Reversing the Inhibition of Metabolic Pathways in the Aluminum Age

 

Reversing the Inhibition of Metabolic Pathways in the Aluminum Age

Dennis N. Crouse 8-16-26

Hypometabolism is a biomarker of Alzheimer’s Disease and is measured as the degree of inhibition of the first step in glycolysis. Glycolysis is the primary pathway that metabolizes carbohydrates. Aluminum inhibits the first step in glycolysis and other metabolic pathways resulting in lower energy production from the food we eat. The metabolic pathways in our bodies that produce energy from carbohydrates and fatty acids are facilitated by several different enzymatic sequences:

·       Glycolysis of carbohydrates to pyruvate from which acetyl-CoA is produced

·       Beta-oxidation of fatty acids to acetyl-CoA

·       Krebs cycle converting acetyl-CoA to carbon dioxide

Remarkedly, the human body’s biochemistry can switch from 100% carbohydrate diet to a 100% fatty acid diet. This dietary switch-over is called the “Schwatka Imperative”.  This is named after Lieutenant Frederick Schwatka who volunteered for a single-handed 19-month 3,000-mile Arctic mission looking for information on why the men of the Franklin Expedition perished in the Arctic¹. Schwatka intentionally took with him only enough carbohydrate to last the first 10 months.  On June 15th of 1879 he ate his last hard bread and then it became imperative that his body switch to a diet (a.k.a. keto diet) of primarily fresh-killed reindeer meat with occasional fish. For the first two or three weeks on the ketogenic diet he felt “… an apparent weakness and inability to perform severe exertive, fatiguing journeys.”  Then miraculously after two to three weeks on the ketogenic diet his strength and stamina returned to normal. For example, during the last two days of the expedition he hiked 75 miles.

Sixteen years later Dr. Fridjof Nansen and Lieutenant Fredrik Hjalmar Johansen made a dash for the North Pole from their ship the “Fram” with the intention of eating a ketogenic diet of freshly shot polar bear meat when their supplies ran out after the first month². Unable to find the “Fram” on the shifting arctic ice they hiked hundreds of miles and after fifteen months they accidentally encountered the Jackson Expedition on June 17th of 1896 on Cape Flora in Franz Joseph Land³.  Remarkably at the time of this encounter both men were in excellent health.  Dr. Nansen, who stood 6 feet 2 inches tall, was 21 pounds over his normal weight of 184 pounds and Lieutenant Johansen was “a sturdy muscular little chap ... the picture of health” according to Jackson³. These dietary experiments proved that a ketogenic diet does provide strength and stamina.    

Schwatka was lucky he traveled ten years before the Bayer Process for aluminum purification from bauxite was developed in 1888. Nansen and Johansen were also lucky as by 1890’s aluminum had not yet entered the food supply on the scale seen during aluminum age that began in 1900. Since 1900 people living in the aluminum age have been dosed with ever increasing levels of aluminum that negatively impact the three metabolic pathways resulting in energy deprivation. This is called hypometabolism and is a biomarker of Alzheimer’s disease (AD). The prevalence of AD has increased exponentially as has the worldwide production of aluminum in the aluminum age (shown in figure 1).

     Figure 1. Exponential growth of AD prevalence and worldwide aluminum production in the aluminum age⁴

Glycolysis, beta-oxidation, and the Krebs cycle comprise the primary biochemical pathways for energy production in living organisms on earth. Aluminum at physiological concentrations (i.e., 36 – 75mcMolar in the brains of those with AD) inhibits these pathways. causing energy deprivation and hypometabolism⁴.

Glycolysis starts with the enzyme hexokinase converting glucose to glucose-6-phosphate and ends with two pyruvic acid molecules, two ATP molecules and two NADH molecules. The concentration of aluminum required to drop an enzyme’s activity to 50% is called IC50.  Aluminum inhibits hexokinase at an IC50 of 4-9mcMolar⁵.

The link between glycolysis and the Krebs cycle is pyruvate dehydrogenase (PDH) and required cofactors thiamine pyrophosphate (a.k.a. vitamin B1) and lipoic acid. Pyruvic acid is oxidized to acetyl-CoA and a molecule of NADH. In addition, the enzyme pyruvate carboxylase (PC), with required cofactor biotin, adds carbonic acid to pyruvic acid making oxaloacetate. Beta-oxidation of fatty acids also produces acetyl-CoA in the body (see below).

This link between glycolysis and the Krebs cycle is inhibited by low levels of thiamine in the plasma of those with AD but not Parkinson’s disease⁶. Low levels of thiamine is caused by oxidation of thiamine. Aluminum generates reactive oxygen species (ROS such as hydrogen peroxide) in human neuronal glial cells⁷. Hydrogen peroxide is converted in the body to hypochlorous acid by the enzyme myeloperoxidase⁸. Hypochlorous acid oxidizes thiamine to three metabolites (shown in figure 2)⁸. Aluminum generated hydrogen peroxide causes thiamine loss by oxidation in the brains of those with MCI and AD.

Note that benfotiamine, a thiamine derivative, when taken as a supplement boosts blood and brain thiamine levels and helps to restore brain glucose metabolism. Benfotiamine at a daily dosage of 25mg or more per day is 2-3-fold more readily absorbed by the intestine than thiamine¹⁵. Benfotiamine does not remove aluminum and is not an FDA-approved medication for AD.  

Krebs cycle starts with citrate synthetase combining acetyl-CoA with oxalacetate making citric acid. The citric acid is then converted to isocitric acid with the enzyme aconitase. Aluminum inhibits aconitase at an IC50 of 25mcMolar⁹. The Krebs cycle is also fed by glutamate being converted to alpha-ketoglutarate by the enzyme glutamate dehydrogenase (GDH).  Aluminum inhibits glutamate dehydrogenase at an IC50 of 25mcMolar^9,10.  

For every molecule of glucose entering glycolysis two molecules of NADH and two molecules of pyruvate are produced. The two pyruvate molecules are oxidized to make 2 more molecules of NADH. Also, the Krebs cycle turns twice producing two ATP (or GTP) molecules, six molecules of NADH and two molecules of FADH₂. Therefore, each molecule of glucose entering glycolysis and Krebs cycles produce an NADH to FADH₂ ratio of 10/2 = 5.   

 

                             Figure 2. Oxidation of thiamine by hydrogen peroxide and myeloperoxidase⁸

Beta-oxidation requires the prior conversion of long-chain fatty acids to acylcarnitine for importation into the mitochondria by the carnitine shuttle. The enzyme carnitine palmitoyltransferase 1 (CPT1) catalyzes the rate-limiting step of transferring the acyl group of acyl-CoA to L-carnitine. A translocase shuttles the acylcarnitine from the cytosol across the inner mitochondrial membrane where it is converted back to acyl-CoA and L-carnitine. Fatty acids other than 16-carbon palmitic acid can be substrates for CPT1. The number of beta-oxidation cycles equals the number of carbons in the fatty acid divided by 2 and then subtract 1. For example, palmitic acid requires 7 cycles for complete beta-oxidation.

Each beta-oxidation cycle produces one molecule of NADH, one molecule of FADH₂ and one molecule of acetyl-CoA. Each cycle of the Krebs cycle requires one molecule of acetyl-CoA and produces one ATP (or GTP) molecule, three molecules of NADH and one molecule of FADH₂. Therefore, each cycle of the beta-oxidation and Krebs cycles produce an NADH to FADH₂ ratio of 4/2 = 2.   

Aluminum (10-100mcMolar) and hydrogen peroxide (40mcMolar) lowers L-carnitine levels by inhibiting the activity of two enzymes involved in the biosynthesis of L-carnitine: gama-butyrobetainealdehyde dehydrogenase (BADH) and butyrobetaine dioxygenase (BBDOX) and lowering expression of BBDOX¹¹.

Aluminum impairs the body’s ability to use stored fatty acids as an energy source by lowering L-carnitine levels in the blood, decreasing beta-oxidation, and causing cellular lipid accumulation. Also since fatty acids are a component of triglycerides, it is not surprising that occupational aluminum accumulation results in both low L-carnitine and high triglyceride levels in the blood¹². In women with amnestic mild cognitive impairment (aMCI) and early-AD  free-carnitine levels are significantly lower than controls¹³. In men and women with AD there are significantly decreased levels of acylcarnitine compared with controls¹³.  

Note that daily dietary carnitine intake for an omnivororus adult provides insufficient carnitine to compensate for urinary losses¹⁶. Therefore, carnitine biosynthesis does contribute to overall carnitine supply. Also, the bioavailability of carnitine supplements is low¹⁶.     

Reversing Aluminum Inhibition of Metabolic Pathways with OSA

Regularly drinking water rich in orthosilicic acid (3-4 cups a day with OSA greater than 48ppm) lowers aluminum levels in the body and restores energy production in the brain. My mother was diagnosed first with aMCI due to declining cognition/memory and then Alzheimer’s due to her accelerated brain atrophy. At age 86 she started regularly drinking OSA (Fiji water 146ppm). Within a year her cognition including memory  improved. My mother was APOE 3,4. My mother lived to 97 and did not die of end-stage AD. 

I am APOE-2,4 age 80 and have been drinking OSA rich water (Silicade 146ppm) for over a decade. I have lowered my aluminum body burden to a level considered safe by the Mayo Clinic (less than 0.48mcMoles/24hr.) as tested by periodic 24-hour urine tests provoked by regularly drinking 3-4 cups of OSA 146ppm daily. I do not have aMCI, MCI, or AD

Palliative Therapy for AD

Lieutenant Schwatka completely switched from carbohydrates to a keto diet with only “… an apparent weakness and inability to perform severe exertive, fatiguing journeys.” He performed the Schwatka imperative in 1879 before the aluminum age that began with aluminum purification from bauxite in the 1890’s. Because we now all have an aluminum body burden, it has become more difficult to completely switch, but the body will still try to adapt.

Adaptation involves reconfiguring the amount of three respiratory complexes (CI, CII, and CIII) in the mitochondrial electron transport chain (mETC) from NADH to FADH₂ dependent enzymes by using ROS to degrade CI to CIII. The NADH to FADH₂ ratio switches from 5 to 2 during the Schwatka imperative. This requires using the redox status of coenzyme CoQ10 as a metabolic sensor of ROS generated by reversed electron transport (RET) of the mETC (see figure 3)¹⁴. The Schwatka imperative does work to provide some palliative relief from AD but does result in added ROS generation due to RET and aluminum accumulation.

Figure 3. During the Schwatka imperative the mETC is optimized to better handle the different fuel using CoQ10 (Q) as a metabolic sensor and ROS generated by RET to degrade CI to CIII¹⁴.

A curative therapy for AD is available that involves lowering the body burden of aluminum to recover normal operation of glycolysis, beta-oxidation, and the Krebs cycle. This therapy does not involve a dietary change and reconfiguration of the mETC as it only requires removing aluminum by daily drinking an OSA rich mineral water.

  

References

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