What is TMG?

TMG stands for trimethylglycine, but is also known as betaine. TMG is produced by the body and found in foods like beetroot, wheat, quinoa, and seafood (1). As a supplement, TMG has been used primarily to optimize athletic performance and to improve heart health. It also plays a role in methylation, which is central to DNA health(2). TMG has anti-inflammatory properties as well as heart, and metabolic-supportive qualities that are therapeutic for disease.

 
TMG has two main functions. It is an osmolyte, which means that it regulates intracellular osmotic pressure, which strengthens protein function and protects cells from osmotic stress (3 -6 ). It is also a methyl-group donor, meaning that it helps to maintain normal methylation activity for optimal DNA health (7).

What are some of the main mechanisms? 
TMG confers health benefits through several mechanisms. While inflammation is a necessary immune reaction to promote healing, prolonged or chronic inflammation is an underlying factor across most diseases of aging. TMG has been noted to combat inflammation and aging pathophysiology by increasing the activity of antioxidant agents, increasing the metabolism of sulfur amino acids (8), inhibiting NFkB and inflammasome-related proteins (9-11), positively impacting the methylation of nucleic acids and proteins (12), and restoring energy metabolism balance. Animal research also suggests that TMG mediates endoplasmic reticulum stress to reduce inflammation (13). This is beneficial as ER stress can lead to cellular death, or apoptosis - a process involved in the pathogenesis of inflammatory diseases and diseases of aging. All of these factors are essential to TMG’s anti-inflammatory and longevity effects (14). 
These mechanisms contribute to TMG’s health benefits across several human diseases including but not limited to: obesity, diabetes, cancer and dementia (14).
 
TMG and Heart Health
Research has suggested that TMG may decrease the risk for heart disease. While the research is conflicting, the main reason TMG is thought to benefit heart health is due to its ability to decrease levels of the amino acid homocysteine in blood. When levels of homocysteine are too high, risk for heart disease increases and blood vessels are at risk of damage (15, 16). A review of studies in healthy adults found that 6 weeks of daily TMG supplementation (4 grams) lead to a decrease in homocysteine blood levels (17). However, TMG supplementation may negatively impact other risk factors for heart disease, thus more research is needed for clarification (18, 19). Animal studies have also found that TMG may suppress NF-kB activity which could otherwise contribute to atherogenesis (20-23).

TMG and Liver Health
For humans and animals alike, betaine has been found to enhance liver function for those with fatty liver disease and steatohepatitis (1, 24-26). This is likely due to TMG’s action as a methyl donor to homocysteine.

TMG and Gut Health
TMG’s activity as a methyl donor is also associated with better intestinal barrier function (7, 27). Animal research has also suggested that TMG can improve microbiome diversity, activate digestive enzymes and strengthen intestinal structure (28). More studies are needed to investigate similar effects for humans.

TMG and Cancer
There is also a body of human research which suggests that TMG is beneficial for cancers including breast cancer, lung cancer, liver cancer, colorectal cancer and nasopharyngeal carcinoma (37-41). A consensus of research in this area has found that higher intake of TMG decreases the risk for cancer. However, the majority of these studies have been case-control studies which are not the golden standard in study design. There is a need for randomized controlled trials to support these findings.

TMG and Brain Health
In human studies, TMG supplementation has been shown to mediate a hallmark of Alzheimer’s disease, hyperhomocysteinemia (42). Another study found that TMG supplementation could improve inflammatory response for those with Alzheimer’s disease (43). Animal studies have also found that TMG can suppress NF-kB activity which could otherwise contribute to neural injury (22-23). A greater body of research is needed to solidify this basis of evidence.

TMG and Athletic Performance
Research suggests that TMG supplementation may enhance athletic performance. A review found that TMG supplements may enhance body composition as well as both resistance and endurance exercise performance (44). However, another review suggested mixed results (45). The mechanisms for potential exercise performance enhancement are unknown but may be due to TMG-induced increased synthesis of creatine, increased protein production and reduced fatigue (44).

TMG and Metabolic Health
Both animal and human research have suggested that TMG supplementation has beneficial effects on metabolic health. These studies have found that TMG levels are inversely correlated with body fat percentages. For instance, higher TMG level correlates with lower body fat percentage. However, in research this has only been found to hold true for men; more research is needed (29-33). It is important to note that this area is still under exploration and overall, results are positive but conflicting (34-36). 

Additionally, a study in mice fed a high fat diet showed that TMG enhanced the metabolism of fat and improved insulin sensitivity (46). Similarly, a study with 2,400 participants found that those who had a higher intake of both choline and TMG had improved insulin sensitivity, and lower fasting glucose (47). Since insulin resistance and high fasting glucose are signs of poor glucose regulation and an increased risk for metabolic conditions, these benefits are significant (48).

Overall, research has suggested that TMG positively contributes to improved lipid and glucose metabolism (49, 50). TMG likely restores an imbalance between fat synthesis and oxidation to prevent fat accumulation (51-53). Animal research has shown that this may be due to involvement of increased AMP-activated protein kinase (AMPK) activity (54). AMPK is an energy sensor and a potent regulator of metabolic homeostasis. Increased AMPK likely contributes to reduced lipogenesis, lipid accumulation, and enhanced glucose uptake and insulin sensitivity (55-56). However, more research is needed.

Dosage 
The dosage of TMG supplements used in most studies is typically between 500-9,000 mg/day (44). However, research suggests that up to 9-15 g/day is safe for humans (1). 

Conclusion
TMG is suggested to have major health promoting physiological effects for the heart, cardiorespiratory, liver, brain and gut health, as well as for the prevention of metabolic conditions and cancer. These beneficial impacts are due to TMGS properties as both an osmoprotectant and methyl-group donor, as well as TMGs abilities to combat inflammation, oxidative stress, and endoplasmic reticulum stress, as well as to regulate apoptosis, sulfur amino acid metabolism and methylation. More research on TMG is warranted, as the benefits may confer alleviation for the pathophysiologies of various diseases.
 

Author: Jacqueline Seymour

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