I'm not sure what epigenetics researchers you've been talking to, but my colleagues and I are all interested in the dynamic interplay between epigenetic modalities (DNA methylation, 3D genome architecture, accessibility, histone modifications, transcription factor binding, transcription, proteomics).

The 2020 paper you cite shows what was, for me, a surprisingly gradual rate of decay in CG methylation after knocking out DNMT3a/b. It seems incompatible with "turnover every few days" in most positions, although that could be happening in some locations. We definitely need a much deeper understanding of DNA methylation dynamics and heterogeneity - especially, in my opinion, at individual CG sites at single-cell resolution.

Just for perspective, demethylation can happen much faster, crashing dramatically genome-wide over just a few days during embryonic development.

And the median mRNA half-life has been estimated at 10h^[1], compared to the time scales of a week to more than a month measured above. So mRNA seems like a relatively stable layer of the epigenome on the whole.

Another interesting aspect of DNA methylation is that CH methylation (methylation at cytosines outside a CG context) accumulates in long-lived post-mitotic cells, like neurons, myofibers, and placental trophoblast. We know it's functional in neurons, but to my eye, in myofibers and trophoblast, it looks like off-target deposition that correlates with CG deposition, and I wonder if it's just off-target methylation that's not getting cleared. If methylation gets deposited or cleared in an off-target manner, then breakdown in whatever role it locally plays in epigenetic regulation can probably set the rest of the mechanism off-balance, resulting in a gradual slide toward dysregulation over time. My expectation is that aging is the result of an overall "smearing" of epigenetic regulation in which accumulated noise and tail events gradually hamper normal cell function more and more until one system or another suffers a catastrophic failure that cascades through the rest of the body.

It appears that partial reprogramming of stem cells can substantially rejuvenate the epigenetic state. I don't have a link handy but I'll have to write about that sometime. My guess is that it will one day be possible to just reset the epigenetic state of stem cells in non-brain tissues and achieve substantial anti-aging therapies that way. I'm less optimistic about near-term solutions for brain rejuvenation, since neurons are canonically post-mitotic and the evidence for adult neurogenesis seems like it's on shaky ground. But who knows? Maybe we'll figure out a neurorejuvenative therapy that treats Alzheimer's, discover the same treatment works as a prophylactic, and then discover it can be applied generally to improve brain function in middle-aged adults!   

At some point, I may write a longer "News and Views" style essay on this topic, and I'll post it on LessWrong if so. I'll also be writing a similar essay on DNA damage and DNA methylation, and I guess I'll post that on here as well if I don't just merge them into the same work.

1. ^{^}

   Wada, Takeo, and Attila Becskei. "Impact of methods on the measurement of mRNA turnover." International journal of molecular sciences 18.12 (2017): 2723.

Also, I'm just going to put this out there because times are tough in the ol' science funding realm. If anybody wants to donate to our lab, we have the world's best assay for profiling DNA methylation at single-cell resolution, sciMETv3. We can profile hundreds of thousands of individual cells in a single assay, with the cost mainly driven by sequencing. If you're interested in donating to the lab, we could almost certainly arrange that through our university's foundation and explore ideas for projects. We are also actively developing multimodal assays. DM me if interested!

I have a pet lay-speculation that there's a pretty mathematically interesting question here, which hasn't been understood yet. I can't formulate the question clearly, but it's something like: "What sort of thing are these states?" We can abstractly talk about stable states of high-dimensional dynamical systems, but this probably isn't very satisfying or helpful in this context. There's some more practical or concrete or specific things we might want to know about the landscape of possible stable or quasi-stable states for gene regulatory networks, and how they transition, and how one could perturb them.

The mistake: methyl groups usually do not stick around long-term; they turn over regularly. Here are two studies which measured the turnover. Turnover timescale varies by location on the DNA strand, but turnover every few days is typical.

I don't know if someone else was making this particular mistake. I certainly find it quite tricky to describe these things with language unless I am extremely careful. I am still confused, but I do find your suggested pathway via transposons more plausible, and the story for why transposons fits into my head. I don't think a correct story for why not epigenetic "bit-flips" currently fits properly into my head, and that correct story would have to be created in order to convince other people. Ideally, some testable predictions^[1].

But if the methyl groups are instead part of a dynamic equilibrium, especially with high redundancy (and therefore stability), then that's a whole different situation.

I don't understand why this has to be such a dichotomy? What I hear you say is that these dynamic equilibria are too stable to be a root cause of aging. I think this is true in the case of X-inactivation^[2], which is redundant across most of the X-chromosome. But as far as I can tell, the number of redundant parts that make up one "unit" that can bit-flip lies on a spectrum. Example: one methylated C is probably too unstable to encode something. But what if I have a local cluster of five of them where each one reinforces each other (because enzymes that change the methylation often check the methylation status of close-by C's)? That's the point of CpG islands, right? So some of these CpG islands are probably more stable than others, and some could be just stable/unstable enough to be a root cause of aging, no?

So you're saying that the persistent epigenetic modification is a change in the "equilibrium state" of a potentially methylated location? 

Does this mean that the binding affinity of the location is the property that changes? i.e. all else being equal, a location with high affinity will be methylated much more often than a location with low affinity, because the methyl groups will tend to stick harder or longer in the high affinity location. 

But if that's the case, it seems like there still must be some persistent structural feature responsible for setting the binding affinity to high or low...