A quick overview of what we’ll cover in this blog post:
- What TMG is
- What role TMG plays in the body
- How TMG potentially complements NAD+
Whether you’ve been taking NAD+ supplements for a while or you’re relatively new to them, you probably know that NAD+ is an important part of your body’s regular function.
As a naturally occurring coenzyme in the body, NAD+ plays a role in a number of key cellular functions, including helping cells create energy from nutrients, supporting cellular repair, and clearing age-related damage. Research suggests it declines in many organs with age and may be associated with age-related conditions like heart disease and Alzheimer’s. That’s why supplementation may help support a healthier life.
A common question we receive is about the role of TMG (trimethylglycine) when supplementing with NAD+. While the timing of taking TMG with NAD+ isn’t an exact science, our recommendations are based on current evidence and patient experiences.
Whether you’re familiar with TMG or not, we’ll break down what it is, why it’s important to take with NAD+, and where you can get it.
Key takeaways:
- NAD+ metabolism depletes methyl groups your body needs for DNA repair, detox, and energy
- Trimethylglycine (TMG) replenishes those methyl groups, making it a useful co-supplement for NAD+ users
- MTHFR gene variants affect up to 40% of some populations, raising demand for methyl donors like TMG
- A daily dose of 1,000mg of TMG may support methylation, whether taken daily or only on NAD+ days
- AgelessRx clinicians can help you assess your methylation capacity and personalize your TMG protocol
What is NAD+ & why is it important?
NAD+ (nicotinamide adenine dinucleotide) is a critical coenzyme in every cell, playing a central role in metabolism, DNA repair, and maintaining cellular health. NAD+ levels decline with age, leading to impaired mitochondrial function, decreased energy, and may contribute to the onset of age-related conditions. Research suggests supplementation may help support energy production and healthy aging.
However, NAD+ metabolism can deplete methyl groups, which are critical for various biological processes like healthy gene regulation and detoxification.
What is TMG’s role in the body?
Trimethylglycine (TMG) is a type of betaine and a key player in a biological process called methylation.
Methylation is the process by which cells “donate” methyl groups, or specific molecules, to proteins or DNA. These methyl groups change how cellular machinery behaves and help cells carry out key biological functions, such as damage repair and the production of signaling factors like hormones and neurotransmitters. This process also helps shape gene expression, detoxify harmful substances, and convert nutrients into usable energy.
TMG is important because it provides methyl groups to cells to carry out these functions (as the name suggests, it provides three methyl groups).
TMG is found naturally in foods like beets, spinach, quinoa, and wheat germ, so most people do get some from their diet. But the amounts in food are generally modest, and research suggests that when you’re actively supplementing with NAD+, your body’s demand for methyl groups goes up considerably. Dietary TMG alone may not be enough to keep your methylation pathways running well under that increased load.
When methylation becomes depleted, the effects can be subtle at first. Low energy, brain fog, and high homocysteine on bloodwork are among the more common signs. Many people don’t connect these symptoms to their NAD+ protocol without some guidance, which is part of why understanding the TMG relationship matters for anyone supplementing regularly.
Why take NAD+ & TMG together?
As your body uses NAD+, some of it gets recycled and the rest gets broken down into waste that needs to be excreted from the body. In order to do this, however, a methyl group is required to clear it from your body. So, the more NAD+ supplement you take, the faster your methyl groups are depleted. That’s why TMG can be an important co-supplement on days you take NAD+, so your body still has healthy levels of methyl groups available for other key functions.
TMG also plays a role in the breakdown of an amino acid called homocysteine, which, while helpful for cell metabolism, becomes harmful in excess by driving inflammation and causing damage to blood vessels. So TMG is generally important to your overall health.
During NAD+ supplementation, the body produces nicotinamide (NAM), which can be recycled back into NAD+, but any excess appears to require methylation for excretion, as research suggests NAM accumulation may be harmful to cells. For individuals with impaired methylation due to genetic factors like MTHFR mutations, this increased demand may strain methylation capacity if the body doesn’t have enough methyl donors available.
MTHFR mutations & methylation
Mutations in the MTHFR gene can reduce the body’s ability to efficiently methylate. This is especially relevant when taking supplements like NAD+, which increase the demand for methylation.
The two most common MTHFR variants (C677T and A1298C) can lead to high homocysteine levels, which increase the risk of cardiovascular issues, depression, and cognitive decline. For these individuals, supplementing with methyl-group donors like TMG or methyl-folate can help support proper methylation pathways.
To understand why MTHFR variants matter, it helps to know what the gene normally does. The MTHFR enzyme converts folate into Vitamin B9, its active, usable form in the body. Vitamin B9 drives the methionine cycle and the production of SAM-e (S-adenosylmethionine), the body’s main methyl-group carrier. When MTHFR function is reduced, the downstream supply of methyl groups can slow, placing more pressure on other sources like TMG to fill the gap.
If you’re unsure whether you carry an MTHFR variant, genetic testing through your clinician can give you a clear answer. Measuring homocysteine through something like the Core Longevity Panel is another practical option: high levels can be an early indicator that your methylation pathways need more support, even before other symptoms appear.
How TMG supports methylation
TMG is a well-recognized source of methyl groups that may help replenish the body’s supply, with research suggesting it can support normal DNA function and detoxification processes. Taking TMG alongside NAD+ supplementation may help keep your methylation pathways from being depleted as the body metabolizes NAD+.
Not everyone requires TMG, especially those without methylation issues. Individuals with normal methylation capacity may find that their body manages NAD+ metabolism without any problems. However, for those with known MTHFR mutations or concerns about methylation, TMG can provide a useful safety net.
Practical recommendations for NAD+ & TMG supplementation
- Timing and dosage
Based on current knowledge, TMG’s role as a long-acting source of methyl groups means it can be taken at any time of the day. There’s no evidence to suggest that TMG must be taken at the same time as NAD+. A typical dosage is 500-1,000 mg of TMG daily, which should be more than enough to support methylation needs. However, for individuals who find daily TMG supplementation burdensome, taking it only on the days they use their NAD+ Injection is also a viable option. - Daily vs. occasional supplementation
While some patients prefer to take TMG daily, others opt to only take it when using their NAD+ Injections. Both methods are acceptable, and individual responses can vary based on personal methylation capacity. - Methylation testing
Unfortunately, there aren’t yet precise tests to measure how well methylation is working or NAD+ metabolism in a way that would inform personalized TMG dosing. However, genetic testing for MTHFR mutations and measuring homocysteine levels can provide insight into your methylation capacity.
|
Approach |
Best for |
Typical dose |
Key benefit |
|---|---|---|---|
|
Daily TMG |
Known MTHFR variants, frequent NAD+ users |
500-1,000mg per day |
Consistent methylation support regardless of NAD+ schedule |
|
TMG on NAD+ days only |
Those without known methylation concerns |
500-1,000mg on dosing days |
Targeted support with fewer daily supplements |
Our guidance
While the precise timing and the amount of TMG patients should use with NAD+ are not set in stone, our approach is based on what seems to work for most people: either take TMG daily or on the days when you use NAD+ supplements, especially if you have known methylation issues. You can easily find TMG supplements at online retailers or most vitamin and supplement shops.
One practical step worth considering is getting your homocysteine levels checked as part of your regular bloodwork. High levels can signal that your methylation pathways would benefit from more support. Talking through your results with your AgelessRx clinician is a good way to decide whether daily TMG or occasional use makes more sense for your situation.
At AgelessRx, we’ll continue to monitor the latest research and provide updated guidance as more is understood about the interplay between NAD+ and methyl donors like TMG.
Frequently Asked Questions
Both approaches are acceptable. A daily dose of 1,000mg of TMG keeps your methylation pathways consistently supported, while taking it only on NAD+ supplementation days is a reasonable alternative if daily use feels like a burden. Your best option depends on your personal methylation capacity, which your AgelessRx clinician can help you assess.
The need for TMG comes from how your body metabolizes NAD+, not the delivery format. Whether you’re using NAD+ injections or patches, your body still produces nicotinamide as a byproduct that requires methyl groups to excrete. TMG helps replenish those methyl groups regardless of which format you’re using.
Methylation is the process by which your cells donate small molecules called methyl groups to carry out functions like gene expression, neurotransmitter synthesis, and detoxification. When you supplement with NAD+, your body uses more methyl groups to process the byproducts, which is why supporting methylation with a donor like TMG becomes relevant for regular users.
Low energy, brain fog, and high homocysteine on bloodwork are among the more common early signs. These symptoms are easy to overlook without context, since they don’t obviously connect to an NAD+ protocol. Getting your homocysteine levels checked is a straightforward way to see whether your methylation pathways need more support.
Yes. MTHFR variants reduce your body’s ability to efficiently produce the active form of folate, which slows the downstream supply of methyl groups your cells rely on. This places greater pressure on alternative donors like TMG to fill the gap, making methylation support more important for anyone with a known MTHFR mutation who supplements with NAD+ regularly.
Note: The above statements have not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure, or prevent any disease.