Characterization of DNA methylation in PBMCs and donor-matched iPSCs shows age-related methylation is reset during stem cell reprogramming

DNA methylation is an important epigenetic mechanism that helps define and maintain cellular functions. It is influenced by many factors, including environmental exposures, genotype, cell type, sex, and aging. Since age is the primary risk factor for developing neurodegenerative diseases, it is important to determine if age-related DNA methylation is retained when cells are reprogrammed to an induced Pluripotent Stem Cell (iPSC) state. Here, we selected peripheral blood mononuclear cells (PBMCs; n = 99) from a cohort of diverse and healthy individuals enrolled in the Genetic and Epigenetic Signatures of Translational Aging Laboratory Testing (GESTALT) study to reprogram to iPSCs. After reprogramming, the resulting iPSCs were evaluated for DNA methylation signatures to determine if they reflect the confounding factors of aging and environmental effects. Data from genome-wide DNA methylation arrays in both cell types showed that age-related methylation measured by epigenetic clocks is largely reset to an early methylation age after reprogramming of PBMCs to iPSCs. We further examined the epigenetic age of each cell type using an Epigenome-wide Association Study (EWAS) and identified a set of methylation Quantitative Trait Loci in each cell type. Our results show that age-related DNA methylation is largely reset in iPSCs, and each cell type has a unique set of methylation sites that are modified by population-level genetic variation.