Fig. 6

A proposed model for age-associated drift in DNA methylation and restorative effects of SIRT1. The stem cell, which has a characteristic DNA methylation signature (blue), divides asymmetrically to generate a differentiated daughter cell with a different DNA methylation signature (red) and a daughter stem cell. The fidelity with which the two daughter cells that arise from this asymmetric division acquire the correct pattern of DNA methylation across the genome is compromised in ageing tissue such that the DNA methylation pattern of the retained stem cell becomes more skewed towards that of the differentiated cell and vice versa, as indicated by the increasing “blending” of the colours representing the different DNA methylation signatures. Additionally, the proportion of stem cells may increase in ageing tissue (by symmetric stem cell division). The age-related drift in DNA methylation in a sample of stem cells, therefore, will be towards the signature of the differentiated cell. In a mixed cell population, however, where differentiated cells predominate, the drift in DNA methylation is towards the signature of the stem cell. Effects of SIRT1 on DNA methylation are to mimic the signature of the stem cell, rather than the differentiated cell; thus, beneficial effects on healthspan are via effects on stem cells, where the correct (“younger”) DNA methylation signature is restored, facilitating “corrected” partitioning of the DNA methylation signature at cell division, and thus restored tissue function