Haidut Interview Haidut Georgi on Mercola - Sept 17, 2023 - Crucial Facts about Your Metabolism Part 2: Oxidative Reductive Stress, Methylene Blue, Niacinamide, etc

Highserotonin90

Highserotonin90

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@sunny If I remember correctly there is a thread on Longecity about mitochondrial fission vs fusion. Does niacinamide appear to promote fission?

Can these be healthy principles to apply to a patient with ALS?
 
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golder

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Does anyone know how to access without having to pay to get through Mercolas paywall?
 
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Kimster

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golder said:
Does anyone know how to access without having to pay to get through Mercolas paywall?
Click to expand...

****Select all, copy, paste of the interview.......no visual . summary



Crucial Facts About Your Metabolism, Part 2

Analysis by Dr. Joseph Mercola  Fact Checked

STORY AT-A-GLANCE


September 17, 2023

  •  What medicine refers to as “oxidative stress” is actually reductive stress resulting in theproduction of free radicals. Once you understand this process, it becomes easier tounderstand how to optimize your health

  •  According to the rate-of-living theory, the higher your metabolic rate — which means thequicker the electrons move from food toward oxygen, which is the nal acceptor ofelectrons — the faster you'll age because there'll be higher oxidative stress. But deeperanalysis reveals the exact opposite appears to be the case

  •  The truth is, the higher your metabolic rate, the slower you age, because high metabolismcreates fewer reactive oxygen species (ROS)

  •  Your metabolism is high when electrons move rapidly and easily through themitochondrial electron transport chain. When electrons are impeded from movingforward, they can back up, leak through the mitochondrial membrane and start movingbackward, where they combine with oxygen to create excessive ROS

    In this video, which is the second half of our two-part interview, Georgi Dinkov and Icontinue our discussion about the biochemistry of human metabolism and the processof aging. Part one can be viewed on my Substack site.

    We begin by reviewing a complex concept that is not understood by any health experts,and that is the concept of reductive stress, which plays a crucial role in acceleratedaging. As it turns out, what science refers to as “oxidative stress” is actually secondary

to reductive stress resulting in the production of excess free radicals. Once youunderstand this process, it becomes easier to determine the best ways to combat it.

Rate-of-Living Theory

To understand this, you rst need to understand what oxidation and reduction reactionsare. Dinkov explains:

“Rate-of-living theory underpins this whole concept of oxidative stress.Currently, pretty much every doctor will tell you that the higher your metabolicrate — which means the quicker the electrons move from food towards oxygen,which is the nal acceptor of electrons — the faster you'll age because there'llbe higher oxidative stress. You'll be producing a higher amount of reactiveoxygen species (ROS).

But if you look at the actual data, and this is even in the medical books, it turnsout it's the exact opposite. ROS are generated from oxygen, but it's actuallywhen you're NOT shuttling the electrons fast enough towards oxygen.

And, when these electrons [from food] build up in various chunks of thisprocess, whether it's in the Krebs cycle or the electron transport chain, you haveto do something with them.

If you look at what a reactive oxygen species is, you'll see that it's actuallyoxygen that has been reduced, in other words, oxygen that has gained anelectron. Now, an electron, by its nature, is a reductive species. Basically, a foodis a donor of electrons, a reductant.

Oxygen is an acceptor of electrons, an oxidant. So, if you have a buildup ofelectrons, this means that you are in a state of excessive reduction, or at leasthigher than optimal.

So, your body has to do something with them. You're giving the body electrons,either from food or through lipolysis, or the cortisol-generating amino acids

from your muscles. Ultimately, all of these things get converted to energy, andthe way energy works is, it's a ow of electrons.

So, electrons, ideally, should be paired at the very end with oxygen throughComplex 4 of the electron transport chain. If that does not happen, then theseelectrons can attack oxygen molecules [moving through the metabolic chain]and reduce them by an electron or two, [which] generates these very reactivespecies.”

Rephrased Summary

To reiterate, when electrons cannot move forward in the metabolic chain, they can buildup. At a certain point, the buildup becomes toxic to that specic step, causing theelectrons to be shuttled backward, where they encounter oxygen molecules.

Molecular oxygen is always present, but it's only useful if it's used at the last step, whichis the cytochrome C oxidase. At any other point, oxygen coming into interaction withthese electrons is asking for trouble. When the electrons build up in Complex 1 or 3,which is usually the case, then the excess electrons leak through the mitochondrialmembrane and start combining with molecular oxygen, creating excess ROS in theprocess.

However, these oxygen species are not oxidative. They're not oxidizing agents anymore.They have accepted either one or two electrons, so they're actually a reductive speciessuch as hydroxyl or superoxide anions.

Combined, hydroxyl radicals and superoxide anions are responsible for approximately90% of the ROS generated, and both are single electron reductive agents. This meansthey can attack and damage DNA, various enzymes and important tissues like the innermitochondrial membrane and cardiolipin.

But hydroxyl radicals and superoxide anions are not oxidants. They're a reduced form ofoxygen, so they're highly reactive and can wreak a lot of havoc, but the very reasonthey're present is because there was an excess of electrons to start with, and an excess

of electrons is, by denition, a reductive state. So, in short, only when you’re in areductive state can you have oxidative stress and subsequent production of ROS.

For some reason, this reductive state became termed "oxidative stress," as if oxygen wasthe cause of it, but oxygen by itself does not do much damage, provided the electrons,the reductants, are owing or moving appropriately. Basically, oxygen is an innocentbystander in this process. The real culprit is excess electrons buildup.

The Easier the Flow of Electrons, the Less Oxidative Stress

What this all means is that the higher your metabolic rate, the more easily theseelectrons ow from food to oxygen and the less oxidative stress you're going to have.The slower your metabolic rate, the greater the buildup of electrons, which combine withoxygen to create ROS or oxidative stress. Again, it’s not truly oxidative stress butdamage caused by excess reductive stress, meaning too many unpaired electrons.Dinkov continues:

“The determining factor for most of the creation of the ROS is the NADH toNAD+ ratio. NADH being the reduced form and NAD+ the oxidized form. Thisratio also controls the speed of metabolism of carbohydrates because the ratelimiting step is pyruvate dehydrogenase.

When you're in the oxidized state, in other words, NAD+ predominates, thenpyruvate-dehydrogenase works well and electrons ow through the Krebs cycleand the electron transport chain ...

When NADH predominates, you have too many electrons ... that are not meetingoxygen properly. This buildup of electrons creates these bottlenecks, either inComplex 1 or Complex 3, mostly ... Then something has to happen with theseelectrons. Two things can happen. One is increased synthesis of the ROS.Second, your body uses these extra electrons to synthesize fats.

So, you can view obesity, or at least extreme obesity, as a desperate mechanismto get rid of electrons that are coming from food but are not getting processed

properly. In other words, you're not combusting the food properly. So, whathappens with it? Well, you store it. That's the only thing that the body can do.

And, by the way, whenever you have obesity or severe overweight, you alwayshave high amounts of ROS, because those are the only two things that the bodycan do with the extra electrons. It cannot simply evaporate them, though there'ssome research on grounding that [shows] you can help get rid of the excesselectrons [that way].”

Antioxidants Aren’t the Best Answer

So, again, when you have an excessive buildup of electrons, which by denition is areductive state or a state of reductive stress, your body can dissipate the electronseither by synthesizing fats or creating ROS. Your body must then deactivate these ROSto avoid excessive damage.

A number of enzymes and antioxidants can do this. But the whole point is, why bothertaking these substances if the whole problem, from the very beginning, was a low basalmetabolic rate, i.e., the metabolic process was not working as fast as it should have toavoid electron buildup?

Paradoxically, the way to get rid of “oxidative stress,” or more correctly reductive stress,is to increase oxidation, i.e., to increase your metabolic rate. This will prevent the ROSfrom being generated in the rst place. Continuously taking antioxidants merely masksthe problem.

As noted by Dinkov, “The solution is to improve metabolism, so the electrons go wherethey should be going and don't build up.” How to improve your metabolic rate is at theheart of the late Ray Peat’s work, which Dinkov has studied extensively.

Best Supplements for Reductive Stress

To reduce this reductive stress (improperly referred to as oxidative stress), you can takeoxidizing quinines such as vitamin K2 and/or methylene blue.

Methylene blue (MB) is the parent molecule for hydroxychloroquine. In its oxidized form,MB is dark blue. Its reduced form is colorless and is now being used in antiaging skincare products. The active form you want to use is the oxidized, blue form, but even if youtook the reduced form, reduced MB tends to easily grab oxygen from the environment tobecome oxidized again.

What makes MB so universally useful is that most people have serious reductive stresssecondary to excessive LA in their diets, so, if there’s a block anywhere in the electrontransport chain, methylene blue simply transfers the electrons straight to oxygen,bypassing the obstruction.

As a result, your cells can generate more energy. Methylene blue can serve as anemergency oxidant not only in the electron transport chain but in the Krebs cycle. It canaccept electrons and allow them to continue moving. For all these reasons, methyleneblue appears to be a fantastic solution for reductive stress.

Methylene blue is also augmented and works synergistically with near-infrared radiation,so you can further boost the benets by combining it with sun exposure or a near-infrared sauna. Also, combined with red light, methylene blue creates singlet oxygenspecies that kill viruses and bacteria.

Methylene blue is classied as a drug and to get USP human grade typically requires aprescription so it can be purchased legally at a compounding pharmacy. There arecompanies that sell the USP grade but it is illegal and you would need to see their thirdparty testing to conrm it was tested for purity. Doses are typically 5-10 mg/day formost unless they are sick then can increase to 50 mg.

Niacinamide is also useful for reducing reductive stress, as it increases NAD+ byproviding fuel for the rate limiting enzyme for creating it, NAMPT. Methylene blue incombination with niacinamide is particularly potent at reducing reductive stress andincreasing energy.

Biohacks for Obesity

At present, a clear majority of people are overweight or obese and metabolicallyinexible. This goes to the point of not being metabolically ecient, which is what we'retalking about. Strategies that will increase your metabolic rate and address obesityinclude the following, each of which is discussed in greater detail in the interview:


  • Avoid PUFAs as much as possible, as they are the primary contributor to reverseelectron ow that shuts down your metabolism and increases reductive stress.PUFAs damage cardiolipin, which prevents it from binding with Complex 4. Oncethat Complex is dysfunctional, even if all the others are working, you’ll get a buildupof electrons.

  • A daily aspirin regimen (325 mg per day).

  • Niacinamide, 50 mg three times a day. Niacinamide activates pyruvatedehydrogenase (PDH), which is the throttle for the Randle switch, discussed in Part1 of this interview.

    Niacinamide is also a precursor for NAD+. According to Dinkov, research shows thatATP levels have an almost perfect correlation with NAD+. So, the higher your NAD+,the higher your ATP synthesis and the better your metabolism works. Niacinamideis also a required cofactor to convert cortisol into the inactive (and far lessdangerous) form of cortisone.

    Ideally, also take magnesium half an hour or so after the niacinamide. If your ATPoutput is low, the magnesium cannot bind to the ATP, and in its free ionic form,magnesium is rapidly excreted. Taking niacinamide will raise NAD+ and hence ATP,allowing your body to more effectively use the magnesium.

  • Drink organic black coffee, and if you get jittery, you probably don’t have enoughglycogen in your liver, so drink your coffee or take a caffeine tablet with some foodor some glycine, beta-alanine or taurine, all of which are GABA agonists.
• Optimize your cellular melatonin production by getting regular sun exposure orusing a near-infrared sauna.

Vitamin E

Another supplement that most people need is vitamin E. That’s going to limit theoxidation of PUFAs such as LA into mutagenic and carcinogenic metabolites. The kindyou want is the “dextro,” not the “levo” kind, and you want primarily alpha, including D-alpha-tocopherol.

According to Dinkov, vitamin E has also been shown to have an antagonistic relationshipwith estrogen, which plays a signicant role in many chronic diseases, including certaincancers. The tocopherol isomers are also moderately strong aromatase inhibitors.

“So, basically, by taking vitamin E, whatever estrogenic effects are out there,even from nonperoxidized PUFA, or if you're producing too much estrogen forwhatever reason, if you have endocrine disruptors which are capable of bindingand activating the estrogen receptor just like estrogen does, tocopherol willblock some of that,” Dinkov says.

“It's really a versatile molecule that has genomic steroid-like effects, but itmimics progesterone, which is also the main anti-estrogen in the body forfemales, testosterone and the dihydrotestosterone being the main anti-estrogens in the body of males.

Tocopherol will have most of these effects. And it probably has much fewer sideeffects than taking steroids. The daily needs have been shown to correlateperfectly with your intake and storage of PUFAs, so the daily need, the real RDA,of vitamin E is about 2 mg of vitamin E for every gram of PUFA consumed,which means, if you're consuming 50 grams of PUFA, you need 100 mg vitaminE to combat its peroxidative and estrogenic potential.

Most people are used to measuring the vitamin E in units. If you take thevitamin E dosage in milligrams and multiply by 1.5, you get the dosage in

international units.”

Animal Protein and Longevity

Dinkov also dives deep into the science behind protein needs. He recommends 80 to120 grams of protein a day for muscle maintenance, which is lower than many others.Typically, if you want to build muscle, experts will recommend twice that.

Dinkov, however, stresses the need for collagen, as it contains higher amounts ofspecic amino acids with anti-inammatory and other healing properties. These includeglycine, proline, hydroxyproline and alanine.

Red meat is higher in amino acids that induce inammation: methionine, histidine,tryptophan and cysteine. On a side note, Dinkov points out that aspirin inhibits theabsorption of methionine, cysteine and tryptophan from food. He believes a single babyaspirin with a meal would suce to inhibit absorption of these proinammatory aminoacids. He also discusses other benets of aspirin, so for more details, listen to theinterview in its entirety.

According to biologist Ray Peat’s work, amino acids in their free state have manyhormone-like functions. For example, during stress, cysteine and tryptophan arereleased in large quantities, and these amino acids have antimetabolic effects. Otheramino acids act as nerve-modiers, triggering excitation or inhibition, while others,especially glycine, have cell-protective, anti-stress effects.

As such, many degenerative and inammatory diseases can be ameliorated by eatingmore collagen and gelatin-rich foods. Red meat, on the other hand, contains far higherlevels of the antimetabolic amino acids cysteine and tryptophan, which you want less ofif you struggle with degenerative and/or inammatory conditions.

Life extension studies have shown that restricting tryptophan or cysteine aloneproduces greater life extension than what is achieved in most calorie restriction studies,which is rather remarkable.1

More Information

You can check out Georgi’s blog at www.haidut.me or follow him on Twitter. He also hashundreds of videos on YouTube on a plethora of topics. A major sampling of Ray Peat’swork is also available for free on these two sites: wiki.chadnet.org/Ray-Peat andRayPeat.com.

Sources and References

1 RayPeat.com Gelatin Stress and Longevity
 
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