Age-related DNA marks largely disappeared after blood cells from 99 donors were reprogrammed in culture

Age-related DNA marks largely disappeared after blood cells from 99 donors were reprogrammed in culture

In a paper published on September 8, researchers reprogrammed blood cells from 99 healthy donors into iPSC, restoring stem cell properties. They compared DNA methylation in the original blood samples and the cells grown from them to determine whether iPSC retain age-related DNA methylation patterns.

DNA methylation consists of chemical marks that influence gene activity; some of these marks change with age. Epigenetic clocks use patterns of these marks across many DNA sites to estimate a cell’s methylation age.

The researchers started with PBMC, a mixture of immune cells found in blood. After reprogramming and quality control, the analysis included 88 cultured iPSC lines from donors aged 22–92 years. For direct comparisons of methylation, they retained 67 matched pairs, each consisting of an original blood sample and iPSC from the same person. Matching samples this way separates differences between cell states from differences between donors.

In the original blood samples, epigenetic clocks estimated higher methylation ages for older donors. In iPSC, the association with donor age disappeared across all five calculations. A genome-wide analysis covered all measured DNA sites, including those outside the clocks, and yielded the same result: age-related signals were present in blood cells and undetectable in iPSC.

The authors also examined methQTL, statistical associations between a DNA variant and methylation levels. Some associations were shared between blood and iPSC, while others were specific to one cell state. Blood and reprogrammed cells therefore reveal different effects of genetic variants on methylation.

Studying age-related methylation patterns in blood requires the original sample: after full reprogramming, iPSC carry a different methylation pattern.