Genetic loci and metabolic states associated with murine epigenetic aging

  1. Khyobeni Mozhui  Is a corresponding author
  2. Ake T Lu
  3. Caesar Z Li
  4. Amin Haghani
  5. Jose Vladimir Sandoval-Sierra
  6. Yibo Wu
  7. Robert W Williams
  8. Steve Horvath
  1. University of Tennessee Health Science Center, United States
  2. University of California, Los Angeles, United States
  3. University of California Los Angeles David Geffen School of Medicine, United States
  4. University of Geneva, Switzerland

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.

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Khyobeni Mozhui

    Department of Preventive Medicine, University of Tennessee Health Science Center, Memphis, United States
    For correspondence
    kmozhui@uthsc.edu
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6623-4112
  2. Ake T Lu

    Department of Human Genetics, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    No competing interests declared.
  3. Caesar Z Li

    Department of Human Genetics, University of California Los Angeles David Geffen School of Medicine, Los Angeles, United States
    Competing interests
    No competing interests declared.
  4. Amin Haghani

    Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6052-8793
  5. Jose Vladimir Sandoval-Sierra

    Department of Preventive Medicine, University of Tennessee Health Science Center, Memphis, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2007-6582
  6. Yibo Wu

    University of Geneva, Geneva, Switzerland
    Competing interests
    No competing interests declared.
  7. Robert W Williams

    Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, United States
    Competing interests
    No competing interests declared.
  8. Steve Horvath

    Department of Human Genetics, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    Steve Horvath, is a founder of the non-profit Epigenetic Clock Development Foundation, which plans to license several of his patents from his employer, University of California Regents. The Regents of the University of California filed a patent application (publication number WO2020150705) related to the HorvathMammalMethylChip40 and clock computation for which he is named an inventor..

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.

Reviewing Editor

  1. Joris Deelen, Max Planck Institute for Biology of Ageing, Germany

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).

Version history

  1. Preprint posted: June 24, 2021 (view preprint)
  2. Received: November 3, 2021
  3. Accepted: April 1, 2022
  4. Accepted Manuscript published: April 7, 2022 (version 1)
  5. Version of Record published: April 28, 2022 (version 2)

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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  1. Khyobeni Mozhui
  2. Ake T Lu
  3. Caesar Z Li
  4. Amin Haghani
  5. Jose Vladimir Sandoval-Sierra
  6. Yibo Wu
  7. Robert W Williams
  8. Steve Horvath
(2022)
Genetic loci and metabolic states associated with murine epigenetic aging
eLife 11:e75244.
https://doi.org/10.7554/eLife.75244

Share this article

https://doi.org/10.7554/eLife.75244

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