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January 19, 2023
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TMG: methylation donor and NMN-helper
TMG participates in a series of methylation reactions (methylation levels also tend to get depleted as we age) and also significantly decreases body fat.
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Compound description
TMG or trimethylglycine, also called betaine, was initially identified as a side product in extracts of the common sugar beet. TMG can serve as an osmolyte (a compound that can protect cell integrity by influencing the properties of biofluids) due to having a zwitterion structure (neutrally charged compound carrying positively and negatively charged groups). TMG is a derivative of amino acid glycine carrying three methyl (-CH3) groups, so it can also serve as a methyl group donor in the methylation process. DNA methylation is the mechanism by which the body regulates gene expression by adding a methyl group to a cytosine nucleobase.
Properties
In the absence of supplementation, TMG is naturally formed in cells through the oxidation of choline – another essential nutrient. A diet is also considered a vital source of TMG, with foods like quinoa, wheat, spinach, shellfish, and, of course, beets being especially rich in it (1). TMG is involved in a series of methylation reactions in the body, mainly occurring in the mitochondria of kidney and liver cells. The most important outcome of these reactions, called the methionine cycle, is a conversion of homocysteine. Homocysteine is an amino acid naturally produced and utilized in metabolic processes. However, high levels of homocysteine may indicate low metabolic activity and serve as a marker for cardiovascular disease, atherosclerosis, and thrombosis (2).
Use as a supplement
Though gaining its popularity as a supplement relatively recently, TMG has been extensively used in animal feeds for more than 50 years. It has provided a substantial amount of data on its safety in animals and shown the effects of decreasing the amounts of fat tissues without affecting the lean tissue (particularly in pigs). However, whether these effects are fully reproducible in humans is still under investigation. In a placebo-controlled, randomized, double-blind, parallel study of 46 obese subjects, a daily dosage of 6g TMG failed to have any effect beyond those of a hypoenergetic diet on body weight, body mass index, and body composition (3). A significant decrease in plasma homocysteine concentration was, however, observed. While confirming a lack of significant effect on body weight, a meta-analysis by Gao et al. showed that a decrease in general body fat was significant (4).
As an anti-aging supplement, TMG is mainly used along with NMN (nicotine mononucleotide) – a supplement targeted at increasing NAD+ (nicotinamide dinucleotide) levels. NAD+ is involved in a range of aging, cellular, and DNA repair processes, and its levels tend to decrease as we age. Methylation levels also tend to get depleted as we age. Another cause can be particular mutations in gene encoding methylenetetrahydrofolate reductase (5). But what is the connection between the two? There is evidence that consumption of NAD+ activating supplements leads to the depletion of the methylation pool in the body (6). Thus, additional supplementation with methylation donors can allow to balance out the deficit and increase the efficiency of, for example, NMN supplementation. It should be pointed out, however, that there are no clinical studies on the long-term effect of such supplementation at the moment. The existing research emphasizes not exceeding the maximal safe dose of 6 grams per day, with recommended doses ranging from 0,5 to 2 grams per day (7,8).
In our Marketplace under the vendor DoNotAge, you can find TMG as capsules. In this dosage form, DoNotAge provides a 500 mg/capsule dosage, making it easy to obtain the necessary dose to maintain your anti-aging routine.
Side effects
While TMG has many putative benefits, one should be aware that much of the existing data needs further confirmation, and this is not an adverse effect-free supplement. Frequent side effects linked to TMG are diarrhea, stomach upset, and nausea. TMG supplementation was found to increase blood low-density lipid (“bad”) cholesterol and triacylglycerol concentrations in healthy humans, which might undermine its benefits for cardiovascular health (9). Due to its metabolism, its use is contraindicated to patients with renal or liver problems. Please, be aware if you are not taking any other methyl donor supplementation, such as B12 or folate. If you have any doubts about TMG supplementation safety in your case, discuss its usage with your doctor or healthcare provider.
References
1. Craig SA. Betaine in human nutrition. Am J Clin Nutr. 2004 Sep 1;80(3):539–49.
2. Herrmann W. The Importance of Hyperhomocysteinemia as a Risk Factor for Diseases: An Overview. Clin Chem Lab Med [Internet]. 2001 Jan 31 [cited 2022 Apr 30];39(8). Available from: https://www.degruyter.com/document/doi/10.1515/CCLM.2001.110/html
3. Schwab U, Törrönen A, Toppinen L, Alfthan G, Saarinen M, Aro A, et al. Betaine supplementation decreases plasma homocysteine concentrations but does not affect body weight, body composition, or resting energy expenditure in human subjects. Am J Clin Nutr. 2002 Nov 1;76(5):961–7.
4. Gao X, Zhang H, Guo X fei, Li K, Li S, Li D. Effect of Betaine on Reducing Body Fat—A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Nutrients. 2019 Oct 16;11(10):2480.
5. Jin Z, Liu Y. DNA methylation in human diseases. Genes Dis. 2018 Mar;5(1):1–8.
6. Pissios P. Nicotinamide N -Methyltransferase: More Than a Vitamin B3 Clearance Enzyme. Trends Endocrinol Metab. 2017 May;28(5):340–53.
7. Shorter KR, Felder MR, Vrana PB. Consequences of dietary methyl donor supplements: Is more always better? Prog Biophys Mol Biol. 2015 Jul;118(1–2):14–20.
8. Mütze U, Gleich F, Garbade SF, Plisson C, Aldámiz‐Echevarría L, Arrieta F, et al. Postauthorization safety study of betaine anhydrous. J Inherit Metab Dis. 2022 Apr 6;jimd.12499.
9. Olthof MR, van Vliet T, Verhoef P, Zock PL, Katan MB. Effect of Homocysteine-Lowering Nutrients on Blood Lipids: Results from Four Randomised, Placebo-Controlled Studies in Healthy Humans. Ludwig D, editor. PLoS Med. 2005 May 31;2(5):e135.
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Compound description
TMG or trimethylglycine, also called betaine, was initially identified as a side product in extracts of the common sugar beet. TMG can serve as an osmolyte (a compound that can protect cell integrity by influencing the properties of biofluids) due to having a zwitterion structure (neutrally charged compound carrying positively and negatively charged groups). TMG is a derivative of amino acid glycine carrying three methyl (-CH3) groups, so it can also serve as a methyl group donor in the methylation process. DNA methylation is the mechanism by which the body regulates gene expression by adding a methyl group to a cytosine nucleobase.
Properties
In the absence of supplementation, TMG is naturally formed in cells through the oxidation of choline – another essential nutrient. A diet is also considered a vital source of TMG, with foods like quinoa, wheat, spinach, shellfish, and, of course, beets being especially rich in it (1). TMG is involved in a series of methylation reactions in the body, mainly occurring in the mitochondria of kidney and liver cells. The most important outcome of these reactions, called the methionine cycle, is a conversion of homocysteine. Homocysteine is an amino acid naturally produced and utilized in metabolic processes. However, high levels of homocysteine may indicate low metabolic activity and serve as a marker for cardiovascular disease, atherosclerosis, and thrombosis (2).
Use as a supplement
Though gaining its popularity as a supplement relatively recently, TMG has been extensively used in animal feeds for more than 50 years. It has provided a substantial amount of data on its safety in animals and shown the effects of decreasing the amounts of fat tissues without affecting the lean tissue (particularly in pigs). However, whether these effects are fully reproducible in humans is still under investigation. In a placebo-controlled, randomized, double-blind, parallel study of 46 obese subjects, a daily dosage of 6g TMG failed to have any effect beyond those of a hypoenergetic diet on body weight, body mass index, and body composition (3). A significant decrease in plasma homocysteine concentration was, however, observed. While confirming a lack of significant effect on body weight, a meta-analysis by Gao et al. showed that a decrease in general body fat was significant (4).
As an anti-aging supplement, TMG is mainly used along with NMN (nicotine mononucleotide) – a supplement targeted at increasing NAD+ (nicotinamide dinucleotide) levels. NAD+ is involved in a range of aging, cellular, and DNA repair processes, and its levels tend to decrease as we age. Methylation levels also tend to get depleted as we age. Another cause can be particular mutations in gene encoding methylenetetrahydrofolate reductase (5). But what is the connection between the two? There is evidence that consumption of NAD+ activating supplements leads to the depletion of the methylation pool in the body (6). Thus, additional supplementation with methylation donors can allow to balance out the deficit and increase the efficiency of, for example, NMN supplementation. It should be pointed out, however, that there are no clinical studies on the long-term effect of such supplementation at the moment. The existing research emphasizes not exceeding the maximal safe dose of 6 grams per day, with recommended doses ranging from 0,5 to 2 grams per day (7,8).
In our Marketplace under the vendor DoNotAge, you can find TMG as capsules. In this dosage form, DoNotAge provides a 500 mg/capsule dosage, making it easy to obtain the necessary dose to maintain your anti-aging routine.
Side effects
While TMG has many putative benefits, one should be aware that much of the existing data needs further confirmation, and this is not an adverse effect-free supplement. Frequent side effects linked to TMG are diarrhea, stomach upset, and nausea. TMG supplementation was found to increase blood low-density lipid (“bad”) cholesterol and triacylglycerol concentrations in healthy humans, which might undermine its benefits for cardiovascular health (9). Due to its metabolism, its use is contraindicated to patients with renal or liver problems. Please, be aware if you are not taking any other methyl donor supplementation, such as B12 or folate. If you have any doubts about TMG supplementation safety in your case, discuss its usage with your doctor or healthcare provider.
References
1. Craig SA. Betaine in human nutrition. Am J Clin Nutr. 2004 Sep 1;80(3):539–49.
2. Herrmann W. The Importance of Hyperhomocysteinemia as a Risk Factor for Diseases: An Overview. Clin Chem Lab Med [Internet]. 2001 Jan 31 [cited 2022 Apr 30];39(8). Available from: https://www.degruyter.com/document/doi/10.1515/CCLM.2001.110/html
3. Schwab U, Törrönen A, Toppinen L, Alfthan G, Saarinen M, Aro A, et al. Betaine supplementation decreases plasma homocysteine concentrations but does not affect body weight, body composition, or resting energy expenditure in human subjects. Am J Clin Nutr. 2002 Nov 1;76(5):961–7.
4. Gao X, Zhang H, Guo X fei, Li K, Li S, Li D. Effect of Betaine on Reducing Body Fat—A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Nutrients. 2019 Oct 16;11(10):2480.
5. Jin Z, Liu Y. DNA methylation in human diseases. Genes Dis. 2018 Mar;5(1):1–8.
6. Pissios P. Nicotinamide N -Methyltransferase: More Than a Vitamin B3 Clearance Enzyme. Trends Endocrinol Metab. 2017 May;28(5):340–53.
7. Shorter KR, Felder MR, Vrana PB. Consequences of dietary methyl donor supplements: Is more always better? Prog Biophys Mol Biol. 2015 Jul;118(1–2):14–20.
8. Mütze U, Gleich F, Garbade SF, Plisson C, Aldámiz‐Echevarría L, Arrieta F, et al. Postauthorization safety study of betaine anhydrous. J Inherit Metab Dis. 2022 Apr 6;jimd.12499.
9. Olthof MR, van Vliet T, Verhoef P, Zock PL, Katan MB. Effect of Homocysteine-Lowering Nutrients on Blood Lipids: Results from Four Randomised, Placebo-Controlled Studies in Healthy Humans. Ludwig D, editor. PLoS Med. 2005 May 31;2(5):e135.
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Dr. Ana Baroni MD. Ph.D.
Scientific & Medical Advisor
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Ana has over 20 years of consultancy experience in longevity, regenerative and precision medicine. She has a multifaceted understanding of genomics, molecular biology, clinical biochemistry, nutrition, aging markers, hormones and physical training. This background allows her to bridge the gap between longevity basic sciences and evidence-based real interventions, putting them into the clinic, to enhance the healthy aging of people. She is co-founder of Origen.life, and Longevityzone. Board member at Breath of Health, BioOx and American Board of Clinical Nutrition. She is Director of International Medical Education of the American College of Integrative Medicine, Professor in IL3 Master of Longevity at Barcelona University and Professor of Nutrigenomics in Nutrition Grade in UNIR University.
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