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PLoS Genet. 2018 Nov 21;14(11):e1007766. doi: 10.1371/journal.pgen.1007766. eCollection 2018 Nov.

Hepatic gene body hypermethylation is a shared epigenetic signature of murine longevity.

Author information

1
Max Planck Institute for Biology of Ageing, Cologne, Germany.
2
Cellular Networks and Systems Biology, CECAD, University of Cologne, Cologne, Germany.
3
Epigenetics Programme, The Babraham Institute, Cambridge, United Kingdom.
4
The Wellcome Trust Sanger Institute, Cambridge, United Kingdom.
5
Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.
6
Department of Genetics, Evolution and Environment, Institute of Healthy Ageing, University College London, London, United Kingdom.

Abstract

Dietary, pharmacological and genetic interventions can extend health- and lifespan in diverse mammalian species. DNA methylation has been implicated in mediating the beneficial effects of these interventions; methylation patterns deteriorate during ageing, and this is prevented by lifespan-extending interventions. However, whether these interventions also actively shape the epigenome, and whether such epigenetic reprogramming contributes to improved health at old age, remains underexplored. We analysed published, whole-genome, BS-seq data sets from mouse liver to explore DNA methylation patterns in aged mice in response to three lifespan-extending interventions: dietary restriction (DR), reduced TOR signaling (rapamycin), and reduced growth (Ames dwarf mice). Dwarf mice show enhanced DNA hypermethylation in the body of key genes in lipid biosynthesis, cell proliferation and somatotropic signaling, which strongly correlates with the pattern of transcriptional repression. Remarkably, DR causes a similar hypermethylation in lipid biosynthesis genes, while rapamycin treatment increases methylation signatures in genes coding for growth factor and growth hormone receptors. Shared changes of DNA methylation were restricted to hypermethylated regions, and they were not merely a consequence of slowed ageing, thus suggesting an active mechanism driving their formation. By comparing the overlap in ageing-independent hypermethylated patterns between all three interventions, we identified four regions, which, independent of genetic background or gender, may serve as novel biomarkers for longevity-extending interventions. In summary, we identified gene body hypermethylation as a novel and partly conserved signature of lifespan-extending interventions in mouse, highlighting epigenetic reprogramming as a possible intervention to improve health at old age.

PMID:
30462643
DOI:
10.1371/journal.pgen.1007766
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Conflict of interest statement

The authors have declared that no competing interests exist.

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