Epigenetic Age Acceleration Assessed In White-Matter Integrity: Towards A Biomarker of Successfully Brain Aging

Background Biological age acceleration as measured by aggregate epigenetic markers has been associated with a number of phenotypes including Parkinson’s, obesity and physical fitness in the elderly. Additionally, epigenetic indices of age acceleration are touted as molecular biomarkers of brain aging, based on findings linking epigenetic age of prefrontal cortex tissue with Alzheimer’s-related phenotypes. Yet, in order to develop a clinically useful brain age acceleration biomarker, peripheral tissue, rather than neural tissue, is preferable. Likewise, in vivo neuroimaging measures are desirable. To that end, we examined the relationship between blood-derived epigenetic measures of age acceleration and white matter integrity, as indexed with diffusion weighted imaging (DWI), in a large randomly ascertained family cohort. Our goal was to investigate processes that underlie inter-individual variability in age-related changes in the white matter tracts. DWI measures of white mater integrity are among the most sensitive imaging measures of aging with demonstrated heritabilities. Methods Using blood DNA methylation data taken from a Mexican-American extended pedigree sample (n=634; mean age=49.16y, range 28.11y-97.52y), epigenetic age was estimated using the method developed by S. Horvath (2013). Epigenetic age acceleration was calculated as epigenetic age regressed upon age, sex, age x sex, age2, age2 x sex, and blood cell count estimates. 379 of these individuals had available DWI scans collected on a Siemens 3T Trio MRI located at the Research Imaging Institute, UTHSCSA. An average fractional anisotropy (FA) map was derived for each subject and skeletonized using the TBSS algorithm, providing FA measures for each of 16 white matter tracts and a global index. Variance decomposition methods were then used to investigate the interrelationship between epigenetic age acceleration and white matter integrity and identify genetic influences on these two phenotypes. Results Consistent with previous reports, both epigenetic age acceleration and white matter integrity measures are heritable in this sample. We observe significant (FDR Discussion Here we demonstrate that age acceleration, as measured via methylation profiles from peripheral blood, is significantly correlated with white matter integrity in a number of tracts within the brain. We also demonstrate evidence of shared genetic influences acting on both age acceleration and white matter integrity. These findings provide an interesting window into the neurobiology of aging processes within the brain and a potential new biomarker of normal and pathological brain aging.