Interesting publication by Sinclair back in 2021: Reprogramming to recover youthful epigenetic information and restore vision<p>> Using the eye as a model CNS tissue, here we show that ectopic expression of Oct4 (also known as Pou5f1), Sox2 and Klf4 genes (OSK) in mouse retinal ganglion cells restores youthful DNA methylation patterns and transcriptomes, promotes axon regeneration after injury, and reverses vision loss in a mouse model of glaucoma and in aged mice.<p>[0] <a href="https://www.nature.com/articles/s41586-020-2975-4" rel="nofollow">https://www.nature.com/articles/s41586-020-2975-4</a>
This doesn't test the "epigenetic information theory of aging."<p>First, there is no survival analysis. How is the mouse younger if it doesn't live longer? Similarly, the OSK "rejuvenated" mice display <i>lower</i> lean muscle mass.<p>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].<p>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.<p>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 (<10% at best in whole organism) get some OSK exposure. Yet, the whole organism is "rejuvenated"? Is there a positive spill-over from OSK expression?<p>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?<p>[0] <a href="https://doi.org/10.1016/j.devcel.2021.11.018" rel="nofollow">https://doi.org/10.1016/j.devcel.2021.11.018</a>
I think its a cool theory and seems the most reasonable from all the other theories of aging. However I am a bit disappointed when I only see David's name on every paper published on this topic. Why dont other institutions start similar studies to verify this claim?
It seems like it should be possible to build a drop-in replacement system for DNA that adds a more robust error detection/correction capability. Each gene gets a checksum at the end and the transcription/translation processes are amended to validate these prior to progressing to building proteins.<p>Obviously it would be more complex than just that but it would be interesting to see how it affects biology. Evolution would now be done primarily though gene mixing vs random mutation, it also seems that things like ionizing radiation could be much more directly harmful, but cancer and autoimmune diseases would seem to be substantially diminished.<p>No idea how it would affect aging. Seems like it would slow it down but I’m sure it’s more complicated than that.
Isn't the term "epigenetic" about non-DNA information, like in mitochondria etc, i.e. not something recoverable by just scanning DNA more precisely? If so, it doesn't seem reversable?
Not an expert here, but it seems like they introduced a specific flaw and saw effects similar to aging, then they corrected for that flaw and saw those effects reversed. This is an interesting result, but it doesn't, imho, prove that actual aging can be reversed in this same manner.