Epigenetic clocks are produced from data on the status of DNA methylation at CpG sites in the genome at various ages via machine learning processes. Thus it is unclear as to what the clocks actually measure. There is no catalog to state how and why each CpG site on the genome is or is not methylated at any given time. There is little to no understanding of the mechanistic links between specific epigenetic marks such as DNA methylation and specific mechanisms and states of aging. In that context, the work here is interesting, demonstrating that stochastic epigenetic dysregulation with age, known as epigenetic drift, contributes to clocks, but isn't the whole story.
Changes in DNA methylation with age are observed across the tree of life. The stereotypical nature of these changes can be modeled to produce epigenetic clocks capable of predicting chronological age with unprecedented accuracy. Despite the predictive ability of epigenetic clocks and their utility as biomarkers in clinical applications, the underlying processes that produce clock signals are not fully resolved, which limits their interpretability.
Here, we develop a computational approach to spatially resolve the within read variability or "disorder" in DNA methylation patterns and test if age-associated changes in DNA methylation disorder underlie signals comprising epigenetic clocks. We find that epigenetic clock loci are enriched in regions that both accumulate and lose disorder with age, suggesting a link between DNA methylation disorder and epigenetic clocks. We then develop epigenetic clocks that are based on regional disorder of DNA methylation patterns and compare their performance to other epigenetic clocks by investigating the influences of development, lifespan interventions, and cellular dedifferentiation.
We identify common responses as well as critical differences between canonical epigenetic clocks and those based on regional disorder, demonstrating a fundamental decoupling of epigenetic aging processes. Collectively, we identify key linkages between epigenetic disorder and epigenetic clocks and demonstrate the multifaceted nature of epigenetic aging in which stochastic processes occurring at non-random loci produce predictable outcomes.
Link: https://doi.org/10.18632/aging.205503
View the full article at FightAging
