• Open Access

Characterization of the role of distinct plasma cell-free DNA species in age-associated inflammation and frailty

Authors

  • Juulia Jylhävä,

    Corresponding author
    1. Gerontology Research Center, University of Tampere, Finland
    • Department of Microbiology and Immunology, The School of Medicine, University of Tampere, Tampere, Finland
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  • Tapio Nevalainen,

    1. Department of Microbiology and Immunology, The School of Medicine, University of Tampere, Tampere, Finland
    2. Gerontology Research Center, University of Tampere, Finland
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  • Saara Marttila,

    1. Department of Microbiology and Immunology, The School of Medicine, University of Tampere, Tampere, Finland
    2. Gerontology Research Center, University of Tampere, Finland
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  • Marja Jylhä,

    1. Gerontology Research Center, University of Tampere, Finland
    2. The School of Health Sciences, University of Tampere, Tampere, Finland
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  • Antti Hervonen,

    1. Gerontology Research Center, University of Tampere, Finland
    2. The School of Health Sciences, University of Tampere, Tampere, Finland
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  • Mikko Hurme

    1. Department of Microbiology and Immunology, The School of Medicine, University of Tampere, Tampere, Finland
    2. Gerontology Research Center, University of Tampere, Finland
    3. Department of Microbiology, Tampere University Hospital, Tampere, Finland
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Correspondence

Juulia Jylhävä, Department of Microbiology and Immunology, School of Medicine, University of Tampere, FIN-33014 Tampere, Finland. Tel.: +358 3 3551 7723; fax: +358 3 3551 6173; e-mail: juulia.jylhava@uta.fi

Summary

Plasma cell-free DNA (cf-DNA) has recently emerged as a potential biomarker of aging, reflecting systemic inflammation, and cell death. In addition, it has been suggested that cf-DNA could promote autoinflammation. Because the total cf-DNA pool comprises different cf-DNA species, we quantified the plasma levels of gene-coding cf-DNA, Alu repeat cf-DNA, mitochondrial DNA (mtDNA) copy number, and the amounts of unmethylated and total cf-DNAs. We identified the relationships between these cf-DNA species and age-associated inflammation, immunosenescence, and frailty. Additionally, we determined the cf-DNA species-specific transcriptomic signatures in blood mononuclear cells to elucidate the age-linked leukocyte responses to cf-DNA. The study population consisted of n = 144 nonagenarian participants of the Vitality 90+ Study and n = 30 young controls. In the nonagenarians, higher levels of total and unmethylated cf-DNAs were associated with systemic inflammation and increased frailty. The mtDNA copy number was also directly correlated with increased frailty but not with inflammation. None of the cf-DNA species were associated with immunosenescence. The transcriptomic pathway analysis revealed that higher levels of total and unmethylated cf-DNAs were associated with immunoinflammatory activation in the nonagenarians but not in the young controls. The plasma mtDNA appeared to be inert in terms of inflammatory activation in both the nonagenarians and young controls. These data demonstrate that the plasma levels of total and unmethylated cf-DNA and the mtDNA copy number could serve as biomarkers of frailty. In addition, we suggest that circulating self-DNA, assessed as total or unmethylated cf-DNA, might aggravate immunoinflammatory reactivity in very old individuals.

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