One of the hallmarks of intelligence is a well-balanced GABA/glutamate ratio

Interestingly neurogenesis significantly improves this, for example via activation of the TrkB receptor by BDNF

TrkB activation:
- upregulates GABA-A receptor expression
- increases glutamate -> GABA conversion by upregulating the GAD pathway
- upregulates KCC2 which maintains low chloride concentration within neurons, maintaining susceptibility to GABA-induced chloride influx

Exercise, as well as various foods/herbs, increase BDNF expression

Several flavonoids also activate TrkB directly including:
- tropoflavin
- eutropoflavin
- norwogonin (Skullcap)
- apigenin (chamomile)
- chrysin

Psychedelics including LSD and psilocin also potently activate TrkB, which likely mediates many of their antidepressant effects Partial TrkB receptor activation suppresses cortical epileptogenesis through actions on parvalbumin interneurons
sciencedirect.com/science/articl…

BDNF-trkB-KCC2-GABA pathway may be related to chronic stress-induced hyperalgesia at both the spinal and supraspinal level
sciencedirect.com/science/articl…

"X, Y, and Z increase neurogenesis"

The unifying mechanism of herbs, foods, and practices like exercise that promote neurogenesis is that they help increase the three main requirements of neurons

Energetic substrate, oxygen, and stimulation

A huge amount of herbs that increase BDNF do so via the latter two mechanisms, they stimulate neurons and increase blood flow

Bacopa, gotu kola, and gingko biloba are good examples, they stimulated neurons by raising acetylcholine/serotonin/dopamine and increase circulation via mechanisms like PDE inhibition

While the brain's preferred fuel is glucose, hyperglycemia inactivates neurogenesis

Many herbs and foods, like ginseng and cacao, promote insulin sensitivity and glucose uptake and utilization by the brain

Alternative fuels that signal energy depletion also drive neurogenesis in a hormetic fashion, specifically ketones and lactate

This is why high cognitive activity and exercise are so beneficial, they are extremely stimulating to neurons, enhance stimulation, and create a shift from glucose -> lactate/ketones There are other specific mechanisms of certain compounds, such as directly binding nerve growth factor receptors like TrkB and TrkA

This is one of the reasons why psychedelics are so remarkable, they bind to these neurogenesis-activating receptors with high affinity

Agonism of certain serotonin receptors like 5HT2A can also cross-activate TrkB through the formation of dimers between the two receptors

I believe dopamine can have a similar effect, though these neurotransmitters also play a role in stimulation

Blue lotus is the serotonin antagonist cyproheptadine wishes it could be Cyproheptadine = antihistamine with some additional serotonin antagonism

Blue lotus = mixed dopamine agonism, serotonin antagonism, and some additional histamine antagonism

Small amounts of DMT are actually synthesized in the lungs from serotonin to protect against hypoxia

Psychedelics have the same effect in the brain

This means DMT-induced near-death experiences may serve as the brain's final attempt to protect itself when major hypoxia occurs "Results showed that DMT robustly increases the survival of these cell types in severe hypoxia"

"We postulate that this compound may be endogenously generated in situations of stress, ameliorating the adverse effects of hypoxic/ischemic insult to the brain"
pmc.ncbi.nlm.nih.gov/articles/PMC50…

Serotonin, hypoxia, and the blood-brain axis

Serotonin is one of the most complex and misunderstood transmitters in biology

It traces a connection between the gut, blood, lungs, and brain that coordinates stress responses throughout the body

THREAD // We can "frame" serotonin in different ways

The mainstream view is that serotonin is a neurotransmitter that regulates happiness, anxiety, and sociability

While there is some truth to this, it exist within a spectrum, excessive serotonin is analgesic and emotionally blunting

Let's talk about flavonoids

THREAD // Flavonoids are one of the most medicinal classes of active compounds found in food and herbs

If you've seen discussion of "polyphenols" or "antioxidants" in fruits and vegetables this essentially always refers to flavonoids

Similarly most plant pigments are actually flavonoids

If you're new to my work, START HERE:

These are ten first principles that the average person can implement to improve their health

THREAD // 1. Magnesium saturation

Magnesium should be dosed daily using well-absorbed forms until a surplus is achieved for your individual biology

Magnesium glycinate, magnesium taurate, and magnesium malate are my favorite oral forms, while magnesium chloride or epsom salt (mag sulfate) can be used topically

Doses should be spread out throughout the day to avoid a laxative effect, higher doses can be taken before bed (breakfast/lunch/dinner is a good schedule to start)

Start with a dose of 100-200mg elemental magnesium and work up from there

You can also make topical magnesium spray with 1/4-1/2 cup of magnesium chloride added to 1 cup of water in a glass spray bottle

1-5+lbs of magnesium can be added to a bath or foot soak tray as well

THE AXES OF AGING

For the last two years I've been working to develop a framework of aging which distills its complex mechanisms into a set of pathways which can be activated or inhibited by diet, lifestyle, and pharmacology

This is still a work in progress which I plan to refine and clarify over time, including finding more practical applications Today I'll simply be introducing each axis and briefly summarizing some of the key factors that modulate it

While these are broadly independent they do overlap, interact, and promote each other, and similarly many factors will target multiple axes at once

The Axes of Aging are:

- Excitation
- Deposition
- Hypoxia
- Inflammation
- Permeability
- Aggregation

The Truth About ATP

In most biology research ATP is referred to as the main energy currency in living organisms, but this actually isn't quite true

In this thread I'll break down ATP's deeper functions, and the impact it has on human biology

THREAD // The energetic resources of mitochondria revolve entirely around the electron transport chain

In the simplest sense this is a series of electron donating/accepting protein complexes, named complex I through IV

These complexes carry an electron current across the membrane

To resolve sleep apnea the first factors I would focus on are evening infrared/sunlight, magnesium, thiamine, CoQ10, baking soda, and Buteyko/bag breathing Thiamine and magnesium work together to support pyruvate dehydrogenase, which funnels pyruvate into the Krebs cycle

This is protective in sleep apnea as brain hypoxia often leads to localized lactic acidosis that can interfere with oxygen delivery and contribute to fatigue

Why does bicarbonate resolve these issues? The answer is two-fold

First, one of the defining factors of sleep apnea is acidosis due to CO2 not being adequately breathed out during apnea episodes when breathing stalls

Heightened sensitivity to CO2 is what generates these breathing pauses as it stimulates hyperventilation, causing a subsequent drop in CO2 that no longer stimulates breathing

Beyond that the acidosis leads to reduced affinity of hemoglobin for O2 leading to poor brain oxygenation, and mild brain hypoxia causes localized lactic acidosis creating a vicious cycle

Bicarbonate bridges the gap between these alternating high and low CO2 states, as it converts back and forth into CO2 via the carbonic anhydrase pathway

In the process it also absorbs free protons, buffering acidity and improving O2 release from hemoglobin in the brain

https://x.com/photobiogenesis/status/2055115145714762131

The second mechanism which Jack and I discussed is improving the amount of "deep sleep" or NREM

This stimulates the glymphatic system to clear accumulated brain waste that's built up from the previous day

When NREM sleep is impaired with issues like sleep apnea it can cause this waste to build up leading to brain fog, lactic acidosis contributes to this as well

While my personal experience has led me to believe baking soda increases NREM through multiple mechanisms, the clearest way it does this is by directly reducing apnea and improving blood flow to the brain

The sudden rise in CO2 that occurs in breathing laps promotes waking and interrupts the sleep cycle
researchgate.net/publication/32…

Magnesium glycinate paired with L-theanine is also useful in supporting NREM and the glymphatic system

Strangest thing I've learned today is that the eyes have an ocular microbiome

It's become pretty common knowledge that the gut microbiome exists, and if you've been in the health space you've probably heard of the oral microbiome and skin microbiome

The eye's bacterial population is probably the least understood, as the strains have to live under specific conditions of light, salinity, and the body's immune defense

This could play a role in certain eye disorders like dry eyes or chronic conjunctivitis, and "ocular dysbiosis" could contribute to eye infection A number of different ocular strains have been detected, and overall diversity is quite low compared to other microbiomes

It is common to detect pathogenic bacteria transiently in the eye which further supports dysbiosis playing a role in eye infection

Even fungal strains like Candida can be detected in the eye in both children and adults

Movement, massage, and tissue hydration

Recently I've come across a surprising group of pieces of evidence, individually they seem unusual, but I think together they point to an interesting neglected aspect of health

THREAD // I've written before about collagen networks in the human body

These networks are electrically conductive, and collagen is piezoelectric, flexoelectric, and pyroelectric, meaning that it can translate energy from pressure, flexion, and heat into a current

https://x.com/photobiogenesis/status/1788602068728533296?s=20

Most people would be shocked if they realized how many of their negative emotional states like depression, anxiety, and irritability are downstream of physical issues like low blood sugar, constipation, histamine/inflammation, and poor quality sleep

I'll share a story from my own life that illustrates this:

In my early 20's when I first got into nutrition I was eating plant-based vegan/vegetarian and working at a vegan "burger" restaurant

It was whole food based and better quality than a lot of more processed options, but over time I noticed a consistent pattern

I got one free shift meal per day, and around one hour after eating it I would consistently experience a bout of straight up suicidal depression and nihilistic thoughts

I'm not someone who's prone to this usually, so it made me think something was VERY wrong, and over time I noticed that it only occurred when I would eat something off of the grill or fryer... At the time I started eating alternatives like salads and couldn't figure out what was happening, but knowing what I know now I have an explanation

In an attempt to be healthier the restaurant owners had opted to use sunflower oil rather than the usual canola/soybean fryer oil, and sunflower oil is one of the highest omega-6 oils

On top of that, they were changing the fryer oil very infrequently, only once a week, so the oil had days to degrade at high heat, sunflower oil has a smoke point of around 450F and on the grill they were cooking with it at 500+F

The compounds produced when overheating PUFA are some of the nastiest and most inflammatory out there, including acrolein, 4-HNE, MDA, trans fats, and aldehydes

These compounds take a few hours to form usually, but fryers are especially bad as they typically exceed the limits of major oxidation, especially with something like sunflower oil!

I was quite literally making myself suicidal every day with how inflamed my brain was, all because no one had ever educated me about these compounds

Brain fog must first be addressed by interrupting the cascade of inflammation

Inflammation impairs cognition via activation of TLR4 receptors leading to cytokine release from glia

This system is activated by endotoxin, histamine, glutamate, biotoxins, and hypoxia

(thread) TLR4 stimulates histamine release, but histamine excess also upregulates this pathway


Methylation is needed to detox histamine via HNMT, and this can be supported with methyl-B12, methylfolate, and B6

These factors should be reintroduced gradually to avoid methyl waste production (homocysteine)pmc.ncbi.nlm.nih.gov/articles/PMC17…

Sleep is perhaps the most reducing (or antioxidant) process in the body

The glymphatic system uses CSF flow to detox oxidative neurotransmitter waste, homocysteine, oxidized lipids, amyloid plaques, lactate, excess glutamate, etc

This is paired with a diffusion of melatonin that stabilizes redox and energy metabolism pathways

Melatonin has two properties that make it uniquely important compared to other antioxidants released during sleep

It is amphiphilic, meaning it is soluble in both lipids and water, allowing it to operate in both membranes and cytosol

It also generates an "antioxidant cascade" where byproducts of its oxidation act as antioxidants themselves, giving it a unique ability to work as a multi-use antioxidant or electron donor

Both glymphatic detox and melatonin release are coordinated by light

THREAD // Blue and green light (which are predominant in "cool" energy-efficient LED and fluorescent lights) are the frequencies that are most suppressive of melatonin release

The ideal way to promote healthy melatonin release is avoiding bright artificial light after sunset, your light environment should be as dark or dim as possible

You can also use selective modulation like blue-blocking glasses or blue-blocking LED bulbs, but these are secondary to darkness and a low-stim environment

What you do during the day matters as well

Bright light in the morning will shift circadian hormone peaks like cortisol and testosterone forward, leading to melatonin being released earlier as well

I've had a renewed interest in creatine recently, it's one of only a handful of supplements I've been taking

Both creatine and thiamine have the ability to support the ATP/ADP ratio by donating extra phosphate groups to turn ADP back into ATP

This means creatine acts as a "phosphate sink" where at any given time 60% of it is in the creatine phosphate form

When ATP levels begin to fall in cell stress, hypoxia, and high metabolic demand creatine opposes the loss of ATP The interesting thing is that some of the benefits of taking glycine may actually be a result of its role in creatine synthesis

Animal research shows that higher glcyine intake produces higher creatine levels in tissue, and it almost certainly works the same in humans

The idea of digestion affecting mental state is reaching a point of being common knowledge

However the gut's neural network is not a "second brain" but a "third brain," as after the CNS the heart and circulatory system have the second most neurons

So in the same way that the gut microbiome and its metabolites alter brain activity, circulation issues can as well

(thread) One of the best examples of this is "biofeedback"

Anxiety involves increased heart rate, but artificially elevating heart rate can also lead to the perception of anxiety

This isn't just the brain noting the heart rate but instead the fact that the same factors that regulate heart rate are those that regulate anxiety

Adrenaline, noradrenaline, glutamate, and elevated calcium are all involved here

Idebenone is an interesting quinone that may be useful in Parkinson's disease

It's an analog of CoQ10 (another quinone) but while CoQ10 binds to complex I to transfer electrons to complex III idebenone can bypass CI and move directly to CIII

It's also a membrane antioxidant Complex I blockage is one of the main underlying drivers of Parkinson's disease

It creates metabolic issues in dopaminergic neurons and has been shown to to elevate neurotoxic dopamine wastes

The main downside is that idebenone does not unblock complex I itself

https://twitter.com/photobiogenesis/status/1823130259287392382

GDNF is a brain growth factor that regulates growth of various neurons, but is particularly targeted toward dopamine

It's considered promising for the treatment of addiction and Parkinson's disease

Let's look at a few ways to stimulate it In addiction, things that increase dopamine have a tendency to increase GDNF in the short term while downregulating it during withdrawal

This is true for alcohol, nicotine, drugs, etc

The psychedelic ibogaine, used in addiction therapy, may work partially by increasing GDNF

Brain normally runs on glucose (more than 50%), under cognitive exertion energy demands outpace oxygen availability and lactate shuttled into neurons from glia becomes the dominant energy source (50-60%)

Lactate also represents the point of "high cognitive load" and fatigue

https://twitter.com/hezerminator/status/1832895070439080308

Now while I don't believe lactate is responsible for exercise-induced fatigue on its own, it does play a role in cognitive fatigue


The point where anaerobic metabolism is reached "indicates that a cognitive task has reached the limits of complexity for a given individual"


Beyond that, it's been suggested that one of the main features of intelligence is better use of glucose by the brain
ncbi.nlm.nih.gov/pmc/articles/P…
sciencedirect.com/science/articl…
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