Longevity principle #4. How to improve cellular energy to live longer? (part 2)

This article was originally published on medium.com on August 1, 2020.

Reading time: 25 min

Disclaimer

This article is based on my research of information from publicly available sources and my personal experience. I’m not an MD or PhD in molecular biology but have a curious mind to figure things out for myself and have good analytical skills (PhD in Economics and former McKinsey consultant). The information, opinions, and references provided in this article are for informational purposes only. This article is not a medical advise and is not intended to treat, diagnose or prescribe for any illness or condition. Please consult your doctor or healthcare provider for your specific diagnosis and treatment.

Introduction

This is the 6th article in the Longevity principle series. In this article, we deep-dive into Longevity principle #4 looking at the what, the why, and the how of mitochondrial health to improve cellular energy:

• The “What”: what we want for longevity
• The “Why”: what is often wrong and why this happens
• The “How”: what you could practically do and how it minimizes aging

This longevity principle is also described in a concise way in Google Slides below. This article offers more details and explanation.

Summary

In the longevity principle #3, we talked the basics of about mitochondrial health which include:

1. Maximizing the number of mitochondria
2. Maximizing energy generated by each mitochondrion
3. Minimizing the number of damaged mitochondria

Points #2 and #3 were addressed in the previous article. In this article, we talk about the point #1 how to maximize the number of mitochondria by growing new mitochondria. This process is called mitochondrial biogenesis.

The rest of this article will go into some details about how we can trigger mitochondrial biogenesis but here’s the gist of it:

Now let’s dive in into the what, the why, and the how.

The “What”: what we want for longevity

This section will get a bit scientific but these details are important to understand how we can grow new mitochondria.

What is mitochondrial biogenesis and why is it needed?

As a refresher and to understand why mitochondrial biogenesis exists, let’s review key concepts related to mitochondria:

• Mitochondria is a primary source of energy generation in our cells— up to 90% of all cellular energy comes from mitochondria.
• There are hundreds to thousand of mitochondria in each cell with metabolically active cells (liver, heart, muscles, and brain) having thousands of mitochondria.
• Mitochondria constantly generate free radicals which attack our genes 10.000 to 100.000 times a day. Free radicals are highly reactive and they don’t usually travel too far (e.g., to the cell nucleus)— they mostly attack mitochondria itself damaging: (i) lipid membranes and proteins which are responsible for ATP (i.e., energy) generation, and (ii) mitochondrial DNA (mDNA) which encodes the most mitochondrial functions (that’s why mDNA was retained in mitochondria — a “free radical danger zone” — instead of being transferred to the cell nucleus where most of our DNA resides).
• To respond to the free radical damage, mitochondria have a system of checks and balances: (i) they commit mitochondrial suicide (mitophagy) to eliminate potentially mutant mitochondria and when their energy production capacity is below a certain threshold (signalling that mitochondria may be damaged); (ii) they constantly remodel their network through fission (splitting) and fusion (combination) to respond to changes in energy capacity and demand. (iii) they also self-replicate and grow new mitochondria in a process called mitochondrial biogenesis — that’s what we focus on in this article. See illustration below to better understand the relationship between fission/fusion, mitophagy, and biogenesis.

Mitochondrial biogenesis is a process by which cells grow new mitochondria to compensate for potential energy deficiencies.

What is required for mitochondrial biogenesis to happen?

To build new mitochondria, the body needs:

• the building blocks — proteins and lipids. New mitochondria are not created from scratch (“de novo”) but rather come from growth and replication of pre-existing mitochondria. That is why you’d better keep your existing mitochondria nice and healthy (we talked about how previously) because you don’t want to replicate deficient mitochondria into more deficient mitochondria.
• the instructions on how to synthesize and assemble mitochondria from the building blocks — genetic code (DNA). Human mitochondria require about 1.500 protein-coding genes. Most of these genes for the mitochondria are encoded in the nuclear genome with mitochondrial genome encoding for only 13 proteins (which are essential for the electron transport chain). As a side note, lipids are not encoded by genes but are defined by metabolic pathways dependent on sets of enzymes (proteins).
• the accurate transcription of the genome. Given that 2 sets of genomes are used — nuclear and mitochondrial — a closed and fine-controlled coordination between them is crucial. This coordination is a complex task because precursor proteins (i.e., components of the final proteins) are built outside of the mitochondria (in the cytosol) and, thus, a process to target (grab the right parts), import to mitochondria, and correct protein assembly is needed to ensure correct mitochondrial function and shape. This process is primarily regulated through a transcription co-activator called PGC-1alpha.

Mitochondrial biogenesis happens primarily through activation of PGC1a signaling pathway. To grow new mitochondria, we need to activate this pathway.

How to activate the PGC1a pathway?

The PGC1a pathway can be activated by different types of stress such as exercise, fasting, low temperature, and oxidative stress. To keep things simple, we won’t talk about the many specific pathways in detail in this article but I’ll briefly mention a few pathways because this will be important for better understanding of the “how” section:

• AMPK: an enzyme that acts as a sensor of the cellular energy state, at both the cellular and whole-body state, based on the changes in intracellular AMP levels or external cues such as nutrients and hormonal signals. See more on AMPK in the longevity principle #2.
• SIRT1: a protein that acts as a sensor of the cellular energy state based on the levels of NAD+, a co-factor that is central to metabolism being involved in redox operations (carrying electrons from one operation to another). See more on SIRT1 in the longevity principle #2.
• Calcineurin: a calcium/calmodulin-dependent protein phosphatase known to be the master regulator of fast-to-slow twitch muscle-fibre-type changes. Some studies suggest that endurance training activates mitochondrial biogenesis via this pathway.
• p38 MAPK: a class of mitogen-activated protein kinases (MAPKs) that are responsive to stress stimuli such as cytokines, ultraviolet irradiation, heat shock, and osmotic shock, and are involved in cell differentiation, apoptosis and autophagy.
• NO (nitric oxide): the exact role of NO in mitochondrial function is still obscure and somewhat controversial. It’s been shown to play a signaling role in the nucleus to induce PGC1a and activate mitochondrial biogenesis. However, NO may play a negative role on the mitochondria by inhibiting the electron transport chain, mainly at Complex IV, regulating oxygen consumption and ATP generation. It seems that the biological effects of NO depend on local concentration of NO, source of NO generation, duration of NO exposure, and microenvironment (ROS). NO has been shown to form a positive feedback loop with AMPK to trigger growth of new mitochondria. The amount of nitric oxide production decreases with aging. The good news that there are some simple ways to at least slow down this process.

Mitochondrial biogenesis is activated by an external stimulus such as exercise, fasting, low temperature, and oxidative stress.

What does the PGC1a pathway do?

PGC1a is considered the master regulator of mitochondrial biogenesis so it regulates key factors involved in this process. Specifically, PGC1a induces the expression of nuclear respiratory factors (ERRα, PPARs, Nrf1, and Nrf2) which upregulate the expression of nuclear genes encoding mitochondrial proteins and the expression of mitochondrial transcription factor A (TFAM). TFAM is subsequently transported into mitochondria where it binds to mitochondrial DNA (mtDNA) and activates the transcription and replication of the mitochondrial genome.

Overall, the process of mitochondrial biogenesis looks something like this:

Schematic representation of mitochondrial biogenesis. Source: Emanuele Marzetti

Before moving on, it’s interesting to emphasize Nrf2 for 2 reasons:

• Nrf2 regulates the expression of the antioxidant genes in response to stress. You might have heard of hormesis, a beneficial type of stress. Now you know — it is mediated by Nrf2.
• Some authors suggest the direct involvement of Nrf2 in mitochondrial biogenesis rather than it being regulated by PGC1a. If that’s the case, then health & longevity interventions should be targeted directly at Nrf2. Indeed, there are interventions which seem to activate Nrf2 independently from PGC1a. Though whether Nrf2 works independently from PGC1a remains a matter of scientific debate.

How is this related to aging?

Growth of new mitochondria is most important in metabolically active tissues — tissues which produce and consume the highest amount of energy. It’s important to point out that ATP (energy produced by mitochondria) is consumed where it is produced — it does not travel outside of the cell and does not circulate in our blood. That means that that the most metabolically active tissues have the highest number of mitochondria. That also means that there is more free radical damage to mitochondria in these cells from a more active metabolic process. That means a stronger need for new mitochondria to compensate for damaged mitochondria as well as to add more extra mitochondria to meet energy demands (to not stress existing mitochondria too much). In the first article in this series, I’ve written that this is one of the main reasons why birds live longer — they stress their mitochondria less.

The most metabolically active tissues have the highest number of mitochondria which experience more free radical damage and, thus, need more new mitochondria to compensate for damage and meet energy demands.

So what are the most metabolically active tissues?

• Oocytes — an immature egg cell which is the beginning of human life. Oocytes contain 100.000 mitochondria per cell because these cells need a lot of energy for oocyte maturation, fertilization, and embryo formation. Lower ATP production and decreased mitochondrial function have been shown to negatively impact fertility (or at least there is a correlation). Conversely, higher ATP production (which is a function of higher mitochondrial quantity) improves fertility. David Sinclair, in his best-selling book “Lifespan”, mentions that his student’s mother and some other women who took NMN experienced a restart of healthy menstrual cycles after menopause. There is some conflicting evidence on whether NMN leads to mitochondrial biogenesis or not but it does lead to improved ATP production.
• Smooth muscles. It is an involuntary muscle, i.e., it contacts without one’s will. These muscles are found in most of our organs including the digestive system, the walls of passageways (e.g., arteries and veins), and interestingly in the skin (they cause hair to stand in response to cold or fear). Smooth muscle cells have fewer mitochondria than oocytes but still a lot of them such as liver cells which have 500–4.000 mitochondria per cell. There is significant evidence on a correlation between disruption of mitochondrial biogenesis leads to aging and dysfunction of smooth muscles (for example, in the vascular system).
• Cardiac (heart) muscle. Similar to smooth muscle it is also an involuntary muscle but striated featuring repeated functional units called sarcomeres (in this sense it is similar to skeletal muscle). Heart muscle cells have about 5.000 mitochondria per cell. Overall, continuously working muscles (striated such as cardiac or skeletal muscle) have more mitochondrial activity and content than sporadically functioning muscles (non-striated such as back muscles). As you might guess, mitochondrial biogenesis is also impaired in aged heart muscle cells.
• Skeletal muscle. This is a muscle type which first comes to mind when we talk about being muscular. This is also a striated muscle tissue (same as cardiac muscle) but it is under the voluntary control of the somatic nervous system. In skeletal muscle, the number of mitochondria per cell depends on the type of muscle — slow-twitch with more mitochondria vs. fast-twitch with fewer mitochondria. While fast-twitch muscles have fewer mitochondria, their mass declines more with aging. After the age of 30, both muscle mass and strengths start to decline at a rate of 0.3% to 1% per year. You guessed it right — resistance training would be one of the recommendations.
• Brown adipose tissue (BAT) or brown fat. There are 2 major types of fat — brown and white. The key function of BAT is to dissolve energy as heat. Interestingly, BAT prevalence decreases with age. The key function of white adipose tissue (WAT) is to store energy (and also to make us look fat). The key difference between brown and white fat is that brown fat has a lot of mitochondria and many lipid droplets while white fat has very few mitochondria and one lipid droplet. The good news is that you can convert white fat into beige fat which has similar properties to brown fat. This is how you can grow more mitochondria and we will talk about it later in this article.

The takeaway from the above overview is that there are different types of cells. Growth of new mitochondria in most of them is activated by the same pathway (PGC1a) but this pathway is often triggered by a different external stimulus specific for that type of cell (for example, different types of supplements and drugs).

Overall, there is ample evidence that mitochondrial biogenesis declines with aging and is inhibited in different diseases of aging such as Parkinson’s disease and Type 2 diabetes.

Putting it all together

Let’s summarize:

• More mitochondria in general is better because it maximizes cell metabolic capacity. The exception is cancer cells where stronger mitochondrial biogenesis is bad because it leads to cancer cell growth. More mitochondria means less mitochondrial capacity is “utilized” which means less damage to mitochondrial DNA, protein, and lipid membranes.
• External stimulus is needed to trigger mitochondrial biogenesis. Different types of external stimuli exist which put stress on mitochondria to induce biogenesis.
• Mitochondrial biogenesis is controlled by PGC1a signaling pathway. It’s useful to know because if you read a scientific article and it mentions that something activates PGC1a, know that it leads to growth of new mitochondria.
• Last but not least, it’s important to keep existing mitochondria nice and healthy because new mitochondria are built using existing ones. I wrote extensively on it in the previous article.

The “Why”: what’s often wrong and why

I will keep this chapter short because the majority of the “whys” behind what inhibits growth of new mitochondria are the same issues which have been covered extensively in the previous article on the longevity principle #3. So what often happens is:

• Constant mode of low energy expenditure and high energy availability from eating too much, eating bad foods or not working out.
• Low cell metabolic capacity which means that mitochondria are “utilized”at full capacity to generate energy. This creates an environment which leads to excessive wear-and-tear of existing mitochondria.

The “How”: what you can practically do and how it minimizes aging

To trigger mitochondrial biogenesis, our bodies need a “stress” signal. As always, let’s look at the key categories of nutrition, physical activity/exercise, environment, accessories, and supplements.

Nutrition

Fasting and caloric restriction do NOT induce mitochondrial biogenesis

Description.
In previous chapters, we talked about fasting and different forms of caloric restriction as an effective and universal way to “stop the growth mode” and “protect mitochondria”. Unfortunately, as universal as they are, fasting and caloric restriction do not trigger growth of new mitochondria. In one study, a group of healthy men fasted for 48-hours but that didn’t induce mitochondrial biogenesis. Same story with caloric restriction (CR) — unlike previously reported in this and other studies, CR (25–30% fewer calories) does not seem to induce mitochondrial biogenesis during 3 months and even as long as 12 months.

Recommendation.
To be clear, both interventions work great for longevity but via different pathways such as SIRT1. Continue doing fasting and CR but know that it don’t seem lead to growth of new mitochondria, unlike many studies claim.

Modified keto-diet

Description.
Ketogenic diet is very effective at inducing mitochondrial biogenesis and I’m particularly excited about this aspect of this diet. While there is some debate about how keto diet does it, it looks like multiple mechanisms are at play. One of the important mechanisms is increased reliance on fat oxidation leading to oxidative stress which in turn triggers hormetic adaptation (i.e., hormesis or beneficial type of stress). However, it’s important to follow a modified keto diet, i.e., regularly add more carbs as last meal to avoid insulin resistance and improve mucous lining. As discussed in the longevity principle #2 “how to pause the growth mode”, being in constant ketosis has been linked to insulin resistance in rats and mice but this might translate to humans too. Our bodies need to sense glucose periodically to secrete insulin and stay sensitive to it. This is called metabolic flexibility.

Recommendation.
Follow a “clean” keto diet but regularly regularly add more carbs as last meal. I will talk more about what modified keto-diet is in future articles but for now — Dale Bredesen offers a good outline of a modified keto-diet in his book “The End of Alzheimer’s”.

Dark chocolate/cocoa

Description.
Dark chocolate/cocoa is very unique — it has the highest amount of PQQ or Pyrroloquinoline Quinone among any foods. PQQ has been shown to induce mitochondrial biogenesis. Chocolate/cocoa has up to 760 ng of PQQ per gram. The second highest PQQ content is in fermented soybeans — up to 61 ng/g or 15x less than in cocoa — but it’s best to avoid them anyway due to mycotoxins. Green tea is also high in PQQ (up to 29 ng/g) but it has 30x less than cacao.

Recommendation.
Consume plenty of dark chocolate. I consume 30–50 grams of 99–100% chocolate on most days. My favorite brands are Montezuma (find at Trader Joe’s), Scharfeen Berger (find on Walmart or Amazon), Vivani (find on eBay), and Blanxart (find on eBay).

Consume “healthy” phytochemicals and avoid “potentially unhealthy” phytochemicals

Description.
Phytochemicals are chemical compounds produced by plants, generally to help them thrive or thwart competitors, predators, or pathogens.

Phytochemicals work to promote stress in our body and our bodies become stronger thanks to a hormetic response via Nrf2 pathway activation.

There are many types of vegetables, fruits, nuts, and herbs containing phytochemicals. Cacao is one of them.
Not all phytochemicals are created equal and good for you. Avoid “potentially unhealthy” phytochemicals: foods high in lectins (mostly nightshade family vegetables, legumes, and grains), potential phytoestrogens (such as soy which may be phytoestrogenic), and high fructose fruits (such as grapes).

Recommendation.
— Consume “healthy” phytochemicals: cruciferous vegetables (broccoli, asparagus, brussels sprouts, cauliflower, radish, etc.), leafy greens, roots, berries, etc.
— Avoid “potentially unhealthy” phytochemicals: foods high in lectins, potential phytoestrogens, and high fructose fruits.

Physical activity/exercise

Endurance exercise

Description.
Endurance, also called aerobic, exercise is mainly related to slow-twitch muscles which have more mitochondria than fast-twitch muscles (mainly related to resistance training). Endurance training is very effective at triggering mitochondrial biogenesis — more effective than resistance training, at least in younger humans. Endurance exercise triggers growth of new mitochondria via PGC1a pathway. Several mechanisms are at play:
(i) AMPK activation due to the alteration of ADP/ATP ratio;
(ii) p38 MAPK activation following oxidative stress — it might explain one of the paradoxes of extreme endurance training (e.g., marathons) that while it leads to high levels of ROS, it doesn’t lead to faster aging;
(iii) SIRT1 activation by the redox state (higher NAD+ levels);
(iv) Ca2+/calmodulin-dependent protein kinase II (CAMKII) and Calcineurin activation due to calcium release from sarcoplasmic reticulum following muscle contraction.

Recommendation.
Practice aerobic exercise (running, cycling, swimming, walking) at at least half of your maximum capacity for 15–20 minutes per session, 3–4 times a week.

Resistance exercise and HIIT

Description.
Resistance exercise mostly trains fast-twitch muscles which have fewer mitochondria than slow-twitch muscles. Fast-twitch muscles are about the muscle size — it is what makes people look muscular. It is also the thing that goes away with aging — at a rate of about 1% per year. Studies show limited to no mitochondrial biogenesis from resistance exercise in younger populations — you do get more mitochondria from large muscle mass (new cells) but not due to mitochondrial biogenesis (new mitochondria in existing cells). The reason is because resistance exercise works via a different pathway — mTOR (modulates growth) vs. AMPK (modulates low-energy state). However, there are clear benefits in mitochondrial biogenesis for older population. One study showed a ~30% increase in the number of mitochondria in a group of 69-year old female and male subjects.
There is one exception to this — HIIT or high intensity interval training seems to grow new mitochondria in both younger and older subjects.

Recommendation.
— Practice resistance training, especially as you get older to compensate for muscle loss and, thus, mitochondrial loss
— Practice high intensity interval training

Environment

Cold exposure

Description.
Remember white fat which makes us look fat? It turns out you can convert that white fat into beige fat which is similar to brown fat in that it is rich in mitochondria and is capable of thermogenesis — burning energy for heat. In addition, cold exposure activates brown fat which has been discovered relatively recently — until fairly recently, it was believed that brown fat exists on in human infants and small mammals because they are more prone to hypothermia. There are many studies on this subject. One study looked at 22 subjects with no or undetectable activity of BAT and subjected one group to 2 hours per day of cold exposure at 17° C (~63° F) for 6 weeks. This resulted in ~60% increase of BAT activity and ~5% body fat mass decrease in the cold exposure group. But it looks like even some cold exposure works (just feeling cold), not necessarily at low temperatures. In one study, 28 healthy non-selected participants were randomized to experience some cold (with no specific temperature target) for 1 hour per day (test group) or to avoid any sense of feeling cold (control group) for 6 week. After 6 weeks, the test group had a ~23% increase in BAT activity compared to no change in BAT activity in the control group.

Recommendation.
— keep the room temperature at 66° F (19° C) or lower
— do cold showers for 0.5–2 minutes daily (morning is better)
— practice cryotherapy
— do ice baths
— walk in the cold, etc.

Accessories

High frequency whole body vibration

Description.
High frequency whole body vibration (WBV) has a ton of benefits. It’s been around for over 15 years but new benefits are still being uncovered. Traditionally enhanced metabolism, increased bone mineral density, reduction of cortisol, elevation of human growth hormone levels, improved lymphatic flow, and stimulation of collagen production have been cited among the benefits. Some recent research shows that whole body vibration triggers growth of new mitochondria mimicking the metabolic effects of exercise. In one study, two groups of rats — normal diet and high-fat diet — were further split in two groups — one subjected to whole body vibration for 15 minutes a day (test) and the other one not subjected any vibration (control). After 8 weeks, both of the WBV groups (normal diet and high-fat diet) had significantly higher activity of BAT with stronger results in high-fat diet (obese) groups of rats.

Recommendation.
Consider getting yourself a vibration platform at home and use it for 10–15 minutes a day — see “In practice” section below for more details.

Red and near-infra-red (NIR) light exposure

Description.
In the previous article, I described benefits of Red/NIR light exposure for improving oxygen uptake in mitochondria by enabling better pairing with Cytochrome C Oxidase. But that is not the only mechanism by which Red/NIR light improves mitochondrial health. The second main mechanism (there are a few more out of scope of this article) is by creating an increase in ROS (free radicals) which activates the cell defense systems. In particular, it activates the Nrf2 signaling pathway which induces antioxidant defense and promotes growth of new mitochondria.

Recommendation.
Use red and near-infrared light therapy every day / every other day for 30–60 minutes.

Mouth tape when sleeping

Description.
How do you breath at night — through your mouth or nose? Chances are you breath through your mouth at least during some stages of sleep. That is bad because oral breathing may lead to many potential issues including increased levels of dental plaques and Gingivitis. Though what concerns us with regards to growing new mitochondria is that oral breathing leads to a 4x lower level of Nitric Oxide (NO) compared to nasal breathing. That’s a lot of new mitochondria you could have grown just by breathing through your nose. Unfortunately, it’s hard to start breathing through your nose at night just by sheer will. That’s why I use a mouth tape. Because we spend almost one third of our life sleeping, nasal breathing at night is so important.

Recommendation.
Use mouth tape when you sleep. You might want to experiment with a few shapes to see what fits you best. I buy this one on Amazon.

Supplements and drugs

There are many supplements and drugs which have been shown to promote mitochondrial biogenesis. I will only focus on the key ones (most studied and/or easily available) grouped by a mechanism of action — PGC1a activators, AMPK activators, and Nrf2 activators.

PGC1a activators

PQQ — Pyrroloquinoline Quinone
We briefly talked about PQQ in the nutrition section — dark chocolate has a lot of PQQ. PQQ has many benefits to mitochondria and it also induces mitochondrial biogenesis via PGC1a activation and likely some other not yet fully understood pathways. Interestingly, in 2003, Nature published an article which presents a direct molecular evidence that PQQ should be classified a B group vitamin. By definition, a vitamin is something our bodies can’t synthesize and need to obtain through the diet. Sadly, most PQQ is sold as stabilized disodium salt (such as Jarrow PQQ) — when exposed to even small amounts of stomach acid, they precipitate (turns into useless chunks). That’s why you need to either take large amounts of PQQ (very expensive) or buy a liposomal form. I don’t take PQQ for these reasons — but I do eat plenty of 100% chocolate.

AMPK activators

Metformin
Metformin has been shown to increase the skeletal muscle content of PGC-1α in rats (suggesting increased mitochondrial biogenesis) likely via AMPK phosphorylation. Metformin is a prescription drug — talk to your doctor before using it. Metformin may also have excess levels of carcinogens such as NDMA so it’s important to make sure you buy a high quality product. I wrote about it here.

Oxaloacetate
Oxaloacetate is an intermediate in the Krebs cycle. It has been shown to activate PGC1a and induce mitochondrial biogenesis in mice. Multiple pathways have been involved in activation of PGC1a including AMPK, p38-MAPK, and NFkB. One of the issues with oxaloacetate supplements is bioavailability — you need a thermally stabilized version. I use benaGenewhich has a patented formula. Disclaimer: I have no affiliation with them.

MCT Oil
As discussed above, the ketogenic diet promotes mitochondrial biogenesis. Medium chain triglycerides oil can put you in a state of ketosis right away. This study has demonstrated that MCT oil promoted mitochondrial biogenesis through AMPK activation. I use Brain Octane Oil by Bulletproof. This is the only product on the market which is 100% C8 oil. All of the other brands have some C10 or C12. Disclaimer: I have no affiliation with them.

D-Glucosamine
Glucosamine is a natural compound found in in the shells of shellfish, animal bones, bone marrow, and fungi. D-Glucosamine is manufactured by processing chitin from the shells of shellfish including shrimp, lobsters, and crabs. In one study, D-Glucosamine has been shown to increase lifespan of nematodes and of ageing mice, possibly by inducing mitochondrial biogenesis via upregulating AMPK pathway.

Nrf2 activators

What are Nrf2 activators?
Nrf2 expression can be increased by consuming foods containing phytochemicals (e.g., broccoli), phytochemical supplements, and drugs. The general logic is that Nrf2 activators promote a small stress which in response activates Nrf2 which mediates antioxidant pathways. We will focus only on a few supplements and drugs here.

It’s worth highlighting that there is still a debate whether Nrf2 actually leads to mitochondrial biogenesis or is only involved in the process but can’t induce it.

Phytochemicals: curcumin, fisetin, quercetin, resveratrol
Phytochemicals is a broad group of chemical compounds with varying properties. Different types of phytochemicals exist generally grouped into polyphenols, terpenoids, and thiols with many additional subgroups.
The best studied Nrf2 activators are probably the following ones:
— curcumin (from turmeric spice);
— fisetin (from strawberries, apples, persimmons, onions, and cucumbers);
— quercetin (from onions);
— resveratrol (from grape skin).
Be aware that phytochemicals can also promote cancer cell growth, for example, sulforophane in colorectal cancer.

Lithium
Lithium is the most commonly prescribed drug for the treatment of bipolar disorder. Lithium promotes mitochondrial biogenesis by activating a stress-dependent Nrf2 pathway and it has been shown to promote lifespan in flies. The issue is that it’s highly dose dependent — in higher doses, it becomes very toxic and test subjects die quickly. I take 1 mg of lithium orotate dailywhich is unlikely to be toxic long-term.

Methylene blue
Methylene blue is an inhibitor of nitric oxide synthase and guanylate cyclase. In multiple studies it has been shown to induce mitochondrial biogenesis, for example, in mid-age mice. It works by upregulating Nrf2 pathway. It’s not a mainstream supplement, at least yet, so make sure you purchase a high quality product and do not exceed the recommended doses as it becomes toxic at high doses.

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‍Nicotine
In addition to being a potent nootropic (nicotine imitates the action of a natural neurotransmitter called acetylcholine), nicotine has been shown to upregulate PGC-1a pathway leading to mitochondrial biogenesis in neuronal cells. So you not only think better short-term but also become smarter long-term. Obviously, you do not want to get nicotine from cigarettes because of carcinogens in tobacco smoke. I prefer to use nicotine spray which gives 1 mg of nicotine per spray. I spray it in ~4oz/~100ml of water instead of spraying in my mouth to avoid throat irritation. The second option is nicotine lozenges but they usually contain artificial sweeteners (which damage your gut microbiome) and have at least 2 mg of nicotine per lozenge (which makes me nauseous).

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In practice

My personal favorites to trigger growth of new mitochondria are:

• Cold exposure
• High frequency whole body vibration
• Near-infra-red and red light exposure

Cold exposure

Cold exposure is my favorite. On a daily basis, I do at least 2 minutes of cold shower. Cold tap water should be between 50°F/11°C to 60°F/16°C degrees which is moderately cold although I haven’t measured it.

I also do “cold therapy treats” when time and circumstances allow. Here is my 15-minute walk in the cold in Utah in November. That’s negative 12°C degrees which is 10°F degrees.

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My second favorite cold therapy treat is ice bath. I fill my bath tub with the coldest tap water, put ~30 lbs of ice from a grocery store, and jump in for 5 minutes. I do this on a monthly basis due to practical limitations of getting ice delivered but doing more often (a few times a week) should be even better. Wim Hof is the guy to learn from on ice bathing. Here is my short Instagram video on it.

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High frequency whole body vibration

The next one on the list is high frequency whole body vibration (WBV). As discussed above, WBV seems to mimic the effect of physical exercise and activate brown and beige adipose tissue (aka fat).

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There are 2 main types of whole body vibration — linear (platform moves up and down) and oscillating (platform moves side to side). Each type has its own benefits. Don’t believe experts which say that either one is better. You’re most likely to hear that oscillating is better because it’s been around for longer and there is more research on it. But that’s not true. Both are good but different.

I prefer a linear platform because you can introduce some activities such as push ups in your daily 10–15 minute vibration session.

Whole body vibration platforms are not cheap but the ROI seems high. A new good platform would cost you anywhere from $1.000 to 5.000 or more. You can find cheaper used options on eBay or elsewhere (I bought a slightly used platform for $700 while the new one costs $1.495).

If you want a vibration platform you have to decide first if you go for a linear or an oscillating platform. To be frank, I’m not an expert on specific brands but here are some options for linear platforms:

• VibePlate. I like 3048 because it’s long enough that you can do yoga on it while vibrating) but it requires a lot of space and weighs 100kg. VibePlate 2424 is another good option.
• Bulletproof. It has only one setting (35Hz) but is relatively cheaper compared to other brands.

Some options for oscillating platforms:

• GalileoFit. It is the gold standard — they invented whole body vibration and most of the studies use their platforms. It is super expensive though.
• VBS. This seems to be a popular machine with a lot of used platforms on eBay at attractive prices.
• HyperVibe. Seems to be a good option at ~$1.000 based on my research.

What’s next to come

In the next article, we will focus on the Longevity principle #5 “How to protect gut-blood barrier to live longer?”.

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