DNA-methylation changes in replicative senescence and aging: two sides of the same coin?

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Replicative senescence is often considered to be a hallmark of aging [1] – but this assumption needs to be challenged by new insights into associated epigenetic modifications. Primary cells can undergo only a limited number of cell divisions in vitro before they enter the state of replicative senescence, which is reflected by unequivocal cell cycle arrest. It was first described half a century ago by Leonard Hayflick [2] – therefore often referred to as ‘Hayflick limit’ – and since then it has been speculated that replicative senescence is tightly associated with aging of the organism [3]. In fact, cellular aging during in vitro culture reflects various molecular features that seem to be indicative for aging, such as telomere attrition, activation of the p53/p21CIP1 and p16INK4A/pRb signaling pathways, alteration of cell morphology and metabolism, increased senescence-associated β-galactosidase activity, loss of differentiation potential, formation of senescence-associated heterochromatin foci and the senescenceassociated secretory phenotype [1]. Cell samples from elderly donors recapitulate many of these parameters, including a higher number of positive staining for senescence-associated β-galactosidase [4]; slower proliferation rate and senescence-like morphological changes already at the initial cell passage [5]; reduced colony-forming unit frequency [6] and concordant gene expression changes [7]. These findings fueled the perception, that replicative senescence in vitro and aging in vivo are governed by the same conserved mechanism – although carried out at a different pace. Cellular changes in the course of culture expansion are therefore often considered as a good in vitro model to unravel the molecular mechanisms that drive the process of aging. Replicative senescence and aging are both reflected by highly reproducible epigenetic changes – particularly in the DNA methylation (DNAm) pattern of developmental genes [8]. DNAm is nowadays the best-characterized epigenetic modification: it represents a covalent addition of methyl groups to cytosine residues in the context of CG dinucleotides, referred to as ‘CpG site.’ Senescence-associated DNAm changes are significantly enriched in genomic regions with repressive histone marks (H3K9me3 and H3K27me3) and at target sites of Polycomb group proteins [9,10]. Similar findings have also been reported for age-associated DNAm changes [11,12]. In fact, direct correlation of age-associated and senescenceassociated DNAm changes in mesenchymal stromal cells (MSCs) revealed a moderate but significant association of the two epigenetic processes [8]. On the other hand, replicative senescence and aging can both be tracked by very specific epigenetic modifications: for example, an ‘epigenetic-senescence-signature’ DNA-methylation changes in replicative senescence and aging: two sides of the same coin?