10 Naturals Tools For Mitochondria Rescue
Research keeps coming back around.
To the alien interlopers we hijacked roughly 1.5 billion years ago. Mitochondria.
So much more than JUST the power plants for every thing you do.
Brain Energy - the revolutionary new book on mental health and metabolism lands squarely at the footstep of these ancient bacteria.
Longevity is quickly being routed here…from every angle.
Just a few quick notes from the longevity frontier:
- Mitochondria lie firmly at the intersection of metabolism (AMPK, SIRT, mTOR, etc)
- Your steroidal hormones are actually made in the mitochondria (see steroids and longevity, estrogen and mental health, testosterone health guide)
- Every longevity hack…can't work without mitochondria effects (fasting, cold exposure, calorie restriction, etc)
The mental health effects are just the canary in the coal mine since those effects are more noticeable.
Same for heart, muscle, bone, organs, etc.
So…how can we support mitochondria…naturally?
Let's go there!
A quick intro the fascinating worker bees in your body:
- Tip 1 - Exercise…sorry, it's the gold standard
- Tip 2 - PQQ - vitamin for bacteria (and therefore...us)
- Tip 3 - pomegranite extract - search for Urolithin A
- Tip 4 - cold exposure - our ancestor's mitochondrial hack
- Tip 5 - CBD isolate - supporting balance in the system
- Tip 6 - COQ10 - the only antioxidant that gets into our mitochondria
- Tip 7 - ALA - the importance of (good) fat
- Tip 8 - Carnitine and Carnosine - reducing the damage from glucose
- Tip 9 - Sleep - clean up in aisle 7
- Tip 10 - Fasting - giving the energy complex a break for repair
- The Grab Bag - magnesium, NAC, glutathione, NMN, and B vitamins.
Let's get started…first, an introduction is due!
A quick intro the fascinating worker bees in your body
We all know the staid description...
Mitochondria produce the energy in our cells.
That's just the start! Energy is literally the stuff of life so they also have powerful sensing and signaling effects within the cell and across the body.
Newer research is really showing mitochondria at the crux of:
- Mental health issues - brain energy imbalance
- Metabolic health issues - broken energy sensing
- Longevity - inability to keep up with cellular housekeeping…especially DNA repair (epigenome is a big focus)
We just named 80% of the TV ads for medications.
Mitochondrial dysfunction, either due to the TCA cycle enzyme defects, mitochondrial DNA genetic mutations, defective mitochondrial electron transport chain, oxidative stress, or aberrant oncogene and tumor suppressor signaling, has been observed in a wide spectrum of human cancers.
To translate…when mitochondria break, the whole cancer detection and removal system goes offline.
We can quickly get lost in the weeds so lets focus on how to support mitochondria function along these lines:
- Mitophagy - removal of faulty mitochondria (focus: PINK1 and Parkin)
- Mitochondrial biogenesis - increasing numbers of new mitochondria (focus: PGC-1α)
- Improved mitochondria function - work better - make more energy (focus: PGC-1α and NRF2 - among others)
This is the trifecta of mitochondria function.
One important note…the whole "antioxidant" push may not be the entire story.
Oxidative stress is a signal to the mito machine to clean out old copies and make new ones. Equivalent of the order down to the boiler room for more power! Or "I need more power, Scotty" for Star Trek fans.
Oxidative stress is also the bullet the immune system uses to kill faulty cells (and mitochondria) including cancer! There's a balance.
Studies have shown that antioxidant supplementation actually COUNTERED the benefits of exercise:
Despite their negative effects on performance, free radicals may act as signaling molecules enhancing protection against greater physical stress. Current evidence suggests that antioxidant supplementation may impair these adaptations.
Goodness. We'll have to shape our list based on this new respect for oxidative stress (within bounds). Onward!
Tip 1 - Exercise…sorry, it's the gold standard
There's just no getting around it. Exercise directly drives mitochondria function.
Makes sense. Mitochondria make energy. Exercise is an extremely high energy hog.
The body will respond accordingly. Across all three requirements above!:
Recent studies show that exercise improves mitochondrial quality and function by stimulating their turnover
Exercise drives AMPK, one of the current frontrunners for longevity (metformin, berberine, etc). We have a huge review on AMPK here.
It's as close to a silver bullet as have.
Look at the relationship to exercise and/or age. An active 70 year old has the mitochondrial function of say a 50 year old judging by the curve.
Let's introduce a key pathway we want to target: PGC-1α
PGC-1α is the band leader of mitochondrial function and exercise's role is many and strong:
Acute exercise initiates a multitude of signals that converge on PGC-1α
Remember how we said that antioxidants may be not be the magic pill once pushed?
A slew of pathways are initiatied to keep everything in order including UPR and PINK1 (removes faulty mitochondria).
The trigger that initiates the upregulation of these chaperones may be ROS
ROS…reactive oxygen species. Antioxidants are neutralizing ROS but taking away the critical signal to turn on an entire complex of mito management paths.
Hence the studies above where antioxidants can neutralize exercises benefits. This also points to a simple fact..
There is no (or little) benefit to exercise without its effect on mitochondria!
See why we get go excited!!
What isn't complicated is that exercise has the most profound effect on mitochondrial energy, function, and housekeeping.
At least 30 minutes daily. Cross between strength, aerobic, and even more intense work. Always work with your doctor and within your physical range.
Endurance training appears to have the greatest effect with 40-50% increase in mitochondrial makeup.
Let's turn to a new hack on the block.
Tip 2 - PQQ
A key player in the bacterial world, PQQ found it's seat at the mammalian table in…mitochondria (ancient bacteria after all).
Through nutritive and environmental exposures, PQQ affects essential biological processes, influencing mitochondriogenesis, reproduction, growth and aging.
It has an important role in managing lactate, a byproduct of our energy production.
More importantly to our discussion, it's a huge boost to mitochondrial function:
PQQ enhances NAD+-dependent sirtuin activity and the expression of sirtuins targets, such as PGC–1α, NRF–1 and 2, and TFAM
- SIRT - a cellular shock sensor and current longevity player (resveratrol, NAD, NMN, pterostilbene, CBD isolate, etc)
- PGC-1a - the mito manager
- NRF1 and Tfam - both drive new mito production and energy as needed
Technically, PQQ also acts an anti-oxidant. Does it adversely affect the results of exercise?
Good news on that front:
Supplementation of PQQ does not appear to elicit any ergogenic effects regarding aerobic performance or body composition but appears to impact mitochondrial biogenesis by way of significant elevations in PGC-1α protein content.
The "stress" of exercise needs to be detected and PQQ doesn't appear to block this.
We use this one and cycle it with our mito stack (full list below). 20mg in the morning matches research and has a stronge safety profile.
PQQ is the heavy lifter in our toolkit for all things mitochondria and we'll do a deep dive shortly. It deserves the spotlight.
One note…high triglycerides or LDL cholesterol and/or low steroidal hormone function may indicate mito dysfunction and benefit from PQQ according to research.
Next up…urolithin a. What??
Tip 3 - pomegranite extract - search for Urolithin A
There's a new kid in town called urolithin a.
What does it do?
Experimental models consistently show that UA increases mitophagy and mitochondrial function and blunts excessive inflammatory responses.
Okay…so removal of worn-out mitochondria (mitophagy) and improved function.
Does this translate??
UA increased biomarkers of mitochondrial function in preclinical models of aging and in healthy elderly people.
And how do we get it?
Urolithin A (UA) is produced by gut microflora from foods rich in ellagitannins.
- Okay…so it's a two parter. First the foods such as walnuts and pomegranate (two high sourced foods).
- Next, we need the right type of gut bacteria to convert and a study found that 40% of people have this make up.
They tend to have more varied gut bacteria so it's time to start eating balanced and varied diets with real food!
UA producers were distinguished by a significantly higher gut microbiome diversity and ratio of Firmicutes to Bacteroides.
So…the Mediterrean diet (walnuts were a huge player there actually...not the olive oil).
The study showed raised levels of urolithin A glucuronides in the urine of the Mediterranean group as than the regular diet group.
The next best way is pomegranate extract such as this one.
There is a pure urolithin A supplement since some people do not have the proper gut microbiome but it's more expensive.
Next up…embrace the cold.
Tip 4 - cold exposure - our ancestors mitochondrial hack
Check out our cold exposure and mental health or dopamine rescue reviews.
Once you understand the benefits of cold exposure, you're going to overcome your fear (hatred??) of the cold.
Most of the benefit resides around…mitochondria function!
In soleus muscle, PGC-1α expression significantly increased in response to cold exposure (p = 0.006) and exercise (p = 0.05).
PGC-1a - the kingpin of mitochondrial juicing.
What's the story?
It mainly revolves around brown fat (BAT - brown adipose tissue). Babies have lots of it and we lose it as we gain the ability to shiver.
Cold exposure brings BAT back online and the what exactly makes brown fat "brown"?
Mitochondria. Actually the iron in mitochondria as their numbers swell.
The body is panicking about the cold and juices up energy production to generate heat. That requires…more mitochondria and better functioning ones!
It also means getting rid of the laggers (mitophagy):
Chronic cold exposure induces autophagy to promote fatty acid oxidation, mitochondrial turnover, and thermogenesis in brown adipose tissue
More mitochondria. Removal of faulty ones. Better energy production.
Holy grail. Sorry…embrace the cold!
10 minutes at 50-60 degrees a few times a week will do the trick. Work with your doctor and listen to your body! Check out the reviews with more guidance and Huberman podcast has a great intro.
Next up…the balancing system.
Tip 5 - CBD isolate - supporting the balance in the system
We have a powerful system in our body designed to keep all other systems in balance (called homeostasis) in the face of stress.
Stress can be anything that pushes a pathway in one direction.
For example…the cold exposure above! After things start to warm up, the body needs to get back to center.
Hello endocannabinoid system!
Of the cannabinoids, CBD isolate is the best way to support this system since the others push or pull in one direction (which leads to tolerance). CBN, CBG, Delta8, and of course…THC.
As for mitochondria??
Goodness…let's get started.
First…the grab bag which speaks to how omnipresent the endocannabinoid system is:
evidence has indicated a role for CBD in the modulation of mitochondrial processes, including respiration and bioenergetics, mitochondrial DNA epigenetics, intrinsic apoptosis, the regulation of mitochondrial and intracellular calcium concentrations, mitochondrial fission, fusion and biogenesis, and mitochondrial ferritin concentration and mitochondrial monoamine oxidase activity regulation.
- Mito energy production
- Mito removal when faulty (apoptosis)
- Internal mito balance (calcium levels)
- New mito creation (fission/fusion and biogenesis)
- Mito Iron levels (ferritin)
The gang's all here.
CBD isolate has a huge impact on reducing the highly destructive waste material from energy production as well:
CBD has been shown to function as a protective molecule for these organelles, it enable the mitochondria to maintain their function in spite of presence of free radicals or other mitochondrial disruptors.
Now watch this trick (this is where we geek out)...
CBD will actually INCREASE oxidative stress in cancerous of virally infected cells!
Remember…that's how our immune system naturally kills wayward cells. Chemo and radiation are just massive hits of oxidative stress.
But..CBD doesn't do this to the surrounding health cells! (see top 10 tools for fighting cancer).
In fact…it can protect neurons when under duress:
Thus, under pathological conditions involving mitochondrial dysfunction and Ca2+ dysregulation, CBD may prove beneficial in preventing apoptotic signaling via a restoration of Ca2+ homeostasis
So...a response depending on the state of the system. Our favorite kind.
THC does not have the same profile unfortunately.
THC exposure alters brain maximal oxidative capacity. It impairs mainly the complexes I, II, and III of the mitochondrial respiratory chain and mitochondrial coupling. THC also increases brain ROS production and mitochondrial free radical leak.
More on how CBD protects the brain from THC.
We use this one and dose range runs from 100mg to 300mg (peak neurogenesis) daily.
Next up…some protection please.
Tip 6 - COQ10 - the only antioxidant that gets into our mitochondria
Whether the oil patch or deep inside our brains, energy production is a messy business.
The waste from our energy production is in the form of free-range oxygen. Little organic scissors running around our sensitive molecular wetware.
We don't want to squash oxidation as it's a powerful signal to tighten up the ship in mitochondria function…but, we could use some back up cleaning crews now and then.
COQ10 is a powerful player with a secret back door into our mitochondria!
We see the usual suspects:
These results show that ubiquinol-10 may enhance mitochondrial activity by increasing levels of SIRT1, PGC-1α, and SIRT3 that slow the rate of age-related hearing loss and protect against the progression of aging and symptoms of age-related diseases.
There's SIRT (cellular shock protein) and PGC-1α, the mito ringleader.
CoQ10 is literally part of the energy production machinery as it carries electrons from one work area (complex 1, 2, and 3) to the next.
Just a head's up…statins rip COQ10 so many people are familiar with supplementing it for heart and brain health.
Just happen to be the two hungriest energy users. Go figure.
PQQ and CoQ10 may work together but the general thought is to take them at different times (PQQ in the morning due to energy).
We use this one here. Let's turn to fat…the good stuff cells are made from.
Tip 7 - ALA - the importance of fat (good fats)
We have a monster review on the importance of Omega 3 fats and ALA is a big part of that discussion.
Alpha Lipoic Acid is a key ingredient of the mitochondrial energy complex:
α-LA acts as an enzymatic cofactor able to regulate metabolism, energy production, and mitochondrial biogenesis.
Biogenesis - making new mitochondria.
Keep in mind that mitochondria only exist for a few days so we're constantly cranking out news ones. Each cell can have a few thousand so this process is mind-blowing.
It's also going down as we age and in many (if not all) disease states.
Energy hungry equals mitochondrial vulnerable so…what about the brain (20% of body's energy usage) with aging?:
In addition, co-administration of LA (alpha lipoic acid) with other mitochondrial nutrients, such as acetyl-L: -carnitine and coenzyme Q10, appears more effective in improving cognitive dysfunction and reducing oxidative mitochondrial dysfunction.
Parkinson's is a very specific example of this and one of the key pathways tied to mitochondria turnover is literally called Parkin:
PINK1 and Parkin mitochondrial quality control: a source of regional vulnerability in Parkinson’s disease
Accumulating evidence indicates that α‑lipoic acid (ALA) decreases this nigral dopaminergic cell loss.
Too bad we're consuming massive amounts of seed oil and omega 6 fats which compete with omega 3 for processing (read the reviews!!).
A little side-hustle of ALA appears to be its ability to offset the damage from iron overload in mitochondria:
Our results showed that FAC results in a significant increase of tissue iron accumulation, oxidative stress, and autophagy and such detrimental effects were reversed by ALA treatment.
In fact, this appears to be a running theme through our tools (see CBD and iron overload).
We use this one here and some brands combine PQQ and ALA.
Next up…the glucose problem.
Tip 8 - Carnitine and Carnosine - reducing the damage from glucose
The prefix ("carn") should indicate our sources for both of these.
Animal products (sorry vegans). There's no getting around a few million years of evolution and there's no way to get them from plantlife (despite our daily Pho habit).
Carnitine plays a critical role in energy production. It transports long-chain fatty acids into the mitochondria so they can be oxidized ("burned") to produce energy. It also transports the toxic compounds generated out of this cellular organelle to prevent their accumulation
Okay…so ALA above is a long chained fatty acid of the Omega 3 variety. It needs transport in and carnitine is the bouncer at the door.
More importantly, it removes the waste material from energy production which gums up the works.
Carnatine levels decrease as we age:
Thus, feeding old rats high levels of key mitochondrial metabolites can ameliorate oxidative damage, enzyme activity, substrate-binding affinity, and mitochondrial dysfunction.
Carnosine is all about sugar. Or the damage from sugar.
We did a huge review on the problem with glucose and the slow build up of AGEs (Advanced Glycation End products).
Essentially, the ability of glucose to "stick" to just about everything in our machinery including fats, proteins, and even each other. The accumulation of which is directly tied to aging and dysfunction.
Carnosine (and GLO2 from glutathione) mop this up!
Carnosine has been shown to prevent AGE formations through reduction of blood glucose, prevention of early glycation, and even reversing previously formed AGEs.
What happens when these "blobs" of broken machinery build up in our mitochondria with aging?
We found that carnosine supplementation in 3xTg-AD mice promotes a strong reduction in the hippocampal intraneuronal accumulation of Aβ and completely rescues AD and aging-related mitochondrial dysfunctions.
Um...that's removal of brain amyloid beta plaques tied to dementia!
Mitochondria just work better when you remove the "gunk":
However, treatment with carnosine significantly attenuated autophagic signaling in the ischemic brain, with improvement of brain mitochondrial function and mitophagy signaling.
Interestingly, carnosine just happens to be the initiator of….COQ10 creation!
L-Carnosine Stimulation of Coenzyme Q10 Biosynthesis Promotes Improved Mitochondrial Function and Decreases Hepatic Steatosis in Diabetic Conditions
Go figure! Big review of carnosine here. We use this one.
Let's turn to the great reset (done nightly).
Tip 9 - Sleep - key to mitochondrial function
Let's move past the the part where mitochondria are the main source of melatonin synthesis (along with steroid hormones which have huge impacts on sleep).
A study just came out that showed circadian rhythm dysfunction may be more dangerous than metabolic dysfunction!
The Circadian Syndrome Is a Significant and Stronger Predictor for Cardiovascular Disease than the Metabolic Syndrome-The NHANES Survey during 2005-2016
Fascinating! How you sleep is more important than how you...eat and excercise (essentially, metabolism bookends)!
Remember that 1/3rd of our whole program above is about removing faulty mitochondria. Mitophagy.
That's the PINK/PARKIN pathway which manage the breakdown of poorly functioning mitochondria.
Sleep is when the trash gets taken out!:
inessential byproducts and proteotoxic compounds, such as β-amyloids, accumulate during the active phase, and are degraded by the proteasome while sleeping
The beautiful lymphatic and glymphatic (brain) systems of waste removal.
That includes all the ROS and waste material from energy production that gums up our cellular machinery.
one potential physiological role of sleep during the inactive phase could be to promote mitochondrial quality control as antioxidant response.
Fine…what about sleep deprivation and mitochondrial function?
HRR analysis showed that sleep deprivation affected mitochondrial bioenergetics capacity, decreasing respiration at oxidative phosphorylation (OXPHOS) and electron transport system (ETS).
Goodness. Total energy-production bomb.
The entire energy complex breaks down:
Our results showed a significant decrease in the activity of complex I–III in the PSD and rebound groups as compared to the control group. The complex II and II–III activity were particularly decreased in the hypothalamus of the sleep rebound group.
The hypothalamus is just the very vulnernable seat of memory and mood control.
Remember…this removal process is happening every day:
A significant percentage of the mitochondrial mass is replaced on a daily basis via mechanisms of mitochondrial quality control.
A big part of sleep may indeed be cellular housekeeping around our energy complex…mitochondria!
We've looked at how progesterone, estrogen, and testosterone all have huge impacts on sleep quality.
They're also managed and manufactured…by our mitochondria which begs the question with aging…which drops first? (see steroids and longevity).
Here's our sleep toolkit and we have a whole section on CBD and sleep (since that's our original focus).
Expect more research on this front. One note…PQQ may directly support our circadian rhythm by re-aligning cortisol (the primary wake signal) rhythm:
Measures for quality of life, appetite, sleep, obsession and pain, also improved significantly. The results of the Oguri-Shirakawa-Azumi Sleep Inventory (Middle Aged and Aged version) showed significant improvement in sleepiness at awakening, sleep onset and maintenance, and sleep duration.
20mg at 8 weeks. Go figure….support of mitochondria causes a virtuous loop that then translates into…
Let's turn to the known player with fascinating results.
Tip 10 - Fasting - giving the energy complex a break for repair
Research is pretty well established on calorie restriction, fasting, intermittent fasting, and even Keto (a selective form of starvation) and longevity or any metric of health for that matter.
We know AMPK gets ramped up.
By reducing energy creation, calorie restriction allows for a more efficient mito complex:
In effect, CR can induce a peroxisome proliferation-activated receptor coactivator 1α-dependent increase in mitochondria capable of efficient and balanced bioenergetics to reduce oxidative stress and attenuate age-dependent endogenous oxidative damage.
To translate, CR (calorie restriction) or fasting or keto, etc:
- Activates PGC1gamma from above which drives mito creation
- Improves efficiency of mito
- Reduces damaging waste product (ROS, etc)
Basically, it's like running your engine below the redline. You could argue it's akin to what happens during sleep!
In fact, removal of bad mito also occurs:
Most of the studies showed that fasting or CR induced mitophagy and mitophagy-related markers such as Binp3 and Parkin.
AMPK and mTOR are big guns managing the show but it's a mitochondrial production through and through.
SIRT is just the foot soldier with access to DNA keys.
Even intermittent fasting (like the 16/8 schedule…no eating for 16 hours..say from 6pm to 10am) can claim this effect.
In conclusion, TCF could represent an effective strategy to limit mitochondrial impairment and metabolic inflexibility that are typically induced by modern western diets or during aging.
TCF is "time controlled fasting". Like 16/8.
Even our energy plants need "downtime" for maintenance. Appears to be a universal law.
That's a wrap. We'll do a deep dive on PQQ since it's so impressive in research.
There are a few stragglers at least deserve a mention.
The Grab Bag - magnesium, NAC, glutathione, NMN, and B vitamins.
We'll go through these fast.
Magnesium glycinate and mitochondria
Magnesium glycinate is a key building block for the mitochondrial complex:
Taken together, the data suggest that Mg2+ has significant impact on the metabolic state, which is mediated by its stimulatory effect on the above-mentioned mitochondrial enzymes.
Mg supplementation improved mitochondrial function, reduced oxidative stress, and prevented DD in DM.
DD and DM are measures of heart dysfunction…a big consumer of energy.
We have a huge review on magnesium glycinate (cross the blood brain barrier…the other big user of energy).
NAC, glutathione and mitochondria
Glutathione is our key detox pathway. The "ox" in detox is from oxygen as in ROS (Reactive oxygen species) that leak out mitochondria.
It's a big deal to keep the local mito environment from burning itself down:
mitochondrial glutathione (mGSH) emerges as the main line of defense for the maintenance of the appropriate mitochondrial redox environment to avoid or repair oxidative modifications leading to mitochondrial dysfunction and cell death.
Big review on glutathione or oxidative stress.
One easy way to support is NAC.
This becomes apparent in disease states that reflect mitochondrial dysfunction:
Our results demonstrate that NAC improves mtGSH levels and mitochondrial function in oligodendrocytes, indicating that it has potential use in the treatment of ALD and related disorders.
Big review on NAC here. Buy here
NMN, NR, and NAD for mitochondrial
We're getting into the currency of energy production now.
There's competing and conflicting views on which is better but they all support NAD, the carrier of energy around the cell.
SIRT requires NAD to function and there's clear interaction with mito function.
NMN administration increases mitochondrial NAD+ pools and drives the reduction of mitochondria generated ROS via a SIRT3 dependent deacetylation and stimulation of SOD2 activity.
NAD can be directly supplemented as well and we'll leave the horse race to others on which is better to support this whole pathway (with NAD being the ultimate goal).
B vitamins and mitochondria.
They're all over the place here:
B-vitamins are water-soluble vitamins (Figure 1) that are essential nutrients in supporting mitochondrial function, predominantly by serving as nutritional cofactors or coenzymes for enzymes that are located in mitochondria
Check for MTRR or MTHFR gene variants and consider a methylated B complex.
It's a simple building block but an essential one!
Of course, Vitamin D and steroidal hormones (bioidentical) are critical to everything we've discussed. Work with your doctor and get your levels tested!
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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.