Can Vitamins And Antioxidants Do The Same Thing As Hb
One may ask, how would redox potential be affected if precursors of NADPH are added by way of the diet so that there was more total NADPH plus NADP? From the data that shows under certain conditions NADP precursors have no effect on their own in the absence of HB making the redox potential more reducing , one can infer that antioxidants and supplements may not work on their own. In the case of nicotinamide ribosides, precursors of NADH and NADPH the effect of having more total purine nucleotides is like having a larger battery, one with more cold cranking power, but the same voltage. The precursor supplement does not change the redox potential unless NADPH utilization goes up. One could expect similar behavior as that found in a battery. There is no difference in the voltage of a 1.5 volt triple A battery and a 1.5 Volt D Battery. Using a volt-meter, one cannot tell a triple A battery from a D battery. If you put both batteries under load, the smaller AAA battery voltage drops faster than the D battery under the same load of current draw. Likewise, If the NADPH has a small load the voltage or redox potential stays the same. It is when one puts a load on the battery or starts to use NADPH rapidly that the voltage drop is greater in the small AAA battery than in the larger D battery. Also, the redox potential or ability to provide electrons is reduced faster when there is a demand for NADPH and the total concentration is lower.
What Closes Or Opens The Gate That Lets Pyruvate Into The Mitochondria Energy Process
Four different enzymes start to close the pyruvate dehydrogenase complex gate and two enzymes can open it once partly closed. These enzymes regulate the opening and closing of the gate to let pyruvate into the mitochondria. The control of these enzymes is complex, but we know the gate is often closed in degenerative disease, infections, and trauma.
Dr. Veech knew HB does not go through the PDC to fuel the mitochondria. There are no gates to stop HB from making ATP once it reaches the mitochondria. This means HB can overcome a lack of energy found when the PDC switch turns off the flow of pyruvate fueling the mitochondria.
Dr. Veechs mentor at Harvard, George Cahill, had demonstrated that the brain could use HB for fuel when a person is fasting. Dr. Veech reasoned that HB could help people who have diseases where the gate that lets pyruvate into the mitochondria has been shut down. This includes many degenerative diseases such as Alzheimers and Parkinsons disease.
How Can A Hydrogen Transfer An Electron
Hydrogen consists of one electron and one proton. It has no charge. The actual transfer from pyruvate to NAD+ is 2 electrons and one proton. This transfer of two electrons and one proton is equal to a hydride ion or H- being transferred. The reaction of pyruvate with NAD to make NADH is a redox reaction in the metabolic pathway. It also is one that collects energy from food and stores it in one of the great controlling nucleotides. This stored energy in NADH will be used to drive other reactions. Each NADH made in the mitochondria eventually creates 3 ATP.
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Telomere Shortening Is Linked To Cellular Redox Status And Metabolism
The work of Hayflick and Moorhead pointed out that shortening of the telomeres set a limit to the number of divisions cells in culture could undergo before senescence occurs. Expression of the telomerase enzyme in certain germ and progenitor cells provides a solution to replicate the ends of linear chromosomes, so that the chromosomes do not become shorter with each new round of DNA replication. Telomeres are lengthened by starvation and shortened by ROS damage . These observations are consistent with aging being a function of reactive oxygen and its reversal a function of the increasing redox potential of the NADPH system brought about by caloric restriction. The FOXO protein FOXO1 was shown to be essential for the calorie restriction-mediated increase in telomerase subunit expression . As cells approach their Hayflick limit, the expression of the FOXO genes FOXO1 and FOXO4 have also been shown to decline , which would lead to decreased SOD2 and catalase expression. Senescent cells and tissues not only show decreased function but also acquire a senescence-associated secretory phenotype , a pro-inflammatory, pro-aging state. Mitochondrial dysfunction that increases ROS/RNS production also induces a cellular senescence program with a modified SASP .
We Dont Know The Long
While it is certainly the case that clinical trials evaluating the long-term effects of KD are yet to be conducted, the long-term effects of the current dietary recommendations appear to be clear. In the United States, for nearly 40 years, the Dietary Guidelines for Americans which strong evidence suggests people have been adhering to, has likely contributed to the doubling the obesity rate, with nearly 75% of adults either overweight or obese . In addition, this eating pattern associates strongly with the development of the spectrum of chronic metabolic diseases that continue to increase in prevalence .
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Measuring The Potential Energy Of The Great Controlling Nucleotide Coenzymes
Figure 1. The great nucleotide coenzymes. illustration by Sam Lally, grandson of Richard L. Veech.
Although pathways are important, it is just as important to know what role is played by these 3 to 5 letter abbreviations of coenzymes that magically appear over and over along those paths. These great nucleotide coenzymes work like a group of circus acrobats jumping from a platform onto a teeter board. The acrobats convert potential energy to kinetic energy when they jump down. Standing on the downside of the teeter board is an acrobat that will be hurled spinning into the air and land in a seat. The coenzymes provide chemical potential energy needed to drive the metabolic pathways. Acrobats must carefully measure the heights and mass and know the formula for the conversion of potential energy to kinetic energy. Potential energy of the launching acrobats that jump from a platform determines if a stunt is likely to succeed. In the same way the potential energy of the great controlling nucleotides determines the likelihood of all the chemical reactions in the metabolic pathways.
Josiah Willard Gibbs provided the thermodynamic equation describing chemical potential. It is known as the Gibbs free energy equation. It is a measure of the energy found in the chemical bonds and a measure of energy related to changes in entropy. Apparently, it takes energy to organize things. Dr. Veech would use this equation along with a close variant proposed by Walther Nernst.
Genetic Mechanisms Of Life Span Extension
There are marked heritable differences in median life span between species: from less than 3 weeks in C. elegans, between 2 and 3 years for the mouse or rat, 10 to 15 years for the dog, around 70 years for humans, and up to over 400 years in a bivalve mollusk Artica islandica. This observation makes it clear that life span has a heritable component.
The first genetically induced increase in life span in C. elegans was reported for a mutation in age-1, encoding a catalytic subunit of the of phosphatidylinositol 3-OH kinase of the insulin/insulin-like growth factor receptor signaling pathway . The Kenyon laboratory insightfully took experimental advantage of the short life span of C. elegans to identify mutations in the abnormal dauer formation-2 insulin/IGF-1 receptor gene of the IIS pathway that led to a twofold increase in C. elegans life span . This life span extension was found to be predominately caused by the decreased phosphorylation and nuclear translocation of the DAF-16/FOXO transcriptional regulator leading to expression of over 200 genes including those involved in metabolism, proteostasis, and antioxidant defenses , . Activation of other factors such as the SKN-1/Nrf2 transcriptional regulator also contributes to the longevity effects of reduced IIS under certain experimental conditions . The increased life span of the daf-2 mutant could be further increased by dietary restriction indicating at least partially distinct mechanisms of action .
Figure 1
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The Deanna Protocol For Als
Most neurologists agree on three general facts about ALS and neurodegenerative diseases such as Parkinsons disease:
The Deanna Protocol was developed by a determined physician, Dr. Vincent Tedone whose daughter Deanna was diagnosed with ALS. He teamed up with Dr. Dominic D’Agostino and other researchers and they developed a protocol to address the third factor of excess glutamate accumulation.
Their work focused on the actions of two normal enzymes necessary to breakdown glutamate:
AKG is an important substrate for the TCA/Krebs cycle which drives cellular energy processes. A lack of AKG stops the Krebs cycle and the affected cell dies. Low levels of GABA contribute to muscle spasticity and stiffness. Mainstream medicine teaches that GABA can’t cross the blood brain barrier so it’s of no use to supplement with it. However, in ALS the BBB isn’t working so well, and when given GABA, Deanna’s symptoms improved. Providing AKG as a supplement added to that improvement.
Eventually, the team developed a protocol for treating Deanna which resulted in a marked improvement in her symptoms. It included supplementation with
- AAKG
Interview With Bill Curtis
This is an excellent interview with William Curtis. I met Mr. Curtis at the Tripping Over the Truth conference in November 2017. Mr. Curtis was diagnosed with Parkinson’s in 2010 and has been keeping his symptoms in check using what he calls “intermittent ketosis” and exogenous ketones. He also has a website. The video is well worth watching if you have or care for someone with Parkinson’s.
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Tribute To Dr Richard Veech
Sometimes it takes a prediction coming true to prove a hypothesis. Einstein predicted the gravity of the sun would bend the light from stars. He had to wait for Edington to take pictures of stars in the background of the sun. These stars are normally hidden by the suns light. A shift in position of those stars would indicate that those beams of light were bent as they raced past the nearby sun into Edingtons camera during the 1919 total eclipse demonstrating Einsteins prediction and changing the scientific paradigm. Dr. Veech made a bold hypothesis in several papers in 2002 and 2003 that ketones would be important in medicine. An examination of his lifes work leads one to ask, Is there evidence of these predictions? Are ketones becoming important in medicine?
His friends and colleagues called him Bud. Everyone who worked in his lab, Martin Kemper, Robert Pawlosky, Todd King, Calvin Crutchfield, Yoshihiro Kashiwaya and many, many others called him Dr. Veech out of respect. Those who worked closest with him held him in highest esteem. Perhaps this was because Dr. Veech understood biochemistry from a different perspective, one that was not taught in books. Rather one that came from having ones work guided by annual reviews and direction from Hans Krebs, Albert Lehninger and others of that stature.
What Does The Future Hold
The study of synergies offers great hope that the therapies will work, given time and further research into other synergies. Perhaps synergies with ketosis will even work with cancer. There are many fields where scientists are beginning to comprehend that metabolic interventions may be needed to tackle treatment of the disease they study. The current thinking is that several interventions will be needed to suppress the cancer cells.
In Dr. Veechs lab, Dr. Robert Pawlosky, and Todd King, are busy making the measurements of potential energies of the great nucleotide coenzymes and producing ketone ester for animal studies for studies in Parkinsons, Alzheimers, heart disease and radiation mitigation to name the major collaborations.
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Synergism Of Ketosis And Nicotinamide Riboside Food Supplements
In some of the Alzheimers experiments it appears that the HB is needed for nicotinamide riboside to have any results. In other words, unless the HB makes NADPH available to provide electrons, eating the nicotinamide riboside precursor of NADPH has no effect, but when the precursor is added to HB the results are synergistic. This can be easily explained if one understands the math behind the redox potential. Both the Nernst redox potential and the Gibbs free energy derived equations Dr. Veech used had terms where the concentration of products over the concentration of the reactants were used to determine the redox potential. In this equation the concentration of the pair of nucleotides cancels out. That means the redox potential at any given steady state or near equilibrium is only proportional to the ratio of to . It is not affected by the number of the total of NADP plus NADPH. In fact, when Dr. Veech or anyone else measured the Gibbs free energy or the redox potential of the great controlling nucleotides, they only had to calculate the ratio of the low energy form to the high energy form.
Ketosis: What It Is And How It Works
It is beyond the scope of this brief review to describe the process of ketogenesis . In brief, ketosis is the metabolic state in which the body switches from using glucose as its primary energy source to using ketones as an alternative source of fuel. This metabolic state, as noted above, is achieved when one consumes a low-carbohydrate, moderate protein, high-fat diet or when one fasts for a few days or experiences starvation. Because of the need to maintain stable glucose levels, even in the context of little or no consumption of carbohydrates, glucose is supplied by gluconeogenesis . Since protein is the major substrate for GNG, it can be depleted quickly, representing the primary threat from starvation or prolonged fasting. The reduction in the hormone insulin, driven by the depletion of glucose, promotes lipolysis providing fatty acids as a major energy source. To reduce the potentially dangerous depletion of lean body protein, fatty acids provide ketone bodies which become a secondary fuel source that partially replaces the brain and CNSs demand for glucose.
Apart from fasting, KD is the most carbohydrate-restricted eating pattern. Therefore, KD keeps circulating insulin levels low which, in turn, gives access to fat stores to be burned as fuel. This explains why diets lower in carbohydrates tend to promote the greatest magnitude of selective depletion of body fat in the treatment of obesity .
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What Is A Realistic Expectation
Let me temper the enthusiasm of any who believe that one could magically cure any of these diseases with metabolic therapy. In the case of Parkinsons disease which the author has had for twenty years, the ketone ester by itself did nothing. One must be in a state of ketosis for the ketone ester to have an additive effect. This is an anecdote, a N of one experiment with no investigational review board approval, but it is straight forward to tell when something has no effect.
The diagram below shows some of the differences between the fasted and the fed state. It demonstrates the complexity of the two states. The ketone ester works in my Parkinsons when I am in the fasted state.
Taking exogenous ketones can put the body into states that were not possible to achieve before the ketone food supplements became available. We know very little about this third state that can allow one to be in the fed state and still have high levels of HB. In the diagram HB is called by its full name -3-hydroxybutyrate.
Figure 3. Blue arrows indicate pathways in the fasted state. Red arrows indicate pathways in the fed state.
Hb Could Provide More Energy Than Other Energy Molecules
Dr. Veech measured these potential energies in the liver, the heart and the brain in both fasted and fed states. His discoveries led him to understand that one of the ketone bodies, HB, had special properties as a fuel. Ketone bodies are small water-soluble energy molecules that fuel the brain, the heart and other organs when we are not continuously consuming carbohydrates or protein.
Dr. Veech found out HB could provide more energy than other energy molecules. This was recently demonstrated at the 2019 Tour de France. Each of the top 3 cyclists ascending the podium for the general classification category was known to be taking ketone monoester, an exogenous source of HB called G®. It was developed by Dr. Veech and his long time Oxford collaborator Prof. Kieran Clarke.
Dr. Veech did not set out to have his work used for athletes to win medals. His heart was in helping people. He wanted the ketone monoester to be used in medicine.
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The Great Controlling Nucleotide Coenzymes
Metabolic pathways plot the conversion of one biochemical to another. This happens as biomolecules are built up to participate in the normal function of cells. Other times biomolecules are broken down into simpler molecules to extract energy or to make a waste product that can be excreted. Dr. Veech had a map of the metabolic pathways that covered a wall in his home office. The two circular pathways of Krebs stand out. All along these pathways one finds compounds entering and leaving the path. One sees the same three to five letter abbreviations for coenzymes appear repeatedly. They seem to come out of nowhere on the path. They are converted to a slightly different set of letters. Not only do the coenzymes change in the reactions, the biochemicals on the main path are changed as well in each reaction. For example, ATP is converted to ADP or vice versa. Sometimes the letter changes are in one direction, sometimes in the other, and sometimes in both directions. NAD converts back and forth to NADH. NADP converts to NADPH. CoA appears to be converted to many forms. Dr. Veech called the coenzymes represented by these letters the great controlling nucleotide coenzymes.