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Xie, K.* ; Ryan, D.P.* ; Pearson, B.L.* ; Henzel, K.S.* ; Neff, F. ; Vidal, R.O.* ; Hennion, M.* ; Lehmann, I.* ; Schleif, M.* ; Schröder, S.* ; Adler, T. ; Rathkolb, B. ; Rozman, J. ; Schütz, A.L.* ; Prehn, C. ; Mickael, M.E.* ; Weiergräber, M.* ; Adamski, J. ; Busch, D.H.* ; Ehninger, G.* ; Matynia, A.* ; Jackson, W.S.* ; Wolf, E.* ; Fuchs, H. ; Gailus-Durner, V. ; Bonn, S.* ; Hrabě de Angelis, M. ; Ehninger, D.*

Epigenetic alterations in longevity regulators, reduced life span, and exacerbated aging-related pathology in old father offspring mice.

Proc. Natl. Acad. Sci. U.S.A. 115, E2348-E2357 (2018)
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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.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Aging ; Epigenetics ; Intergenerational Inheritance ; Sperm ; Mtor; Genetically Heterogeneous Mice; Paternal Age; Mammalian Target; Dna Methylation; Gene-expression; Telomere Length; Mtor Pathway; Birth-cohort; Rapamycin; Inflammation
Language english
Publication Year 2018
HGF-reported in Year 2018
ISSN (print) / ISBN 0027-8424
e-ISSN 1091-6490
Journal Proceedings of the National Academy of Sciences of the United States of America
Quellenangaben Volume: 115, Issue: 10, Pages: E2348-E2357 Article Number: , Supplement: ,
Publisher National Academy of Sciences
Publishing Place Washington
Reviewing status Peer reviewed
Institute(s) Institute of Pathology (PATH)
Institute of Experimental Genetics (IEG)
Research Unit Genome Analysis Center (IEG-GAC)
POF-Topic(s) 30504 - Mechanisms of Genetic and Environmental Influences on Health and Disease
30201 - Metabolic Health
Research field(s) Enabling and Novel Technologies
Genetics and Epidemiology
PSP Element(s) G-500300-001
G-500600-001
G-500692-001
A-630440-001
DOI 10.1073/pnas.1707337115
WOS ID WOS:000426671900026
Scopus ID 85042919828
PubMed ID 29467291
Erfassungsdatum 2018-03-09
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