DNA methylation dynamics in aging: how far are we from understanding the mechanisms?

Abstract

DNA methylation is currently the most promising molecular marker for monitoring aging and predicting life expectancy. However, the mechanisms underlying age-related DNA methylation changes remain mostly undiscovered. Here we discuss the current knowledge of the dynamic nature of DNA epigenome landscape in mammals, and propose putative molecular mechanisms for aging-associated DNA epigenetic changes. Specifically, we describe age-related variations of methylcytosine and its oxidative derivatives in relation to the dynamics of chromatin structure, histone post-translational modifications and their modulators. Finally, we are proposing a conceptual framework that could explain the complex nature of the effects of age on DNA methylation patterns. This combines the accumulation of DNA methylation noise and also all of the predictable, site-specific DNA methylation changes. Gathering information in this area would pave the way for future investigation aimed at establishing a possible causative role of epigenetic mechanisms in aging.

Alteration of the brain methylation landscape following postnatal inflammatory injury in rat pups

“…[79][80][81] In all, 102 identical DMRs were identified between P4 and P24 for which half preserved their methylation status and the other half shifted to the opposite status. [88][89][90][91][92] Although the DNA methylation changes seen in this study were mostly subtle compared to changes occurring during development or in cancer, their accumulation could have the potential to impact the normal neurodevelopmental course. [82][83][84] During normal aging, GO analysis of peripheral blood samples from pediatric and aged population revealed that methylation changes were highly related to developmental and inflammatory pathways.…”

“…87 Furthermore, alteration of DNA methylation by adverse events can lead to discrepancy between chronological age and methylome age, which is associated to accelerated aging processes and age-related pathologies including neurodegenerative diseases and decreased white matter integrity. [88][89][90][91][92] Although the DNA methylation changes seen in this study were mostly subtle compared to changes occurring during development or in cancer, their accumulation could have the potential to impact the normal neurodevelopmental course. 30 Therefore, it is possible that the changes in the epigenome seen in this study could play a major role in potentiating brain injury after neuroimmune challenges later in life.…”

Quantitative translation of dog-to-human aging by conserved remodeling of epigenetic networks

“…We observe that epigenetic changes during aging center on highly conserved modules of developmental genes, in which methylation generally increases with age. Although the enrichment of developmental pathways has been generally observed in mammals previously (Field et al 2018;Ciccarone et al 2018 (Urfer et al 2017) .…”

A decade of epigenetic change in aging twins: genetic and environmental contributions to longitudinal DNA methylation

“…Epigenetic changes may accelerate over time and potentiate the development of health and aging conditions earlier in life. Indeed, methylation is correlated with age (5,14), is used to define biological clocks that may more closely track biological aging (15), and is associated with mortality (16) and a number of physical and neuropsychiatric health traits (1,9). Longitudinal studies of twins represent a valuable approach to evaluate genetic and environmental contributions to stability and change in methylation across the methylome (17).…”

“…Epigenetic changes may accelerate over time, whereby changes in gene expression due to exposures become more abundant and salient to phenotypic changes, hence potentiating the development of health and aging conditions earlier in life. Indeed, methylation is correlated with age (Ciccarone, Tagliatesta, Caiafa, & Zampieri, 2018;van Dongen et al, 2016), is used to define biological clocks that may more closely track biological aging (Field et al, 2018), and is associated with mortality (Y. Zhang et al, 2017) and a number of physical and neuropsychiatric health traits (Kanherkar et al, 2014;Lappe & Landecker, 2015).…”