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Repetitive element transcript accumulation is associated with inflammaging in humans

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Abstract

Chronic, low-grade inflammation increases with aging, contributing to functional declines and diseases that reduce healthspan. Growing evidence suggests that transcripts from repetitive elements (RE) in the genome contribute to this “inflammaging” by stimulating innate immune activation, but evidence of RE-associated inflammation with aging in humans is limited. Here, we present transcriptomic and clinical data showing that RE transcript levels are positively related to gene expression of innate immune sensors, and to serum interleukin 6 (a marker of systemic inflammation), in a large group of middle-aged and older adults. We also: (1) use transcriptomics and whole-genome bisulfite (methylation) sequencing to show that many RE may be hypomethylated with aging, and that aerobic exercise, a healthspan-extending intervention, reduces RE transcript levels and increases RE methylation in older adults; and (2) extend our findings in a secondary dataset demonstrating age-related changes in RE chromatin accessibility. Collectively, our data support the idea that age-related RE transcript accumulation may play a role in inflammaging in humans, and that RE dysregulation with aging may be due in part to upstream epigenetic changes.

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Data availability

Additional data supporting the present findings are presented in the Supplementary Data file, and raw RNA-seq and WGBS data are available on the NCBI Gene Expression Omnibus website (GEO accession number GSE263013).

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Acknowledgements

The authors wish to thank Dr. Duygu Ucar and The Jackson Laboratory for providing access to raw data on the European Genome-phenome Archive (EGA, accession number EGAS00001002605), which was used for analyses of RE chromatin accessibility.

Funding

This study was supported by the National Institutes of Health grants: R21AG060302 and R01AG078859 (T.J.L.); R01AG013038, R21AG049451, R21AG042795 and R21HL107105 (D.R.S.); and R01AG043452 (A.D.B.).

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Authors and Affiliations

  1. Department of Health and Exercise Science, Colorado State University, Fort Collins, CO, USA

    Meghan E. Smith, Devin Wahl, Alyssa N. Cavalier, Gabriella T. McWilliams & Thomas J. LaRocca

  2. Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO, USA

    Matthew J. Rossman & Douglas R. Seals

  3. Department of Psychology and Neuroscience, University of Colorado Boulder, Boulder, CO, USA

    Gregory R. Giordano & Angela D. Bryan

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  1. Meghan E. Smith
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Contributions

T.J.L. and M.E.S. conceptualized this study. D.R.S. and A.D.B.’s research groups conducted the studies from which samples were obtained. D.W., A.N.C., G.T.M., M.E.S. and T.J.L. performed RNA and DNA isolation and analyses. M.E.S. and T.J.L. performed statistical analyses and transcriptome and epigenome analyses. M.E.S. and T.J.L. wrote the manuscript with editing assistance from all co-authors.

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Correspondence to Thomas J. LaRocca.

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Smith, M.E., Wahl, D., Cavalier, A.N. et al. Repetitive element transcript accumulation is associated with inflammaging in humans. GeroScience (2024). https://doi.org/10.1007/s11357-024-01126-y

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  • DOI: https://doi.org/10.1007/s11357-024-01126-y

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