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

Xylena Reed and colleagues compared genome-wide DNA methylation in peripheral blood mononuclear cells and donor-matched induced pluripotent stem cells from 99 healthy participants in the GESTALT study. The question was whether age-related methylation and environmental signatures remain after reprogramming. After PBMCs were converted to iPSCs, epigenetic clock measures were largely reset to an early methylation age. The study also identified methylation quantitative trait loci that differed between PBMCs and iPSCs, showing that cell type and inherited variation shape the methylation landscape. The result is relevant to stem-cell manufacturing and disease modeling. It suggests that iPSCs can erase much of the donor cell’s chronological and exposure-related methylation history. That reset can be useful when the goal is to model early developmental cells, but it may complicate attempts to model late-life disease unless aging features are reintroduced. This is not evidence that iPSC therapy rejuvenates a person. It does not test transplantation, clinical outcomes, tumor safety, or longevity. Reprogramming can also introduce genomic and epigenomic abnormalities that require product-specific testing. The paper supports careful characterization of cell products and caution against treating epigenetic age reset as whole-body age reversal.

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.