Loss of epigenetic information as a cause of mammalian aging

In reality, it will probably just mean a bunch of snake oil 'epigenetic health supplements' on the shelves that don't actually do anything.

First, there is no survival analysis. How is the mouse younger if it doesn't live longer? Similarly, the OSK "rejuvenated" mice display lower lean muscle mass.

Second, the causality is (willfully?) misinterpreted. The endonuclease used to causes DNA double-strand breaks does NOT directly alter the epigenome. Instead, it induces DNA-damage repair stress. One consequence, of many, is epigenetic (chromatin) dysregulation. DNA damage stress is well known to accelerate aging phenotypes. In fact, David published on how p53 stress from repeated DNA damage - using the same endonuclease setup - initiates a DNA damage response in turn promoting cell-cycle exit and cell elimination [0].

Third, cutting "non-coding" DNA in this case involves cutting specific ribosomes (cell translation machinery). Given that this pressure is constitutive, it's likely that these ribosomes evolve resistance to the nuclease by mutating functional sequences. However, the authors never assessed the mutation and function of these ribosomes.

Lastly, the in vivo AAV transduction efficiency isn't measured. This makes the OSK "rejuvenation" result hard to interpret. All cells get DNA damage (germline edit), but only transduced cells (All the core claims about epigenetic information are either incorrect or grossly misleading. The perturbation, site-specific DNA damage, does not cause only loss of whole-cell epigenetic information. Hard to imagine how this got into Cell. I guess a big name and 20+ figures is all you need these days?

[0] https://doi.org/10.1016/j.devcel.2021.11.018

You can't just fix the DNA, it must also figure out whether it should become a hair follicle or one of the many subtypes of cells that make up your skin layers. We know that this differentiation seems to be controlled by ion/electrical signals early in life.

So a key question is: Why does differentiation accuracy seem to degrade with aging, and is there anything we can do to stop it?

CRISPR is pretty good at fixing DNA, we definitely need to optimize our use of that tool but at least there's a path. We really don't have a clear path to fix the differentiation/epigenome problem.

Cell differentiation seems to be similar to Conway's Game of Life where cells differentiate based on neighboring cells. Significant ordered complexity can emerge from simple rules. Now if you go and reset random cells, often it is either a no-op or they pick up the correct state from neighbors, but if you keep doing it, you eventually reset an important cell and break the functionality.

In biology, it likely looks a little more like this: https://www.youtube.com/watch?v=7-97RhAZhXI