> 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.
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?
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).
The interesting part here is that they narrow down which loss of information is important.
Also, we aren’t made from the same biological stuff, or we would be rats. It’s easy to think of biology in overly simplified terms but cells aren’t legos.
https://twitter.com/charlesmbrenner/status/16135817576344576...
> Sinclair and colleagues injected the reprogramming-factor genes into the eyes of 1-year-old healthy mice, roughly the mouse equivalent of middle-age. By this stage, the animals had visual acuity scores about 15% lower than their 5-month-old counterparts. Four weeks after treatment, older mice had similar acuity scores to younger ones.
https://www.science.org/content/article/researchers-restore-...
I'm sure someone else is trying, but there's an agglomerative effect here, where a competing lab would be starting at a disadvantage and playing with a B-team.
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.
No idea how it would affect aging. Seems like it would slow it down but I’m sure it’s more complicated than that.
Those molecules can get out of place, and not line up correctly anymore. This research shows that that's a major cause of aging, and that it's possible to reverse it.
The theory here is that as we age the cells epigenetics fuzz out, so that skin cells start to look a bit more like neurons and other cells and vice versa.
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.
In reality, it will probably just mean a bunch of snake oil 'epigenetic health supplements' on the shelves that don't actually do anything.
Ok, so how do we reverse the loss of epigenetic information?
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
Randomized clinical trials are not as golden a standard as they seem and methodologically they are designed for human cattle, who do not choose what to consume and do not care to read a Wikipedia page or more about the drug they're taking or its target receptors they have, let alone any research on it. Thus, in an instruction label for an approved drug you'll see dozens of adverse effects, established in randomized clinical trials, yet close to zero information about the probability of you personally being affected by these adverse effects.
Likewise, there are ~thousands of "biohackers" taking the safe metformin off-label, for "anti-aging" purposes. And any interested individual can choose an experimental treatment, taking all the risks etc.
As per Hippocrates Oath [1]: 1) I swear to fulfill, to the best of my ability and judgment, this covenant: 2) I will apply, for the benefit of the sick, all measures [that] are required 3) I will prevent disease whenever I can, for prevention is preferable to cure.
How would you ensure a physician is employing the best of their ability? By their brain oxygenation level? Or dopamine receptors occupancy in prefrontal "executive" cortex? Thus ~90% of physicians regularly violate at least 2) and 3) statements of the oath, by not offering the possible experimental treatments in relevant sets&settings.
• Cellular responses to double-stranded DNA breaks erode the epigenetic landscape
• This loss of epigenetic information accelerates the hallmarks of aging
• These changes are reversible by epigenetic reprogramming
• By manipulating the epigenome, aging can be driven forward and backward
