Neurons and Exercise

Neurons and Exercise

Tuesday, April 10, 2018

PQQ as an Oral Supplement to Prevent Dementia and Possibly Autism

This is an excerpt from my book.  Order Book

PQQ as an Oral Supplement to Prevent Dementia and Possibly Autism


PQQ (a.k.a. pyrroloquinoline quinone) is a molecular super-hero for the body. PQQ is found in mother’s milk at concentrations five times higher than any food. Its’ presence in mother’s milk is no evolutionary accident. PQQ promotes generation of both new mitochondria for brain energy and new neurites for memory storage. PQQ is a heavyweight antioxidant that can deliver 20,000 knockout punches to oxidants compared to only 4 delivered by a lightweight antioxidant like vitamin C.

 

PQQ was first isolated in 1979, but only a few milligrams could be obtained from natural sources. This low availability prevented PQQ’s chemistry and mode of action from being defined.  In order to obtain larger quantities of PQQ a total organic synthesis from readily available chemicals became a vital part of improving our understanding. My former doctoral thesis advisor, Professor E. J. Corey was awarded a noble prize for developing a logical “retro-synthetic” method of designing synthetic routes to complex molecules. Corey and Alfonso Tramontano performed the first total synthesis of PQQ at Harvard in 1981260.  This synthesis made large amounts of PQQ available for research and has opened our eyes to PQQ’s remarkable properties. PQQ has been claimed to be a vitamin. This claim is controversial as PQQ is produced by our bodies, so for now we will call PQQ a cofactor or coenzyme.

 

There are six reasons to take PQQ:

 

·         PQQ protects mitochondria from oxidative stress due to nitric oxide (NO) produced by the brain’s glial cells in response to aluminum.  PQQ lowers NO production by inhibiting the expression of genes responsible for the production of inducible nitric oxide synthase (iNOS)121,261-263. With the help of glutathione PQQ also acts as a stable antioxidant264,265. 

·         PQQ promotes the generation of new mitochondria, called mitochondrial biogenesis266 that increases energy efficiency of mitochondria267.

·         PQQ increases production of nerve growth factor (NGF) in the mitochondria268 that results in increased neurite growth and improved memory269,270.  

·         PQQ when taken before and after a stroke can help to avoid vascular dementia by reducing memory impairment due to lack of oxygen271,272.  Since we don’t know when a stroke might occur, taking PQQ daily is advised.

·         PQQ partially inhibits Aβ oligomer formation from Aβ peptides, one of the hallmarks of AD273.

·         PQQ binds to α-synuclein preventing formation of aggegates274.  Formation of α-synuclein aggregates is believed to be the first step in Lewy body formation leading to Lewy body dementia (see Appendix I).

PQQ as an Antioxidant:  Too much or too little oxygen or some metal ions act as physiological stressors in the brain by stimulating brain cells to produce oxidizing chemicals (a.k.a. ROS)121,122. The metal ions stimulate inducible nitric oxide synthase (iNOS) in microglial and astroglial cells of the brain to produce nitric oxide (NO) that reacts to produce ROS. This ROS can damage and kill neurons creating inflammation in the brain.  Aluminum tops the list of metal ions as a generator of ROS by the brain’s glial cells58.

PQQ inhibits genetic expression of iNOS and thereby inhibits ROS formation in the brain263.  Also oxidized PQQ and reduced PQQ (a.k.a. PQQH2) both exist in the brain as a highly stable redox cycle that protects the brain. The redox cycle works by glutathione first reducing PQQ to PQQH2 and then by PQQH2 reducing ROS and regenerating PQQ264,265.  PQQ’s high stability allows this redox cycle to be repeated 20,000 times before PQQ becomes degraded as opposed to only four cycles for vitamin C264.  The PQQ redox cycle protects the mitochondria, from oxidative stress due to too much or too little oxygen or toxic metals122. 

Safety of PQQ Supplementation:  There have been no toxicological signs or symptoms reported as a result of daily PQQ supplementation given orally to humans at a dose of 20mg (milligrams, thousandths of a gram) per day264,270.  In a 13 week study of PQQ given orally to rats a no-observed-adverse-effect-level (NOAEL) of 100mg per kilogram body weight per day was observed275.    Experiments with mice showed no interaction with DNA (i.e. genotoxicity)276.  High daily doses of PPQ in excess of 60mg/day should be avoided due to the potential of kidney damage as observed in rats exposed to high doses of PQQ264.

PQQ Bioavailability and Sources:  PQQ is biosynthesized by the human body at a rate of 100-400 ng/day (100-400 billionths of a gram per day) with an estimated tissue concentration of 1-3 ng/gr of body weight (5-15nM)269.  Oral supplementation of 20 mg of PQQ in humans resulted in a PQQ serum peak of 9nM after each dose in 2-3 hours and a half-life in the serum of 3-5 hours269.  Ingested PQQ is both metabolized and reacts with proteins in humans resulting in only 0.1% being eliminated in the urine as PQQ.  PQQ is a natural product found in human breastmilk and some foods277-279.       

Dietary Sources of PQQ277-279
Food
Nanograms PQQ per gram
Human Breastmilk
160*
Parsley
34
Kiwi Fruit
30
Papaya
30
Green Peppers
28
Tofu
24
Spinach
22
Celery
6

*Note: Currently PQQ is not listed as an ingredient in any baby formula

PQQ and Autism:  Biochemical characteristics of autism include activation of iNOS in glial brain cells with increased ROS production280.  This is a neuro-inflammatory process leading to local cell damage, synapse destruction, and brain under-connectivity280.  PQQ prevents this situation by both decreasing the expression of iNOS and chemically reducing ROS. PQQ also prevents brain under-connectivity by enhancing nerve growth factor (NGF) production that in turn stimulates the growth of neuronal connections.    It is therefore not surprising that PQQ is found in mother’s milk at a concentration 5 times higher than found in any other food279.  However PQQ is not found as an ingredient in any currently available baby formula. Since an amount of PQQ equivalent to 160 nanograms per gram of mother’s milk is inexpensive, there is no reason to continue the practice of not adding it to baby formula. 

PQQ as an Oral Supplement for Reversing Brain Ageing


PQQ stimulates neurite growth in the ageing brain.  A neurite is a projection grown from the cell body of a neuron resulting in an axion or dendrite that can extend a considerable distance in the brain in order to make a synaptic contact with another neuron’s neurite.  The process of neurite growth involves each neuron growing hundreds of neurites resulting in a complex neural network that allows the brain to store and process memory.  Neurite growth is stimulated by neural growth factor (NGF), a protein made in the brain.  NGF induces tau and MAP protein production that promotes microtubule assembly during neurite growth.  When NGF is removed from neurons, neurites disappear, microtubule mass decreases, and tau and MAP proteins decline to lower levels281.  Neurite growth is important for short to long term memory conversion, brain plasticity, and for damage repair due to stroke.

PQQ stimulates both neurite growth and mitochondrial biogenesis. CoQ10 improves the energy efficiency of mitochondria. PQQ taken together with CoQ10 improves cognition in the ageing brain.  A study of how oral supplements of PQQ and CoQ10 enhance cognition involving 75 people who were 53 years old was recently conducted and published in Japan270.  In the 12 week study 1/3 of the group were given 20mg/day of PQQ at breakfast, 1/3 were given 20mg/day of PQQ and 300mg/day of CoQ10 at breakfast, and 1/3 were a control given a placebo.  People taking just PQQ and PQQ plus CoQ10 significantly out-performed the control group on the CogHealth test.  The group on PQQ plus CoQ10 significantly out-performed both the PQQ and control groups on the Stroop test.

Biochemistry of PQQ Stimulating NGF Production


PQQ administered to mouse astroglial cells induces the production of NGF by the astroglial cell282.  Astroglial cells are star shaped and are located at synapses.  Astroglial cells produce extracellular signaling chemicals that remove excess potassium ions, and control the flow of chemicals from the blood to the brain.  Astroglial cells form a membrane called the glial limitans that regulates the movement of molecules, such as PQQ, from the blood into the brain.  This membrane forms what is called the blood-brain barrier.  Like PQQ the methyl ester of PQQ (2-carbomethoxy-pyrroloquinoline quinone) induces NGF production in cells from the CA1 region of the hippocampus283.  This methyl ester of PQQ has low toxicity and is believed to more readily cross the blood-brain barrier than PQQ.  Unlike PQQ, the methyl ester of PQQ is not yet commercially available or approved as an oral supplement.

 

Monday, March 19, 2018

Lose Weight by Decreasing Aluminum


Lose Weight by Decreasing Aluminum    
There are two primary energy sources for the body:

·         Carbohydrates in the form of sugars (i.e. glucose) produce energy by glycolysis to make acetyl CoA for the citric acid cycle.

·         Fats in the form of triglycerides produce energy by beta-oxidation to make acetyl CoA for the citric acid cycle.
Carbohydrates and fats are converted to energy in cellular organelles called mitochondria. Energy is produced by both glycolysis and the citric acid cycle.  Environmental toxins can inhibit the production of energy from both carbohydrates and stored fats resulting in obesity. For instance aluminum at a concentration of some drinking water in the U.S. inhibits glycolysis.

Since development of the Bayer process for aluminum purification from bauxite in 1888, there has been a steady increase in the amount of aluminum humans ingest and accumulate.  Aluminum, at levels found in some drinking water (108ppb,108mcg/liter, 4mcM), inhibits hexokinase, an enzyme that catalyzes the first step in carbohydrate  metabolism (i.e. glycolysis)1.  The biochemical response to the inhibition of glycolysis is the conversion of carbohydrates to fat as triglycerides comprised of long chain fatty acids2.  This fat can be stored in adipose tissue or metabolized for energy.  However, aluminum also inhibits the production of L-carnitine required for movement of long chain fatty acids in stored fat to the mitochondria for conversion to energy3-6.   Therefore aluminum inhibits two key steps in metabolizing carbohydrates and fats for energy generation:
·         Aluminum inhibits the first step of carbohydrate metabolism called glycolysis1. Inhibition of glycolysis promotes the conversion of carbohydrates to stored fats (e.g. lipogenesis)2.

·         Aluminum inhibits the biosynthesis of L-carnitine3-6. L-carnitine is required for mobilizing stored fat as long chain triglycerides for mitochondrial energy production7.

The result of aluminum ingestion is therefore, more fat from carbohydrate, more fat being stored, and less fat being utilized for energy, resulting in obesity that does not respond to dieting.

Ketogenic Diet of Medium Chain Triglycerides for Coping with Aluminum Toxicity

 Switching from a low fat – moderate carbohydrate diet to a high fat – low carbohydrate diet results in higher than normal levels of chemicals called ketones in the blood.  For this reason the high fat diet is called a ketogenic diet.  The source of fat on a ketogenic diet can be from plant and/or animal sources, such as canola oil, coconut oil, and/or beef tallow.  All fats are primarily triglycerides comprised of fatty acids of varying chain length and unsaturation that are esterified to glycerol. These fatty acids are of three types: 

·         Long chain essential fatty acids (e.g. linoleic and alpha-linolenic acids)

·         Long chain non-essential fatty acids (i.e. EPA and 22C DHA)

·         Medium chain fatty acids  (i.e. lauric acid found as 50% of coconut oil)

 History of the Ketogenic Diet

 The fact that the human body can switch from carbohydrates to triglycerides as its primary source of energy is called the “Schwatka Imperative”.  This is named after Lieutenant Frederick Schwatka who volunteered for a 19 month 3,000 mile Arctic mission, taking with him only enough carbohydrate to last 10 months8.  On June 15th of 1879 he ate his last hard bread and then it became imperative that his body switch to a 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.

 Lieutenant Schwatka was looking for information on why the men of the Franklin Expedition perished in the Arctic a quarter century earlier. Schwatka was lucky he traveled ten years before the Bayer Process for aluminum purification from bauxite was developed in 1888. Since 1888 people in general have been dosed with ever increasing levels of aluminum that is impacting how their mitochondria generate energy.            

 Moderate Carbohydrate Diet with Supplements for Losing Weight and Aluminum
Johnston in 2006 compared 10 overweight people on a low fat and moderate carbohydrate diet with 9 overweight people on a ketogenic diet with high fat and low carbohydrate diet.  The groups were fed diets providing the following percentages of energy:

Moderate Carbohydrate Diet:    30% fat   -   40% carbohydrate   -   30% protein

Ketogenic Diet:   60% fat   -     5% carbohydrate   -   35% protein

After eight weeks the moderate carbohydrate dieters lost more weight than the ketogenic dieters.  The researchers concluded that the ketogenic diet did not offer any significant metabolic advantage over the moderate carbohydrate diet12.
There are supplements of biochemicals naturally found in your body that taken daily will result in improved stored fat utilization and weight loss.  These supplements are:

·         Dissolved silica (a.k.a. OSA) for lowering your body-burden of aluminum13-15

·         CoQ10 for improving your energy and cognition16

·         PQQ for increasing mitochondrial biogenesis and cognition16-18

 
By lowering aluminum levels in your body, glycolysis and fat metabolism will return to normal.  This coupled with new mitochondria will allow you to metabolize or “burn” stored fat resulting in dieting with weight loss.

 There are also supplements of biochemicals naturally found in your body that will lower LDL and triglycerides, both of which are linked to an increased risk of vascular disease, such as stroke and heart attack: 

·         EPA (eicosapentaenoic acid) for reducing triglycerides by 5 to 10%19

·         PA (palmitoleic acid) for reducing triglycerides by 15% and LDL by 8%20

·         Vitamin D for reducing triglycerides by 23%21

Lowering triglycerides and LDL decreases the risk of vascular disease, heart attack, and stroke.  For more details on these supplements see my book “Prevent Alzheimer’s, Autism, and Stroke”22.

Ketogenic Diet with Fat from Medium Chain Triglycerides

Medium chain triglycerides (MCT), as opposed to long chain (i.e. 18 carbon atoms) triglycerides (LCT), do not require L-carnitine for mobilization and conversion into energy by the mitochondria10.  Therefore the metabolism of MCT is not inhibited by aluminum. Also the oxidative utilization (sum of digestion, absorption, and oxidation) of MCT can be 3 to 4 times greater than for LCT10.  These results were obtained with animals preconditioned to survive, like Lieutenant Schwatka, on a ketogenic diet10. 
 
Therefore the modern equivalent of the “Schwatka Imperative” is to either:
·         Remain obese while surviving on a diet of medium chain triglycerides or

·         Lose some weight by decreasing aluminum accumulation and eating a moderate carbohydrate diet.  

Many people are opting for the MCT diet, such as coconut oil, without lowering aluminum.  This will provide more energy and improved cognition. Unfortunately it will not result in weight loss since aluminum is still inhibiting the mobilization and conversion of stored long chain fatty acids to energy. Also:
·         MCT or Coconut oil does not contain essential fatty acids (e.g. linoleic and alpha-linolenic acid)

·         Lauric acid, comprising 50% of coconut oil, increases LDL by 16% in humans and LDL is linked to vascular disease, such as stroke and heart attack11

References

1. Lai, J.C., and Blass, J.P.; Inhibition of brain glycolysis by aluminum; J. Neurochem.; Feb.; 42(2):438-46 (1984)

2. Mailloux, R.J., et al.; Hepatic response to aluminum toxicity: Dsylipidemia and liver diseases; Exper. Cell Res.; 317:2231-2238 (2011)

3. Gaballa, I.F., et al.; Dyslipidemia and disruption of L-carnitine in aluminm exposed workers; Egyptian J. Occup. Med.; 37(1):33-46 (2013)

4. Lemire, J., et al.; The disruption of L-carnitine metabolism by aluminum toxicity and oxidative stress promotes dyslipemia in human astrocytes and hepatic cells; Toxicol. Lett.; Jun.; 203(3):219-26 (2011)

5. Waly, M. I-A., et al.; Activation of methionine synthase by insulin-like growth factor-1 and dopamine: a target for neurodevelopmental toxins and thimerosal; Mol. Psychiatry; 9:358-70 (2004)

6. Waly, M. I-A., and Deth, R.; Neurodevelopmental toxins deplete glutathione and inhibit folate and vitamin B12-dependent methionine synthase activity – a link between oxidative stress and autism, FASEB J.; 22:894 1 (2008)

7. Fritz, I.B., Kaplan, E., Yue, K.T.; Specificity of carnitine action on fatty acid oxidation by heart muscle; Am. J. Physiol.; Jan.; 202:117-21 (1962)

8. Schwatka, F.; The Long Arctic Search; Stackpole, E.A., Editor; No. 44; The Marine Historical Association, Inc.; Mystic, CT (1965)

9. Beattie, O., and Geiger, J.; Frozen in time – The fate of the Franklin Expedition; Bloomsbury (2004)

10. Heo, K.N., et al.; Medium-chain fatty acids but not L-carnitine accelerate the kinetics of [14C]triacylglycerol utilization by colostrum-deprived newborn pigs; J. Nutr.; 132:1989-1994 (2002)

11. Tsai, Y.H., et al.; Mechanisms mediating lipoprotein responses to diets with medium chain triglyceride and lauric acid; Lipids; Sep.; 34(9):895-905 (1999)

12. Johnston, C.S., et al.; Ketogenic low-carbohydrate diets have no metabolic advantage over nonketogenic low-carbohydrate diets; Am. J. Clin. Nutr.; 83:1055-61 (2006)

13. Edwardson, J.A., et al.; Effect of silicon on gastrointestinal absorption of aluminum; The Lancet; 342(8865):211-12 (1993)

14. Carlisle, E.M., and Curran, M.J.; Effect of dietary silicon and aluminum on silicon and aluminum levels in rat brain; Alzheimer Dis. Assoc. Disord.; 1(2):423-30 (2013)

15. Davenward, S,, et al.; Silicon-rich mineral water as a non-invasive test of the 'aluminum hypothesis' in Alzheimers disease; J. Alzheimer's Dis.; 33(2):423-30 (2013)

16. Nakani, M., et al.; Effect of pyrroloquinoline quinone (PQQ) on mental status of middle-aged and elderly persons; Food Style; 21 13(7):50-3 (2009)

17. Chowanadisai, W., et al.; Pyrroloquinoline quinone stimulates mitochondrial biogenesis through cAMP response element-binding protein phosphorylation and increased PGC-1 alpha expression; J. Biol. Chem.; Jan.; 285(1):142-52 (2010)

18. Onyango, I.G., et al.; Regulation of neuron mitochondrial biogenesis and relevance to brain heath; Biochim Biophys Acta; jan.; 1802(1):228-34 (2010)

19. Bernstein, A.M., et al.; Purified palmitoleic acid for the reduction of high-sensitivity C-reactive protein and serum lipids: a double blinded, placebo controlled study; J.Clin. Lipidol.; 8(6):612-7 (2014)

20. Harris, W.S.; n-3 Fatty acids and serum lipoproteins: human studies; A. J. Clin. Nutr.; 65(suppl.):1645S-54S (1997)

21. Rejnmark, L., et al.; Simvastatin does not affect vitamin D status, but low vitamin D levels are associated with dyslipidemia; Results from a randomized, contolled trial: Internat. J. Endrocrin.; Article ID 957174 (2010)

22. Crouse, D.N.; Prevent Alzheimer's, autism, and stroke, with 7 supplements, 7 life-style choices, and a dissolved mineral; Etiological Publishing (2016)