Linus Pauling held that loss of the ability to synthesize vitamin C in the forerunners of humans was an evolutionary error that had best be compensated for in humans by mega-dosages of vitamin C. The difficulty with this view is that the forerunners of humans after the loss of the gene required to synthesize vitamin C had much less vitamin C available in tissues than before the loss. Given huge decreases in vitamin C bioavailability were a great disadvantage in terms of evolutionary fitness then the gene would not have been lost or at least would have once again been selected for. The animal forerunners who lost the ability to synthesize vitamin C were eating lots of fruit but were still getting a lot less vitamin C after the loss of the gene. Gulonolactone (L-) oxidase, the lost gene, is widely expressed in rats. Animals who synthesize vitamin C can synthesize huge amounts of vitamin C.
Even with fruit trees all around the loss of the gene to synthesize vitamin C would not have been a neutral mutation given the high levels of vitamin C in tissuses with the gene. The loss of the gene could not come about through genetic drift in a high fruit environment. A high fruit environment could have been permissive which is not to say that the loss of the gene and lessened bioavailability of vitamin C in tissues did not enhance evolutionary fitness.
Loss of the gene to synthesize vitamin C apparently had some evolutionary advantage which argues against supplementing with much more than RDA amounts of vitamin C now.
There are four human molybdenum containing enzymes, sulfite oxidase, xanthine oxidoreductase, aldehyde oxidase, and mitochondrial amidoxime reductase. Sulfite oxidase is expressed in the gastrointestinal tract and is highy expressed in the liver. Xanthine oxidoreductase is expressed in the gastrointestinal tract. Aldehyde oxidase is highly expressed in the liver.
Sodium molybdate supplmentation in rats increases levels of molybdenum containing proteins in the gastrointestinal tract and liver. 2000 micrograms of molybdenum a day is the Tolerable Upper Intake Level for molybdenum set for humans by the Institute of Medicine which did not study molybdenum glycinate. Giving rats by gavage the rat equivalent of 2000 micrograms a day of molybdenum from molybdenum glycinate in three divided dosages and then comparing levels of sulfite oxidase, xanthine oxidoreductase and aldehyde oxidase in intestines and livers of rats to levels of sulfite oxidase, xanthine oxidoreductase, aldehyde oxidase in intestines and livers of rats given by gavage the rat equivalent of 2000 micrograms a day of molybdenum from sodium molybdate would test the effect of molybdenum glycinate on molybdenum-containing gastrointestestinal enzymes and on molybdenum-containing liver enzymes. Molybdenum would be given in three divided dosages so molybdenum bound to glycine would always be in the gastrotintestinal tract and liver. Two divided dosages of molybdenum in humans would not be unusual. With molybdenun-containing enzymes there are only a few enzymes to look at simplyfing the experiment.
The prediction is that rats given molydenum glycinate will have lower levels of molybdenum-containing gastrointestestinal enzymes and lower levels of molybdenum-containing liver enzymes than rats given sodium molybdate.
Almost always clinical trials of supplements are run for short periods of time and moreover only certain side-effects are examined. Supplements programs though very frequently modified are usually started with the intention of being on the supplement for life. I think, for example that acetyl-L-cysteine and lipoic acid can have terrible long term effects though there could be postive effects on some dimensions in the short term. With prescription drugs doctors report side-effects that develop over the long term but that is not the case with supplements as usually doctors do not prescribe supplements.
Carnitine is frequently bound to fumarate in carnitine supplements and mineral supplements are very, very frequently bound to glycine. Fumarate can inhibit enzymes that demethylate DNA and histones. Leiomyomatosis and renal cell cancer can be caused by mutations of fumarate hydratase which metabolizes fumarate. Carnitine fumarate suppplements could be making wild epigenetic changes which could be highly undesirable. My opinion which must now be deeemed a personal opinion is that minerals bound to glycine are not bioavalable in the gastrointestinal tract whereby gylicnated minerals can have many negative effects. On many systematic measures glycinated minerals are very effective though I personally hold there can be higly unforeseen negative effects when supplementing with glycinated minerals.
There is mounting evidence that both sugar sweented and diet drinks have negative effects on cardiovascular health over the long term. What if it is not the artificial sweeteners in diet drinks that raise the difficulties but rather the citric acid and polyphenols and perhaps phosphoric acid are what is raising the difficulties? Many calcium supplements contain citrate. Could calicum citrate have the same adverse effects on cardiovascular health as do diet soft drinks and for the same reasons? I think citric acid based soft drinks can befuddle indivduals. There could be truth in advertising with Mountain Dew. Women under 65 who are on calcium citrate are not going to tell their doctors that they feel befudded and besides increasisng citric intake can lead to lots of fun.
Linus Pauling, who viewed orthormolecular medicine as the practice of delivering ‘the right molecules in the right amounts’, was correct in his view that mental illnesses are orthomolecular in nature and that supplements are required in the treatment of mental illnesses. That is not to say that supplements are not a minefield now.
High levels of homocysteine are associated with increased risks for a number of illnesses. Hyperhomocysteinemia is a risk factor far osteoporosis, Alzheimer’s disease, Parkinson’s disease, stroke, cardiovascular disease, cancer, aortic aneurysm, hypothyroidism and end renal stage disease among other illnesses. I would add schizophrenia and bipolar disorder.
I have been arguing that high homocysteine levels point to the transsulfuration pathway being dysregulated. That there are so many illnesses associated with high homocysteine combined with the ineffectiveness of folic acid in reducing risk ratios for various illnesses point to high homocysteine levels being a proxy for other dysregulated biological processes. I have been arguing than high homocysteine levels are associated with increased risks for epigenetic dysregulations.
Folic acid supplementation, which reduces homocysteine levels, does not decrease risk ratios for the various illnesses that high homocysteine levels are associated with, for example, cardiovascular illnesses. Folic acid is ineffective as homocysteine must be metabolized through the transsulfuration pathway. Increasing remethylation of homocysteine to L-methionine does not fix the transsulfuration pathway leaving folic acid ineffective in decreasing risk ratios for various illnesses. Very unfortunately increasing levels of L-cysteine through supplementation with N-acetyl-L-cysteine, cysteine, cystine or lipoic acid also does not work where such supplementation can be very dangerous.
Taurine regulates intracellular sodium levels. Long term supplemental taurine decreases levels of intracellular sodium. That taurine can affect intracellular sodium levels is clear. What is not clear is the effect of taurine on various sodium-dependent transporters. I have argued than low taurine levels by affecting sodium levels can dysregulate the sodium-dependent multivitamin transporter.
Neurotransmitter sodium symporters, which co-transport a neurotransmitter and sodium, among other molecules transport taurine, GABA, dopamine, serotonin and noradrenaline. Taurine is clearly involved in calcium homeostasis. Taurine could also be involved in sodium homeostasis.
Dysregulation of sodium homeostasis could dysregulate the transport of dopamine, serotonin, noradrenaline and GABA which play large roles in the regulation of mood. Antidepressants, antipsychotics and anioxylitcs target serotonin, dopamine, noradrenaline and GABA. Antidepressants, antipsychotics and anioxylitcs could be called for now in the treatment of mental illness due to dysregulation of sodium homeostasis which dysregulates dopamine, serotonin, noradrenaline and GABA.
Quite frequently individuals with major mental illnesses will take medications that affect dopamine, serotonin, noradrenaline and GABA. Dysregulation of sodium homeostasis could underlie the need by individuals with major mental illnesses to take medications from all three major classes of drugs used to treat mental illness. Supplemental taurine could help with re-regulation of sodium homeostasis. No argument is being made that only dysregulation of sodium homeostasis is the biological basis of major mental illnesses.
Pyruvate carboxylase is a biotin-dependent enzyme involved in gluconeogenesis and lipogenesis, in the biosynthesis of neurotransmitters, and in glucose-induced insulin secretion by pancreatic islets. Pyruvate carboxylase is a key to beta cell adaptation to insulin resistance where pyruvate carboxylase reduction can lead to beta cell failure. In Agouti-K mice reduction of pyruvate carboxylase in pancreatic islets could play a role in the development of Type 2 diabetes.
Biotin deficiencies both by decreasing metabolism of branched-chain amino acids and decreasing activity of pyruvate carboxylase could lead to the development of metabolic syndrome in humans. Both biotin and pantothenate would have to be taken to treat metabolic syndrome where biotin would be taken three times a day and pantothenic acid taken once a day away from biotin. Both biotin and pantothenate are transported by the the sodium-dependent multivitamin transporter (SMVT). Pantothenic acid taken alone could competitively inhibit transport of biotin by the SMVT while biotin taken alone could decrease transport of pantothenic acid by biotinylation of histones at the SMVT locus.
Elevated circulating levels of branched-chain amino acids have been associated with insulin resistance where decreased degradation of branched-chain amino acids could be what is leading to elevated circulating levels of branched-chain amino acids.
Methylcrotonyl CoA carboxylase and propionyl-CoA carboxylase are two biotin-dependent enzymes in the branched-chain amino acid degradation pathway. Dysregulation of the sodium-dependent multivitamin transporter which transports biotin could dysregulate the branched-chain amino acid degradation pathway leading to high levels of circulating branched-chain amino acids and insulin resistance.
Insulin resistance is present in 52% of individuals with bipolar disorder. Insulin resistance develops is brains of individuals with Alzheimer’s disease. In China in individuals with schizophrenia the prevalence of insulin resistance is 37.2% Both disease processes and drugs used to treat these illnesses could increase insulin resistance in theses illnesses. A commonality among these illnesses could be dysregulation of the sodium-dependent multivitamin transporter both by disease processes and drugs used to treat these illnesses.
Biotin supplementation decreases hyperglycemia, normalizing glucose levels, in patients with non-insulin dependent diabetes. There is reduced hyperglycemia is diabetic patients taking biotin.
The sodium-dependent multivitamin transporter transports both biotin and pantothenate. Pantothenate is needed to synthesize coenzyme A which is closely tied to the actions of biotin-dependent enzymes. Biotinylation of the sodium-dependent transporter reduces transport by the sodium-dependent multivitamin transporter. High levels of biotin could decrease transport of pantothenate by the sodium-dependent multivitamin transporter. A combination of pantothenic acid and biotin where 500 mg. of pantothenic acid is taken once a day away from supplemental biotin and 5 mg of biotin is taken three times a day could word work better in controlling hyperglycemia than biotin alone.
Only the abundance of biotinylated 3-methylcrotonyl-CoA carboxylase (holo-MCC) and propionyl-CoA carboxylase (holo-PCC) can distinguish between biotin-deficient and biotin-sufficient individuals. Methylcrotonyl CoA carboxylase and propionyl-CoA carboxylase could be particularly sensitive to biotin deficiencies.
Low levels of vitamin D are associated with schizophrenia, bipolar disorder Alzheimer’s disease and Parkinson’s disease. Vitamin D is a fat soluble vitamin. Bile acids are required for fat absorption. Taurocholic acid is a bile acid that is a conjugation of cholic acid with taurine. Taurochenodeoxycholic acid is a bile acid formed in the liver by conjugation of chenodeoxycholic acid with taurine. Taurine increases absorption of vitamin D.
There are low levels of vitamin D in schizophrenia, bipolar disorder, Alzheimer’s disease and Parkinson’s disease due to dysregulation of taurine synthesis in these illnesses attendant on dysregulation of the transsulfuration pathway which synthesizes L-cysteine from which taurine is synthesized.
Supplementation with vitamin D in these illnesses heretofore has not helped much as difficulties in fat absorption have not been addressed. Taurine, which regulates calcium homeostasis besides aiding in fat absorption, calcium hydroxyapatite and vitamin D are required to address low levels of vitamin D where there are also chronic illnesses.
Determining biotin deficiencies demands specialized tests. Only the abundance of biotinylated 3-methylcrotonyl-CoA carboxylase (holo-MCC) and propionyl-CoA carboxylase (holo-PCC) can distinguish between biotin-deficient and biotin-sufficient individuals
Beta-oxidation is up-regulated in schizophrenia. Malonyl-CoA inhibits beta-oxidation. Malonyl-CoA is synthesized by acetyl-CoA carboxylase which is a biotin-dependent enzyme. With deficiencies in biotin due to dysregulation of the SMVT malonyl-CoA will not be synthesized which will lead to low levels of malonyl-CoA and increased beta-oxidation which is what is seen in schizophrenia.