Thank you for the as usual cogent summary of the latest research!
Here I would like to point to a widespread misconception about epigenetics that is so prevailing that most are not aware of it. A critical thinker would ask how are these epigenetic marks that underlie the epigenetic clock, mechanistically related to the phenotype - in this case, aging.
Since it is thought that epigenetic modifications (e. DNA methylation) affect, or are affected by, gene transcription at a given gene locus, and gene transcription is what ultimately governs the phenotype, what really matter for aging (and its acceleration by alcohol) will be the transcriptome - and only secondarily, the epigenetic mark, be it either as marker or as controller of gene activity.
Here is the problem: There are two disparate uses, hence meanings, of the very term "epigenetics":
One is the modern meaning used here, which pertains to molecular tags on DNA and chromatin. This meaning was hijacked by the discoverer of DNA methylation in the 1970s. Thus, there is a preexisting meaning.
This older meaning, dating back to Conrad Waddington in the 1930s (and made famous by the “epigenetic landscape” of 1956) is more profound: It relates to the machinery, now known as the gene regulatory network (GRN) that connects all the genes of the genome and establishes the gene expression patterns, which we measure as transcriptome, and governs the various phenotypes that one single genome can consistently produce. The DNA methylation and chromatin modifications (epigenetics in the modern sense) is just an intermediate herein.
So perhaps, what alcohol and aging do, is to change the (average) genome-wide gene expression profile (=transcriptome) of these blood or skin cells (where he epigenetic clock is measured). Said age-specific transcriptome is governed by the GRN according to its wiring diagram. It may even be that alcohol and aging change the cell type composition of these tissues, hence the average transcriptome, which is linked to the epigenetic marks on DNA and chromatin (the modern meaning of epigenetics) being measured - that’s all. Nothing magical to the epigenetic clock.
The latest explanation of these two meanings of epigenetics here.
