CBD and SIRT Study - Key to Longevity?

CBD and SIRT for Longevity

 

We've covered CBD as part of our longevity toolkit and even went deeper into other key areas of current research: 

 

A recent study looked at CBD and found fascinating results in the SIRT pathway with an effect of protecting neurons. This is similar to other studies on Parkinson's (see CBD and Parkinson's) but with new advances in technology, they can really pinpoint the pathways affected.

 

SIRT is one of the few bright spots in real longevity tech till Yamanaka comes online

 

We'll get into that below.

 

While there, let's also cover the key longevity pathways that CBD directly impacts.

 

This result is not surprising to us since CBD's general effect is to support the endocannabinoids system which is tasked with balancing every other key system.

 

Here are the topics we'll cover: 

  • A quick lay of the longevity landscape
  • The rise of SIRT pathways for aging
  • CBD and SIRT
  • CBD and other pathways (AMPK, mTOR, mitochondria, inflammaging, oxidative stress, etc)

 

Let's get started! 

A quick lay of the longevity landscape 

The longevity space is full of marketing and misleading statements.

 

It's also exploding in raw research and advances which is unprecedented.

 

Segments of legitimacy are also emerging such as the ITP (Intervention Testing Protocol) which tests promising strategies across three different sites with the required protections in testing design.

 

Many promising substances in animals studies (and marketing) are not meeting the measure when tested this way.

 

Anti-oxidants? Not so great. (aside from glutathione). Senolytics (remove so-called "zombie" cells)? Meh.

 

Some potential stars do appear with surprises as well (aspririn, estrogen, etc).

 

Here are the current pathways that are most exciting: 

  • mTOR - rapamycin and other mTOR inhibitors appear to really move the dial
  • SIRT - a cellular shock protein tied to resveratrol, pterostilbene, etc
  • AMPK - an energy sensor tied to calorie restriction, intermittent fasting, cold/heat exposure
  • AGEs - Advanced Glycation End-products - the damage of sugar

 

What's interesting is that these all surround…metabolism!

 

  • mTOR deals with protein (or the lack thereof)
  • SIRT does the heavy lifting for AMPK
  • AMPK senses periods of drought, famine, etc
  • AGEs reflect too much glucose and/or carbs (just a different storage of glucose)

 

We'll look at how CBD affects these pathways directly.

 

Let's turn our attention to the new research surrounding SIRT. What is SIRT? 

The rise of SIRT pathways for aging 

Sirt is short for sirtuin and this whole longevity pathway gained recognition with resveratrol. You remember the whole red wine buzz!

 

SIRT is intimately tied to AMPK which the body uses to determine energy needs.

 

AMPK is triggered when energy is running low and it forces the body into a housekeeping mode versus a pro-growth (think reproduction) mode.

 

There's a range of positive health effects from this with clear indications for aging.

 

The MILES study with metformin really opened people's eyes as it showed a reversal in epigenetic aging.

 

As Dr. Sinclair is known to say, people with diabetes on metformin were living longer than people without diabetes who do not take metformin.

 

More info is needed and newer updates show the longevity issues may actually come from keeping glucose under check (see carnosine or the problem with sugar).

 

Berberine is a natural analog for metformin but SIRT is downstream from this umbrella "systemic" manager.

 

In fact, AMPK, mTOR, and SIRT are all connected: 

In particular, mTOR, AMPK, and sirtuins are known to play an essential role in the management of metabolic stress and energy balance in mammals. 

https://biosignaling.biomedcentral.com/articles/10.1186/s12964-021-00706-1

 

As for SIRT, it actually carries out the orders and maybe the epigenetic power player.

 

This is important…the new Yamanaka factor push is going to revolutionize longevity. As in reverse it!

 

That's the basic thrust behind Altos Labs (Bezos) and others with billions of dollars behind them.

 

We covered Yamanaka here.

 

A quick primer is required as we get into SIRT.

 

The epigenome is the layer of instructions that sits atop our DNA. It controls which genes, how long, and when they are turned on.

 

Think of the bass/mid/treble dials on a stereo where you can increase or decrease levels. The underlying song is the same but it sounds much different depending on how you adjust these dials.

 

The Yamanaka studies are showing that our epigenome gets "marked up" as we age and by removing this edit, we can reverse cells back to an original, young state.

 

This is groundbreaking!

 

Another way to do this is with chemical pathways that remove these edits called HDACs, demethylases, and deglycation pathways.

 

These all remove different types of edits from our epigenome: 

  • Acetyl markers (HDACs)
  • Methyl markers
  • Glycation (glucose) markers

 

So…why the chemistry walk-through?

 

The role of SIRT1 in epigenetics is achieved via several different mechanisms, such as regulating chromatin structure by histone deacetylation, regulating the activity of transcription factors by deacetylation, and regulating the activity of other epigenetic enzymes by deacetylation 

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

 

Okay…so to translate.

 

SIRT manages our DNA read-out via…histone deacetylation (HDAC)

 

This is the removal of "mark-ups" to our epigenome that works like a discount version of Yamanaka factors (which strip everything back to zero).

 

SIRT is incredibly dependent on NAD (energy source) to function which is likely the tie with NAD, NMN, NR, and the entire swaft of longevity tools being marketed.

 

NAD decreases as we get older.

 

Do we see this whole epigenetic effect in actual longevity studies?

 

First, a look at gene variants (more or less SIRT activity naturally): 

The oldest people carrying AG genotypes for rs7895833 have the highest SIRT1 level suggesting an association between rs7895833 SNP and lifespan longevity. 

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

 

A look at mice analyzed glucose and energy function since metabolism is at the heart of longevity: 

To mediate these changes, mechanistically, SIRT6 increases hepatic gluconeogenic gene expression, de novo NAD+ synthesis, and systemically enhances glycerol release from adipose tissue. These findings show that SIRT6 optimizes energy homeostasis in old age to delay frailty and preserve healthy aging. 

https://www.nature.com/articles/s41467-021-23545-7

 

The key comes back to editing our epigenome from the markups of aging: 

Sirtuins participate in the epigenetic modifications related to aging. 

https://www.sciencedirect.com/science/article/pii/S1568163717300065

 

Okay…so on to CBD and SIRT. 

CBD and SIRT 

So…where does CBD fall in this pathway?

 

Early studies on Parkinson's teased out a connection a few years back.

 

The study looked at how CBD protected neurons from the ravages of Parkinson's: 

Further mechanistic investigation showed that Cannabidiol induced SH-SY5Y cells autophagy to protects cells from mitochondrial dysfunction by upregulating SIRT1 to Inhibits NF-κB and NOTCH Pathways. 

https://www.frontiersin.org/articles/10.3389/fncel.2021.654340/full

 

Let's translate, please.

 

Essentially, CBD supported the removal of faulty cells (the immune system controls this) by ramping up…SIRT!

 

In doing so, key inflammatory pathways were slowed down.

 

The net net…

 

  • Taken together, Cannabidiol acts as a protector in PD.
  • PD is Parkinson's Disease.

 

That was the teaser. The new study is even more telling.

 

From GeroScience (aging-related publication), the title: 

Cannabidiol induces autophagy and improves neuronal health associated with SIRT1 mediated longevity 

https://link.springer.com/article/10.1007/s11357-022-00559-7

 

First, what is autophagy?

 

It's the removal of faulty cells. This is the entire "senolytics" wing of longevity research.

 

The new study on CBD and SIRT

The new studies are so much more sophisticated!

 

They can dive down into what pathways are actually working by turning genes on and off. 

 

cbd and sirt longevity

https://link.springer.com/article/10.1007/s11357-022-00559-7

 

 In addition, a range of improvements on "healthspan" were also present.  This matters!  Both quantity AND quality.

 

So...what's driving this effect from CBD?  

 

This study found that CBD's positive effects in animal studies for longevity were dependent on autophagy genes.

 

CBD-mediated lifespan extension was dependent on autophagy genes (bec-1, vps-34, and sqst-1) confirmed by RNAi knockdown experiments.

 

CBD was shown to block aberrations in neurons that accumulate with aging.

 

The critical piece there??

 

Further investigation demonstrated that CBD-induced lifespan extension and increased neuronal health require sir-2.1/SIRT1. 

https://link.springer.com/article/10.1007/s11357-022-00559-7

 

This puts CBD up with resveratrol and pterostilbene (both drive SIRT) with many other positive effects across the body and brain.

 

Check out the study...they really go into the "weeds" (pardone) of CBD's effects and pathways that drive this.  

 

What's fascinating is that CBD does not work in one direction. It supports the endocannabinoid system which is tasked with balancing other systems.

 

For example, CBD can have opposite effects on cancer cells…effects that essentially make it more difficult for them to survive and spread.

 

See CBD and cancer but a quick look specific to sirt.

 

In neuroblastomas, CBD led to a reduction in sirt function: 

Upregulation of hsa-mir-1972 caused decreased expression of BCL2L1 and SIRT2 genes. Together, our studies suggest that CBD-mediated apoptosis in NBL cells is regulated by miRNA. 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6343753/

 

CBD would lead to death (autophagy) of the cancerous cells and…

 

CBD also significantly reduced NBL cell migration and invasion in vitro. 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6343753/

 

Fascinating.

 

So upregulating sirt to protect or preserve healthy cells/neurons but block it in cancerous cells.

 

This really is the beauty of working within the endocannabinoid system in a feedback mechanism.

 

THC pushes in one direction (too long and too strong at CB1 receptor) so the body actually builds tolerance and pushes the other way long term.

 

CBD does not have this effect (see CBD versus THC).

 

We look forward to more studies. What about the other key longevity systems? 

CBD and other pathways (AMPK, mTOR, mitochondria, inflammaging, oxidative stress, etc) 

As we mentioned, all of the main longevity pathways are tied to metabolism. Let's take a quick look at how CBD affects them.

 

CBD and AMPK for longevity

 

AMPK is a master energy sensor with ties to: 

  • Metformin and Berberine
  • Calorie restriction
  • Intermittent fasting
  • Hot and Cold exposure

 

The interaction between AMPK (an ancient, evolutionarily conserved pathway) and the endocannabinoid system (dating back about 600M years) is just getting teased out.

 

There's a clear connection: 

Cannabinoids increase AMP-activated protein kinase (AMPK) enzyme activity in the hypothalamus and heart via different signaling pathways – studies in CB1 knockout animals


https://www.endocrine-abstracts.org/ea/0011/ea0011oc25

 

CBD supports CB1 activity when low (feedback mechanism).

 


Since AMPK is triggered as a response to metabolic stress and the endocannabinoid system is tasked with homeostasis (rebalancing following stress), we look forward to more research.

 

Big review on AMPK here.

 

What about the partner in crime, mTOR? 

CBD and mTOR for longevity 

Most of the research is on CBD increasing mTOR when downregulated due to diseases such as: 

Our results showed a clear downregulation of the PI3K/Akt/mTOR pathway following EAE induction. CBD treatment was able to restore it, increasing significantly the phosphorylation of PI3K, Akt and mTOR. 

https://pubmed.ncbi.nlm.nih.gov/27890794/

 

EAE is an animal proxy for MS.

 

We don't have research on reducing mTOR like rapamycin which seems to be the most prominent approach for now.

 

Sticking with the energy complex. 

CBD and mitochondria for longevity 

CBD is a powerful antioxidant but the relationship with mitochondria goes much deeper.

 

In fact…CBD is all over the energy production complex: 

Recently, CBD has been found to regulate intracellular and mitochondrial calcium concentrations [20], mitochondria-mediated intrinsic apoptosis [21], mitochondrial DNA epigenetics [22], mitochondrial ferritin concentrations [22], electron transport chain activity [23], mitochondrial biogenesis [24], and mitochondrial network dynamics 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8159073/

 

It can even disrupt this in faulty (cancerous or virally infected cells).

 

Cannabidiol directly targets mitochondria and disturbs calcium homeostasis in acute lymphoblastic leukemia


https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6791884/

 

At the heart of AMPK is sensing this energy complex. This is the NAD, NMN, etc longevity toolkit.

 

Check out CBD and mitochondria here.

 

Let's turn to inflammation. 

CBD and inflammaging for longevity 

CBD has powerful effects on the immune system which governs inflammation.

 

A study looked at how CBD would impact the inflammation profile over the lifespan with interesting results: 

Similar to other model systems, control aged zebrafish exhibited increased kyphosis as well as increased expression markers of senescence, and inflammation (p16ink4ab, tnfα, il1b, il6, and pparγ) in the liver. Exposure to CBD significantly reduced the expression of several of these genes in a dose-dependent manner relative to the age-matched controls 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7205952/

 

Read that back over. It's too important.

 

Essentially, inflammatory signals increase as we get older (inflammaging) and CBD reduced these pathways at the genetic (epigenetic really) level.

 

Okay…what about general studies on longevity?

 

So…c elegans (the guinea pig of longevity studies) first.

 

Notably, whole-life exposure of C. elegans to 10-100 μM CBD revealed a maximum life extension of 18% observed at 40 μM CBD. In addition, motility analysis of the same groups revealed an increase in late-stage life activity by up to 206% compared to controls. 

https://pubmed.ncbi.nlm.nih.gov/33998871/

 

We look forward to further studies but the new SIRT research clearly indicates a need for further investigation on CBD and longevity.

 

Learn more here:

AMPK pathways for longevity

CBD and tools for longevity

Yamanaka factor research and longevity

Pterostilbene and SIRT

Psilocybin and epigenetic "markup"

Steroidal hormones and longevity

 

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