Meta-analysis on blood transcriptomic studies identifies consistently coexpressed protein–protein interaction modules as robust markers of human aging

Authors

  • Erik B. van den Akker,

    1. Department of Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands
    2. The Delft Bioinformatics Lab, Delft University of Technology, Delft, The Netherlands
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    • The authors wish it to be known that, in their opinion, the first 2 authors should be regarded as joint First Authors.
  • Willemijn M. Passtoors,

    1. Department of Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands
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    • The authors wish it to be known that, in their opinion, the first 2 authors should be regarded as joint First Authors.
  • Rick Jansen,

    1. Department of Psychiatry, VU University Medical Center, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands
    2. EMGO Institute for Health and Care Research, Neuroscience Campus Amsterdam, Amsterdam, The Netherlands
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  • Erik W. van Zwet,

    1. Department of Medical Statistics, Leiden University Medical Center, Leiden, The Netherlands
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  • Jelle J. Goeman,

    1. Department of Medical Statistics, Leiden University Medical Center, Leiden, The Netherlands
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  • Marc Hulsman,

    1. The Delft Bioinformatics Lab, Delft University of Technology, Delft, The Netherlands
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  • Valur Emilsson,

    1. Icelandic Heart Association, Kópavogur, Iceland
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  • Markus Perola,

    1. National Institute for Health and Welfare, Helsinki, Finland
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  • Gonneke Willemsen,

    1. Department of Biological Psychology, VU University, Amsterdam, The Netherlands
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  • Brenda W.J.H. Penninx,

    1. Department of Psychiatry, VU University Medical Center, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands
    2. EMGO Institute for Health and Care Research, Neuroscience Campus Amsterdam, Amsterdam, The Netherlands
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  • Bas T. Heijmans,

    1. Department of Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands
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  • Andrea B. Maier,

    1. Section of Gerontology and Geriatrics, Department of Internal Medicine, VU University Medical Center, Amsterdam, The Netherlands
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  • Dorret I. Boomsma,

    1. EMGO Institute for Health and Care Research, Neuroscience Campus Amsterdam, Amsterdam, The Netherlands
    2. Department of Biological Psychology, VU University, Amsterdam, The Netherlands
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  • Joost N. Kok,

    1. Department of Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands
    2. Department of Algorithms, Leiden Institute of Advanced Computer Science, University of Leiden, Leiden, The Netherlands
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  • Pieternella E. Slagboom,

    1. Department of Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands
    2. Netherlands Consortium for Healthy Ageing, Leiden University Medical Center, Leiden, The Netherlands
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  • Marcel J.T. Reinders,

    Corresponding author
    1. The Delft Bioinformatics Lab, Delft University of Technology, Delft, The Netherlands
    • Correspondence

      Marian Beekman, Molecular Epidemiology, Leiden University Medical Center, Einthovenweg 20, 2333 ZC, Leiden, The Netherlands. Tel.: +31 71 526 9735; fax: +31 71 526 8280; e-mail: M.Beekman@lumc.nl

      and

      Marcel Reinders, The Delft Bioinformatics Lab, Delft University of Technology, Mekelweg 4, 2628 CD Delft, The Netherlands. Tel.: +31 15 278 6324; fax: +31 15 278 1843; e-mail: m.j.t.reinders@tudelft.nl

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  • Marian Beekman

    Corresponding author
    1. Department of Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands
    2. Netherlands Consortium for Healthy Ageing, Leiden University Medical Center, Leiden, The Netherlands
    • Correspondence

      Marian Beekman, Molecular Epidemiology, Leiden University Medical Center, Einthovenweg 20, 2333 ZC, Leiden, The Netherlands. Tel.: +31 71 526 9735; fax: +31 71 526 8280; e-mail: M.Beekman@lumc.nl

      and

      Marcel Reinders, The Delft Bioinformatics Lab, Delft University of Technology, Mekelweg 4, 2628 CD Delft, The Netherlands. Tel.: +31 15 278 6324; fax: +31 15 278 1843; e-mail: m.j.t.reinders@tudelft.nl

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Summary

The bodily decline that occurs with advancing age strongly impacts on the prospects for future health and life expectancy. Despite the profound role of age in disease etiology, knowledge about the molecular mechanisms driving the process of aging in humans is limited. Here, we used an integrative network-based approach for combining multiple large-scale expression studies in blood (2539 individuals) with protein–protein Interaction (PPI) data for the detection of consistently coexpressed PPI modules that may reflect key processes that change throughout the course of normative aging. Module detection followed by a meta-analysis on chronological age identified fifteen consistently coexpressed PPI modules associated with chronological age, including a highly significant module (= 3.5 × 10−38) enriched for ‘T-cell activation’ marking age-associated shifts in lymphocyte blood cell counts (R2 = 0.603; = 1.9 × 10−10). Adjusting the analysis in the compendium for the ‘T-cell activation’ module showed five consistently coexpressed PPI modules that robustly associated with chronological age and included modules enriched for ‘Translational elongation’, ‘Cytolysis’ and ‘DNA metabolic process’. In an independent study of 3535 individuals, four of five modules consistently associated with chronological age, underpinning the robustness of the approach. We found three of five modules to be significantly enriched with aging-related genes, as defined by the GenAge database, and association with prospective survival at high ages for one of the modules including ASF1A. The hereby-detected age-associated and consistently coexpressed PPI modules therefore may provide a molecular basis for future research into mechanisms underlying human aging.

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