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> Do we currently have the ability to do targeted methylation or de methylation at sites in cells?

No, and you probably wouldn’t want it if you could. You don’t know what mutations are lurking in the genes that have been switched off or the consequences of turning them back on.

I’ve thought about this a bit, and what resetting the methylation map really requires, in addition to actually resetting that map, is resetting your genome to a known good state.

That’s pretty radical, but to selectively switch methylation on and off with precision you’re already talking about science beyond anything we have, featuring custom engineered constellations of proteins that unwrap your chromatin from around histones and then walk along it changing methylation state, then pack everything back.

And doing it for each cell type, without applying the wrong map anywhere.

And knowing what all the cell types and their correct methylation maps actually are.

And assuming that methylation isn’t used anywhere, for example in the brain, in a way we don’t expect.

And methylation isn’t the only kind of epigenetic modification.

So, if we’ve solved all of those problems, rebuilding your DNA to a clean, mutation free state at the same time should be a breeze.

We really do need AI for this if any of it is going to be remotely feasible.

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Is “at the same time” a hard requirement?
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in my futile searches for meaning I’ve wondered whether cancers in humans are a failsafe to something else or preventing something worse

more specifically the lack of more failsafes seen in some other mammals are a reaction to something besides happenstance

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Cancer is the price we pay for complex multicellular life. It’s not a failsafe, it’s the failure of all failsafes to regulate cellular growth within an organism.
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Larger mammals with many more cells have additional protections against cancer

Such as longer and more numerous telomeres

Hence why the human situation stands out to me and can’t be reduced to “it just is“. Some other mammals have it worse though

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> wondered whether cancers in humans are a failsafe

I don't think so, but in the context of theories that are more-interesting than "stuff just breaks sometimes", I'd like to suggest the atavistic aspect.

Some cancers resemble a return towards unicellularity, as if "newer" multicellular rules have broken down. Not in any remotely-effective "our genes shall survive the dark times as goo" way, though.

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> We really do need AI for this if any of it is going to be remotely feasible.

Would you give your life into the hands of AI skynet slop?

I understand your rationale, of course, but I for one don't want big fat mega-corporations dictate over our life here. Naturally, all of this hinges whether AI can even solve this problem. I assume it can, but I doubt it can do so initially - and the legal implications are still enormous. I really am not ready to turn my hands to claude's gene therapy slop.

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Good news! Research shows that hope reduces stress! [0]

[0]: https://www.forbes.com/sites/tracybrower/2024/09/15/how-bein...

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Sadly, AI just made many of us lose all hope.
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AI is an amazing Rorschach test in this regard. In the way that two people will look at it -- not just AI in general but in a specific implementation of it (coding, vidgen, etc). And one will feel deep dread and knots in their stomach while the other is filled to the brim with hope and optimism.

I think the former group almost certainly outweighs the latter group at least in the Western hemisphere, but I know the Western hemisphere has been steeped in a deep malaise of anti-optimism for several decades preceding AI to begin with. That it's almost a game to identify all the ways anything new might be bad, rather than celebrating the obvious ways they are good. And this penchant invariably biases their developing opinions of all new technology, be it AI or anything else.

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What if I'm super optimistic about most technology but also scared of AI?

Space, nuclear fusion, advanced fission, the internet since about 1993, blockchain, anti-aging, I've been a big fan of all of it. But I've read the AI safety arguments and seen what a lot of researchers say about it, and I'm seriously worried.

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>one will feel deep dread and knots in their stomach while the other is filled to the brim with hope and optimism.

Ignorance is bliss

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It makes me concerned on many levels, but perhaps also more hopeful. It was inevitable that we would eventually develop AI if we didn't go extinct first, and while there are myriad risks and challenges, there is also massive potential, which seems like it could be a source of hope. As the earlier comment said, the only way that therapies like these could be remotely viable on any kind of near to medium timeframe would be with AI assistance, and this is just one example.
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You spelled SI wrong.
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Sometimes I like to close my eyes and dream of electric sheep.
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Thanks, Obama
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What about Xanax or medication. Hypothetically ignoring the ill effects of the drugs themselves will chemical stress relief have the same anti-aging benefits?
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If you believe that HRV is inversely correlated with stress then Xanax has the opposite of your intended effect.
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Yes we can do targeted (de)methylation at cells via a system called CRISPRon/off. It’s a CRISPR with the DNA cutting part deactivated but retaining the DNA binding part. They then attach a protein that adds methylation (DNMT3A) or removes it (TET1). So it’s a huge protein machine and it has only been tested in a petri dish (maybe mice, not sure).

There’s a lot left to figure out. Delivery is hard. It would be hard to get it inside the right set of cells in a real person, you usually would only want to demethylate in a subset of cell types. There’s pretty steady progress being made in that area, but I think it will be several years before we fully solve that. Existing methods for doing this include hijacking a virus to deliver the DNA of the CRISPR system but those are one time only treatments because your immune system recognizes the virus and destroys it after one treatment. We use these viral delivery systems for some gene therapy treatments in real patients now. It presents a pretty terrible conundrum for patients who have to choose taking their one shot on an experimental treatment which may not work. Brave people!

Anyways, yes it is possible but it’s quite early in development.

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I just don't understand. Wouldn't we have evolved in an environment with constant stress? Constant fear of disease, starvation, predation, attacks by neighboring tribes? Why would our body's natural response to our environment be to immediately grenade itself.
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I'm no biologist, but it's pretty easy to imagine a plausible mechanism.

Stress doesn't cause your body to "immediately grenade itself", it causes gradual problems over an extended period. But you can imagine that evolutionarily speaking, a stressful situation would frequently be a situation involving imminent danger. A response that prioritizes short-term survival (e.g. releasing adrenaline and cortisol) regardless of the long-term consequences could easily improve evolutionary fitness.

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I suppose the stress was running away from a lion, not having the all-eating thought of meeting deadlines, a bad boss, backstabbing coworkers and so on, i.e. intense, but short, not persistent and chronic.
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There always has been a lot of stress, but there used to be relaxed moments as well. The issue is that we don't calm down anymore.

Relevant video by Kurzgesagt – In a Nutshell: https://www.youtube.com/watch?v=Mo1A45ShcMo

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Considering that aging only happens later in life, it wouldn't have much of an effect on how efficient humans produce offspring, so it wouldn't be selected against. It is the same explanation for why Huntington's and Alzheimer's are still around.
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> Considering that aging only happens later in life,

In other news, widows outlive their husbands.

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The idea that pre-agricultural societies are subjected to constant stress reflects modern biases somewhat. I remember years ago I saw a talk from Spencer Wells where he described how pre-agricultural life might have been like in Anatolia. Fields and fields of wild wheat stretching across the horizon. Long periods of seasonal abundance. Occasional periods of hunger and privation where families would often have to rely on the help of friends and acquantainces, with the understanding that one day the debt would be repaid if similar ill circumstances befell your neighbors.

You can see some of how life might have been like in modern Papua New Guinea. War is nothing like modern warfare with artillery and guns. Its two groups of people firing arrows at each other from stand off distances while shouting at each other with minimal casualties. If you look at casualty rates from some of the early Greek warfare during the hoplite era, it's also surprisingly low.

Also note that in this post, and from research, caloric restriction counteracts some of these inflammatory effects. In many ways modern life can be stressful in its own ways, especially as we remove ourselves more and more from the active lifestyles that necessitated survival in previous eras.

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You only need to get to reproduction once, regularly, for a gene to keep getting passed on.

Other mitigating factors: not eating much of the ultra-processed garbage we have today, regular high-intensity exercise, and a vastly-more interconnected community. Multigenerational homes make it easier to dump the kids off with grandma and go for a long hike with the wife or a party with the village or whatever. Etc. etc. etc.

Were safer and healthier, but I don’t think we’re necessarily happier.

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> Wouldn't we have evolved in an environment with constant stress?

Well, humans did not reach an old age if you look back to history. Only in recent times, say, 2000 years or so, or, if you want to be strict, the last 100 years, did humans reach very old ages. Back in older days, 30 years was considered old. Then 40 or so.

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I heard that is mostly a myth due to misunderstanding what life expectancy means. It's an average over populations, pulled down mostly by enormous infant mortality. If you made it to 15 then there was a good chance you'll make it to 60.
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Yet, people who have had 100% stress-free lives get old and die like everyone else.
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