Is Psilocybin a Mini Yamanaka Factor We Can Do Now?
March 24, 2022
Okay…we're going down the rabbit hole with this one and into pretty new territory.
The studies we're leaning on are all in the last few years for the most part.
If the title is confusing, don't worry…we're going to unpack everything below.
The two pieces may connect the greatest recent (and rediscovered with psilocybin) discoveries in health research.
Yamanaka factors (more here) are the breakthrough new discovery for reversing aging and the damage caused by it.
Psilocybin is the future of mental health treatment from magic mushrooms with an uncanny ability to reset brain pathways.
Our focus is actually more on the effects of trauma/infection and mental health which we covered here.
Sit back. Take a deep breath. We're going to pull on the threads and see if we can unravel the sweater (like Weezer!).
Here are the threads we'll cover:
- A quick intro to Yamanaka Factor (OSK) revolution
- Psilocybin's effect must be epigenetic
- The fascinating connection between sigma1 and mushrooms
- Sigma1 and histone effects
- Psilocybin and entropy reset
- Threading it all together
Let's go!
A quick intro to Yamanaka Factor (OSK) revolution
First, we need to at least recap this new revolution. We have a full review here.
There's a series of pathways that can revert any cell in your body back into a pluripotent stem cell.
We've been working with these for almost 2 decades now but you can't use all four pathways in a living body as it turns the cells into undifferentiated masses.
They don't retain their identity (skin cell, muscle cell, etc).
The breakthrough was when the 4th pathway was removed in the process leaving only the first 3 (O, S, and K).
With this narrowed process, the cells behave like young again but keep their identity!
This is the basis behind a whole new advance in the theory of aging being an epigenetic process.
Our epigenome is the layer of instruction that sits on top of our genome and turns genes on and off.
The Yamanaka factor breakthrough was in stripping the "rust" of aging off of the epigenome which elicited juvenile cells. Cells that behaved like young cells.
They literally saw sight return to old blind (not just three) mice and even mice with crushed optic nerves.
This is thought to be methyl markups to the epigenome but it may also be the removal of damage from glucose (glycation) and other types of changes.
So…the epigenome may be the key to stripping aging off of living systems since the raw DNA isn't really changing that much.
Epigenetic effects. So….let's introduce psilocybin.
Psilocybin's effect must be epigenetic
We did a deep dive on psilocybin here.
The fascinating piece is that 1-2 doses (hero doses) can have long lasting effects on very serious mental health issues that appear intractable (treatment resistant depression, bipolar, etc).
What caught our eye is this study here:
Immune-related genes constituted the largest group of genes impacted one week after psilocybin administration, suggesting that the long-lasting effects of the psychedelic substance might be related to neuroinflammation.
So…the longer term effects were due to genes being turned on/off (epigenetic) and primarily in the immune system area.
That's not surprising…check out how the future of mental health is in the immune system.
BDNF alone is a secret weapon.
You can't cause long term effects from just one dose of anything (aside from bad effects…overdose, etc).
If you stop benzos or SSRIs, the effects go away almost immediately (tolerance and/or addiction doesn't help).
Psilocybin doesn't build classic tolerance in that you're not up or downregulating pathways which then get exhausted (rebound, withdrawals).
Indeed…just like Yamanaka factors, the area of domain is the epigenome:
Additionally, a single dose of DOI led to changes in chromatin organization particularly at enhancer regions of genes involved in synaptic assembly that stretched for days after the psychedelic exposure
https://www.biorxiv.org/content/10.1101/2021.02.24.432725v1.full.pdf
It's not just serotonin!
Chromatin is the structural "wrap" of DNA that is controlled by our histone complex to fold/unfold in a particular way which controls which genes are "read" and for how long.
Hello epigenome!
So…how on earth is psilocybin doing this besides being a little gift down here on a very difficult Earth (for life anyway).
This thread is just plain weird.
The fascinating connection between sigma1 and mushrooms
We all have a gene called sigmar1 which makes a key component called sigma1.
Okay… so what does sigma1 do in the body? Among many things:
Specifically, SIGMAR1 was shown to create a dose-dependent interaction between emerin and histone deacetylase (HDAC) 1, HDAC2 and HDAC3 and to therefore affect chromatin compaction and gene expression
To translate, sigma1 is involved in the complex that governs epigenetic changes.
Chromatin is the structure of our DNA that compacts and unravels under the control of our epigenome. It's the physical construct of everything we're talking about.
Here's the strange part:
One peculiarity of the human SIGMAR1 gene is that, unlike any other, it only shares 30.3% homology with any other mammalian protein, while sharing 66.7% identity with the enzyme sterol isomerase found in fungi,
Okay…so our sigma1 gene shares more with fungi than with other mammals!
Double so. Head scratcher.
Let's look at one particular aspect tying psychedelics, epigenetics, and trauma.
This is in line with the hypothesis here presented, since reconsolidation and fear extinction of traumatic memories both seem to require the involvement of epigenetic mechanisms
https://www.frontiersin.org/articles/10.3389/fphar.2018.00330/
Fear extinction is how the body over-writes the effects of trauma which is so front and center with mental health later in life. Include infection in that same calculus.
Interestingly, sigma1 leans into another pathway close to our heart for this reset process:
Aside from promoting anti-amnesic and regulating epigenetic intracellular pathways, activated SIGMAR1 modulates the cannabinoid receptor 1 (CB1)/NMDA receptor interaction to prevent NMDA receptor dysfunction
Ahhh….CB1, the primary site for endocannabinoid function. See CBD and endocannabinoid deficiency or CBD and trauma.
We digress.
To digest…sigma1 had powerful effects on epigenetic changes that addressed a key effect of psychedelics to "erase" the trauma.
Remember, the Yamanaka factors are able to "reset" our epigenome to it's original (or close to it) state before all the "mark ups" of life, damage, and…trauma.
Let's drill down into this more.
Sigma1 and histone effects
So, what does sigma1 do with our epigenome?
Let's introduce three key players:
- Histones
- Chromatin
- HDAC's
- Demethylation
It's epigenome 101!
Histones are the modeler of our DNA…constantly spooling and unspooling strands to be read.
Histone proteins (H2A, H2B, H3, H4) help organize DNA into structured units called nucleosomes
https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC6952751/
They are the hands of the modeler and our environment and history (even our ancestor's histories) dictate how they shape.
The clay is chromatin
The nucleosomes can be thought of as “beads” and are connected by linker DNA forming a collection of “beads on a string” called chromatin.
https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC6952751/
The system uses chemicals called acetylases and deacetylases to carry out the work and methyl groups to "bookmark" changes from our experience:
Chemical alteration or modification of histones–through acetylation or deacetylation–influences the structure of chromatin, remodeling it to either coil or uncoil and altering the ability of RNA polymerase to transcribe genes.
Okay…this is the mechanics of the process.
Interestingly, SIRT is an HDAC (histone deacetylase) and it has powerful effects on longevity.
As histone acetylation is strongly associated with gene activation (Wang et al., 2008b), sirtuins are in general silencers of gene expression by the deacetylation of histones.
https://www.sciencedirect.com/science/article/pii/S0092867412000049
This is the star behind caloric restriction, resveratrol, and other prominent longevity tools.
HDAC's remove the "markup" from the epigenome separately from methyl groups.
This brings us to psilocybin and methylation, the supposed star behind the Yamanaka reset.
A quick intro to methyl groups.
Think of them as dogtags on your genes.
Let's say you go through trauma or infection (even in utero), then a series of methyl groups are added as specific sites across your DNA.
Read this gene more. Read this one less.
For example, early trauma can upregulate inflammation and downregulate GABA (brain's brake pedal), serotonin (master mood and stress manager), and BDNF (brain's fertilizer).
Hence the connection with early traumal/infection and mental health (read much more here).
The future of mental health is the immune system (more here), by the way.
So…what about psychedelics and methyl markers.
A new study looked at LSD treatment and rats with the following effects:
we observe long-lasting changes in gene expression, particularly in neuroplasticity and neurotransmission genes, in line with previous reports, but also in circadian rhythm and, importantly, in epigenetic modifiers.
https://onlinelibrary.wiley.com/doi/pdf/10.1111/jnc.15534
"Epigenetic modifiers" (hint hint, methyl markers). Do tell!
Indeed, Tet1, involved in the erasure of DNA methylation (Wu & Zhang, 2017), increases its expression upon LSD, and the “histone modification” GO category shows strong enrichment for up-regulated genes.
Aha! TET1 is a key player in the methylation effects from Yamanaka reset.
This removal of methyl markups in the epigenome is the "rust" of aging (and trauma).
It's the smoking gun to everything we're talking about.
In fact, in the original Yamanaka factor paper, look at what happens when the TET family is blocked:
The knockdown of either Tet1 or Tet2 blocked the ability of OSK to increase Stat3 mRNA levels and promote RGC survival and axon regeneration
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7752134/
So…say goodbye to your epigenome reset!
TET1 is very fascinating to this whole equation. It's role:
Its function, regulation, and utilizable pathways remain a matter of current research while it seems to be involved in DNA demethylation and therefore gene regulation.
Basically, it starts the removal or demethylation process rolling.
so….
Psychdelic's effects:
“covalent chromatin modification” and “histone modification” showed strong enrichment for up-regulated genes, among which we found Tet1 (Ten-eleven translocation methylcytosine dioxygenase 1), involved in the erasure of DNA methylation (Wu & Zhang, 2017).
https://onlinelibrary.wiley.com/doi/pdf/10.1111/jnc.15534
You can't hear it but we're dropping the mic now.
Psychedelics boost the very process that drives Yamanaka factor reset.
Let's go deeper (and much more current), please.
Psilocybin and entropy reset
We're getting into the weed a bit here but it's worth it.
Entropy is a measure of chaos or the lack of structure.
In terms of genetics, it's a measure of how "flexible" a given cell is.
Meaning….a stem cell has the most flexibility (entropy) since it can change in so many different directions.
A mature skin cell has less entropy (locked in as skin type). A younger version of that same skin cell has more entropy.
This decrease in entropy speaks to a younger or more juvenile set of DNA processing.
Alright…that's a mouthful but it's important.
The effects of psychedelics on this process:
Using multiple metrics, we show that LSD-induced transcriptional entropy is more reflective of a plastic stem-like state than an aged state, suggesting the induction of a potentiality-expansion process with organised and reproducible features.
https://www.biorxiv.org/content/10.1101/2021.06.23.449556v1.full
Wait what?
So…psychedelics reset the DNA processing state to a more "youthful" setting.
Alright, let's climb out of the rabbit hole (before we stumble too wide).
Threading it all together
We covered a great deal and yes, this research is mostly in the last 24 months. CRISPR has really opened up the whole epigenetic landscape.
Here's the general wrap.
Exciting new research on the first three Yamanaka factors (OSK) may reset aging by stripping epigenetic "markups"
Altos Labs (the 3B+ invested Bezos venture) and others (Dr. Sinclair) are leading the charge here. A big review on just how exciting this research is here.
Psilocybin and other psychedelics have shown to have powerful, long-term effects from a few doses.
Epigenetic changes are being uncovered as the driving force behind these changes.
Sigma1 may be a critical connection in how this process occurs as it drives the machinery of epigenetic change (deacetylases)
Methyl marker removal is also a shared pathway between psychedelics and Yamanaka (OSK) factor process.
Psychedelics show a more youthful gene expression as measured by transcriptional entropy.
We'll look forward to more research to tease this process out but it speaks to something much bigger (and closer to our heart).
Our epigenome is not just the arbiter of aging. It's tied to every insult, assault, and injury we've received.
Keep in mind that epigenetic markups may go back generations!
Both psychological and physiological effects are found from ancestors of holocaust survivors and it's thought that epigenetic changes can go back up to 14 generations!
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6720013/
And
Then, there's the early childhood trauma. A great deal of this migrates forward via the immune system for mental health effects later. We covered it in detail at our trauma review and immune system review.
So…does the epigenetic reset above also address our trauma/infection history (and debris).
To see the results of psilocybin (here) and with John Hopkins lead speaks to deep changes at this level in order to have long term changes.
We look forward to this future since we're all carrying around the baggage of past trauma/infection.
Imagine what you are unencumbered by this past damage. It's breathtaking.
Be well. Take care of each other. Take care of yourself.
Always work with a doctor or naturopath with any supplement!
The information provided here is not intended to treat an illness or substitute for professional medical advice, diagnosis, or treatment from a qualified healthcare provider.