Epigenetic alterations in longevity regulators, reduced life span, and exacerbated aging-related pathology in old father offspring mice
| Autor: | Eckhard Wolf, Ramon O. Vidal, Anna Matynia, Frauke Neff, Birgit Rathkolb, Valerie Gailus-Durner, Anna-Lena Schütz, Helmut Fuchs, Gerhard Ehninger, Dan Ehninger, Devon Ryan, Dirk H. Busch, Jan Rozman, Cornelia Prehn, Martin Hrabě de Angelis, Stefan Bonn, Melvin Schleif, Isabelle Lehmann, Walker S. Jackson, Michel E. Mickael, Jerzy Adamski, Magali Hennion, Thure Adler, Kristin S. Henzel, Brandon L. Pearson, Susanne Schröder, Kan Xie, Marco Weiergräber |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Male Aging Medical Sciences Rodent Offspring media_common.quotation_subject Longevity Physiology Epigenetics Intergenerational Inheritance Sperm Mtor Disease Mechanistic Target of Rapamycin Complex 1 intergenerational inheritance sperm Epigenesis Genetic 03 medical and health sciences Fathers Mice Life Expectancy biology.animal metabolism [Mechanistic Target of Rapamycin Complex 1] Animals Humans Risk factor Promoter Regions Genetic Gene PI3K/AKT/mTOR pathway media_common aging epigenetics mTOR metabolism [Spermatozoa] Multidisciplinary biology Age Factors genetics [Mechanistic Target of Rapamycin Complex 1] Biological Sciences DNA Methylation physiology [Aging] Spermatozoa ddc Pedigree 030104 developmental biology PNAS Plus genetics [Aging] Female ddc:500 |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America Proceedings of the National Academy of Sciences of the United States of America 115(10), E2348-E2357 (2018). doi:10.1073/pnas.1707337115 Proc. Natl. Acad. Sci. U.S.A. 115, E2348-E2357 (2018) |
| DOI: | 10.1073/pnas.1707337115 |
| Popis: | Significance Aging-associated diseases are increasingly common in an aging global population. However, the contributors and origins of differential risk for unhealthy aging remain poorly understood. Using a mouse model, we found that offspring of aged fathers exhibited a reduced life span and more pronounced aging-associated pathologies than animals sired by young fathers. Tissue of offspring and aged fathers revealed shared epigenetic signatures and showed altered activation states of longevity-related cell signaling. Our results suggest that variability in aging trajectories could derive, in part, from the age at conception of the father, a possibility that warrants human epidemiological investigation. 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|