Young at heart: a DNA methylation's tale

Aging is an incessant and unavoidable process that affects all organisms from birth to death. However, behavioural and economic conditions, lifestyle, diet, and physical activity, as well as genetic and epigenetic variables, play a pivotal role in its progression. Several strategies have been considered to interfere with the aging process--for example, caloric restriction, food integrators, and senolytic and senomorphic drugs. More recently, genetically based interventions, including the Yamanaka's protocol of staminalization, have been applied in vivo to revert the aging process in mouse models. While the long-term effect of these interventions remains unclear, the difficulty in assessing their effect on the biological age representsa further significant limitation of these studies. Getting old and healthy is the consequence of a complex biological process modulated, during the lifetime, by multiple intrinsic and extrinsic factors, including hereditary, environmental, dietary, lifestyle, and stochastic factors, among others. At the molecular level, the consequence of aging is also complex and multifaceted and includes loss of proteostasis, genomic instability, telomere attrition, and various epigenetic alterations, such as changes in genomic DNA methylation. The introduction of this DNA modification is mediated by DNA methyltransferases which add a methyl group from the precursor S-adenosylmethionine to the carbon in the fifth position of cytosine (5mC), often in cytosine-guanine dinucleotides (CpG).2 This is a dynamic process: the loss of global 5mC, which occurs during aging, is in some cases associated with the increase of hydroxymethylcytosine (5hmC)3 determined by the ketoglutarate-dependent dioxygenases named ten-eleven-translocation proteins (TETs), which in turn can convert the 5mC into 5hmCand, further, into formyl and carboxylcytosine (5fC; 5caC, respectively). Finally, the 5caC is converted in an abasic site and restored to the naïve unmethylated Cytosine form by a DNA repair mechanism.2 It is worth noting here that DNA methylation status at particular CpG sites has been unequivocally associated with aging, up to the point of being used in accurate age-predictive models.