Figure 1

Age-associated DNAm is reversed by reprogramming into induced pluripotent stem cells. (a) A heatmap of 102 AR-CpG sites from 575 DNAm profiles derived from blood cells from donors of different ages (HumanMethylation27 BeadChip platform). All of these loci revealed relatively linear DNAm changes during aging (r < −0.85 or r > 0.85). (b) Based on these AR-CpGs, we generated a multivariate model to predict donor age and these predictions were compared to the corresponding chronological age. A combination of all 102 AR-CpGs facilitated reliable age predictions with a mean absolute deviation (MAD) of about 3.34 years. (c) Age-related-CpGs were subsequently analyzed in mesenchymal stromal cells (MSCs), induced pluripotent stem cells (iPSCs), and embryonic stem cells (ESCs) (heatmap clustered by Euclidean distance). Overall, AR-CpGs that are hypomethylated during aging are highly methylated in pluripotent stem cells and vice versa. (d) Subsequently, we used a multivariate model to predict donor age in these cells (early passage, P2 or P3; late passage, P7 to P16). Notably, iPSCs generated from these MSCs as well as ESCs were predicted to be of negative age, indicating that AR-DNAm changes are, overall, reversed by reprogramming into pluripotent cells.