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

被引：103

作者：

Xie, Kan ^{[1
]}

Ryan, Devon P. ^{[1
,15
]}

Pearson, Brandon L. ^{[1
,16
]}

Henzel, Kristin S. ^{[1
]}

Neff, Frauke ^{[3
,4
]}

Vidal, Ramon O. ^{[5
]}

Hennion, Magali ^{[5
]}

Lehmann, Isabelle ^{[1
]}

Schleif, Melvin ^{[2
]}

Schroeder, Susanne ^{[1
]}

Adler, Thure ^{[4
,6
,17
]}

Rathkolb, Birgit ^{[4
,7
]}

Rozman, Jan ^{[4
,8
]}

Schuetz, Anna-Lena ^{[5
]}

Prehn, Cornelia ^{[4
]}

Mickael, Michel E. ^{[5
]}

Weiergraber, Marco ^{[9
]}

Adamski, Jerzy ^{[4
,10
]}

Busch, Dirk H. ^{[6
]}

Ehninger, Gerhard ^{[11
]}

Matynia, Anna ^{[12
]}

Jackson, Walker S. ^{[2
]}

Wolf, Eckhard ^{[7
]}

Fuchs, Helmut ^{[4
]}

Gailus-Durner, Valerie ^{[4
]}

Bonn, Stefan ^{[5
,13
,14
]}

de Angelis, Martin Hrabe ^{[4
,8
,10
]}

Ehninger, Dan ^{[1
]}

机构：

[1] German Ctr Neurodegenerat Dis DZNE, Mol & Cellular Cognit Lab, D-53127 Bonn, Germany

[2] German Ctr Neurodegenerat Dis DZNE, Select Vulnerabil Neurodegenerat Dis Lab, D-53127 Bonn, Germany

[3] Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Pathol, D-85764 Neuherberg, Germany

[4] Helmholtz Zentrum Munchen, Inst Expt Genet, German Mouse Clin, D-85764 Neuherberg, Germany

[5] German Ctr Neurodegenerat Dis DZNE, Computat Syst Biol Lab, D-37077 Gottingen, Germany

[6] Tech Univ Munich, Inst Med Microbiol Immunol & Hyg, D-81675 Munich, Germany

[7] Ludwig Maximilians Univ Munchen, Gene Ctr, Chair Mol Anim Breeding & Biotechnol, D-81377 Munich, Germany

[8] German Ctr Diabet Res DZD, D-85764 Munich, Germany

[9] Fed Inst Drugs & Med Devices, Res Grp Expt Neuropsychopharmacol, D-53175 Bonn, Germany

[10] Tech Univ Munich, Ctr Life & Food Sci Weihenstephan, Chair Expt Genet, D-85350 Freising Weihenstephan, Germany

[11] Tech Univ Dresden, Univ Hosp Carl Gustav Carus, Dept Internal Med 1, D-01307 Dresden, Germany

[12] Univ Calif Los Angeles, Jules Stein Eye Inst, Los Angeles, CA 90095 USA

[13] German Ctr Neurodegenerat Dis DZNE, D-72076 Tubingen, Germany

[14] Univ Med Ctr Hamburg Eppendorf, Ctr Mol Neurobiol, D-20251 Hamburg, Germany

[15] Max Planck Inst Immunobiol & Epigenet, Bioinformat Unit, D-79108 Freiburg, Germany

[16] Columbia Univ, Dept Environm Hlth Sci, Mailman Sch Publ Hlth, New York, NY 10032 USA

[17] Helmholtz Zentrum Munchen, Inst Stem Cell Res, German Res Ctr Environm Hlth, D-85764 Neuherberg, Germany

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2018年 / 115卷 / 10期

关键词：

aging; epigenetics; intergenerational inheritance; sperm; mTOR; PATERNAL AGE; MAMMALIAN TARGET; DNA METHYLATION; TELOMERE LENGTH; GENE-EXPRESSION; BIRTH-COHORT; INFLAMMATION; RISK; DISTINCT; PATHWAY;

D O I：

10.1073/pnas.1707337115

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];

摘要：

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.

引用

页码：E2348 / E2357

页数：10

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