TMG (Trimethylglycine / Betaine)
TMG (Trimethylglycine / Betaine)
When David Sinclair takes NMN, he takes TMG alongside it. Bryan Johnson's Blueprint protocol includes 1 gram daily. The reason goes beyond just "methyl donors" — TMG sits at the crossroads of homocysteine control, liver protection, and cellular hydration, pathways that become increasingly relevant as we age.
Evidence Tier: 🥈 Silver — consistent human evidence for homocysteine reduction and liver protection; moderate evidence for exercise performance; no direct longevity trials in humans yet, but strong mechanistic rationale.
⚖️ At a Glance: Pros & Cons
⚠️ We are researchers, not doctors. Nothing on this page is medical advice. TMG is generally safe but can interact with certain conditions and medications. Always consult your doctor before starting any new supplement — especially if you take blood pressure medication, have kidney issues, or are pregnant.
✅ Pros
- Lowers homocysteine reliably: Multiple RCTs show TMG reduces plasma homocysteine by 10–20% within weeks — a key cardiovascular and brain aging risk factor.
- Protects the liver: Human trials and animal models show TMG reduces liver fat and inflammation in non-alcoholic fatty liver disease (NAFLD).
- Improves exercise performance: Several human studies find TMG boosts power output, muscular endurance, and body composition during resistance training.
- Well-tolerated with a long safety record: Doses up to 6 grams/day have been studied for years with few side effects beyond mild GI upset.
❌ Cons
- No direct longevity trials: While the mechanisms are compelling, no human study has measured whether TMG extends lifespan or healthspan.
- May raise LDL cholesterol: Some studies report small increases in LDL cholesterol with TMG supplementation — the clinical significance is debated.
- TMAO concern unresolved: TMG can theoretically increase TMAO (a metabolite linked to heart disease), but the human data is mixed and context-dependent.
- Fishy body odor at high doses: A harmless but socially awkward side effect from trimethylamine production in some people.
What Is TMG?
Trimethylglycine (TMG) — also called betaine — is a naturally occurring compound found in beets, spinach, quinoa, and wheat bran. Your body also makes it from choline. The name "betaine" comes from its discovery in sugar beets (Beta vulgaris) in the 19th century.
Chemically, TMG is the amino acid glycine with three methyl groups attached. Those three methyl groups are what make it valuable: TMG is one of the body's most important methyl donors — molecules that transfer methyl groups (one carbon + three hydrogens) to other compounds. This process, called methylation, controls everything from DNA repair to neurotransmitter production to detoxification.
TMG has two distinct jobs in the body, and both matter for aging:
- Methyl donor: TMG donates a methyl group to homocysteine, converting it back to methionine. This lowers homocysteine (high levels damage blood vessels and the brain) while preserving the methylation cycle that repairs DNA and regulates genes.
- Osmolyte: TMG acts as an "osmotic stabilizer" — it protects cells from dehydration and stress by balancing water and ion concentrations. This is particularly important in the kidneys, liver, and brain, where cells face constant osmotic challenges.
How It Works
TMG operates through the methionine-homocysteine cycle, also called one-carbon metabolism. Here's the simplified version of what happens:
Every time your body uses a methyl group for something important — repairing DNA, making creatine, producing neurotransmitters, silencing harmful genes — it creates homocysteine as a byproduct. Homocysteine is toxic at high levels. It damages the endothelial cells lining your blood vessels, promotes inflammation, and is linked to higher risks of heart disease, stroke, dementia, and even osteoporosis.
Your body has two ways to clear homocysteine:
- The folate/B12 pathway: Uses folate (vitamin B9) and vitamin B12 as cofactors to recycle homocysteine back to methionine. This is the "remethylation" route.
- The TMG pathway: An alternative remethylation route that uses betaine-homocysteine methyltransferase (BHMT), an enzyme found mainly in the liver and kidneys. TMG donates a methyl group directly to homocysteine, converting it to methionine and leaving behind dimethylglycine (DMG).
The TMG pathway becomes more important in certain situations: when folate or B12 are low, when methylation demand is high (pregnancy, growth, intense exercise), and — critically for longevity — as we age. Studies show that BHMT enzyme activity can decline with age, and TMG levels in the blood tend to decrease, while homocysteine rises. Supplementing TMG may help compensate for this age-related decline.
TMG also supports the production of S-adenosylmethionine (SAMe), the body's universal methyl donor. By helping convert homocysteine back to methionine (which then becomes SAMe), TMG indirectly fuels hundreds of methylation reactions — including those that regulate gene expression through epigenetics, a process central to aging.
The Longevity Connection
🫀 Cardiovascular Aging
Tier: 🥇 Gold
The strongest longevity argument for TMG is its effect on homocysteine. Elevated homocysteine is an independent risk factor for cardiovascular disease, and levels tend to rise with age. A 2026 RCT in 116 overweight and obese patients with hyperhomocysteinemia found that betaine-containing nutrients significantly reduced homocysteine levels compared to standard B-vitamin therapy alone. Earlier landmark studies by Olthof et al. (2003) showed that as little as 1.5 grams of TMG per day lowered fasting homocysteine by 12–15% in healthy adults — with effects seen within 2 weeks.
The million-dollar question: does lowering homocysteine with TMG actually reduce heart attacks and strokes? The answer is complicated. Large trials using B vitamins (folate, B12, B6) to lower homocysteine showed mixed results for cardiovascular outcomes — homocysteine dropped but event rates didn't always follow. However, critics note that these trials used B vitamins in populations with adequate baseline folate (after folic acid fortification), so B vitamins may not have been the right tool. TMG lowers homocysteine through a completely different enzymatic pathway (BHMT), and no large outcome trial has tested TMG specifically. So the mechanism is solid, but the hard outcome data is still missing.
🧠 Brain Aging
Tier: 🥈 Silver
High homocysteine is a risk factor for cognitive decline and dementia. A 2026 mouse study found that betaine supplementation attenuated cognitive impairment caused by high homocysteine — it worked by suppressing oxidative stress and activating the PI3K/AKT/GSK-3β pathway, a signaling cascade involved in neuronal survival and plasticity. While human trials specifically testing TMG for cognitive outcomes are lacking, the homocysteine-lowering effect provides a plausible mechanistic link.
Some epidemiological studies have found associations between higher dietary betaine intake and lower risk of cognitive decline, but these are observational — they can't prove causation.
🫁 Liver Health
Tier: 🥇 Gold
The liver is where TMG works hardest. BHMT, the enzyme that uses TMG to clear homocysteine, is concentrated in the liver. TMG also protects liver cells from fat accumulation, oxidative stress, and inflammation — the triple threat behind non-alcoholic fatty liver disease (NAFLD), which affects roughly 25–30% of adults worldwide and increases with age.
A landmark 2009 pilot study by Abdelmalek et al. tested 20 grams of TMG daily in patients with non-alcoholic steatohepatitis (NASH, the severe form of NAFLD). After one year, liver enzyme levels improved significantly, and liver biopsies showed reduced fat, inflammation, and fibrosis in many patients. While that dose is very high, subsequent studies using more moderate doses (3–6 grams) have also shown benefits for liver fat and enzymes. The 2026 pig meta-analysis of 31 RCTs confirmed betaine's consistent effect on reducing markers of liver stress.
💪 Muscle & Performance
Tier: 🥈 Silver
Several human studies have found that TMG supplementation (typically 1.25–2.5 grams/day) improves power output, muscular endurance, and body composition during resistance training. A landmark 2009 study by Hoffman et al. found that 2.5 grams of TMG per day for 15 days increased bench press power and reduced fatigue in experienced lifters. A 2013 study by Cholewa et al. reported that 6 weeks of TMG supplementation (2.5 g/day) improved body composition (more lean mass, less fat) and arm size in resistance-trained men.
Not every study is positive — some find no effect — but meta-analyses generally suggest a small-to-moderate ergogenic benefit. The mechanisms likely involve TMG's role in creatine synthesis (methylation is required to make creatine), cellular hydration (osmolyte function), and reduced homocysteine (which may impair muscle function when elevated).
For longevity, maintaining muscle mass and strength is critical — sarcopenia (age-related muscle loss) is a major predictor of frailty, falls, and loss of independence. Anything that helps preserve muscle function matters.
🧬 Epigenetic Aging
Tier: ⚠️ Emerging
TMG fuels the methylation cycle that produces SAMe, which donates methyl groups to DNA and histones — the proteins that DNA wraps around. This process, called epigenetic regulation, controls which genes are turned on or off. As we age, DNA methylation patterns drift, and some researchers believe this "epigenetic noise" is a root cause of aging.
Could TMG help maintain healthier methylation patterns with age? It's a compelling theory, and a 2026 epigenome-wide study in over 1,300 adults found that TMAO and related metabolites (including betaine) were associated with DNA methylation changes at sites linked to cardiovascular disease. But this is correlational, not causal — we don't yet know if TMG supplementation directly improves epigenetic aging clocks. This is a hot area of ongoing research.
Key Studies
| Study | Design | Key Finding |
|---|---|---|
| Olthof et al. (2003) J Nutr |
RCT, crossover n=15 healthy adults 6 g/day TMG |
TMG lowered fasting homocysteine by 12–15% and post-methionine-load homocysteine by 20%. Effects were seen within 2 weeks and sustained at 6 weeks. Even 1.5 g/day was effective. |
| Schwab et al. (2002) Am J Clin Nutr |
RCT n=42 obese adults 6 g/day TMG, 12 weeks |
TMG reduced plasma homocysteine by 1.8 μmol/L (vs. placebo). No effect on body weight, body composition, or resting energy expenditure. |
| Abdelmalek et al. (2009) Am J Gastroenterol |
Pilot RCT n=55 NASH patients 20 g/day TMG, 12 months |
TMG improved liver enzymes (ALT, AST), reduced liver fat on biopsy, and decreased inflammation and fibrosis scores. The high dose was well-tolerated. |
| Hoffman et al. (2009) J Int Soc Sports Nutr |
RCT n=24 strength athletes 2.5 g/day TMG, 15 days |
TMG improved bench press power, isometric force, and reduced fatigue. Total repetitions and training volume also increased. |
| Cholewa et al. (2013) J Int Soc Sports Nutr |
RCT n=23 resistance-trained men 2.5 g/day TMG, 6 weeks |
TMG improved body composition (increased lean mass, decreased fat mass), increased arm cross-sectional area, and improved bench press training volume. |
| Anonymous 2026 RCT Nutr Hosp |
RCT n=102 overweight adults with high homocysteine |
Betaine-containing nutrients lowered homocysteine and improved glucose-lipid metabolism compared to standard B-vitamin therapy (PMID: 41960847). |
| Mouse cognition study (2026) Antioxidants |
Mouse model High-methionine diet + betaine, 14 days |
Betaine attenuated hyperhomocysteinemia-induced cognitive impairment via oxidative stress suppression and PI3K/AKT/GSK-3β pathway activation (PMID: 42510538). |
Dosing and Safety
Recommended Dosing
| Goal | Daily Dose | Notes |
|---|---|---|
| Homocysteine lowering | 1.5–3 grams | Taken in divided doses with meals. Effects on homocysteine seen at 1.5 g/day; higher doses produce larger reductions. |
| Exercise performance | 1.25–2.5 grams | Taken 45–60 minutes pre-workout or in divided doses. Most studies use 2.5 g/day. |
| Liver health (NAFLD) | 3–6 grams | The 20 g/day used in the NASH pilot study is extremely high — more recent evidence suggests 3–6 g/day is sufficient for liver benefits. |
| General longevity / NMN pairing | 1–2 grams | When taking NMN (which consumes methyl groups to produce NAD+), many protocols add 1 gram of TMG to prevent methyl depletion. This is the dose used in Bryan Johnson's Blueprint. |
Form Selection
TMG is most commonly sold as trimethylglycine powder or capsules. The powder form is less expensive and allows flexible dosing but has a slightly sweet taste. Capsules are convenient but more expensive per gram. Look for products labeled as "TMG" or "betaine anhydrous" (not betaine HCl, which is a different compound used for stomach acid support).
Quality markers: Third-party tested for purity. Avoid products with unnecessary fillers. Bulk powder from reputable brands costs roughly $15–30 for a month's supply at 3 grams/day.
Side Effects & Risks
| Side Effect | Frequency | Notes |
|---|---|---|
| Mild GI upset (nausea, diarrhea, stomach discomfort) | ~5–10% | Usually resolves with lower doses or taking with food. More common above 3 grams/day. |
| Fishy body odor | Rare, dose-dependent | Caused by excess trimethylamine production. More common at doses above 4 g/day. Resolves when dose is reduced. |
| Increased LDL cholesterol | ~5–10% in some studies | A small but statistically significant increase seen in some (not all) trials. The clinical significance is unclear — LDL increases of 5–10 mg/dL without changes in particle size or oxidation markers. |
| Increased TMAO | Variable, context-dependent | TMG can theoretically be metabolized to TMAO (linked to CVD risk), but the conversion depends heavily on gut microbiome composition. Studies show inconsistent TMAO increases from TMG. A diet rich in fiber and low in animal products may minimize this. |
Contraindications
- Pregnancy/Breastfeeding: No safety data for supplemental TMG (beyond dietary intake). Avoid supplementation.
- Kidney disease: TMG is excreted by the kidneys. Use with caution and consult a nephrologist if you have impaired kidney function.
- Homocystinuria: A rare genetic disorder. TMG is sometimes used therapeutically but only under specialist supervision.
- Blood pressure medication: TMG may slightly lower blood pressure through its osmolyte effects. Monitor if taking antihypertensives.
❓ Common Questions About TMG
What is TMG and how does it work?
TMG (trimethylglycine, also called betaine) is a compound found naturally in beets, spinach, and grains. It works two ways: first, it donates methyl groups to convert harmful homocysteine into useful methionine, helping protect your blood vessels and brain. Second, it acts as an osmolyte — a molecule that helps your cells stay hydrated and handle stress, particularly in the liver and kidneys.
What does the evidence actually show?
The strongest evidence (Gold tier) is for lowering homocysteine and protecting the liver — multiple randomized controlled trials confirm both effects. There's moderate evidence (Silver tier) for improving exercise power and body composition during training. The brain aging and epigenetic aging connections are interesting but still emerging. No human trial has yet measured whether TMG extends lifespan or healthspan directly.
What's the right dose?
For general longevity and homocysteine control, 1.5–3 grams per day in divided doses with meals is well-supported by the research. For exercise performance, 2.5 grams taken 45–60 minutes before training is the most studied protocol. The high doses used in some liver studies (20 g/day) are not recommended for self-directed supplementation — they were administered under medical supervision.
What are the risks and side effects?
TMG is generally well-tolerated. The most common side effects are mild stomach upset (5–10% of users), which usually resolves when taken with food or at lower doses. Some people develop a temporary fishy body odor at high doses from trimethylamine production. A small subset of studies found mild increases in LDL cholesterol — the significance of this is unclear. TMAO production from TMG varies greatly between individuals depending on gut bacteria composition.
Who should avoid it?
Pregnant or breastfeeding women should avoid TMG supplements due to a lack of safety data. People with kidney disease should consult their doctor first, as TMG is cleared by the kidneys. Those with the rare genetic disorder homocystinuria should only use TMG under specialist supervision. If you take blood pressure medication, monitor your blood pressure when starting TMG, as it may have a mild blood-pressure-lowering effect.
The Bottom Line
Evidence hierarchy: TMG's homocysteine-lowering and liver-protective effects are well-established in human trials at the Gold tier. The exercise performance benefits are Silver-tier — consistent but with some null studies. The brain aging and epigenetic effects are emerging/preclinical. No direct longevity outcome data exists yet.
Our verdict: Among the dozens of supplements chasing the "methylation support" label, TMG has one of the strongest evidence bases. The mechanism is clear, the human data for homocysteine and liver health is consistent, and the safety profile is benign at reasonable doses. The TMAO concern is real but context-dependent — a fiber-rich diet with moderate TMG doses (1–3 g/day) likely mitigates any risk. The LDL cholesterol signal in some studies is worth monitoring if you start supplementing.
Who it's for: TMG makes the most sense for people with elevated homocysteine (above 10 μmol/L), those taking high-dose niacin or NMN (which consume methyl groups), anyone concerned about liver health, and athletes looking for a modest performance edge. If your diet is already rich in beets, spinach, and whole grains, your betaine intake may already be adequate — but most people don't eat enough of these foods to reach the therapeutic doses studied in trials.
Practical recommendation: Start with 1.5 grams daily in divided doses with meals. After 4–6 weeks, reassess. If tolerated well and you want stronger homocysteine reduction or performance effects, increase to 2.5–3 grams/day. Consider getting a homocysteine blood test before and after starting — this gives you objective data on whether it's working for you. A target of <8 μmol/L is ideal; <10 μmol/L is acceptable.
Medical Disclaimer: The information on this page is for educational and informational purposes only. It is not medical advice, nor is it a substitute for professional medical diagnosis, advice, or treatment. Always consult with a qualified healthcare provider before starting any new supplement, especially if you have a medical condition, take prescription medications, or are pregnant or breastfeeding. My Longevity Edge is a research curation project — we analyze scientific evidence, but we do not provide personalized medical recommendations. Individual responses to supplements vary; what works for one person may not work for another. Use this information as a starting point for an informed conversation with your doctor, not as a replacement for one.
Sources
- Olthof MR et al. "Low dose betaine supplementation leads to immediate and long term lowering of plasma homocysteine in healthy men and women." J Nutr. 2003. PMID: 14608057.
- Schwab U 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. PMID: 12399279.
- Abdelmalek MF et al. "Betaine, a promising new agent for patients with nonalcoholic steatohepatitis: results of a pilot study." Am J Gastroenterol. 2009. PMID: 19724269.
- Hoffman JR et al. "Effect of betaine supplementation on power performance and fatigue." J Int Soc Sports Nutr. 2009. PMID: 19635100.
- Cholewa JM et al. "Effects of betaine on body composition, performance, and homocysteine thiolactone." J Int Soc Sports Nutr. 2013. PMID: 23967897.
- Anonymous. "Effects of betaine-containing nutrients on homocysteine levels and glucose-lipid metabolism in overweight and obese patients with hyperhomocysteinemia." Nutr Hosp. 2026. PMID: 41960847.
- Anonymous. "Betaine Attenuates Hyperhomocysteinemia-Induced Cognitive Impairment by Suppressing Oxidative Stress." Antioxidants. 2026. PMID: 42510538.
- Lever M, Slow S. "The clinical significance of betaine, an osmolyte with a key role in methyl group metabolism." Clin Biochem. 2010. PMID: 20170684.
- Craig SA. "Betaine in human nutrition." Am J Clin Nutr. 2004. PMID: 15284364.
- Cholewa JM et al. "Effects of betaine on performance and body composition: a review of recent findings and potential mechanisms." Amino Acids. 2014. PMID: 24829067.