As in all things biology, that's not necessarily a good thing, otherwise we would have evolved it already. Surely there are downsides (cancer, ...)
> it has been suggested that cellular senescence evolved as a way to prevent the onset and spread of cancer. Somatic cells that have divided many times will have accumulated DNA mutations and would be more susceptible to becoming cancerous if cell division continued. As such, it is becoming apparent that senescent cells undergo conversion to an immunologic phenotype that enables them to be eliminated by the immune system.
You are correct. But it's also a probability distribution game. Increase probability to get cancer at advanced age, you will also increase it (maybe just a bit) for the younger population.
>>Evolution doesn't seem to optimize for longer lifespans.
Not quite true (if not weighting high on optimization). There are multiple species which are outliers by lifespan in their niches: whales, hydras, etc. Even within rodent family there is a wide range of lifespans typical for a species - from ~2 years for a mouse to ~30 years for a naked mole rat.
There are regenerative species with incredibly messy genomes which are biologically immortal. So relying on evolution as a main explanatory principle is not comprehensive enough (especially given that you can't currently reverse engineer much of the evolution subjects).
Me doesn't quite understand the rationale behind this widely used argument. Ok, senescent cells emerge as a mechanism to ward off cancer. They are basically semi-cancerous cells with an arrested cell division cycle ("zombies"). The goal of cancer therapies is to eliminate cancer cells. So what's wrong with the elimination of senescent cells? (especially if you get new stem cells differentiating into new healthy tissue in place of senescent ones or let the surrounding healthy tissue to proliferate there)
There is nothing wrong with eliminating them. But this study says psylocybin slows down cells becoming senescent, not that it eliminates them. So in fact it makes them live longer.
Yep, they show it's not a senolytic, but I'd like to see an experimental human group (preferably with a dopamine transporter allele making them more prone to placebo-like responses) being given psilocybin and told that it is a senolytic.
"Psilocybin treatment led to a dose-dependent decrease in cell cycle arrest markers (p21, p16, and p53) and an increase in markers of DNA replication
(phosphorylated-Retinoblastoma protein; pRB) and proliferation (PCNA), as compared to vehicle-treated cells". They don't say it IS carcinogenic. At least this statement favors taking psilocybin after fasting/senolytics/autophagy induction.
"may mediate SIRT1-dependent pathways which impact cellular senescence". So if senescence is delayed by it and during this period SIRTs are activated, it may be anti-cancerous.
Anti-oxidants prevent cell damage caused by reactive oxygen. People thought that's a good thing. But it turns out that can actually promote cancer, because cells expect to be damaged in time, and kill themselves when that happens, and anti-oxidants mess with this mechanism.
> Some of the largest clinical trials, in fact, had to be aborted because the patients receiving antioxidants had a higher incidence of cancer than patients who did not receive them.
I heard about this anti-oxidant hype, so the original psilocybin study now seems a bit incomplete.
There are a ~dozen of studies on dasatinib (anti-cancer drug) + quercetin (senolytic) for curing osteoarthritis in humans, improving heart tissue etc, with dasatinib used as a senolytic. Navitoclax (anti-cancer drug) also used as senolytic in some studies.
In this context it seems that adverse effects from senolytics may be more pronounced in cancer-prone, in younger age or if taking them continuously (not like 5 days per month or so letting some senescent cells to emerge). Yet Sinclair's new venture TallyHealth, for example, are selling a 5 in one capsule, containing apart from other stuff 500 mg quercetin and 100 mg fisetin (senolytics) with an expectation of daily intake. And his 80y old dad is taking senolytics daily with still no cancer.
As long as it's not known to be dangerous, people are free to experiment. But they should make it clear that there are no comprehensive studies showing an improvement, just speculation based on mechanics and some animal studies.
Another example is NAD+, people messing around with billion years old hyper-conserved mechanism (citric acid cycle). What could possibly go wrong, right?
Ion channels are also a hyper-conserved mechanism as every cell needs to maintain a resting potential, and there are tons of ion channel modulating drugs approved and used messing with the with billion years old hyper-conserved mechanism.
I heard about NAD+ on Dave Asprey podcast, that with age the NAD cleavage system cleaving NAD excess is also degraded and a Nuchido company makes this supplement with additives targeting NAD cleavage system restore as well.
This study has some nice data in it, but they didn't really start with a very strong hypothesis, to my understanding. The paper starts with a citation about stress being inversely associated with telomere length, and proposes that psilocybin decreases psychological stress, but then goes on to demonstrate decreases in entirely different in vitro physiological stress markers. How is one to tell that this isn't just cherry-picking dependent variables that look good?
State of senescence in cells can also be caused by mechanical stress [1], this is the basis of senescent cell formation in osteoarthritis etc. So maybe psilocybin is somehow generalizing.
This experimental design is flawed. It's important to remember that orally dosed psilocybin acts as a prodrug for psilocin. It is metabolized into psilocin in the gut before absorbing into circulation. It is psilocin that is primarily responsible for the physiological and psychoactive effects.
Therefore, in vitro (cell culture) studies like this one that only focus on psilocybin and not psilocin are limited in translational value. They fail to accurately mimic the physiological context, where psilocin, not psilocybin, would interact with these cell types. For translational relevance, we need to study the actual bioactive compound (psilocin) in systems that closely replicate human physiology. Thus, in vitro studies with psilocybin provide an inaccurate picture. I would be surprised if this made it through peer review anywhere.
Seems like psilocin is dephosphorylated psilocybin. But the main working indole structure with the side chain is preserved. So for a cell to get an extra phosphate rich in energy while producing psilocin for the host should be a bonus.
The general rationale seems rather feasible, given the application of the SSRI antidepressant fluvoxamine [1] to reduce severity of COIVD infection, as James Kirkland on STEM talk from the link below mentioned that senescence also may be induced by infections.
Indeed, you're correct in stating that psilocin is dephosphorylated psilocybin, and the core indole structure with the side chain is preserved. However, my point is that psilocybin would never make it to most cells in the body. I suggest researching the known pharmacokinetics of psilocybin to better understand the nuances here.
In terms of physical properties, psilocin and psilocybin differ significantly due to this transformation. These differences have meaningful consequences at the receptor level, which is where the physiological and psychoactive effects are primarily mediated. The key concern is how the resultant psilocin molecule interacts with cellular receptors and proteins, which almost certainly differs from psilocybin's interactions.
This distinction is quite similar to drug design concepts, where seemingly minor modifications to structure can drastically alter a drug's efficacy and interactions. The difference between a phosphate group (as in psilocybin) and a hydroxyl group (as in psilocin) may appear subtle, but in pharmacological terms, this can easily distinguish between an active and inactive compound.
Do you mean that it is the OH group on psilocin that binds with the receptor?
There probably are many other compounds with an OH group and another backbone, and they are not supposed to bind with 5HT2a.
The OH group is ~0.62% of the whole molecule, so there are way more molecule positions in space in which the OH group will be facing away from the receptor, so the active compound will not react.
I honestly cannot tell if you are trolling now, but I'll oblige one last time. In good faith, I think you might be oversimplifying the situation a bit. The binding of psilocin (or any other ligand) to its receptor is not just about the presence or absence of a particular functional group such as the OH group. The entire structure and dynamics of the molecule, including its overall conformation and the spatial orientation of its functional groups all play crucial roles in how it interacts with the receptor.
In the case of psilocin, the 4-hydroxyl group does not act alone, but is rather a part of the larger molecule. Apart from it's induction effects with the indole ring, this group has been shown to form a very unique intramolecular hydrogen bond with the distal amine that significantly influences the overall conformation of the drug, and this in turn affects how the drug binds to and activates the receptor. Remarkably, this intramolecular hydrogen bond is largely responsible for many of the unique pharmacological and physical properties of psilocin.
Moreover, receptors like 5HT2A do not interact with their ligands in a one-size-fits-all manner. Rather, they have unique, intricate 'lock-and-key' or 'induced-fit' relationships with each ligand, where the spatial orientation of every atom matters. Hence, just because a molecule has an OH group doesn't automatically qualify it to bind with the 5HT2A receptor; it needs to have the right molecular structure and conformation.
Lastly, while the OH group constitutes a small percentage of the overall molecule, its position and the way it influences the conformation of the psilocin molecule cannot be overlooked. Drug-receptor interactions are not solely dictated by the size or quantity of a particular group, but by the precise alignment of these molecular features. This is the reason even minute changes in the structure of a drug can dramatically alter its pharmacological activity.
I'm not trolling, this probably is some effect of the psychoactives' field itself and thinking about it.
I am researching the topic about how signalling molecules find their intra- and extracellular targets amongst multiple potential "distractions" along their way.
What you describe as 'lock-and-key' or 'induced-fit' relationship is established only at the direct contact of a ligand with the receptor. While the ligand in vivo if not injected locally first needs to move fast through vast distances (relative to its size) until it reaches the receptor. It seems that it is just accepted for granted, as if the ligand "knew" where the receptor is.
Your link and explanation are very informative, it seems like this intramolecular hydrogen bond completes a "virtual" third heterocycle in the whole molecule.
While senolytic quercetin, for example, also has 3 benzene rings.
There's a doctor in my contacts who weighs heavily on heterocycles due to the delocalized electron they contain.
22 comments
[ 4.3 ms ] story [ 55.4 ms ] thread> it has been suggested that cellular senescence evolved as a way to prevent the onset and spread of cancer. Somatic cells that have divided many times will have accumulated DNA mutations and would be more susceptible to becoming cancerous if cell division continued. As such, it is becoming apparent that senescent cells undergo conversion to an immunologic phenotype that enables them to be eliminated by the immune system.
https://en.wikipedia.org/wiki/Cellular_senescence
Put otherwise, there is no free lunch. Just compromises.
Long lifespan is usually not in the interest of the species. While it's very much in the interest of individual and worth pursuing.
Not quite true (if not weighting high on optimization). There are multiple species which are outliers by lifespan in their niches: whales, hydras, etc. Even within rodent family there is a wide range of lifespans typical for a species - from ~2 years for a mouse to ~30 years for a naked mole rat.
There are regenerative species with incredibly messy genomes which are biologically immortal. So relying on evolution as a main explanatory principle is not comprehensive enough (especially given that you can't currently reverse engineer much of the evolution subjects).
Me doesn't quite understand the rationale behind this widely used argument. Ok, senescent cells emerge as a mechanism to ward off cancer. They are basically semi-cancerous cells with an arrested cell division cycle ("zombies"). The goal of cancer therapies is to eliminate cancer cells. So what's wrong with the elimination of senescent cells? (especially if you get new stem cells differentiating into new healthy tissue in place of senescent ones or let the surrounding healthy tissue to proliferate there)
"Psilocybin treatment led to a dose-dependent decrease in cell cycle arrest markers (p21, p16, and p53) and an increase in markers of DNA replication (phosphorylated-Retinoblastoma protein; pRB) and proliferation (PCNA), as compared to vehicle-treated cells". They don't say it IS carcinogenic. At least this statement favors taking psilocybin after fasting/senolytics/autophagy induction.
"may mediate SIRT1-dependent pathways which impact cellular senescence". So if senescence is delayed by it and during this period SIRTs are activated, it may be anti-cancerous.
> Some of the largest clinical trials, in fact, had to be aborted because the patients receiving antioxidants had a higher incidence of cancer than patients who did not receive them.
https://www.cancer.gov/news-events/cancer-currents-blog/2015...
Preventing cellular senescence sounds like the same kind of thing, messing with an existing mechanism put in place to prevent cancer.
There are a ~dozen of studies on dasatinib (anti-cancer drug) + quercetin (senolytic) for curing osteoarthritis in humans, improving heart tissue etc, with dasatinib used as a senolytic. Navitoclax (anti-cancer drug) also used as senolytic in some studies.
In this context it seems that adverse effects from senolytics may be more pronounced in cancer-prone, in younger age or if taking them continuously (not like 5 days per month or so letting some senescent cells to emerge). Yet Sinclair's new venture TallyHealth, for example, are selling a 5 in one capsule, containing apart from other stuff 500 mg quercetin and 100 mg fisetin (senolytics) with an expectation of daily intake. And his 80y old dad is taking senolytics daily with still no cancer.
As long as it's not known to be dangerous, people are free to experiment. But they should make it clear that there are no comprehensive studies showing an improvement, just speculation based on mechanics and some animal studies.
Another example is NAD+, people messing around with billion years old hyper-conserved mechanism (citric acid cycle). What could possibly go wrong, right?
I heard about NAD+ on Dave Asprey podcast, that with age the NAD cleavage system cleaving NAD excess is also degraded and a Nuchido company makes this supplement with additives targeting NAD cleavage system restore as well.
[1]. https://www.ihmc.us/stemtalk/episode-122/ (47:30)
Therefore, in vitro (cell culture) studies like this one that only focus on psilocybin and not psilocin are limited in translational value. They fail to accurately mimic the physiological context, where psilocin, not psilocybin, would interact with these cell types. For translational relevance, we need to study the actual bioactive compound (psilocin) in systems that closely replicate human physiology. Thus, in vitro studies with psilocybin provide an inaccurate picture. I would be surprised if this made it through peer review anywhere.
The general rationale seems rather feasible, given the application of the SSRI antidepressant fluvoxamine [1] to reduce severity of COIVD infection, as James Kirkland on STEM talk from the link below mentioned that senescence also may be induced by infections.
[1] https://www.thelancet.com/journals/lanwpc/article/PIIS2666-6...
In terms of physical properties, psilocin and psilocybin differ significantly due to this transformation. These differences have meaningful consequences at the receptor level, which is where the physiological and psychoactive effects are primarily mediated. The key concern is how the resultant psilocin molecule interacts with cellular receptors and proteins, which almost certainly differs from psilocybin's interactions.
This distinction is quite similar to drug design concepts, where seemingly minor modifications to structure can drastically alter a drug's efficacy and interactions. The difference between a phosphate group (as in psilocybin) and a hydroxyl group (as in psilocin) may appear subtle, but in pharmacological terms, this can easily distinguish between an active and inactive compound.
The OH group is ~0.62% of the whole molecule, so there are way more molecule positions in space in which the OH group will be facing away from the receptor, so the active compound will not react.
In the case of psilocin, the 4-hydroxyl group does not act alone, but is rather a part of the larger molecule. Apart from it's induction effects with the indole ring, this group has been shown to form a very unique intramolecular hydrogen bond with the distal amine that significantly influences the overall conformation of the drug, and this in turn affects how the drug binds to and activates the receptor. Remarkably, this intramolecular hydrogen bond is largely responsible for many of the unique pharmacological and physical properties of psilocin.
( https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002... )
Moreover, receptors like 5HT2A do not interact with their ligands in a one-size-fits-all manner. Rather, they have unique, intricate 'lock-and-key' or 'induced-fit' relationships with each ligand, where the spatial orientation of every atom matters. Hence, just because a molecule has an OH group doesn't automatically qualify it to bind with the 5HT2A receptor; it needs to have the right molecular structure and conformation.
Lastly, while the OH group constitutes a small percentage of the overall molecule, its position and the way it influences the conformation of the psilocin molecule cannot be overlooked. Drug-receptor interactions are not solely dictated by the size or quantity of a particular group, but by the precise alignment of these molecular features. This is the reason even minute changes in the structure of a drug can dramatically alter its pharmacological activity.
I am researching the topic about how signalling molecules find their intra- and extracellular targets amongst multiple potential "distractions" along their way. What you describe as 'lock-and-key' or 'induced-fit' relationship is established only at the direct contact of a ligand with the receptor. While the ligand in vivo if not injected locally first needs to move fast through vast distances (relative to its size) until it reaches the receptor. It seems that it is just accepted for granted, as if the ligand "knew" where the receptor is.
Your link and explanation are very informative, it seems like this intramolecular hydrogen bond completes a "virtual" third heterocycle in the whole molecule. While senolytic quercetin, for example, also has 3 benzene rings.
There's a doctor in my contacts who weighs heavily on heterocycles due to the delocalized electron they contain.