| This doesn't test the "epigenetic information theory of aging." 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 (<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? 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 |
There was no claim that the whole mouse was rejuvenated, so far as I can tell. The only metrics they presented on actual rejuvenation were some chemical markers in a couple of organs - heart and liver, IIRC. In a CNN interview published ~5 days ago, Sinclair points out that he hasn't yet figured out how to deliver the OSK to the whole organism - which is presumably why he's only demonstrated rejuvenation at very localized sites. He also mentions that another team has figured it out, and did actually manage to extend a mouse's lifespan (see my other post with the CNN link). Thus,
> How is the mouse younger if it doesn't live longer?
It isn't, because it doesn't, because the study didn't aim to show that.
> Yet, the whole organism is "rejuvenated"?
Again, no. That was not the claim, according to the actual published article.
So I think you missed a couple things. Probably not "willfully". I may have the advantage of you, though, because I did manage to find a copy of the Cell article itself (and I did a bit of additional digging).