Development and validation of an epigenetic clock in Fischer 344 rats.

National Institute On Aging

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Abstract

The past year has been spent wrapping up the analysis and preparing a publication that is in the latest stages of review at Journals Of Gerontology; Biological Sicence. In this manuscript we report Epigenetic changes in DNA methylation are a hallmark of aging. Computed by weighting and averaging methylation at specific cytosine-guanosine pairs (CpGs), epigenetic clocks are thought to estimate biological age, independently from chronological age, and predict adverse health and functional outcomes. We previously developed an epigenetic clock in Fischer 344 rats. Fischer 344 rats often develop large granular lymphocyte leukemia (LGL), which affects white blood cell composition and may potentially bias the epigenetic signal of DNA and reduce the validity of the epigenetic clock. Here we found clear histological markers of LGL pathology in the spleens and livers of 27 out of 61 rats aged 17-27 months. We assessed DNA methylation by reduced representation bisulfite sequencing with coverage of 3 million cytosine residues. We found a greater number of sites with increased variability in rats with advanced stage LGL. LGL significantly affected methylation at specific CpGs sites, which only minimally overlapped with those selected for the rat age-epigenetic clock. In conclusion, while the presence of LGL determines characteristic changes in DNA methylation, the epigenetic clocks tuned on chronological age remains valid across the life span in rats with and without LGL.