Pterostilbene and Epigenetics - the SIRT Connection for Longevity

April 9, 2022

There are very few pathways with real research supporting longevity gains in both stopping and perhaps reversing aging.

Aside from the breathtaking Yamanaka (OSK) revolution (and it is that!)....

We have the energy sensor complex (AMPK, mTOR, etc).

The work on senescent cells has potential as well.

One of the biggest real prospects is around cellular shock proteins. Ancient proteins (shared across life) that are tasked with responding to adversity.

This still speaks to AMPK to some extent but accessing the components of this process may be a bridge till Yamanaka comes online.

This begs a question….are there options that act similarly to Yamanaka?

We looked at psilocybin and epigenetic changes here.

What about the powerful SIRT family and pterostilbene specifically?

That's where we're going with these topics:

The epigenetic landscape of longevity ushered in with the Yamanaka factor
SIRT's epigenetic pathway and longevity
Pterostilbene as the best way to access SIRT

Let's get started. We have histones to modify!

The epigenetic landscape of longevity ushered in with the Yamanaka factor

We have a review on Yamanaka here but a quick recap with the lens for what we'll discuss below.

Yamanaka factors speak to the series of enzymes discovered which can return any cell back into a pluripotent stem cell.

This was groundbreaking roughly 20 years ago but the real magic happened in 2018.

The problem is that reversing completely back to the original stem cell makes these cells useless to release back into our living bodies.

They essentially become a mass of tissue…a tumor of sorts.

There's no differentiation (skin cell, heart cell, etc).

The genius was when the 4th factor was left off and only OSK was applied.

In this case, the cell returned back to a juvenile or youthful state but retained its identity.

With that setup, researchers were able to repair (regrow actually) a crushed optic nerve and return sight to blind (due to age) mice.

They have since applied it to the full body of a mouse with startling results.

Okay…that's the setup but let's dig deeper.

The current theory is that aging is an accumulation of "markups" to our epigenome, the layer that turns our DNA on and off.

DNA is the hardware. The epigenome is the software and this software changes with time due to the influence of the environment (trauma, stress, exercise, fasting, etc).

The Yamanaka reset is to the epigenome!

So…what exactly is being reset?

The current thought is that the "markups" occur via a series of different pathways that "adjust" the reading of our DNA.

Methylation
Acetylation
Glycation

Those are the big ones but there are others.

Methyl groups can be added to certain areas of the DNA to affect how genes are read (how long, how often, if at all, etc).

Acetylation is a different form of editing.

Glycation is our favorite choice. It's essentially damage from glucose (see the problem with sugar or our review on carnosine).

Our DNA is spooled into a tight compact which when stretched out, would be about 6 feet long.

That all fits into the nucleus of a cell.

We have an entire complex that is tasked with unwinding and winding up this spool so that certain genes can be accessed and read to make proteins and more.

It's thought that aging is the modification of this process to where it's not as efficient or correct as accumulating "markups" grow.

The Yamanaka OSK process strips away the markups. Back to square one!

Aging is an accumulation of these markups according to set degradation or damage.

We looked at psilocybin and its fascinating effects on the epigenome as a way to explain how one course can have profound and lifelong effects.

Let's now dive into the SIRT pathway to see if we have another one!

SIRT's epigenetic pathway and longevity

Sirtuin's are fascinating.

We'll skip the usual anti-inflammatory and antioxidant effects since those have been studied across different supplements and don't directly drive longevity with much success.

We want to focus on the epigenetic effects since that is where everything is going after the Yamanaka revolution.

So…what are the sirtuin's in that perspective?

Sirtuins are NAD+-dependent histone deacetylases (HDACs) known to regulate metabolic homeostasis, chromatin structure and DNA repair thereby regulating genomic stability.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5104590/

Okay…so there's the NAD connection. NAD and its many varieties are popular supplements in the longevity space and they just so happen to be necessary for SIRT to work properly.

In fact, SIRT's effects drop without the presence of NAD so combining the two is important.

The second piece is more fascinating.

"Histone deacetylase"

Translation…it removes the acetyl "markups" to our epigenome!

That's just the beginning….it turns out that the SIRT family is a powerhouse of histone (epigenetic) management:

Sirtuins regulate many aspects of chromatin biology, such as transcription, recombination, and genome stability, by modifying histones, transcription factors, and epigenetic enzymes.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4610301/

Newer studies are slowly teasing out these effects such as this one:

SIRT1/2-mediated gains of methylation concur with decreases in activating histone marks, and their inhibition revert these histone marks to resemble an open chromatin.

https://academic.oup.com/nar/article/48/2/665/5651320

Let's break that down.

Essentially, they exposed cells to bacterial signatures (LPS) and watched how SIRT activation affected inflammation.

SIRT blocked the "markup" that would normally result (essentially upregulating inflammation longer term). The SIRT effect "closed" the DNA bundle so it was less "edited".

Our interest is more in removing existing markups that constitute aging (and maybe even the imprint of past trauma!!).

There's a laundry list of this "de" editing:

The different activities of SIRT1–3 (class I, mainly deacetylation but can also remove long chain fatty acyl groups), SIRT5 (class III, desuccinylation, demalonylation, deglutarylation), and SIRT6 (class IV, more efficient at defatty-acylation but can also remove acetyl)

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4610301/

These are all different types of "edits" that happen after the fact…meaning…not coded directly into our DNA.

This…is…the…epigenome!

The current theory is that Yamanaka removes all these post-edits back to the original copy.

SIRT appears to have a similar role but with less vigor…discount Yamanaka.

NAD levels decrease as we age (we blame glucose and glycation) and so as a result…SIRT does as well. Remember, SIRT is NAD dependent.

So…how does this translate out to longevity studies?

First, you can tie many of the other current tools to SIRT such as:

Calorie restriction induces an oxidative metabolic state manifested in high NAD+ levels and, consequently, high Sirtuin activity.

https://www.cell.com/cell/pdfExtended/S0092-8674(16)31000-5

AMPK and mTOR are energy sensors (times of abundance versus times of difficulty).

SIRT carries out the epigenomic changes as part of this energy complex's directive per NAD signaling.

After all…NAD is the lowest common denominator and simplest signal for energy (just above ATP).

So that's metformin, berberine, rapamycin.

A new study looked at SIRT1 gene variants found the following:

We observed a significant increase in the SIRT1 level in older people and found a significant positive correlation between SIRT1 level and age in the overall studied population.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4365019/

More SIRT1 = longer life and less age-related disease. Even when other factors like oxidative stress, etc were taken into account.

Alright. So how do we directly target SIRT?

Pterostilbene as the best way to access SIRT

We mentioned that AMPK, mTOR, and other tools all drive SIRT.

There are two known ways to target it directly:

Resveratrol
Pterostilbene

Resveratrol, from red wine fame, is the original player in this space.

Pterostilbene is the new entrant as a naturally-derived analog for resveratrol and the difference is stark:

Results: Resveratrol and pterostilbene were approximately 20 and 80% bioavailable, respectively.

https://pubmed.ncbi.nlm.nih.gov/21116625/

Resveratrol just doesn't make it past the gut very well.

Pterostilbene has 4 times the bioavailability from oral supplementation!

As for safety:

There were no adverse drug reactions (ADRs) on hepatic, renal, or glucose markers based on biochemical analysis. There were no statistically significant self-reported or major ADRs. Conclusion. Pterostilbene is generally safe for use in humans up to 250 mg/day.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3575612

We love all the downstream pathways affected but we're after Yamanaka trickery till Altos Labs and the bunch bring out new options.

This is next-gen and we're on the search for epigenetic cleansing!

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