The idea that free radicals = bad and antioxidants = good is a major oversimplification
When we talk about redox state it's not just about maintaining as little oxidation as possible, but rather keeping an appropriate balance in place between reduction and oxidation
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Chemistry 101:
Put simply, oxidation refers to any chemical reaction involving the loss of an electron, when something is oxidized it just means that one of its electrons is transferred to another molecule
Reduction is the inverse of this, a molecule or atom gaining an electron from another molecule or atom
As you can see, it's impossible for reduction to occur without oxidation, and vice versa, hence the shorthand "redox" refers to this category of reactions
Now when we look at how this occurs in the body free radical production is an excellent example
A "free radical" is any molecule with an unpaired electron, which makes it highly reactive and unstable, it will neutralize itself by reacting with the first available electron donor
The most common source of free radicals in the body is oxidative phosphorylation (the main ATP synthesis pathway in mitochondria), which involves an electron circuit that sometimes cross-reacts with nearby oxygen or water molecules creating "reactive oxygen species" as a result
Reactive oxygen species (ROS) refers to free radicals containing oxygen, while the less common reactive nitrogen species (RNS) refers to nitrogen containing free radicals
RNS are created primarily as byproducts of the metabolism of nitric oxide, which regulates blood flow
These free radicals are neutralized by antioxidants, which act as electron donors, oxidizing themselves in order to reduce free radicals before they have the chance to react with nearby protein, lipids, or DNA instead
Antioxidants are then recycled back into their reduced form
This process maintains the balance referred to broadly as the "redox state"
It's true that too much oxidation can be harmful, playing a role in the pathology of cancer, heart disease, and aging
I've discussed this frequently in the context of iron, light environment, etc
But this isn't the whole story, oxidation can also be beneficial, and some antioxidants can paradoxically increase the risk of these same diseases
As an example, ROS are used as signaling molecules between the mitochondria and cell nucleus, altering gene transcription
This ROS signaling is what allows light to dynamically alter gene expression and regulate circadian rhythm (via genes like CLOCK, Bmal1, etc)
This is an example of how changes like these can play out during infrared light exposure via sunlight or therapy:
If we block this signaling we may impair these processes and potentially alter circadian rhythm or other aspects of cell metabolism
The interaction between ROS and muscle growth is another example, certain antioxidants have been shown to slow hypertrophy ncbi.nlm.nih.gov/pmc/articles/P…
The question is nutrient antioxidants is also complex
While vitamin C is an very beneficial antioxidant, it also paradoxically increases iron oxidation, so it may not be so beneficial in all cases or at very high doses ncbi.nlm.nih.gov/pmc/articles/P…
The takeaway from all this is that in many cases oxidative stress is actually a hormetic response and provides benefit
Things like living at high altitude, exercise, sunlight exposure, cold thermogenesis, saunas, etc, all operate via this mechanism
If you want to balance redox state apply oxidative stress via these activities, while also utilizing appropriate antioxidants
In particular, plant compounds are highly beneficial here, especially those in the flavonoid or quinone classes (polyphenols in general are excellent)
Focus on food sources for these phytochemicals, as well as most nutrients
There are definitely cases where nutrient supplements are necessary or beneficial, but especially when it comes to antioxidants like retinol, vitamin C, and vitamin E, food sources are king
Lastly, it's important to avoid things that create imbalances in this redox state
Some like isolated blue light disrupt circadian signaling, while others like iron accumulation or alcohol consumption quickly outpace any hormetic benefits they may provide at low doses
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When megadoses of vitamin D supplements are taken orally, the body may actually shunt conversion away from the active form of vitamin D (1,25D), instead increasing production of its analogs in the epi-25D pathway
These analogs are significantly less calcemic, so this shunt may be used to minimize increases in serum calcium seen with excess vitamin D
Unfortunately this pathway has not been studied in humans, but we see this consistently in studies in rodents with supplemental vitamin D
Infants also demonstrate a higher ratio of epi-25D to 1,25D and 25D (aka D3), perhaps to preserve calcium in the skeletal system as much as possible during early development
Bowel flush from high doses of magnesium is caused by excess of it reaching the large intestine/colon
Magnesium is hydroscopic, so it draws water more than other minerals, and past the small intestine there is almost no ability to absorb it so it pulls water into the bowel
The flush reaction is directly proportionate to the unabsorbed magnesium fraction
This also plays a role in why forms that are less soluble in water like magnesium hydroxide, citrate, or oxide, are the most laxative as they are the least well-absorbed
The solution to minimize flush is to opt for more soluble forms like magnesium chloride, and to space out intake as much as possible throughout the day
I like to fill a liter jar with water and add 1-2tsp mag chloride to gradually drink, start small (~0.5 tsp) and taper up
The idea of a "debate" around CICO is pretty ridiculous, in the sense that the role that thermodynamics plays in metabolism is well-established and agreed on by everyone
What we're actually seeing is a shift in emphasis away from calories in and more towards calories out
What I mean by this is that more and more nutritionists seems to be recognizing the error in the initial premise of the amount of calories eaten being the only significant factor in weight gain/loss
This is obvious in cases like hypothyroidism, etc, where metabolism is impaired
This isn't a new idea or mutually exclusive with CICO, just a shift in emphasis from one side of the equation to the other
I think most everyone would agree that the amount of food you eat matters, but also that lack of exercise, hormone imbalance, etc, can impair weight loss
I've been digging more into the connections between the "big three" sex hormones (testosterone, estrogen, and progesterone), and glutamatergic disorders like epilepsy
Interestingly, androgens like testosterone and DHT are actually anticonvulsant, which seems counterintuitive since they increase force production
This seems to result from their conversion into the neurosteroids androsterone and 3a-androstenediol which increase GABA sensitivity
Progesterone is also anticonvulsant as a result increased neurosteroid production, most notably allopregnanolone, but to lesser extent other dihydroprogesterone derivatives
I've reviewed hundreds of rodent and human studies on various herbs and the potential benefits of bacopa in epilepsy have always stood out to me as being some of the most promising, yet the relevant human data seems to be totally lacking
When we consider the role that GABA/glutamate imbalances play in nearly every mental illness and neurodegenerative disorder, the potential applications of these herbs is extensive
N-acetylserotonin, the chemical byproduct of serotonin and precursor to melatonin, acts as an agonist of the TrkB receptor (the same receptor that BDNF activates)
This is another interesting pathway by which MAO inhibition may enhance the actions of neurotrophic factors
Increasing serotonin is also known to raise BDNF levels itself via activation of various serotonin receptors, we see this in SSRI's and other serotonergic supplements/drugs
This pathway could replicate a portion of these effects even if serotonin is not increased significantly
Mostly I find this interesting in the context of beta-carboline containing herbs which act as mild reversible MAO inhibitors, like ginseng or polygala
Most herbs with these properties behave well in rodent metrics of increasing neurogenesis