Eg a loss of methylation (more so than hypermethylation) seems associated with epigenetic age given that methyl marks usually but not always silence genes.
One thing about Methylation clocks is that it’s not obvious to me is whether they are detecting aberrant methylation patterns in a small subset of “methyl-escent” cells with the rest being healthy, or if the clocks are detecting a phenomena that is occurring in each cell.
Has there been any success in a “single cell” methyl clock? This would provide decent evidence for one or the other.
Here’s a preprint that ran a randomized control trial to see how exercise, breathing, methyl donor rich diet + polyphenols affecting Horvath DNAm Age. They found a reversal of about ~2 years of epigenetic age for the treatment group. (8 week treatment)
Reversal of Epigenetic Age with Diet and Lifestyle in a Pilot Randomized Clinical Trial
Caveat: “Trending towards significance”. So it was not statistically significant. Small n. Small effect size (though treatment was only 8 weeks).
I will preface by saying I am not 100% sure on this as it is something I’ve very recently become interested in.
But I would bet that the methylation process is much more complex than to just say hypo vs hyper drives epigenetic age. In general hypo is more correlated with age, but these things are region specific typically. I also wouldnt be surprised if we eventually uncover other DNA modifications like acetylation that also play a role in the aging process.
Lifespan-related cytosines are located in transcriptional regulatory regions, such as bivalent chromatin promoters and polycomb-repressed regions, which were hypomethylated in long-lived species
Cells that retain youthful DNA methylation patterns have (highly) active methylation going on, that is the major reason why. With age, global demethylation is the main driver of epiaging in epigenome. Hypermethylation happens with age, only, in specific areas (mainly the inflammatory ones/cancer/oncogenic ones/hypermethylation in CpG-rich DNA), the rest (the Large rest/which encompasses anti-inflammation and anti-oxidative/repair/redox mechanisms/hypermethylation in CpG-poor DNA) is becoming demethylated. In a sense that, inflammatory genes are unsilenced with age, while anti-inflammatory ones are silenced; and that’s when things go bad, health worsens and you see clear advancement of epiclock age too.