The New Age of Yamanaka Factors and Longevity

This is off the beaten path for us.

We like to stay in our CBD sandbox in terms of research but occasionally, some piece of research or insight comes along and makes us stop in our tracks.

The last time that happened was with CRSPR.

We immediately understood that it was a complete game-changer and will likely dominate all healthcare within 10 years.

There was a logical tie-in with CBD there since FAAH is one of the targets of most interest with CRSPR and CBD has a similar effect.

Basically, you can "tune down" anxiety, depression, pain, inflammation.

Just 80% of the meds you see on TV assuming you're still held hostage by commercials.

So CRSPR was big and we've noticed its imprint everywhere...especially in NIH research where researchers can turn a gene on or off and look at the knock-on effects.

Total gamechanger.

Jump ahead 10 years, and we have a new target for awe and admiration.

It's Dr. Sinclair's work from Harvard on the Yamanaka factors.

Yes, it sounds like Star Trek (and sort of is) but stays with us...we feel it's going to be the biggest discovery of the last...well...since people have searched for the fountain of youth...so a few 100,000 years at least.

Here are the topics we'll cover:

• A top-level view of Dr. Sinclair's discovery
• What are the Yamanaka factors?
• A new theory of what drives aging
• How Yamanaka factors reverse the damage
• How Yamanaka factors reverse aging
• Other longevity tools till we Yamanaka factors are available

Let's get started. Buckle up because the societal changes derived from this discovery will be nothing short of spectacular.

A top-level view of Dr. Sinclair's discovery

First, an introduction is in order.

David Andrew Sinclair is an Australian biologist who is a professor of genetics and co-director of the Paul F. Glenn Center for the Biology of Aging at Harvard Medical School.

He has a history of interesting work on aging including studies on NMN, resveratrol, AMPK, and mTOR pathways, plus much more.

We cover AMPK and mTOR at our deep dives on metformin and berberine.

This goes to the heart of what was, at the time, a revolutionary study on aging called the MILES study involving metformin.

We'll cover that below in the tools section.

Where those studies were revolutionary in that they slowed or reduced markers of aging, this new work from Sinclair is different in kind...not degree.

Essentially, Dr. Sinclair's work points to a simple way to strip the "history" of aging from our cells and reset the original program.

The simple tools are the Yamanaka factors which we'll introduce below.

At the heart of it, this is a total reframing of what aging looks like in the body and the result of the ingenious discovery of a biological quirk... just like catching CRISPR's use by bacteria to protect themselves from viruses.

To really understand this, we need to dive a bit deeper into the mechanics of how cells function (and age).

First, what are these factors if not some reference to warp drive technology in Star Trek?

What are the Yamanaka factors?

Scientists have known for some time that when exposed to a series of very specific chemicals, cells will revert back to an original "blank slate" state.

These are called pluripotent stem cells.

The four genes (which make up the factors) are:

• Oct3/4,
• Sox2
• Klf4
• c-Myc

You weren't expecting something that rolls the tongue, were you?

After all, these genes are heavy hitters in the embryo during the stage where default or building block cells (the stem cells) get signals to transform into whatever is next on the assembly line (brain, bone, heart, etc).

You can take a skin cell, for example, apply these factors in a sequence (like the trays for photo development if you're old enough to remember), and voila..building block cells!

We'll get into why this works below.

There was original interest in applying these factors to adult animals but the steps went too far...essentially creating tumors or masses of undifferentiated cells.

The cells lost their "identity" with all four factors.

Here's where the genius (and just pure intellectual curiosity) came in…

Dr. SInclair and his group applied only 3 of the factors, leaving off c-Myc.

The results were astounding. Literally breathtaking.

Two studies draw our attention right away:

• Optic nerve regeneration
• Twin mouse age reversal or acceleration

In the first one, they crushed the optic nerve of a mouse.

Optic nerves are like spinal cords in that they don't regenerate...blindness is the outcome.

When Dr. Sinclair's group applied the three factors, the optic nerve regrew and became fully functioning.

The blind mice regained their eyesight.

This same effect occurred with an aged mind who became blind due to advanced age.

The second study involved twin mice with one receiving the Yamanaka factors.

Check out the video to see the difference...it's literally night and day (or young and old).

You can see both here:

There's a host of new studies including applying the 3 factors directly to older dogs and our estimation for people is probably 5-7 years although, we're sure there are biohackers out there now exploring the option since these factors are readily easy to work with (in scientific terms).

Keep in mind that almost all illness is directly tied to aging.

We've covered some of the key reasons with the following:

• Vitamin D production decreases with age
• Steroidal hormones decrease with age (and drop off with women)
• Immune system response decreases with age
• Gut microbiome loses its robustness with age
• Mitochondria accumulate errors with age

Check out our reviews on oxidative stress, age and neurogenesis, CBD and gut inflammation, CBD and mitochondria, plus our CBD and longevity review.

Lots of research on this front but the key question is...

What actually is aging?

And why does the 3-factor approach work?

.
Let's go there now

A new theory of what drives aging

First, you have your genes which function like hardware.

Errors can occur here but we have pretty robust systems to detect them and either fix them or have the immune system kill the cell.

Our mitochondria, the power plants for our cells, are not so protected, and that a major issue long term since their DNA accumulate errors more readily.

Dr. SInclair's discovery actually focuses one step up from genes.

The software!

Epigenetics is the new hot spot of research for genetics and it focuses on the system that control how protein-encoding genes are turned on or off.

This "layer" of coding acts as the interface between nature and nurture.

One quick example dear to our heart.

In our review of CBD and benzos, we noted how the body will start to build a tolerance to benzos really quickly.

GABA, the main target of benzos, will see its receptors lose both numbers and sensitivity as a result longer-term.

This goes all the way down to the genetic level where the genes that make the 5 proteins that form the receptor are turned off!

That's epigenetic folks! By the way, those genes will come back after about 30 days of avoiding benzos as we detail in our CBD for benzo addiction review.

Dr. Sinclair's wades deeper into this process in regards to the Yamaka factors.

As he explains, our DNA strands are actually incredibly long and yet fit inside each cell.

In order to do this, they have to spooled uptight like a bundle of fishing wire.

When tightly packed like this, the genes aren't even accessible to make proteins from.

RNA floats around the sites looking to carry DNA's instructions but there's no available surface for a gene when it's "packed up".

The system in play with the Yamanaka factors deals with the control mechanism for unspooling specific genes so they can be "processed" by RNA.

The "error" of aging deals with this system accumulating damage over time.

Turning wrong genes off and not turning the right genes (for a given process or period of time) on.

Think of aging as an accumulated rust in the software that controls DNA management.

The technical term for this control system is called methylation (which is why B vitamins are so important).

Histones actually operate the system to pack and unpack DNA for reading.

Essentially, Dr. Sinclair discovered that the 3 factors above reset this system so they function as if young (before errors).

They stripped the accumulated errors in our DNA reading control system.

The revolutionary takeaway…..

They remove the edifice of aging from our cells!

Most importantly, when only the three factors are used (excluding the 4th), the cells keep their identity (heart, brain, bone, blood, etc).

This is critical since a mass of undifferentiated cells is essentially a tumor!

The 4th factor exclusion prevents this but still removes the rust of aging.

Are you geeking out yet? It's a once-in-a-century discovery akin to antibiotics or electricity or...CRISPR.

With a decade between them, you can see how advances are coming faster and faster.

So...let's apply this top-level understanding to the two experiments above.

How Yamanaka factors reverse damage

In the case of the crushed optic nerve in an adult mouse, what's going on here?

Remember how the Yamanaka factors are heavily expressed during embryonic development?

This is a period of rapid cell growth and specialization.

It turns out that with the three factors, rebuilding is not any different from building.

I.e… rebuilding an optic nerve (or spinal column or islet cell, etc) is the same as rebuilding a crushed one!

Keep in mind that once built, there's no repair possible in mammals.

A crushed optic nerve is blindness for life. The genes that are turned on (via epigenetic clock) for the initial build are turned off forever.

Till now.

Essentially, the cells are reset to this state but they still know how to be optic nerves.

Very important as you don't want undifferentiated tumors!

Here's the picture of the before and after optic nerve.

https://www.nature.com/articles/d41586-020-03119-1

The net effect?

The mice were able to see again!

This also occurred with older mice who lost their vision due to age-related issues.

We'll see studies similar across every pathway since the damage is seen throughout the body based on this same mechanism (albeit, in a slow, accumulating fashion)...

What about aging in general?

How Yamanaka factors reverses aging

What about the rest of the body?

The optic nerve is just so much more telling since this tissue isn't able to repair at all generally.

If you did deeper, it's really a question of sub-optimal gene activation.

Remember the associations with aging we mentioned above?

Vitamin D production? Steroidal hormone production? Immune production?

All of these are controlled by the control mechanism we described above.

What Sinclair's research is showing is that these deficiencies arise from errors in gene expression control.

And the Yamanaka Factors (3 of them) reset this control. A reboot if you will….of the software.

Now explode this effect across every pathway in the body.

Let's take an example to show how all these systems are inter-related.

Think of serotonin. Our so-called "feel-good' hormone.

It's so much more than that!

In fact, serotonin is a master regulator of all human behavior. Just check out the review on serotonin.

• Too little serotonin - depression, risk-taking, poor self-esteem, anxiety, etc
• Too much serotonin - irritation, mood disorders, suicidal and homicidal ideation?

Yes.

That's called serotonin syndrome and it's deadly.

It's one of the reasons we geek out on CBD since research shows that CBD helps to support serotonin function when depleted (from stress, pain, trauma, etc) but not push it over the way an SSRI can.

Here's where it gets interesting.

Estrogen directly drives serotonin function! And estrogen drops off a cliff late 40's for women.

Estrogen also drives acetylcholine which is becoming the linchpin for dementia (see acetylcholine).

That's downstream from serotonin.

Upstream, serotonin drives BDNF, our brain's fertilizer.

Look...BDNF may be the most underrated pathway in the brain.

• Why is exercise and mindful meditation good for the brain? BDNF
• What drives the incredible results of psilocybin? BDNF
• How does CBD help with depression? BDNF

Every mental health issue we covered fell back on BDNF.

The two biggest triggers for drug addiction relapse?

Stress and…reduced BDNF levels.

Goodness.

So...when control starts to wind down estrogen production (most likely further upstream with pregnenolone...the mother of all steroidal hormones), you lose serotonin (mood) and BDNF (brain repair and neurogenesis).

• With serotonin loss, there goes stress response, pain control, and gut function.
• With BDNF loss, there goes brain connectivity (depression) and mood control (hippocampus loss).

Men...you're not off the hook! The male brain is seat to a lot of aromatase which converts testosterone to estrogen for these same effects! See our monster review of testosterone.

But hey...when your doctor says your hormones are fine for your age, sure...that makes sense.

See how just one pathway can have such powerful effects?

Now magnify this by everything that's controlled by gene expression...which is everything.

That's aging!

What will be really interesting is to see if steroidal hormones come back online with future experiments.

Keep in mind that a 20-year-old body is turning different genes on and off versus a 50-year-old body.

The right genes!

If everything we've read is correct, the Yamaka factors and Dr. Sinclair's discovery resets this control.

We'll know in the next few years but don't say we didn't warn you just how monumental this discovery is.

Until that's available, what can we do again?

Other longevity tools till we Yamanaka factors are available

We have a deep dive on CBD and longevity which goes into other key tools.

A quick synopsis:

• Metformin and/or berberine - powerful supporters of AMPK - a cellular efficiency housekeeping pathway (key to fasting, keto, cold exposure, etc)
• Quercetin/Fisetin - supports mTOR and removal of senescent "zombie" cells
• CBD - calms inflammation tied to aging; supports mitochondria function; reduces oxidative stress
• NMN or NAD - supports mitochondrial energy production and cellular function
• NAC - support glutathione and detox system
• Methylated B vitamins - supports the unpacking/packing control system mentioned above
• Pterostilbene - powerful SIRT player
• Intro to rapamycin - the gold standard of longevity

That's a shortlist but you learn all about it at our longevity review.

Otherwise, we look forward to adding the results of studies coming which center around Dr. Sinclair's work on the Yamanaka factors.

Be well. Take care of each other. Take care of yourself.

Related Research:

AMPK guide

Is psilocybin a mini-Yamanaka factor editor?

CBD and SIRT for epigenetic editing

Rewrite your mental health past

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.