Health Psilocybin treatment extends cellular lifespan and improves survival of aged mice

[neversickanymore]

We need to take into consideration that cellular life span may propose risks as well. Old cells like old humans regularly have more issues. Just saying you have to look at it from all sides. Look at modern western medicine.. it extends life but doesn’t really include the quality of that life.

 

[perpetualdawn]

@neversickanymore they also looked at whole-mouse lifespan and found that they died less and were subjectively less senescent. That sounds to me like the trippy mice might have had a better old age. Anecdotally old trippers that I've met often seem more vivacious and bright that their peers, but there's all kinds of room for bias in that observation.

I do debate if modern medicine has had a negative impact on quality of life at old age. There are definitely cases where that's true, I don't deny it, but I think there are more cases where the opposite is true, where modern medicine that we take for granted gives old people a much higher quality of life than they would have had 100 years ago.

Examples:

- Cataract surgery essentially cures a lot of old people of near-blindness. It's a really simple and reliable procedure that has totally life altering impact.
- Hearing aids. Have you ever seen the old fashioned ear-horns?
- Hip and knee surgeries/replacements etc are keeping a lot of old people mobile. In a lot of these cases these people would be stuck in bed or in a chair in the old days.
- Heart stuff - there are lots of interventions with heart conditions that keep people alive, active, and happy with relatively little "cost" to QOL, a lot more benefit. On the other hand it's probably true that a lot of the heart problems could be avoided in the first place without a shitty industrialized diet and industrialized lazy lifestyle.
- MAID - medical assistance in dying. This is pretty leading edge stuff and not available everywhere in the world, but in a lot of places we're finally recognizing that it's not always right thing to prolong someones life at all costs and that the most humane thing to do is to support an early exit when the end is in sight. This can curtail a lot of suffering and the downside of modern medicine's ability to keep the body ticking along when the person inside that body is suffering. I think there's good reason for this to be debated and rolled our carefully, but I've seen MAID first hand and it was definitely a blessing of modern medicine that the person could die with dignity and peace surrounded by the people who loved them the most.

If I had the choice to be an old person now or any time in history, I would definitely pick now.

But I do take your point @neversickanymore I think it's really important to consider and debate if longevity interventions are actually a good thing. Imagine a dystopian scenario like a world ruled over by 1000 year old oligarchs who are rich enough to keep living while the poor toil away and die young and have no chance to become gods.

Luckily, if mushrooms really do help live a long and healthy life, they are very democratic, springing out of cow poop and easily cultivated on the sly in closets out of sight.

 

[iom]

What are some of these examples of epigenetic changes induced by 5ht receptor activation outside of neurobiology?

I'm having a hell of a time finding good references (I need to stop trying to rely on Google which just keeps getting worse), but my understanding is that serotonin has a general pro-growth effect on a variety of tissues including muscles, skin, blood vessels, nerves and so on. I believe these are mediated in both cases via 5-HT2A and 5-HT2B receptors. (IIRC, 5-HT2C have not been found peripherally.) For example, serotonin is released from platelets in the vicinity of a wound, and the resulting cascade upregulates genes that govern growth and remodeling. It seems to me that the neuroplasticity and/or neurogenesis observed in brains treated with psychedelics is very analgous to what occurs when serotonin is exposed to other tissues as well.

In the case of valulopathy, 5-HT2B stimulation contributes to a pathological overproliferation of fibroblasts. Fibroblasts are essentially like scaffolding for other cells to attach to, and when healing from wounds, a well-established scaffold to attach stuff to is to be desired. However, in the case of many pathological fibroses (not limited to valvulopathy in the heart) this proliferation, which is mediated in part by 5-HT2B stimulation, is excessive and leads to dysfunction.

True and also understandable, it's hard to weigh the unknowns! But I think I understand your criticism is that we can do better by stepping back and taking a broader and fuzzy view to get a sense of what the scope of the unknown risks might be without having to know their specifics. Like in this case with serotonin, you say there are a ton of serotonin histones in biology, so the "risk surface" could be large for chronic 5ht activation.

Yes, and moreover many serotonergic pharmaceutical drugs do cause people serious problems such as extreme dependence and/or side-effects that take years to decades to resolve.

I am also speaking very generally though, with regard to all kinds of drugs, but also to all kinds of knowledge. I'm speaking abstractly and philosophically here, but to give a concrete analogy, consider blackholes. Light cannot escape a blackhole, so one cannot see a blackhole. However, one can observe the consequences of matter being sucked into it. I've now made more than one "discovery" of sorts by setting aside what is known and contemplating the shape of what "the science" on a particular topic is ignorant of. I advocate for more of this kind of thinking in general.

I think I remember learning that serotonin is one of the OG signalling molecules in life, like it goes way back to (near?) the bottom of the evolutionary tree of life, so this makes sense.

Yeah. It's very primitive. This insight is kind of trippy in itself in the sense that by taking a psychedelic, I'm sort of "talking" to these very primitive parts of myself which very much foundational to my existence and which I share (to a great extent in terms of DNA and functionality) with most other living things. The idea that psychedelics are a window into plant consciousness could be literally true in a sense.

I do debate if modern medicine has had a negative impact on quality of life at old age. There are definitely cases where that's true, I don't deny it, but I think there are more cases where the opposite is true, where modern medicine that we take for granted gives old people a much higher quality of life than they would have had 100 years ago.

I think on average medicine is beneficial, but individual outcomes are highly variable. If interested in health outcomes (quantity and quality both), one needs to widen the frame and include factors like infrastructure, public health (including environment), economic means, workplace safety, and cultural trends. IF these other factors promote health, then people will be much less likely to be sick and hurt. If not sick or hurt, people will be able to stay away from the medical system and avoid the serious risks that come with seeking treatment.

Unfortunately, we are living in a time in which health is declining despite continued advances in medicine because of decline of the other aforementioned factors. This leads to more people becoming dependent on on-going medical care and on larger numbers of prescriptions with greater potential for unancitipated adverse reactions of all kinds. Prevention is and probably always will be the best cure.

 

[Img_9999]

Try doing a Google search for "serotonin histones", lol. Trust me.

So I have been doing some reading, and yeah, apparently fairly recently it has been described how serotonin can directly modify H3 histones to increase gene expression, which is something very cool I didn't know, thanks for calling my attention to this !
Here's an article that was published a couple of weeks ago that starts with a brief but nice summary of some of the most recent findings regarding this: https://doi.org/10.1093/nar/gkaf612

This article cites studies showing that histone sertonylation "has been identified across various organisms and tissues, with a preference for the brain, gut, and testis". There's a caveat though, serotonylation doesn't seem to happen on its own; and it's appearance is concomitant to histone methylation; so it seems serotonin epigenetic action is regulated by additional pathways (which makes sense; I mean I would expect gene expression to be tightly controlled). This makes me think serotonin by itself won't do the job unless some other factors are also at play. Still, there seems to be evidence that antidepressant treatment can regulate neuronal gene expression through the modulation of serotonylation of histones and some authors speculate it can even be their primary mode of action ( https://doi.org/10.1038/s41467-024-49336-4 ). Here is another interesting literature review discussing serotonin mediated gene regulation: https://pmc.ncbi.nlm.nih.gov/articles/PMC6662934/

Also, serotonylation of H3 histones is catalyzed by transglutaminase 2, and if psychedelics were capable of being attached to histones as serotonin is, they would have to be recognized as substrates by this enzyme. Would be cool doing some assays to verify this, I guess some studies must be underway regarding this. Intuitively I wouldn't think bulky ones like LSD would be suitable susbtrates, maybe for stuff like DMT it can be more likely.

I must add that all this doesn't seem particularly concerning though. To be fair, I'm much more worried about the possibility of ingesting leftover metal catalysts or organic solvents when I take random research chemicals than about the possible epigenetic effects of regularly dosing psychedelics haha. There's truly much more we don't know about how this molecules affect our body, and even more we don't know that we don't know haha, but at the same time, psychedelics have such a long history of human use, with plenty of examples of pre colonial cultures in the americas using them regularly for ceremonial purposes, that any deleterious effect must surely be minor. Probably skipping sleep and drinking alcohol is far more dangerous, and I still do this things sometimes. I feel fairly confident that psychedelics are as bening as a xenobiotic can be, and their benefits outweight the potential unknown risks for me. I could of course be wrong and maybe as research intensifies 20 years down the line we find out about ways in which psychedelic induced basal activation of genes involved in cell growth can result in cancer. But again, that can be said about just about anything. People used lead for ages for water distribution before finding out it was a fucking terrible idea. You can never be too safe I guess?

 

[pupnik]

Histones which jacket the DNA in chromosomes are very much involved in gene expression, both in the development of organisms and in the daily response to environmental chemistry.

The delayed effect of serotonergic antidepressants (i.e. you have to take them for a week or a month before noticing benefits) would support a mechanism that was gene expression related, such as histone distortion or binding. the short term blocking of serotonin receptors on neurons by antidepressant meds does not seem to cause psychedelic effects although it can dampen psychedelic effects.

I hope more work on histone binding of serotonergic antidepressants is followed up, along with some investigation of histone binding with psilocybin and LSD etc. Not just histones, but which genes become exposed when serotonergic compounds engage with those reactive histones. i.e. which proteins become more present in the neurons, and how does that change neuronal structure and behavior.

 

[Img_9999]

I hope more work on histone binding of serotonergic antidepressants is followed up,

Just to be clear, serotonergic antidepressants do not bind histones, but they regulate the level of serotonin bound on them. Interestingly, they seem to actually decrease the level of serotonylation of histones. In the study I quoted in my previous comment, they show how chronic stress seems to increase serotonin bound to histones on certain parts of the brain, and then fluoxetine treatment seems to revert this effect. The beheavioural effect observed was described as an increased "stress-resilience" in mice treated with fluoxetine. There doesn't seem to be yet a proposed mechanism explaining how SSRI treatment could decrease serotonylation of histones, but the authors of the study differentiate between the gene-mediated effect of intracellular serotonin and the receptor mediated effect of extracellular serotonin, and speculate on how antidepressant treatment could affect these two populations.


I certainly hope as well that more studies come out exploring the relationship between serotonin and gene regulation, and potentially the role psychedelics could have in these pathway.

 

[Allylbenzene]

...and then fluoxetine treatment seems to revert this effect. The beheavioural effect observed was described as an increased "stress-resilience" in mice treated with fluoxetine. There doesn't seem to be yet a proposed mechanism explaining how SSRI treatment could decrease serotonylation of histones...

I'd be careful when interpreting research showing benefits of SSRI drugs. The non-serotonin effects of SSRI drugs are more likey to be responsible for the positive effects. These include increasing BDNF and allopregnanolone which can be done in much safer ways. A well-known drug that increases BDNF is ketamine, called a "fast-acting antidepressant". Pure allopregnanolone is prescribed for depression (the body naturally makes it from pregnanolone too).

The serotonin theory of depression remains a dubious theory.

The rudimentary approach of increasing serotonin is a highly questionable approach for treating drug addiction and could easily make things worse.

To anyone considering this:
PLEASE BE CAREFUL before using SSRI drugs.
At least learn about the common side effects so you can make an informed choice.

On the SSRI fluoxetine (Prozac) causing depression:

Three years before Prozac received approval by the US Food and Drug Administration in late 1987, the German BGA, that country's FDA equivalent, had such serious reservations about Prozac's safety that it refused to approve the antidepressant based on Lilly's studies showing that previously nonsuicidal patients who took the drug had a fivefold higher rate of suicides and suicide attempts than those on older antidepressants, and a threefold higher rate than those taking placebos.
Using figures on Prozac both from Lilly and independent research, however, Dr. David Healy, an expert on the brain's serotonin system and director of the North Wales Department of Psychological Medicine at the University of Wales, estimated that "probably 50,000 people have committed suicide on Prozac since its launch, over and above the number who would have done so if left untreated.
...
Dr. Joseph Glenmullen, a clinical instructor in psychiatry at Harvard Medical School and a clinician at the Harvard University Health Services, says he wrote the book ["Prozac Backlash"] because he was alarmed by the number of patients who were reporting severe side effects from the serotonin-boosting antidepressants including Prozac, Paxil, Zoloft, and Luvox. "The two most upsetting side effects were patients becoming suicidal on the drugs, and the development of disfiguring facial tics," he said in an interview.

The Boston Globe, 2000.

Prozac Revisited [Boston Globe]

 

[red22]

"And today we know that actually new neuronal connections are being formed under LSD, that's why some researchers call it a 𝘣𝘳𝘢𝘪𝘯 𝘧𝘰𝘰𝘥 or it's even 𝘩𝘦𝘢𝘭𝘵𝘩𝘺 to take LSD—in small dosages—if the effect is not overwhelming. Even now, there's research for the so-called non-psychedelic psychedelic, like an LSD type where you don't have a trip, you just have the new neuronal enhancement effect. So it's a very interesting medication."

Mind control, Nazi Germany, and the CIA | Norman Ohler. @TheInstituteOfArtAndIdeas20. 25-07-22. YouTube. [6:17–6:45]

 

[tryptakid]

My experience from the outside looking in in - SSRIs create a plastic wall in the soul. It buffers the bad scary basement so you don't have to see it anymore, but it's still there. They create the illusion of elevated mood by numbing the extremes, tamping down the subjective experiences that provide color in life.

 

[emkee_reinvented]

 

[jveiojajoivioedsac]

At its peak, tens of millions of people were being prescribed daily fenfluramine[*] for extended periods, and that's not including the truly enormous numbers of people who were obtaining it from the 'grey market'. Fen-phen really was the ozempic of its day and was everywhere. If 5-HT2B agonists were anywhere near as long term harmful as some people make them out to be there should have been an epidemic of people suffering heart conditions by now. It hasn't happened.

That's not to excuse the pharmaceutical industry's behaviour over this matter, which was irresponsible, but a sense of proportion about this should be maintained.


[*]Fishman, A.P. Aminorex to Fen/Phen: An Epidemic Foretold. Circulation 1999, 99, 156–161.

30% of fenphen users having fucked up ECGs isnt nothing. Also unless the users were tracked we don't know their heart status.

 

[idle_curiosity]

30% of fenphen users having fucked up ECGs isnt nothing. Also unless the users were tracked we don't know their heart status.

??? You wouldn't have to track them. If 30% of former fen-phen users were exhibiting "...fucked up ECGs..." we'd be experiencing a monumental medical crisis, right now. There were literally 10s of millions of people taking fenfluramine. As we're not experiencing such a crisis, it rather suggests that some of the dangers of 5-HT2B agonists might just possibly be a little overblown... maybe...?

 

[perpetualdawn]

Ultra wealthy and competitive ager Bryan Johnson seems to have taken notice of this study and recently took his first mushroom trip with the intention of looking at how it might help with his quest to live forever. He's been posting about it and is doing a bunch of measurements on his own body to look at this potential. He can be pretty cringe but this will surely be some interesting data. I think his plan is to do a mushroom trip once a month at around 5g for 5 months and assess, so I'll be keeping an eye on what he and his team report.

I'm not really sure the best channel to keep tabs on this but here's his initial facebook post on the topic: www.facebook.com/bryanjohnsonblueprint/posts/811333098541781
I think you might have to follow him first to be able to see that post: https://www.facebook.com/bryanjohnsonblueprint/

 

[Allylbenzene]

...it rather suggests that some of the dangers of 5-HT2B agonists might just possibly be a little overblown... maybe...?

I'd agree. Look at the relevance of 5-HT2B for these common drugs...

npKi values below about 2.0 should be imperceptible, while values above about 2.0 should be perceptible, and the higher the npKi value, the more perceptible a receptor should be at a particular drug.

5-HT2B: 4.00 DOB, 4.00 MDA, 4.00 Aleph-2, 4.00 2C-B-fly, 4.00 2C-B, 4.00 TMA, 4.00 psilocin, 4.00 TMA-2, 4.00 2C-E, 4.00 2C-T-2, 4.00 4C-T-2, 4.00 MEM, 4.00 DOM, 3.97 mescaline, 3.93 6-F-DMT, 3.91 5-MeO-DIPT, 3.91 DMT, 3.88 DPT, 3.70 DOET, 3.64 MDMA, 3.48 DIPT, 3.32 5-MeO-MIPT, 3.13 DOI, 3.11 LSD, 3.01 lisuride, 2.72 cis-2a, 2.17 SS-2c, 1.81 RR-2b, 0.69 5-MeO-DMT; 0.00 salvinorin A
ND: 5-MeO-TMT, ibogaine, EMDT, morphine, THC

Ultra wealthy and competitive ager Bryan Johnson seems to have taken notice of this study and recently took his first mushroom trip with the intention of looking at how it might help with his quest to live forever.

Maybe he will gain some practical insights into toroidal physics and how it applies to biology and it's built-in regenerative capacity (thats not a joke).

Psilocybin might extend cellular lifespan but it's probably more practical for most people to maximise their metabolic function which is what governs cellular regeneration. That's pretty feasible for anyone to accomplish. Best bit, it's 100% OTC and cheap as chips.

 

[xdrc]

Well, with 5 g of mushrooms he may lose his fear of death after all.

 

[xdrc]

Also, serotonylation of H3 histones is catalyzed by transglutaminase 2, and if psychedelics were capable of being attached to histones as serotonin is, they would have to be recognized as substrates by this enzyme.

https://www.biorxiv.org/content/biorxiv/early/2025/02/17/2025.02.13.638188.full.pdf

Note the comments of the author and the "schizo-Dunning-Kruger"-ramblings, this was conducted at quite high concentrations not at all resembling reasonable drug dosages.

 

[jveiojajoivioedsac]

Well, with 5 g of mushrooms he may lose his fear of death after all.

He's a fucking nazi so maybe he will decide enough is enough and be done with life itself

 

[xdrc]

He's a fucking nazi so maybe he will decide enough is enough and be done with life itself

I don't know anything about Bryan Johnson to make any claims in one or the other direction, but it has been seen again and again that psychedelics unfortunately don't magically fix all dickheads, if that's where you are going.

 

[F.U.B.A.R.]

I don't know anything about Bryan Johnson to make any claims in one or the other direction, but it has been seen again and again that psychedelics unfortunately don't magically fix all dickheads, if that's where you are going.

Fuckin brilliant!!!

 

[iom]

Ultra wealthy and competitive ager Bryan Johnson seems to have taken notice of this study and recently took his first mushroom trip with the intention of looking at how it might help with his quest to live forever.

He hasn't tried it already? I know a lot of super rich have been doing a lot of dabbling with psychedelics lately. I heard a rumor that recently (the last few years?) an "ayahuasca shaman" was doing "healings" at World Economic Forum in Davos, Switzerland. As much as I'd like to think that getting the super rich to trip would lead to a positive global transformation, I expect their experiences will simply reinforce their existing attitudes. I must say, I feel very sorry for that "shaman" or anyone else who is a sitter for these kinds of people, even if they are being paid a lot.

I also rather doubt that he will make a good anecdote for study because he is not very representative of the "average" human---he's already doing all kinds of other "aging interventions" that aren't being controlled for.

I also want to say generally, that even if psilocybin has anti-aging properties in humans, it is a mistake to assume that any 5-HT2A agonist will do. I like to think of a receptor like 5-HT2A as more like an access panel, which allows activation of multiple effects, depending not just on the drug but also the environment of each individual receptor in the body (i.e. pH, presence of co-factors. etc.). Throw in pharmacokinetic effects, and the array of possible effects mediated by a "5-HT2A agonist" may be very vast indeed.