5 ms·

Psilocybin Decelerates Cellular Senescence

31 points by amts 3y ago

thumbuddy 3y ago
So if we all trip balls so hard that every cell in our body is covered in psilocybin we will live longer?
- dyno12345 3y ago
  only one way to find out
florinutz 3y ago
[dead]
dist-epoch 3y ago
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. https://en.wikipedia.org/wiki/Cellular_senescence https://en.wikipedia.org/wiki/Cellular_senescence Put otherwise, there is no free lunch. Just compromises.
- scotty79 3y ago
  I don't know. Evolution doesn't seem to optimize for longer lifespans. So it would not optimize for substances that aid it. Long lifespan is usually not in the interest of the species. While it's very much in the interest of individual and worth pursuing.
  - dist-epoch 3y ago
    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.
  - amts 3y ago
    >>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).
- amts 3y ago
  >>Surely there are downsides (cancer, ...) 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)
  - dist-epoch 3y ago
    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.
    - amts 3y ago
      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.
      - dist-epoch 3y ago
        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. https://www.cancer.gov/news-events/cancer-currents-blog/2015/antioxidants-metastasis 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.
_nhynes 3y ago
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?
- amts 3y ago
  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. [1]. https://www.ihmc.us/stemtalk/episode-122/ https://www.ihmc.us/stemtalk/episode-122/ (47:30)
TheToadKnows 3y ago
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.
- amts 3y ago
  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. [1] https://www.thelancet.com/journals/lanwpc/article/PIIS2666-6065(23)00034-2/fulltext https://www.thelancet.com/journals/lanwpc/article/PIIS2666-6...
  - TheToadKnows 3y ago
    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.

31 points by amts 3y ago

thumbuddy 3y ago

So if we all trip balls so hard that every cell in our body is covered in psilocybin we will live longer?

dyno12345 3y ago
only one way to find out

florinutz 3y ago

[dead]

dist-epoch 3y ago

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. https://en.wikipedia.org/wiki/Cellular_senescence https://en.wikipedia.org/wiki/Cellular_senescence Put otherwise, there is no free lunch. Just compromises.

scotty79 3y ago
I don't know. Evolution doesn't seem to optimize for longer lifespans. So it would not optimize for substances that aid it. Long lifespan is usually not in the interest of the species. While it's very much in the interest of individual and worth pursuing.
- dist-epoch 3y ago
  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.
- amts 3y ago
  >>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).
amts 3y ago
>>Surely there are downsides (cancer, ...) 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)
- dist-epoch 3y ago
  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.
  - amts 3y ago
    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.
    - dist-epoch 3y ago
      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. https://www.cancer.gov/news-events/cancer-currents-blog/2015/antioxidants-metastasis 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.

_nhynes 3y ago

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?

amts 3y ago
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. [1]. https://www.ihmc.us/stemtalk/episode-122/ https://www.ihmc.us/stemtalk/episode-122/ (47:30)

TheToadKnows 3y ago

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.

amts 3y ago
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. [1] https://www.thelancet.com/journals/lanwpc/article/PIIS2666-6065(23)00034-2/fulltext https://www.thelancet.com/journals/lanwpc/article/PIIS2666-6...
- TheToadKnows 3y ago
  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.