The Toolkit for Longevity till CRSPR Comes Online

by Indigo Naturals January 07, 2021

We're not ones for fancy fleets of fantasy.

The 1 million+ words we have on CBD research should attest to that.

Turning our attention to longevity (living longer and better) is finally ready for prime time.

There have been major leaps in our understanding of the aging mechanism but more importantly, how to slow or even reverse it.

This is real science. Hard science. Fascinating science.

As we mentioned in the title, this will be a waystation still CRSPR comes fully on board.

We give that 5-8 years based on current progress and we'll explain why it's revolutionary below.

Our interest really jumped when studies showed that simple steps could reverse signs of biological aging in humans! We'll get into that below.

This can get technical but we'll try to translate it down as best as we can.

We're skipping the "what is aging" generalities and treating this more like a current handbook of new advances we can take advantage of.

Here are the major topics we'll cover:

A quick summary of new advances in longevity
The AMPK and mTOR pathways
Removal of senescent (zombie) cells
Hormones and aging (DHEA, pregnenolone, estrogen, progesterone, testosterone, and yes...melatonin)
The aging immune system - perhaps a first shoe to drop
Methylation and aging
Mitochondria as the linchpin of aging
Is Vitamin D the driving factor for longevity?
The case for CBD and longevity
The coming CRSPR revolution for aging

In each section, we'll cover available tools (right now) to support the pathways.

Let's get started.

A quick summary of new advances in longevity

There's been anti-aging quackery since the dawn of time.

For that reason, we tend to disregard much that smacks of longevity.

Until the MILES study.

Essentially, researchers looked at metformin, a common diabetes medication, and its effect on key measurements of aging.

They found metformin slowed down the aging process and even reversed key benchmarks.

This effect accelerated in the last 3 months of the yearlong study.

We did a huge review on metformin (and berberine - it's a natural analog) to dig deeper into what was going on.

It's all about stimulating powerful and ancient pathways in our body designed for harsh times.

AMPK and mTOR. More on that below.

This leads us to research other powerful players in those pathways and you'll find them below.

Then, new research started to come fast and furious.

Senescent cells - broken cells that don't quite die and leak inflammation into surrounding tissue
Powerful effects of retreating hormones from the usual suspects like estrogen and testosterone to further upriver like DHEA and pregnenolone.
New research on whether the immune system is the first to go setting off a cascade of aging effects. We'll look at the thymus as a master controller.
New advances in genetics are shown that there's a layer above our genes that is quite different between old and young bodies - epigenetics and methylation
The little powerful plants of our cells - mitochondria - may be first to leave the party (youth)
Finally, Vitamin D. All life is tied to the sun on our planet and our link to it may falter early in the process

We're going to get into all of this with a final look at the promise of CRSPR.

It's the biggest revolution since...the computer. Maybe electricity.

As for longevity, it's the long sought after the fountain of youth (and pain control and mental health and...just about everything).

We just gave a sampling of the new advances….let's dig into it further with an eye on how to turn back the clock.

The AMPK and mTOR pathways

Cold. Heat. Starvation. Thirst. Any shock to the system really.

We have an ancient system in our bodies which is designed to turn on when things get rough.

It's the connecting piece behind so many different efforts to slow aging:

Coldwater exposure
Exercise
Fasting
Keto diet
Calorie restriction
Sirtuins, resveratrol, and rapamycin

We have to go back a few 1000 if not 10's of thousands of years to understand what's going on here.

The body, like it or not, is all about reproduction.

Our selfish genes.

In times when things are very harsh (drought, heatwave, cold waves, famine, etc), the body switches modes from a pro-growth, reproduce bent to a much more efficient, way and see function.

AMPK formally ramps up our cellular housekeeping to last through the current period of threat so we can survive to the other side and...reproduce!

Unfortunately, it's that simplistic.

This causes a whole cascade of effects within the body that literally slows down aging.

It's a form of cellular hibernation for our bodies and brains. A state of stasis and maximum efficiency.

The MILE study found that metformin was able to elicit a powerful AMPK response and that is what drove its anti-aging effects.

Check out our massive review on metformin to learn more.

You may ask...why would a diabetes drug affect AMPK and aging?

As part of AMPK's tightening of the ship, our metabolism (energy, fat, etc) is ratcheted up to be more efficient.

Again, we may not eat for weeks!! At least, that's what AMPK is anticipating.

This naturally affects sugar, fat, and insulin which happen to be intimately tied to diabetes as a result of quite the opposite of famine...too much fat and caloric intake.

Of course, metformin is not the only substance to do this!

We investigated the following as well:

Berberine - most close alternative to metformin
Curcumin
Exercise
Vitamin D

We have a full review on berberine since it's primary role is via AMPK and gut barrier support.

Curcumin from a study of weight gain due to antipsychotics:

We further demonstrated that CUR appears to be a novel AMP-activated protein kinase (AMPK) agonist,

https://www.n cbi.nlm.nih.gov/pmc/articles/PMC5632657/

Exercise:

Resistance exercise increases AMPK activity and reduces 4E-BP1 phosphorylation and protein synthesis in human skeletal muscle

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1890364/

Believe it or not, the body sees exercise as stress or hardship and responds accordingly!

Finally, Vitamin D:

the observed effect of vitamin D on muscle fat accumulation and mRNA levels involved in mitochondrial biogenesis and function with AMPK/SIRT1 activation may demonstrate the beneficial effect of vitamin D on obesity and its associated metabolic disorders.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6893473/

You're going to see Vitamin D over and over in this study. It's the most underrated thing you can do for health and longevity right now.

Removal of senescent (zombie) cells

mTOR is a pathway that governs the delicate balance of cell inventory.

We are constantly changing our cells as they go bad.

Yes, errors accumulate in cells primarily in the DNA coding of various structures within and the little power plants, the mitochondria.

There are signals that cells are starting to err and the immune system then destroys them.

This is the role of mTOR to keep our cellular stock healthy and in balance.

Cancer is a primary example of when this oversight goes wrong.

As for aging, there's another interesting aspect that's just starting to be researched.

Senescent cells.

These are cells that are clearly malfunctioning but for some reason, are being recalled.

The issue is that these "zombie" cells continue to leak out inflammatory and broken machinery to their surrounding neighborhood.

Despite the cell cycle arrest, the senescent cells remain metabolically active. It is known that senescent cells can secrete various pro-inflammatory cytokines, chemokines, growth factors and proteases.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4113516/

The tie-in with aging?

The use of such methods has provided convincing evidence that senescent cells indeed accumulate in tissues of humans, primates, and rodents with age

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4214092/

Cellular clutter and garbage builds as we age with very negative effects.

All the above studies suggest that rapamycin treatment, which decreases the activity of mTOR, can decelerate cellular senescence caused by different stimuli.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4113516/

That's all about slowing down the process of creating zombie cells.

In fact, new advances are looking at removing senescent cells to stop or reverse aging.

These are called senolynics and have become a powerful new weapon against aging.

We did a major review of Fisetin which is one of the best and safest senolytics available.

According to these results, fisetin is able to destroy 25-50% of senescent cells, depending on the tissue/organ type on which it is tested.

https://www.lifespan.io/news/fisetin-clears-senescent-cell/#

It had comparable effects to the chemo drug used in the MILES study but with a much safer profile. It's also a powerful antioxidant.

A brand new study just came out on hyperbaric pressure and oxygen treatment for aging.

The primary pathway?

Focusing on immune cells containing DNA obtained from the participants' blood, the study discovered a lengthening of up to 38% of the telomeres, as well as a decrease of up to 37% in the presence of senescent cells.

https://www.sciencedaily.com/releases/2020/11/201120150728.htm

Telomeres are the end caps of our DNA whose lengths have long been tied to aging.

That's last century's news...we're more excited by the 37% reduction in senescent cells.

Remember how we said the immune system might be where aging starts!

So for now with senescent cells:

Fisetin
Hyperbaric/oxygen treatment
Let's turn to hormones.

Hormones and aging (DHEA, pregnenolone, estrogen, progesterone, testosterone, and yes...melatonin)

First, the steroidal hormones. Estrogen. Progesterone. Testosterone.

These hormones are not just for reproduction. They are intricately threaded through almost every aspect of our body.

We did huge reviews on estrogen and progesterone since they drop off and directly affect everything.

Just a sampling:

Estrogen drives serotonin which drives BDNF, our brain's fertilizer
Progesterone and estrogen shape the heartbeat directly
Testosterone fosters growth in muscle, tendons, ligaments, and just about everything.

Look at the brain:

Concerning cognitive function, T supplementation has positive effects on verbal, spatial63 –65 and working memory,66 visuospatial function,67 –69 and executive function

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4116364/

Here's the deal...the body and brain are in a constant tug-of-war between damage (stress, injury, daily wear, and tear, etc) and repair.

The steroidal hormones are needed to support the repair and growth side.

In fact, some of the main symptoms from loss of estrogen at perimenopause reflect atrophy of key tissue in the body.

Atrophy is literally the loss or shrinking of mass. That's not good in the brain (see CBD and dementia or CBD and perimenopause brain fog).

As we age, our steroidal hormones drop naturally.

Progesterone drops by 50% at age 40
Estrogen falls off a cliff around age 47-50
Testosterone slowly declines starting in the early '20s

Supporting these pathways with bioidentical (very important) hormones is essential.

We can actually look upstream in the hormonal milieu to help here.

There are two key players with a third bonus

Pregnenolone - the mother of all steroidal hormones
DHEA - a key building block for hormone cascade
Melatonin - known for sleep but with a finger on the aging trigger

All of these can be supplements but let's look at the connection with aging for each.

We'll focus on the brain since every pathway of the body (bone, heart, liver, muscle, etc) is dependent on steroidal hormones.

Pregnenolone - Preg is where it all starts. It's made from cholesterol (the so-called "bad cholesterol" LDL).

All your steroidal hormones (dozens) start with preg.

The interest started with animal studies...aged animals to be specific.

Such as…

The above, together with the findings that DHEA acted even when given at 1 hr after training and that P, PS, and DHEA improved retention over a much wider dose range than do excitatory memory enhancers

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC48493/

Memory sits in the hippocampus...one of our brain's most dynamic and as a result, vulnerable areas.

It's also one of the few places where extensive neurogenesis (brain growth) can occur.

Check out CBD and hippocampus neurogenesis or CBD and brain repair to learn more.

We have a whole review on pregnenolone here. Very fascinating.

DHEA actually is the next step in the cycle as it's made from pregnenolone.

Ever wonder why it gets harder to sleep as we age?

DHEA is a big reason why.

Here's the quick synopsis.

DHEA is made by the adrenal glands and it pulses with greater release at night.

Another hormone governs this release and as we age, it stops regulating the pulses of DHEA.

Cortisol (our stress and "awake" hormone) however continues unabashed.

Most people think of DHEA as being stimulatory (it can be) but it's also critical for sleep!

A specific and very important type of sleep:

DHEA administration increases rapid eye movement sleep and EEG power in the sigma frequency range

https://pubmed.ncbi.nlm.nih.gov/7840167/

This is just one aspect as DHEA requires a full review but sleep quality for longevity is not in doubt.

Finally, intimately tied to DHEA and sleep quality.

Melatonin.

It's not just about sleep and managing our biological clocks.

Scientists transplanted pineal gland tissue (where melatonin is made) from younger mice to older mice and prolonged their life.

https://www.sciencedirect.com/science/article/pii/S0005272806000673

The "lifespan" clock is also affected by dropping levels of melatonin.

Animal studies were the first to point to this with shrews and signs of aging:

By continuously administering melatonin, starting a little before 12 months, the appearance of these first signs was delayed by at least 3 months, which is a considerable period in relation to the lifespan of this shrew*.

https://www.sciencedaily.com/releases/2009/06/090622064807.htm

We've all heard how caloric intake extends life.

Look at the interesting connection between this and melatonin?

These findings, coupled with previous observations in humans, suggest that peak plasma melatonin levels may represent a possible candidate “biomarker of aging” in primates. Moreover, this index of age-associated physiological decrement seems to be inhibited by dietary CR.

https://academic.oup.com/jcem/article/86/7/3292/2848966

Two important takeaways:

Reduced caloric intake increases melatonin levels
Melatonin levels are a tell-tale sign of biological age

We can spend all day on hormones but the key takeaway is that they drop as we age and much to our chagrin.

Let's turn to the new kid on the longevity block.

The aging immune system - perhaps a first shoe to drop

Much of the new research on longevity focuses on the thymus.

The what?

It's a small gland right behind the breastplate and just below the little u-shaped indention at the top.

The thymus is a key hub in the immune system.

The new hot topic is thymus involution...literally the withering or shrinking of this organ.

In fact, one of the markers to look for with longevity is the preservation or strengthening of this organ.

This deterioration is one key driver of increased, chronic inflammation.

Inflammation is clearly under the wings of our immune system and if left unchecked, it's one of the key attributes of aging:

Most older individuals develop inflammageing, a condition characterized by elevated levels of blood inflammatory markers that carries high susceptibility to chronic morbidity, disability, frailty, and premature death.

https://www.nature.com/articles/s41569-018-0064-2

This is where the host of anti-inflammatory agents are incredibly important including the following:

CBD - a known powerhouse of immune response balancing
Curcumin - powerful anti-inflammatory
Berberine - calms gut where inflammation starts
NAC - supports detox system - glutathione
Fisetin - powerful anti-inflammatory and key to mTOR above
PEA - supports endocannabinoid system - key player in inflammation response
Vitamin D - the critical piece in immune response balance
Exercise and Mindful Meditation
Progesterone (for women) - the hormonal lever for calming immune response

We've covered the role of inflammation in-depth at different reviews

A study on metformin, human growth hormone, and DHEA were able to reverse thymic involution.

https://onlinelibrary.wiley.com/doi/full/10.1111/acel.13028

Let's turn our attention to the genes now. Actually, the layer on top of the genes.

Methylation and aging

What on earth is methylation?

It's the turning on and off of genes essentially.

Our genes are hard-wired but there's an active layer that responds to the environment and actually turns genes on and off.

What's interesting is that new research is showing that the difference between your 50-year-old and your 20-year-old body is the sequence and rate of this upstream firing.

This is called epigenetics and it may be the key to aging (and reversal):

As the aging process is associated with altered epigenetic mechanisms of gene regulation, such as DNA methylation, histone modification and chromatin remodeling, and non-coding RNAs, the manipulation of these mechanisms is central to the effectiveness of age-delaying interventions.

https://www.nature.com/articles/s41580-019-0204-5

This is where CRPSR will likely have its biggest impact on aging.

The epigenetic landscape is like one of those old punch-card looms in the industrial revolution.

You switch out the punchcard and you get a different design.

If you switch out (or bolster/remove) certain pieces of the epigenome, you get a different "phenotype" or set of biological functioning.

This is the basis behind all the "blood boy" and young plasma memes.

The genes haven't changed (much) but the epigenome has.

There's a great review from a thought leader on aging, David Sinclair, here:

https://www.youtube.com/watch?v=QRt7LjqJ45k

His lab is investigating whether loss of epigenome information leads to instability of genetic protein production and eventual aging.

Our work has led us to the conclusion that the loss of epigenetic information is likely the root cause of aging. By analogy, if DNA is the digital information on a compact disc, then aging is due to scratches.

https://genetics.med.harvard.edu/sinclair/research.php

With CRISPR, we could potentially, reboot these systems.

They are also looking at reversing cells back to stem cells but not just generic, all-purpose stem cells but ones specific to the original origin (skin, heart, muscle, etc).

Methylation is a key component and we can affect that.

In fact, many people have two key genetic mutations:

MTRR
MTHFR

These results in a poor ability to "methylate" or activate critical B vitamins.

Hence, you now see methylated B vitamins on the market.

You can check your status on these genes (and more) at Stratagene here:

https://www.seekinghealth.com/collections/strategene

The "Dirty Genes" book is a great introduction to key genes we can affect.

For example, I have bad versions of VDR so I don't process Vitamin D well.

At 10,000 IU daily, it's slowly moving up (goal is around 80).

A big part of retaining genetic integrity is to offset potential damage.

This can be from many sources:

UV radiation
Chemicals and pesticides
Oxidative stress

The last one is critical since the very furnace of energy creation in our cells (mitochondria) comes at a high price.

A constant outflow of chemical scissors in the form of oxygen.

These scissors are quick to cut DNA, RNA, and anything it comes in contact with.

Think of it as the waste product of our body's energy and we have complicated systems to keep this highly destructive element neutralized.

To this effect, here are critical tools:

CBD - a more powerful antioxidant than Vitamin E and C!
NAC - acts as a buffer for glutathione, our primary antioxidant
Vitamin C - support the glutathione cycle

Let's turn to the powerplants of the cell which may be where aging really starts.

Mitochondria as the linchpin of aging

Our ancient ancestors struck a deal (kidnapped more likely) with bacteria to power everything we do.

Mitochondria actually have their own DNA and it is.....bacterial DNA!

Here's the issue…

Our own DNA has robust error correction systems so that when a highly charged UV light cuts a DNA strand, we do a pretty good job of fixing it.

Mitochondria DNA does not have this.

Errors accumulate and even divide and spread.

If the errors reach a certain level, our immune system is supposed to take out the cell but occasionally, this doesn't work and you have the senescent cells (zombie cells) from above proliferate.

Simply put:

Mitochondrial DNA has an estimated 10-fold greater mutation rate than nuclear DNA and less repair capacity, and this plays an important role in aging and cancer

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6627182/

That link has powerful reviews across a range of health issues with mitochondria.

How can we support general mitochondrial health and function?

Here are key steps:

Exercise - directly boosts production and numbers of mitochondria
Red light therapy - impressive studies on this pathway - great book here
NAC - reduce oxidative stress which damages mitochondria
NAD and NMN - drives energy production
B vitamins - key for the process
Magnesium glycinate - key for the final stage of energy production
COQ10 - not just for heart health - the key to mitochondria function

As for some of the detriments:

Oxidants leaked while ATP is produced
Aging (accumulated oxidative damage to mtDNA)
Genomic susceptibility (especially ApoE4)
Toxic metals
Persistent organic pollutants (POPs)
Many prescription drugs
Alcohol

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4684129/

Pretty self-explanatory...avoid toxins whether from outside or inside (oxidation).

Interestingly, NSAIDs and statins are listed as medications that hurt Mitochondrial function.

It's not surprising with statins once you realize they rip COQ10 (see the book, Drug Muggers).

Read that link...so fascinating and well put together!

Let's turn to Vitamin D - our link to the sun.

Is Vitamin D the driving factor for longevity?

The red light therapy research is fascinating.

We were designed to spend hours out in the sun. Better put, we adapted to being in the sun all day.

Just 100 years ago, the majority of Americans were farmers and that still stands for most of the world.

1000 years ago? 10,000 years ago (about where most of our epigenetic settings probably came from)?

Sun all day.

UV light exposure is the key way to get Vitamin D barring supplementation.

We did a huge review of Vitamin D for mental health, immune system, and longevity.

Vitamin D levels drop as we age and it's basically tied into every aspect above.

Immune system? Check. Master regulator
Hormones? Check. Vitamin D actually is a steroidal hormone itself!
Mitochondria? D is essential for the function and removal of oxidative stress
Senescent cells? D directly reduces the level of senescent cells
AMPK? Vitamin D is integrally tied into the metabolic cycle (insulin, fat, sugar, etc)

It's everywhere and we're mostly deficient!

This deficiency increases as we age since our skin is less able to convert Vitamin D.

It begs the question...is Vitamin D the driving factor since it's tied into every other aspect?

They looked at Vitamin D and the much-used elegans worm for longevity:

We found that Vitamin D3-induced lifespan extension requires the stress response pathway genes SKN-1, IRE-1, and XBP-1.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5689451/

They went to find that Vitamin D affects the very stability of proteins:

D3 suppressed an important molecular pathology of aging, that of widespread protein insolubility, and prevented toxicity caused by human β-amyloid.

B amyloid happens to be the toxic material that builds up in the brain with dementia.

This makes sense since it's a component of our immune system (see CBD and dementia) and Vitamin D directly supports our immune response!

Here's the issue...the guidelines at 20-30 levels are mainly to prevent rickets and bendy knees.

The endocrinologist wants levels closer to 70-80.

Finally, let's look at CBD after new research has come out.

The case for CBD and longevity

Sure, we're partial.

What happens after you've written million+ words on CBD research.

We wouldn't go to that length unless it was pretty fascinating in NIH studies.

Before we jump to the most recent study on CBD extending lifespan in the Elegans worm (shares 80% of our genes), let's touch base on the various pathways we discussed above:

CBD and AMPK for longevity
CBD and mTOR for longevity
CBD and inflammation for longevity
CBD and gut barrier for longevity
CBD and neurogenesis for longevity
CBD and mitochondria
CBD and longevity

We need to first understand how CBD works.

CBD is a feedback mechanism in our naturally existing endocannabinoid system.

This system is tasked with balancing other key pathways:

Nervous system
Endocrine system
Immune system

The endocrine and immune systems are at the crux of most of what we looked at above.

This feedback aspect is essential because we don't want to push pathways up or down in one direction.

Check out our review on CBD and serotonin as a perfect example.

Too much serotonin is just as bad as too little.

Let's go back to our topics.

CBD and AMPK for longevity

We mentioned how AMPK is probably our best tool in the current kit based on the MILES study.

In a study of epilepsy, the following is found:

CBD increases phosphorylation of AMPK signaling proteins at early time points.

https://www.researchgate.net/figure/CBD-increases-phosphorylation-of-AMPK-signaling-proteins-at-early-time-points-A-B_fig2_341935024

Phosphorylation is the activation of AMPK.

Other studies show similar effects in different pathways.

It turns out that our main endocannabinoid receptor (CB1) drives AMPK activity. Anandamide is a key driver of CB1 activity.

CBD's effect on anandamide has been established in many different studies such as this one for schizophrenia:

Biochemical studies indicate that cannabidiol may enhance endogenous anandamide signaling indirectly, by inhibiting the intracellular degradation of anandamide catalyzed by the enzyme fatty acid amide hydrolase (FAAH).

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3316151/

Check our reviews on endocannabinoid deficiency and how to boost endocannabinoids.

One note...THC mimics anandamide and boosts CB1 activity but the body will push back and actually reduce CB1 receptor numbers and sensitivity since THC lingers too long.

This is the opposite direction we want to go.

What about mTOR?

CBD and mTOR for longevity

CBD's effect on mTOR is popping up across studies with different disease models.

For example..Parkinson's:

The protective effects of CBD seem to be mediated by the activation of ERK and AKT/mTOR pathways.

https://pubmed.ncbi.nlm.nih.gov/32184097/

When they blocked mTOR, the protective effects went away.

And MS (the animal model called EAE):

These results provide an interesting discovery about the regulation of the PI3K/Akt/mTOR pathway by cannabidiol administration, that could be a new potential therapeutic target for MS management.

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

Remember that mTOR is involved with managing cell birth/death which is critical for cancer.

CBD's effect via mTOR there:

Cannabidiol reduced phosphorylation of mTOR, PKB and S6 pathways related to survival and cell size.

https://www.frontiersin.org/articles/10.3389/fphar.2017.00144/full

Specifically, CBD boosts the oxidative stress to cancer cells (but not surrounding healthy cells).

Oxidative stress is our immune system's natural way to kill wayward cells (cancerous or virally infected).

Chemo and radiation are essentially massive doses of oxidative stress.

Let's turn our attention to inflammation.

CBD and inflammation for longevity

Remember the "inflammaging" - an increasing level of chronic inflammation that accompanies aging?

CBD's greatest trick may be that of calming hyperactive inflammation and immune response.

See CBD and neuroinflammation or CBD and autoimmune as examples.

A study looked at CBD specifically for inflammatory markers with zebrafish and found the following:

control aged zebrafish exhibited increased kyphosis as well as increased expression markers of senescence, and inflammation (p16 ink4ab , 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/

Goodness….that's exactly what we're after. Reduced markers of senescence and inflammation.

Let's look at some of the markers of inflam-aging.

Since inflammation is under the control of our very complicated immune system, this can quickly fall down the rabbit's hole so let's focus on a few key players.

For instance, interleukin (IL)-6, tumor necrosis factor (TNF)-α, and their receptors, are upregulated in aged tissues and cells

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6457053/

Okay...IL6 (a cytokine or immune assassin) and TNF.

IL-6 is readily inhibited by CBD in inflammatory models, including diabetes,124 asthma,127 pancreatitis,128 and hepatitis

https://www.liebertpub.com/doi/10.1089/can.2018.0073

Notice it reduces IL-6 in diseased models...where it's too high. We need IL-6 as part of our immune response.

Just not chronically.

That's the fascinating piece..CBD's effect appears to depend on the state of the cell.

For example, in rheumatoid arthritic cells, CBD would target diseased cells specifically with the aid of TNF:

This effect was enhanced by pre-treatment with TNF suggesting that CBD preferentially targets activated, pro-inflammatory RASF.

https://www.nature.com/articles/s41419-020-02892-1

This is really the beauty of our endocannabinoid system which is a masterful balancing act across the entire body.

In diabetes:

CBD treatment also resulted in the significant reduction of plasma levels of the pro-inflammatory cytokines, IFN-γ and TNF-α.

https://www.tandfonline.com/doi/abs/10.1080/08916930500356674

Again, diseased, inflammatory state.

Other inflammatory markers:

The levels of IL-4, IL-5, IL-13, IL-6, IL-10, and TNF-α were determinate in the serum. CBD treatment was able to decrease the serum levels of all analyzed cytokines except for IL-10 levels.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4458548/

What gives with IL-10? It happens to be a natural ANTI-inflammatory!

Then, there's the general "setting" of our immune response.

TH1 is more inflammatory
TH2 is more restorative and resolving in focus

Look at the effect of aging:

Old and nonagenarian individuals revealed increased TH1, TH2 cell numbers and a decreased TH2/TH1 ratio in comparison to young individuals

https://pubmed.ncbi.nlm.nih.gov/18166287/

The immune system shifts to TH1 (inflammatory) as we get older.

CBD actually directly affects this balance:

CBD treatment also resulted in the significant reduction of plasma levels of the pro-inflammatory cytokines, IFN-gamma and TNF-alpha. Th1-associated cytokine production of in vitro activated T-cells and peritoneal macrophages was also significantly reduced in CBD-treated mice, whereas production of the Th2-associated cytokines, IL-4 and IL-10, was increased when compared to untreated control mice.

https://pubmed.ncbi.nlm.nih.gov/16698671/

This is so important as chronic inflammation is essentially a heightened TH1 response over decades.

Let's look at the thermostat for inflammation in the body and brain...the gut.

CBD and gut barrier for longevity

There are many triggers to inflammation and most of them reside outside of us...till they get in!

Chemicals
Pesticides
Drugs
Medications
Bacteria and Viruses

Our main barrier to them (especially bad bacteria) gaining entrance to our inner workings is the gut.

Gut inflammation is usually the canary in the coalmine for systemic inflammation.

Vitamin D is key to keeping this gut barrier intact and it's dropping as we get older.

What about CBD and the gut barrier?

Researchers introduced C diff, the nasty antibiotic resistance bacteria found in hospitals, to gut lining cells and looked at CBD's effect there:

Cannabidiol restores intestinal barrier dysfunction and inhibits the apoptotic process induced by Clostridium difficile toxin A in Caco-2 cells

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5721977/

We have a whole review on CBD and leaky gut or CBD and probiotics to learn more.

CBD and the blood-brain barrier is fascinating as well!

Berberine and metformin both happen to have the effect of boosting our gut barrier which tells you something (considering their effects on AMPK and longevity).

Let's turn to the brain.

CBD and neurogenesis for longevity

A key part of mental health/function and longevity is neurogenesis.

The process of growing and repairing brain tissue.

It's the trick behind:

SSRIs - see how SSRIs actually work
Psilocybin - an explosion of neurogenesis
Exercise - big boost to neurogenesis
Mindful Meditation
Red Light Therapy

The main player is BDNF, our brain's fertilizer.

Look at BDNF levels as we age:

In particular, brain-derived neurotrophic factor (BDNF) plays a fundamental role during age-related synaptic loss, preventing cerebral atrophy and cognitive decline.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7287884/

So...CBD's effect on BDNF and neurogenesis?

From studies on depression (see CBD and depression):

Cannabidiol Induces Rapid and Sustained Antidepressant-Like Effects Through Increased BDNF Signaling and Synaptogenesis in the Prefrontal Cortex

https://pubmed.ncbi.nlm.nih.gov/29869197/

The prefrontal cortex is exactly where we want it as this area is tied to the type of thought that makes us human.

The other big area is the hippocampus which governs memory and mood control.

CBD there?

Preclinical studies have shown CBD to induce synaptic plasticity and facilitate hippocampal neurogenesis,29,30 with some evidence suggesting that the proneurogenic action of CBD via the hippocampus may underlie its anxiolytic effects.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5908414/

We did big reviews on:

CBD and hippocampus neurogenesis (plus research on exercise and mindful meditation)
CBD and brain repair

We use neurogenesis as an example of the "growth" side that starts to falter as we get older.

Yes, this is in the brain (or nervous system) but different pathways govern heart, bone, muscle, etc.

Since the endocannabinoid system governs balance across the body, the brain is a great example!

By the way, you're going to see an explosion of activity in psilocybin over the next few years as the research is pretty profound. We did a full review here.

Next up...the power plants of our cells and maybe the first thing to go with aging.

CBD and mitochondria

We want to look at two key aspects.

Supporting mitochondrial function
Reducing the toxic by-product (oxidants) of energy production

First, supporting energy production.

A study looked at CBD's effect following stroke in brain neurons where mitochondria are severely affected:

Using the Seahorse XFe24 Extracellular Flux Analyzer, we found that CBD significantly improved basal respiration, ATP-linked oxygen consumption rate, and the spare respiratory capacity, and augmented glucose consumption in OGD/R-injured neurons.

https://www.sciencedirect.com/science/article/pii/S221323171630338X

Let's translate that Klingon please.

Respiration is the key process of making energy within mitochondria
ATP is the main energy packet that's made (which requires oxygen)
Spare capacity speaks to the level of energy mitochondria are able to make
Glucose is the main fuel for energy production

Goodness...CBD was able to bring energy production back online following a stroke.

Usually, neurons start to die after a stroke as the brain literally starves of energy.

One note...in cancer cells, CBD will actually target the mitochondria and DOWNREGULATE their activity to kill off the cell.

In leukemia cells:

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

https://www.nature.com/articles/s41419-019-2024-0

It's basically sabotaging the corrupted cell.

Calcium is the basic currency of cellular activity.

But on the flip side, when a healthy cell needs more of it?

Thus, under pathological conditions involving mitochondrial dysfunction and Ca2+ dysregulation, CBD may prove beneficial in preventing apoptotic signaling via a restoration of Ca2+ homeostasis.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6666323/

But for cells that need to be removed, it actually disrupts mitochondrial function and INCREASES oxidative stress.

See why we've spent 1000's of hours research CBD?

That leads us to the next section.

CBD's real power may be as a significant anti-oxidant.

Remember that oxidation is a byproduct of energy production. It's extremely lethal to all organic matter (including neurons, cells, DNA, etc).

Little chemical scissors.

Technically, it's called ROS or Reactive Oxygen Species.

We have a whole system to mop up this oxidation and mute its ability to destroy.

Glutathione is our primary anti-oxidant (see CBD and glutathione).

What about CBD?

Let's compare it to two powerful anti-oxidants:

In an in vitro glutamate neuronal toxicity model, CBD was shown to be more protective than either α-tocopherol or vitamin C

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3085542/

CBD actually prevents the creation of our most destructive oxidants:

CBD reduces oxidative conditions by preventing the formation of superoxide radicals, which are mainly generated by xanthine oxidase (XO) and NADPH oxidase (NOX1 and NOX4).

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7023045/

Free radicals.

Why is all this important?

The mitochondria are the most vulnerable links in the chain.

Remember that they don't have the robust error correction systems that our DNA have.

When ROS cuts through a piece of mitochondria DNA, it's likely a one way trip to default.

More importantly, mitochondria live in the most dangerous neighborhood...they are literally making the energy which generates the ROS.

Hazard pay indeed.

Disarming this ROS is essential. Check out CBD and oxidative stress to see how this impacts health and aging.

Finally, do we have studies on CBD and longevity itself?

CBD and longevity

Here's where the excitement really starts.

A brand new study (Nov 2020) looked at C Elegans (the worm goalpost for longevity studies) on and long term CBD exposure. Whole life in fact.

The results:

otably, whole-life exposure of C. elegans to 10–100 μM CBD revealed a maximum life extension of 18% observed at 40 μM CBD.

https://doi.org/10.1089/can.2020.0103

An 18% increase in lifespan with no other changes than CBD exposure.

Maybe more interesting was this:

In addition, motility analysis of the same groups revealed an increase in late-stage life activity by up to 206% compared to controls.

This is a measure of movement, a key expression of vitality for worms as they age.

Remember, it's about living longer but with good health!

We've looked at long term CBD use specifically but this is very exciting.

The C elegans is a go-to model for health research since so many pathways and genes are shared with more complex organisms like humans.

Another common animal model is zebra fish.

CBD's effect with early exposure:

At 30 months of age, 60% of control male and female fish had died (Fig. 1a, b ). Male fish treated with increasing doses of CBD had significantly increased survival than controls

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

We look forward to more studies and expect they'll follow after the C Elegans study.

That result is similar to calorie restriction….and much easier to actually accomplish.

That wraps our CBD section.

A quick recap of our toolkit.

Our current Longevity Toolkit

CBD - multiple pathways
NAC - powerful anti-oxidant and brake for glutamate
Berberine or Metformin - AMPK and gut barrier support
Fisetin - mTOR and anti-oxidant
Vitamin D - steroid we get from the sun
Methylated B vitamins - especially with MTRR and MTHFR gene variants
Red Light Therapy - back to the sun...powerful booster to mitochondria
Steroidal Hormones - Estrogen/Progesterone, Testosterone, DHEA, Pregnenolone, Melatonin, Human Growth Hormone (can get from compound pharmacies)
PEA - supports endocannabinoid function
Arginine and Ornithine - proteins essential for human growth hormone

That's our current toolkit.

Let's look at what's coming briefly.

The coming CRSPR revolution for aging

Probably the most exciting "frontier" of longevity deals with epigenetics.

The layer of malleable code that sits on top of our DNA and turns various genes on and off.

David Sinclair from Harvard is a pioneer here and he believes that aging is essentially loss of information in the epigenetics.

Our DNA is intact and we have robust methods to correct errors.

The epigenome (which interacts with the environment) gives us our flexibility.

It's why human exist in every available niche on Earth.

This flexibility is also its weakness.

It reminds of the hippocampus, our seat of memory.

The hippocampus is the most dynamic and changing area of the brain since memory is constantly being added, removed, and changed.

This "plasticity" makes it the most vulnerable to stress, chemicals, trauma, etc.

Sinclair has run experiments where mice are caused to age significantly (over night) by affecting the epigenome integrity.

The question (and goal) now is to buttress this middleware of aging.

CRPSR will profoundly affect every aspect of health in a general progression:

Serious diseases like Sickle Cell and Parkinsons
Pain, mental health and more (see the woman who can't feel pain due to FAAH gene)
Longevity and general wellness

There are genes that directly drive longevity (dealing with inflammation, metabolism, BDNF, etc)

More importantly, if we can "add" epigenome firepower with a "young" setting, it's game over for aging.

You'll see people say, "Oh, CRSPR is decades away for that".

They just solved protein folding calculations with AI which was supposed to be "decades away".

You'll see dog gene longevity therapy within a few years and we wouldn't bet against human by the end of this decade if not sooner.

We hope you enjoy the journey through current pathways of longevity. We're sure it will need updates by the year!

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.