NAC - cysteine excess and negative feedback control of methylation cycles.

And many other things that can disrupt the interconnected one-carbon methylation cycles. Post got too long for email. Methylation cycles are reviewed and there is a Retinoid Toxicity tangent.

The reason to not take too large of a dose of N-acetylcysteine if you are healthy, is because excess will cause signaling to shut down our own production of it in the methylation cycles - which may be shutting down the methylation cycle instead of helping it function better.

“Methylation is disturbed by: High cysteine leads to reduced endogenous levels (via negative feedback)” Methylation & MTHFR Manual v3.3 (nutripath.com.au)

My recommendation for N-acetylcysteine is 600 mg a day in normal health, as a prevention, and increase frequency if ill. Twice a day if less severe, maybe 3 to 4 times if more severely ill. See jenniferdepew.com/cofactors.

“Cysteine, N-Acetyl-Cysteine, (NAC), 600 mg / x 4 - 2400 mg

Cysteine is a cofactor within the Citric Acid Cycle of mitochondria. Cysteine may help angina pain of CVD, cancer, autoimmune conditions, infertility, and it has shown respiratory and antiviral benefits. (ref) Excess in normal health may not be helpful, taking 600 mg once a day as prevention can be increased to more frequent use during an illness.” (jenniferdepew.com/cofactors)

Other things that can affect/disrupt the interconnected methylation cycles include:

• Diet - excess animal proteins, saturated fats (above 10% of total calories inhibits the Citric Acid Cycle), sugars, coffee, and alcohol may deplete B vitamins and magnesium.

• Lack of cofactors that are needed for the enzymes that keep the methylation cycles progressing forward through the multiple steps of each (Low Zn, Mg, B2, B3, B6, B9-folate).

• Medications e.g. Antacids (lowers B12 and magnesium), oral contraceptive pill, diuretics (loss of magnesium).

• Poor digestion or a leaky gut can affect methylation as malabsorption of magnesium and B vitamins may occur. Any older adult may need to use apple cider vinegar or lime/lemon juice with meals to improve digestion and absorption of B vitamins. We make less stomach acid as we get older. I use about 1-2 tablespoons for a serving of soup or salad.

• Smoking depletes folate, and SAMe. Lower folate, B12 and bioactive B6 levels were found in chronic smokers compared to nonsmokers and the forms of folate present were different in the smokers, (“pteroylmonoglutamate, formyltetrahydrofolate, and 5,10-methenyltetrahyrofolate”). Genetic damage was also found in the lining of the mouth of the chronic smokers. (Gabriel, et al., 2006) Magnesium was reduced for smokers of 15 or more cigarettes per day which may be due to reduced appetite and intake of healthy foods or damaged digestive linings may reduce absorption. Inflammation uses more magnesium. (Hilal, 2023) Vitamin C, beta-carotene,* and selenium may be depleted. (Preston, 1991) B12 was reduced in chronic smokers and homocysteine was elevated. (Singh, 2016)

  • Retinoid Toxicity tangent: *Supplements of vitamin A/carotenoids increased lung cancer risk in smokers, (Mount Sinai, Vit A, Retinol), so the beta-carotene deficiency mentioned by (Preston, 1991) may actually involve excess active Retinoids which leads to lack of inactive forms of vitamin A or carotenoids. Yes, disruption of retinoid metabolism does occur with chronic smoking, (seen in fetal and placenta development of women who were chronic smokers during pregnanc. Rouzaire, et al., 2017) This would make supplements of vitamin A or carotenoids potentially harmful instead of helpful and they are not recommended for chronic smokers or alcohol users. (Mount Sinai, Vit A, Retinol)

• Niacin uses up methyl groups but increases other areas of the methylation cycles so a good balance is needed for optimal function - or take additional methyl donor nutrients along with a high dose niacin protocol.

• Environmental toxins e.g. acetaldehyde (either alcohol, or made be yeast overgrowth in the gut), heavy metals - Arsenic (As), Mercury (Hg).

• Genetic mutations (MTHFR, CBS, COMT, MS/MTR, BHMT, SHMT, others) Some gene alleles that can lead to excess homocysteine and dysfunctional methylation cycles are included in this post about my own gene differences: microRNA, elevated homocysteine and is there a role for excess Retinoic Acid? (Substack)

• High SAMe also is a negative feedback control which causes reduced endogenous levels — so excess supplements of it might throw off the rest of the methylation cycles. And it isn’t normally something we need from the diet, so if methylation isn’t working, then something else must be missing or wrong. SAMe is made by parts of the cycles - it is an end product of functioning one carbon methylation cycles. It is needed for DNA methylation to take place in the cell nucleus. SAMe supplements are also fairly expensive - they might be a helpful as a temporary lift at the beginning of working through the rest of the list of things that might be wrong. The goal needs to be resolving why methylation wasn’t working - the SAMe is something you should make for yourself.

• Elevated levels of Glutathione (GSH) from IV or oral sources also has a negative feedback effect and leads to reduced endogenous production. That means we make less if we take excess supplements. Same story as SAMe - we are not supposed to get glutathione from the diet, we are supposed to make our own with functioning one-carbon methylation/transsulfuration/methionine/folate cycles. Think of glutathione supplements as a temporary support during a healing period - and it likely needs to be liposomal to bypass digestion.

Figure 1. SAM is the major Methyl donor. (Hayden, Tyagi, 2022, Figure 1)

The interconnected cycles/pathways include:

• Folate Pathway - uses the SHMT and MTHFR genes to add a methyl group back to inactive folate (THF) to form the bioactive methyl donor 5-MTHF. Coenzyme nutrients: Folate, Vitamin C, 5MTHF, B6, B2, B3, methyl/hydroxy B12, Iron, Zinc; Supportive nutrients: TMG, (caution with dose NAC), Histadine, Choline, Methionine; Minerals that may negatively affect: Cu, Pb, Co, Hg, Ni, Cd; excess Ca, Fe, Mg.

• Methionine Pathway - the MTR gene then can use the methyl group from the bioactive 5-MTHF to form methionine from homocysteine, converting 5-MTHF back into the inactive form of folate - THF. Or methionine can be made from homocysteine with a methyl group donation from betaine (TMG) using the BHMT gene to convert it into dimethylglycine (DMG). Coenzyme nutrients: Mg, potassium (K), Methionine; Supportive nutrients: Folate, Vitamin C, methylhydroxy B12, B2, B3, Zinc, Taurine, protein, (caution - SAMe, NAC); Minerals that may negatively affect: Pb, Cd; elevated Ca, P, Fe, Mn.

• SAMe Pathway - This article shows the cycles with SAMe as a central player. The conditions it mentions as potentially being helped by SAMe supplements is saying in other words that those conditions are having problems creating SAMe for themselves - they have methylation cycle dysfunction for unknown reasons. As we have seen in this post, there can be many reasons for dysfunction to occur and it would be better to figure out what needs to be corrected rather than relying on an expensive supplement that we should be making for ourselves. Coenzyme nutrients: B12, Zinc, SAMe; Supportive nutrients: for low SAMe – Mg, Methionine, Histidine, B3, protein; for excess SAMe – Glycine, Nicotinamide.

• Transsulfuration Pathway - uses the CBS gene to make cysteine from homocysteine and it may then be used to make the antioxidant glutathione or be converted into pyruvate and taurine. Coenzyme nutrients: B6, Fe, NAC (the cysteine should come from the homocysteine part of the methionine cycle - it can go either direction in the cycles. Cysteine is an available amino acid in normal diets, and typically isn’t deficient.) Supportive nutrients: Taurine, Folate, Vitamin C, Zinc, methyl/hydroxy B12, B2; Minerals that may negatively affect: Pb.

• Betaine Pathway - uses the BHMT gene to take a methyl group from betaine (TMG) and convert it into Dimethylglycine (DMG). Coenzyme nutrients: Trimethylglycine (TMG), Zinc, Choline, Phosphatidylcholine; Supportive nutrients: Folate, Vitamin C, B6, methyl or hydroxy B12, B2, (caution: NAC, SAMe); Minerals that may negatively affect: Cu, Pb, Co, Hg, Ni, Cd, excess Ca.

Excerpts with my additions and some changes to the recommendations from Methylation & MTHFR Manual v3.3 (nutripath.com.au). See pages 18 and 19 for medications and lifestyle factors that may negatively affect each pathway. Caution - I have not fact checked all of their information.

I don’t recommend folic acid for anyone, and I do recommend individualized guidance for everyone - example here is betaine/DMG and the BHMT gene.

» Important to note - not everyone needs supplements of the same things. Too much methyl folate supplementation may be a concern for some people with lack of other cofactors causing the cycles to malfunction rather than it being a problem with folate. Excess folic acid can be a negative for anyone as it competes with bioactive folate but isn’t active - like a puzzle piece filling up a space, but the picture doesn’t match - not a perfect fit. I encourage people to learn natural food sources of important nutrients and learn to enjoy cooking and eating them. Fortified foods use folic acid so breakfast cereal type foods are not a natural folate food. Asparagus, peas, and orange juice pulp/whole oranges are good sources.

» Also worth mentioning - the resource: Methylation & MTHFR Manual v3.3 (nutripath.com.au), is a guide for clinicians to use, rather than being written for a patient, AND, it is recommending that supplements of betaine (trimethylglycine) be consistently made rather than dimethylglycine for support of the methylation cycles. I would say, oops, that is a mistake. »Individuals need individualized guidance.« Someone like me who has a BHMT dysfunctional gene allele can’t convert betaine to DMG or make methionine. Betaine rich food sources like quinoa make me feel queasy. I need to supplement with dimethylglycine quite regularly or I get migraine headaches more easily - and it helps me to be cheerful too! Not having a migraine is worth cheering about. (Puntentional)

When I first tried dimethylglycine (DMG) and methionine as a bulk powder, about 2.5 -5 grams in water, 1/2 to 1 teaspoon of each, within 20 minutes I was suddenly energetic and cheerful. It was amazing but tasted bad, like a protein flavored acidic lemonade, so I named it Cheerful Juice as a motivator to keep drinking the vile drink. I have since modified the recipe to be tastier. The recipe is at the end of this post: What is health? and how to maintain or restore it? (Substack). I am not sure if the DMG or methionine is the more cheerful amino acid as I tried them together initially and most frequently, but the DMG specifically alone can help with my migraines and can help the body cool and prepare for sleep when taken prior to bed. DMG is a calming, inhibiting chemical within the brain and may help slow down overactive insomnia along with the cooling effect.

An anti-aging product company (NOVOS Labs) has a blog post explaining why they do not use TMG and do use ‘glycine’ in their anti-aging product. See: Why does NOVOS use glycine instead of trimethylglycine (TMG) or betaine? (novoslabs.com) *I am unaffiliated with the company or product and it is expensive.

They mention adverse side effects that may occur with TMG and that it may lead to excess methyl groups more than supplementing with choline, phosphatidylcholine, and a B vitamin complex, as it is farther along in the methylation cycles than ‘glycine’. I think DMG must be ‘glycine’ which is a word used in some of the methylation cycle graphics rather than the more specific DMG. Yes, I think that is what they mean as their article about glycine mentions the sleep benefit and that is specifically DMG, not TMG. Other benefits they mention are research shows supplementing with glycine extends lifespan and reduces aging effects. Less glycine tends to be present in older adults. It helps with stable blood sugar and can help restore mitochondrial function in older adults. See: Longevity Ingredients - Glycine, (novoslabs.com).

Retinoid Toxicity tangent: They explain why choline and phosphatidylcholine are beneficial in this article (*I don’t agree with all of their dosing recommendations) which also mentions that their products may contain a large amount of vitamin A - it may harm some people instead of helping. If overactivation of retinoids to the active forms is occurring, then symptom flair-up would be the next day after eating a vitamin A rich food - the liver needs time to convert it to the inflammatory active retinoids. The immediate same-day affect might feel good because inactive vitamin A can become low in people who over-activate it - liver injury seems involved.

See this post for more about the interconnected one-carbon methylation cycles:

• Food sources of methyl donors folate, B12, B6, betaine, and choline are in this older post along with information about an environmental toxin in plastic and coatings on register receipts called BPA. It is a methyl robber and an endocrine disrupting chemical. Methyl Donors and BPA (Substack)

Disclaimer: Opinions are my own and the information is provided for educational purposes within the guidelines of Fair Use. While I am a Registered Dietitian this information is not intended to provide individual health guidance. Please see a *functional health professional for individual health care purposes.

*Caution: ’functional’ may mean ‘relies on lab tests and may insist on them instead of giving educational guidance on what symptoms to watch out for, as things can be tried in a ‘Therapeutic Trial’. It had been standard practice for a doctor to simply recommend trying a safe treatment if the symptoms seemed to fit the diagnostic need. Then if it worked, “Yes, that seems to be your diagnosis, simply continue use.” If you are seeing a health practitioner who seems to be pushing their own agenda instead of listening to you and working with you - then find someone else. They may just want to sell supplements or lab tests on a never-ending basis. I do encourage food first if the budget is tight. Shop for the nutrient dense super foods, organic preferably, and look into foraging if you are near natural areas that don’t have ChemLawn type treatments.

If you have tried a supplement and it seems to help, then you may need it and should continue if you can afford it. The Methylation manual (nutripath.com.au) is quite insistent that clinicians should make their clients stop using supplements as soon as symptoms have improved. In my own health experiences, I get worse again when I go back to former habits or stop some of my more critical supplements. A genetic screening can be worth the money - private companies ideally rather than Ancestry.com or the google one - your DNA may not be private there.

I try to teach you to fish instead of selling you a monthly subscription for fresh fish purchases.

Random aside - the annual dietitian conference (A.N.D.) is going to be held in Denver, Colorado. So, we can go look at the Satanic airport. (I will have to decline.) Be cautious who you trust these days. They may not be telling you everything, or they may not know as much as they confidently think they know.

Your body knows whether you feel better or worse - learn to pay attention. Something can have a feel-good effect today and then feel worse tomorrow. Keeping daily logs of what you eat and symptoms you feel can help to see patterns emerge.

Disclaimer: Opinions are my own. Peace be with you.

Reference List

Methylation & MTHFR Manual v3.3 (nutripath.com.au) http://nutripath.com.au/wp-content/uploads/2016/09/NPATH-METHYLATION-MTHFR-Manual-v3.3.pdf

(Gabriel, et al., 2006) Gabriel HE, Crott JW, Ghandour H, Dallal GE, Choi SW, Keyes MK, Jang H, Liu Z, Nadeau M, Johnston A, Mager D, Mason JB. Chronic cigarette smoking is associated with diminished folate status, altered folate form distribution, and increased genetic damage in the buccal mucosa of healthy adults. Am J Clin Nutr. 2006 Apr;83(4):835-41. doi: 10.1093/ajcn/83.4.835. Erratum in: Am J Clin Nutr. 2006 Jul;84(1):263. PMID: 16600936. https://pubmed.ncbi.nlm.nih.gov/16600936/

(Hayden, Tyagi, 2022) Hayden, M.R., Tyagi, S.C., (2022). Impaired Folate-Mediated One-Carbon Metabolism in Type 2 Diabetes, Late-Onset Alzheimer’s Disease and Long COVID. Medicina. 58(1):16. https://doi.org/10.3390/medicina58010016 Available at https://www.mdpi.com/1648-9144/58/1/16

(Mount Sinai, Vit A, Retinol) ‘Vitamin A - Retinol,’ mountsinai.org, https://www.mountsinai.org/health-library/supplement/vitamin-a-retinol

(Preston, 1991) Preston AM. Cigarette smoking-nutritional implications. Prog Food Nutr Sci. 1991;15(4):183-217. PMID: 1784736. https://pubmed.ncbi.nlm.nih.gov/1784736/

(Rouzaire, et al., 2017) Rouzaire, M., Comptour, A., Belville, C., Bouvier, D., Sapin, V., Gallot, D., Blanchon, L., (2017). Cigarette smoke condensate affects the retinoid pathway in human amnion, Placenta, 58;98-104, ISSN 0143-4004, https://doi.org/10.1016/j.placenta.2017.08.076. https://www.sciencedirect.com/science/article/pii/S0143400417311037

(Singh, 2016) Singh, D., Effect of Cigarette Smoking on Serum Homocysteine and Vitamin B12 Level in Male Population of Udaipur, Biochem Anal Biochem 2016, 5:2 DOI: 10.4172/2161-1009.1000282 https://www.dropbox.com/s/uhluurnjgg0k8x9/effect-of-cigarette-smoking-on-serum-homocysteine-and-vitamin-b12level-in-male-population-of-udaipur-2161-1009-1000282.pdf?dl=0