Genetic loci and metabolic states associated with murine epigenetic aging
Abstract
Changes in DNA methylation (DNAm) are linked to aging. Here, we profile highly conserved CpGs in 339 predominantly female mice belonging to the BXD family for which we have deep longevity and genomic data. We use a 'pan-mammalian' microarray that provides a common platform for assaying the methylome across mammalian clades. We computed epigenetic clocks and tested associations with DNAm entropy, diet, weight, metabolic traits, and genetic variation. We describe the multifactorial variance of methylation at these CpGs, and show that high fat diet augments the age-associated changes. Entropy increases with age. The progression to disorder, particularly at CpGs that gain methylation over time, was predictive of genotype-dependent life expectancy. The longer-lived BXD strains had comparatively lower entropy at a given age. We identified two genetic loci that modulate rates of epigenetic age acceleration (EAA): one on chromosome (Chr) 11 that encompasses the Erbb2/Her2 oncogenic region, and a second on Chr19 that contains a cytochrome P450 cluster. Both loci harbor genes associated with EAA in humans including STXBP4, NKX2-3, and CUTC. Transcriptome and proteome analyses revealed associations with oxidation-reduction, metabolic, and immune response pathways. Our results highlight concordant loci for EAA in humans and mice, and demonstrate a tight coupling between the metabolic state and epigenetic aging.
Data availability
The normalized microarray data and raw files are available from the NCBI Gene Expression Omnibus (accession ID GSE199979). The HorvathMammalMethylChip40 array manifest files and genome annotations of CpGs can be found on Github at https://github.com/shorvath/MammalianMethylationConsortium.79 Individual level BXD data, including the processed microarray data are available on www.genenetwork.org on FAIR+ compliant format; data identifiers, and way to retrieve data are described in Supplementary file 13.
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Genetic Loci and Metabolic States Associated With Murine Epigenetic AgingNCBI Gene Expression Omnibus, GSE199979.
Article and author information
Author details
Funding
National Institute on Aging (R21AG055841)
- Khyobeni Mozhui
National Institute on Aging (R01AG043930)
- Robert W Williams
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All animal procedures were in accordance to protocol approved by the Institutional Animal Care and Use Committee (IACUC) at the University of Tennessee Health Science Center. Protocol numbers 12-148.0 (2012-2015), 15-124.0 (2015-2018), and 18-094.0 (2018-present).
Copyright
© 2022, Mozhui et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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