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Proc Natl Acad Sci U S A. 2018 Mar 6;115(10):E2348-E2357. doi: 10.1073/pnas.1707337115. Epub 2018 Feb 21.

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

Author information

1
Molecular and Cellular Cognition Lab, German Center for Neurodegenerative Diseases (DZNE), 53127 Bonn, Germany.
2
Institute of Pathology, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany.
3
German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
4
Computational Systems Biology Lab, German Center for Neurodegenerative Diseases (DZNE), 37077 Göttingen, Germany.
5
Selective Vulnerability of Neurodegenerative Diseases Lab, German Center for Neurodegenerative Diseases (DZNE), 53127 Bonn, Germany.
6
Institute for Medical Microbiology, Immunology and Hygiene, Technische Universität München, 81675 Munich, Germany.
7
Chair of Molecular Animal Breeding and Biotechnology, Gene Center, Ludwig-Maximilians-Universität München, 81377 Munich, Germany.
8
German Center for Diabetes Research (DZD), 85764 München-Neuherberg, Germany.
9
Research Group Experimental Neuropsychopharmacology, Federal Institute for Drugs and Medical Devices, 53175 Bonn, Germany.
10
Chair of Experimental Genetics, Center of Life and Food Sciences Weihenstephan, Technische Universität München, 85350 Freising-Weihenstephan, Germany.
11
Department of Internal Medicine I, University Hospital Carl Gustav Carus, Technical University Dresden, 01307 Dresden, Germany.
12
Jules Stein Eye Institute, University of California, Los Angeles, CA 90095.
13
German Center for Neurodegenerative Diseases (DZNE), 72076 Tübingen, Germany.
14
Center for Molecular Neurobiology, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany.
15
Molecular and Cellular Cognition Lab, German Center for Neurodegenerative Diseases (DZNE), 53127 Bonn, Germany; dan.ehninger@dzne.de.

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.

KEYWORDS:

aging; epigenetics; intergenerational inheritance; mTOR; sperm

PMID:
29467291
PMCID:
PMC5877957
DOI:
10.1073/pnas.1707337115
[Indexed for MEDLINE]
Free PMC Article

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