea><placeName><region type="land" nuts="1">Saxe (Land)</region><region type="district" nuts="2">District de Dresde</region><settlement type="city">Dresde</settlement></placeName></affiliation></author><author><name sortKey="Matynia, Anna" sort="Matynia, Anna" uniqKey="Matynia A" first="Anna" last="Matynia">Anna Matynia</name><affiliation wicri:level="2"><nlm:affiliation>Jules Stein Eye Institute, University of California, Los Angeles, CA 90095.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Californie</region></placeName><wicri:cityArea>Jules Stein Eye Institute, University of California, Los Angeles</wicri:cityArea></affiliation></author><author><name sortKey="Jackson, Walker S" sort="Jackson, Walker S" uniqKey="Jackson W" first="Walker S" last="Jackson">Walker S. Jackson</name><affiliation wicri:level="3"><nlm:affiliation>Selective Vulnerability of Neurodegenerative Diseases Lab, German Center for Neurodegenerative Diseases (DZNE), 53127 Bonn, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Selective Vulnerability of Neurodegenerative Diseases Lab, German Center for Neurodegenerative Diseases (DZNE), 53127 Bonn</wicri:regionArea><placeName><region type="land" nuts="1">Rhénanie-du-Nord-Westphalie</region><region type="district" nuts="2">District de Cologne</region><settlement type="city">Bonn</settlement></placeName></affiliation></author><author><name sortKey="Wolf, Eckhard" sort="Wolf, Eckhard" uniqKey="Wolf E" first="Eckhard" last="Wolf">Eckhard Wolf</name><affiliation wicri:level="4"><nlm:affiliation>Chair of Molecular Animal Breeding and Biotechnology, Gene Center, Ludwig-Maximilians-Universität München, 81377 Munich, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Chair of Molecular Animal Breeding and Biotechnology, Gene Center, Ludwig-Maximilians-Universität München, 81377 Munich</wicri:regionArea><placeName><region type="land" nuts="1">Bavière</region><region type="district" nuts="2">District de Haute-Bavière</region><settlement type="city">Munich</settlement></placeName><orgName type="university">Université Louis-et-Maximilien de Munich</orgName></affiliation></author><author><name sortKey="Fuchs, Helmut" sort="Fuchs, Helmut" uniqKey="Fuchs H" first="Helmut" last="Fuchs">Helmut Fuchs</name><affiliation wicri:level="1"><nlm:affiliation>German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, 85764 Neuherberg</wicri:regionArea><wicri:noRegion>85764 Neuherberg</wicri:noRegion><wicri:noRegion>85764 Neuherberg</wicri:noRegion><wicri:noRegion>85764 Neuherberg</wicri:noRegion></affiliation></author><author><name sortKey="Gailus Durner, Valerie" sort="Gailus Durner, Valerie" uniqKey="Gailus Durner V" first="Valerie" last="Gailus-Durner">Valerie Gailus-Durner</name><affiliation wicri:level="1"><nlm:affiliation>German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, 85764 Neuherberg</wicri:regionArea><wicri:noRegion>85764 Neuherberg</wicri:noRegion><wicri:noRegion>85764 Neuherberg</wicri:noRegion><wicri:noRegion>85764 Neuherberg</wicri:noRegion></affiliation></author><author><name sortKey="Bonn, Stefan" sort="Bonn, Stefan" uniqKey="Bonn S" first="Stefan" last="Bonn">Stefan Bonn</name><affiliation wicri:level="3"><nlm:affiliation>Computational Systems Biology Lab, German Center for Neurodegenerative Diseases (DZNE), 37077 Göttingen, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Computational Systems Biology Lab, German Center for Neurodegenerative Diseases (DZNE), 37077 Göttingen</wicri:regionArea><placeName><region type="land" nuts="2">Basse-Saxe</region><settlement type="city">Göttingen</settlement></placeName></affiliation><affiliation wicri:level="3"><nlm:affiliation>German Center for Neurodegenerative Diseases (DZNE), 72076 Tübingen, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>German Center for Neurodegenerative Diseases (DZNE), 72076 Tübingen</wicri:regionArea><placeName><region type="land" nuts="1">Bade-Wurtemberg</region><region type="district" nuts="2">District de Tübingen</region><settlement type="city">Tübingen</settlement></placeName></affiliation><affiliation wicri:level="1"><nlm:affiliation>Center for Molecular Neurobiology, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Center for Molecular Neurobiology, University Medical Center Hamburg-Eppendorf, 20251 Hamburg</wicri:regionArea><wicri:noRegion>20251 Hamburg</wicri:noRegion><placeName><settlement type="city">Hambourg</settlement><region type="land" nuts="2">Hambourg</region></placeName></affiliation></author><author><name sortKey="Hrab De Angelis, Martin" sort="Hrab De Angelis, Martin" uniqKey="Hrab De Angelis M" first="Martin" last="Hrab De Angelis">Martin Hrab De Angelis</name><affiliation wicri:level="1"><nlm:affiliation>German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, 85764 Neuherberg</wicri:regionArea><wicri:noRegion>85764 Neuherberg</wicri:noRegion><wicri:noRegion>85764 Neuherberg</wicri:noRegion><wicri:noRegion>85764 Neuherberg</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:affiliation>German Center for Diabetes Research (DZD), 85764 München-Neuherberg, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>German Center for Diabetes Research (DZD), 85764 München-Neuherberg</wicri:regionArea><wicri:noRegion>85764 München-Neuherberg</wicri:noRegion><wicri:noRegion>85764 München-Neuherberg</wicri:noRegion><wicri:noRegion>85764 München-Neuherberg</wicri:noRegion></affiliation><affiliation wicri:level="4"><nlm:affiliation>Chair of Experimental Genetics, Center of Life and Food Sciences Weihenstephan, Technische Universität München, 85350 Freising-Weihenstephan, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Chair of Experimental Genetics, Center of Life and Food Sciences Weihenstephan, Technische Universität München, 85350 Freising-Weihenstephan</wicri:regionArea><wicri:noRegion>85350 Freising-Weihenstephan</wicri:noRegion><orgName type="university">Université technique de Munich</orgName><placeName><settlement type="city">Munich</settlement><region type="land" nuts="1">Bavière</region><region type="district" nuts="2">District de Haute-Bavière</region></placeName></affiliation></author><author><name sortKey="Ehninger, Dan" sort="Ehninger, Dan" uniqKey="Ehninger D" first="Dan" last="Ehninger">Dan Ehninger</name><affiliation wicri:level="3"><nlm:affiliation>Molecular and Cellular Cognition Lab, German Center for Neurodegenerative Diseases (DZNE), 53127 Bonn, Germany; dan.ehninger@dzne.de.</nlm:affiliation><country wicri:rule="url">Allemagne</country><wicri:regionArea>Molecular and Cellular Cognition Lab, German Center for Neurodegenerative Diseases (DZNE), 53127 Bonn</wicri:regionArea><placeName><region type="land" nuts="1">Rhénanie-du-Nord-Westphalie</region><region type="district" nuts="2">District de Cologne</region><settlement type="city">Bonn</settlement></placeName></affiliation></author></analytic><series><title level="j">Proceedings of the National Academy of Sciences of the United States of America</title><idno type="eISSN">1091-6490</idno><imprint><date when="2018" type="published">2018</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Age Factors (MeSH)</term><term>Aging (genetics)</term><term>Aging (physiology)</term><term>Animals (MeSH)</term><term>DNA Methylation (MeSH)</term><term>Epigenesis, Genetic (MeSH)</term><term>Fathers (MeSH)</term><term>Female (MeSH)</term><term>Humans (MeSH)</term><term>Life Expectancy (MeSH)</term><term>Longevity (MeSH)</term><term>Male (MeSH)</term><term>Mechanistic Target of Rapamycin Complex 1 (genetics)</term><term>Mechanistic Target of Rapamycin Complex 1 (metabolism)</term><term>Mice (MeSH)</term><term>Pedigree (MeSH)</term><term>Promoter Regions, Genetic (MeSH)</term><term>Spermatozoa (metabolism)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Animaux (MeSH)</term><term>Complexe-1 cible mécanistique de la rapamycine (génétique)</term><term>Complexe-1 cible mécanistique de la rapamycine (métabolisme)</term><term>Espérance de vie (MeSH)</term><term>Facteurs âges (MeSH)</term><term>Femelle (MeSH)</term><term>Humains (MeSH)</term><term>Longévité (MeSH)</term><term>Mâle (MeSH)</term><term>Méthylation de l'ADN (MeSH)</term><term>Pedigree (MeSH)</term><term>Pères (MeSH)</term><term>Régions promotrices (génétique) (MeSH)</term><term>Souris (MeSH)</term><term>Spermatozoïdes (métabolisme)</term><term>Vieillissement (génétique)</term><term>Vieillissement (physiologie)</term><term>Épigenèse génétique (MeSH)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Mechanistic Target of Rapamycin Complex 1</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Aging</term></keywords><keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Complexe-1 cible mécanistique de la rapamycine</term><term>Vieillissement</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Mechanistic Target of Rapamycin Complex 1</term><term>Spermatozoa</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Complexe-1 cible mécanistique de la rapamycine</term><term>Spermatozoïdes</term></keywords><keywords scheme="MESH" qualifier="physiologie" xml:lang="fr"><term>Vieillissement</term></keywords><keywords scheme="MESH" qualifier="physiology" xml:lang="en"><term>Aging</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Age Factors</term><term>Animals</term><term>DNA Methylation</term><term>Epigenesis, Genetic</term><term>Fathers</term><term>Female</term><term>Humans</term><term>Life Expectancy</term><term>Longevity</term><term>Male</term><term>Mice</term><term>Pedigree</term><term>Promoter Regions, Genetic</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Animaux</term><term>Espérance de vie</term><term>Facteurs âges</term><term>Femelle</term><term>Humains</term><term>Longévité</term><term>Mâle</term><term>Méthylation de l'ADN</term><term>Pedigree</term><term>Pères</term><term>Régions promotrices (génétique)</term><term>Souris</term><term>Épigenèse génétique</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Advanced age is not only a major risk factor for a range of disorders within an aging individual but may also enhance susceptibility for disease in the next generation. In humans, advanced paternal age has been associated with increased risk for a number of diseases. Experiments in rodent models have provided initial evidence that paternal age can influence behavioral traits in offspring animals, but the overall scope and extent of paternal age effects on health and disease across the life span remain underexplored. Here, we report that old father offspring mice showed a reduced life span and an exacerbated development of aging traits compared with young father offspring mice. Genome-wide epigenetic analyses of sperm from aging males and old father offspring tissue identified differentially methylated promoters, enriched for genes involved in the regulation of evolutionarily conserved longevity pathways. Gene expression analyses, biochemical experiments, and functional studies revealed evidence for an overactive mTORC1 signaling pathway in old father offspring mice. Pharmacological mTOR inhibition during the course of normal aging ameliorated many of the aging traits that were exacerbated in old father offspring mice. These findings raise the possibility that inherited alterations in longevity pathways contribute to intergenerational effects of aging in old father offspring mice.</div></front></TEI><pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">29467291</PMID><DateCompleted><Year>2018</Year><Month>10</Month><Day>30</Day></DateCompleted><DateRevised><Year>2018</Year><Month>11</Month><Day>13</Day></DateRevised><Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1091-6490</ISSN><JournalIssue CitedMedium="Internet"><Volume>115</Volume><Issue>10</Issue><PubDate><Year>2018</Year><Month>03</Month><Day>06</Day></PubDate></JournalIssue><Title>Proceedings of the National Academy of Sciences of the United States of America</Title><ISOAbbreviation>Proc Natl Acad Sci U S A</ISOAbbreviation></Journal><ArticleTitle>Epigenetic alterations in longevity regulators, reduced life span, and exacerbated aging-related pathology in old father offspring mice.</ArticleTitle><Pagination><MedlinePgn>E2348-E2357</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.1073/pnas.1707337115</ELocationID><Abstract><AbstractText>Advanced age is not only a major risk factor for a range of disorders within an aging individual but may also enhance susceptibility for disease in the next generation. In humans, advanced paternal age has been associated with increased risk for a number of diseases. Experiments in rodent models have provided initial evidence that paternal age can influence behavioral traits in offspring animals, but the overall scope and extent of paternal age effects on health and disease across the life span remain underexplored. Here, we report that old father offspring mice showed a reduced life span and an exacerbated development of aging traits compared with young father offspring mice. Genome-wide epigenetic analyses of sperm from aging males and old father offspring tissue identified differentially methylated promoters, enriched for genes involved in the regulation of evolutionarily conserved longevity pathways. Gene expression analyses, biochemical experiments, and functional studies revealed evidence for an overactive mTORC1 signaling pathway in old father offspring mice. Pharmacological mTOR inhibition during the course of normal aging ameliorated many of the aging traits that were exacerbated in old father offspring mice. These findings raise the possibility that inherited alterations in longevity pathways contribute to intergenerational effects of aging in old father offspring mice.</AbstractText><CopyrightInformation>Copyright © 2018 the Author(s). Published by PNAS.</CopyrightInformation></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Xie</LastName><ForeName>Kan</ForeName><Initials>K</Initials><AffiliationInfo><Affiliation>Molecular and Cellular Cognition Lab, German Center for Neurodegenerative Diseases (DZNE), 53127 Bonn, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Ryan</LastName><ForeName>Devon P</ForeName><Initials>DP</Initials><AffiliationInfo><Affiliation>Molecular and Cellular Cognition Lab, German Center for Neurodegenerative Diseases (DZNE), 53127 Bonn, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Pearson</LastName><ForeName>Brandon L</ForeName><Initials>BL</Initials><AffiliationInfo><Affiliation>Molecular and Cellular Cognition Lab, German Center for Neurodegenerative Diseases (DZNE), 53127 Bonn, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Henzel</LastName><ForeName>Kristin S</ForeName><Initials>KS</Initials><AffiliationInfo><Affiliation>Molecular and Cellular Cognition Lab, German Center for Neurodegenerative Diseases (DZNE), 53127 Bonn, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Neff</LastName><ForeName>Frauke</ForeName><Initials>F</Initials><AffiliationInfo><Affiliation>Institute of Pathology, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Vidal</LastName><ForeName>Ramon O</ForeName><Initials>RO</Initials><AffiliationInfo><Affiliation>Computational Systems Biology Lab, German Center for Neurodegenerative Diseases (DZNE), 37077 Göttingen, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Hennion</LastName><ForeName>Magali</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Computational Systems Biology Lab, German Center for Neurodegenerative Diseases (DZNE), 37077 Göttingen, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Lehmann</LastName><ForeName>Isabelle</ForeName><Initials>I</Initials><AffiliationInfo><Affiliation>Molecular and Cellular Cognition Lab, German Center for Neurodegenerative Diseases (DZNE), 53127 Bonn, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Schleif</LastName><ForeName>Melvin</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Selective Vulnerability of Neurodegenerative Diseases Lab, German Center for Neurodegenerative Diseases (DZNE), 53127 Bonn, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Schröder</LastName><ForeName>Susanne</ForeName><Initials>S</Initials><AffiliationInfo><Affiliation>Molecular and Cellular Cognition Lab, German Center for Neurodegenerative Diseases (DZNE), 53127 Bonn, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Adler</LastName><ForeName>Thure</ForeName><Initials>T</Initials><AffiliationInfo><Affiliation>German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Institute for Medical Microbiology, Immunology and Hygiene, Technische Universität München, 81675 Munich, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Rathkolb</LastName><ForeName>Birgit</ForeName><Initials>B</Initials><Identifier Source="ORCID">0000-0003-1239-0547</Identifier><AffiliationInfo><Affiliation>German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Chair of Molecular Animal Breeding and Biotechnology, Gene Center, Ludwig-Maximilians-Universität München, 81377 Munich, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Rozman</LastName><ForeName>Jan</ForeName><Initials>J</Initials><AffiliationInfo><Affiliation>German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>German Center for Diabetes Research (DZD), 85764 München-Neuherberg, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Schütz</LastName><ForeName>Anna-Lena</ForeName><Initials>AL</Initials><AffiliationInfo><Affiliation>Computational Systems Biology Lab, German Center for Neurodegenerative Diseases (DZNE), 37077 Göttingen, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Prehn</LastName><ForeName>Cornelia</ForeName><Initials>C</Initials><AffiliationInfo><Affiliation>German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Mickael</LastName><ForeName>Michel E</ForeName><Initials>ME</Initials><AffiliationInfo><Affiliation>Computational Systems Biology Lab, German Center for Neurodegenerative Diseases (DZNE), 37077 Göttingen, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Weiergräber</LastName><ForeName>Marco</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Research Group Experimental Neuropsychopharmacology, Federal Institute for Drugs and Medical Devices, 53175 Bonn, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Adamski</LastName><ForeName>Jerzy</ForeName><Initials>J</Initials><AffiliationInfo><Affiliation>German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Chair of Experimental Genetics, Center of Life and Food Sciences Weihenstephan, Technische Universität München, 85350 Freising-Weihenstephan, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Busch</LastName><ForeName>Dirk H</ForeName><Initials>DH</Initials><AffiliationInfo><Affiliation>Institute for Medical Microbiology, Immunology and Hygiene, Technische Universität München, 81675 Munich, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Ehninger</LastName><ForeName>Gerhard</ForeName><Initials>G</Initials><AffiliationInfo><Affiliation>Department of Internal Medicine I, University Hospital Carl Gustav Carus, Technical University Dresden, 01307 Dresden, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Matynia</LastName><ForeName>Anna</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>Jules Stein Eye Institute, University of California, Los Angeles, CA 90095.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Jackson</LastName><ForeName>Walker S</ForeName><Initials>WS</Initials><AffiliationInfo><Affiliation>Selective Vulnerability of Neurodegenerative Diseases Lab, German Center for Neurodegenerative Diseases (DZNE), 53127 Bonn, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Wolf</LastName><ForeName>Eckhard</ForeName><Initials>E</Initials><Identifier Source="ORCID">0000-0002-0430-9510</Identifier><AffiliationInfo><Affiliation>Chair of Molecular Animal Breeding and Biotechnology, Gene Center, Ludwig-Maximilians-Universität München, 81377 Munich, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Fuchs</LastName><ForeName>Helmut</ForeName><Initials>H</Initials><AffiliationInfo><Affiliation>German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Gailus-Durner</LastName><ForeName>Valerie</ForeName><Initials>V</Initials><AffiliationInfo><Affiliation>German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Bonn</LastName><ForeName>Stefan</ForeName><Initials>S</Initials><Identifier Source="ORCID">0000-0003-4366-5662</Identifier><AffiliationInfo><Affiliation>Computational Systems Biology Lab, German Center for Neurodegenerative Diseases (DZNE), 37077 Göttingen, Germany.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>German Center for Neurodegenerative Diseases (DZNE), 72076 Tübingen, Germany.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Center for Molecular Neurobiology, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Hrabě de Angelis</LastName><ForeName>Martin</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>German Center for Diabetes Research (DZD), 85764 München-Neuherberg, Germany.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Chair of Experimental Genetics, Center of Life and Food Sciences Weihenstephan, Technische Universität München, 85350 Freising-Weihenstephan, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Ehninger</LastName><ForeName>Dan</ForeName><Initials>D</Initials><Identifier Source="ORCID">0000-0001-7464-1335</Identifier><AffiliationInfo><Affiliation>Molecular and Cellular Cognition Lab, German Center for Neurodegenerative Diseases (DZNE), 53127 Bonn, Germany; dan.ehninger@dzne.de.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType><PublicationType UI="D013485">Research Support, Non-U.S. Gov't</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2018</Year><Month>02</Month><Day>21</Day></ArticleDate></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>Proc Natl Acad Sci U S A</MedlineTA><NlmUniqueID>7505876</NlmUniqueID><ISSNLinking>0027-8424</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>EC 2.7.11.1</RegistryNumber><NameOfSubstance UI="D000076222">Mechanistic Target of Rapamycin Complex 1</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D000367" MajorTopicYN="N">Age Factors</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D000375" MajorTopicYN="N">Aging</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="Y">genetics</QualifierName><QualifierName UI="Q000502" MajorTopicYN="N">physiology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D000818" MajorTopicYN="N">Animals</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D019175" MajorTopicYN="N">DNA Methylation</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D044127" MajorTopicYN="Y">Epigenesis, Genetic</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D005220" MajorTopicYN="N">Fathers</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D005260" MajorTopicYN="N">Female</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D008017" MajorTopicYN="N">Life Expectancy</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D008136" MajorTopicYN="Y">Longevity</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D008297" MajorTopicYN="N">Male</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D000076222" MajorTopicYN="N">Mechanistic Target of Rapamycin Complex 1</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D051379" MajorTopicYN="N">Mice</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D010375" MajorTopicYN="N">Pedigree</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D011401" MajorTopicYN="N">Promoter Regions, Genetic</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D013094" MajorTopicYN="N">Spermatozoa</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading></MeshHeadingList><KeywordList Owner="NOTNLM"><Keyword MajorTopicYN="Y">aging</Keyword><Keyword MajorTopicYN="Y">epigenetics</Keyword><Keyword MajorTopicYN="Y">intergenerational inheritance</Keyword><Keyword MajorTopicYN="Y">mTOR</Keyword><Keyword MajorTopicYN="Y">sperm</Keyword></KeywordList><CoiStatement>The authors declare no conflict of interest.</CoiStatement></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="pubmed"><Year>2018</Year><Month>2</Month><Day>23</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2018</Year><Month>10</Month><Day>31</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2018</Year><Month>2</Month><Day>23</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">29467291</ArticleId><ArticleId IdType="pii">1707337115</ArticleId><ArticleId IdType="doi">10.1073/pnas.1707337115</ArticleId><ArticleId 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