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Trimethylglycine, commonly known as TMG or betaine, is an amino acid derivative that naturally occurs in various plant and animal sources. With its three methyl groups attached to a glycine molecule, TMG has garnered attention in both the dietary supplement market and the scientific community due to its role as a [[Methyl Donors|methyl donor]] in vital biochemical processes.
[[File:Betain2.svg|right|frameless]]
'''Trimethylglycine (TMG)''', commonly known as '''betaine''', is an amino acid derivative that naturally occurs in various plant and animal sources. With its three methyl groups attached to a glycine molecule, TMG has garnered attention in both the dietary supplement market and the scientific community due to its role as a [[Methyl Donors|methyl donor]] in vital biochemical processes.


The story of TMG traces back to the early 20th century when it was first isolated from sugar beets, hence the name "betaine" after the Latin name for beet, ''Beta vulgaris''. Over the years, researchers have identified its presence in numerous foods and its key functions within human metabolism. As the exploration of its potential benefits continued, TMG started to gain traction, especially in discussions related to heart health, liver function, and, more recently, longevity.
The story of TMG traces back to the early 20th century when it was first isolated from sugar beets, hence the name "betaine" after the Latin name for beet, ''Beta vulgaris''. Over the years, researchers have identified its presence in numerous foods and its key functions within human metabolism. As the exploration of its potential benefits continued, TMG started to gain traction, especially in discussions related to heart health, liver function, and, more recently, longevity.
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=== Heart Health and Homocysteine Levels ===
=== Heart Health and Homocysteine Levels ===
* '''Homocysteine Reduction''': TMG acts as a methyl donor in the conversion of homocysteine, a non-proteinogenic α-amino acid, back to methionine. Elevated homocysteine levels are a known risk factor for cardiovascular diseases. By helping to lower these levels, TMG can potentially contribute to reduced risks of heart diseases. The US [[wikipedia:Food_and_Drug_Administration|Food and Drug Administration]] (FDA) approved betaine trimethylglycine (also known by the brand name Cystadane) for the treatment of [[wikipedia:Homocystinuria|homocystinuria]], a disease caused by abnormally high [[wikipedia:Homocysteine|homocysteine]] levels at birth. <ref name="homocysteine">{{cite journal|pmid=15550695|first1=P. I.|doi-access=free|display-authors=etal|first3=S. E.|last3=Vollset|first2=P. M.|last2=Ueland|last1=Holm|doi=10.1161/01.ATV.0000151283.33976.e6|pages=379–385|journal=Arterioscler. Thromb. Vasc. Biol.|date=February 2005|title=Betaine and folate status as cooperative determinants of plasma homocysteine in humans|issue=2|volume=25|title-link=doi}}</ref>
* '''Homocysteine Reduction''': TMG acts as a methyl donor in the conversion of homocysteine, a non-proteinogenic α-amino acid, back to methionine. Elevated homocysteine levels are a known risk factor for cardiovascular diseases. By helping to lower these levels, TMG can potentially contribute to reduced risks of heart diseases. The US [[wikipedia:Food_and_Drug_Administration|Food and Drug Administration]] (FDA) approved betaine trimethylglycine (also known by the brand name Cystadane) for the treatment of [[wikipedia:Homocystinuria|homocystinuria]], a disease caused by abnormally high [[wikipedia:Homocysteine|homocysteine]] levels at birth. {{#pmid:15550695|pmid15550695}}
* '''Endothelial Function''': Some studies suggest that TMG might improve endothelial function, thus potentially benefiting cardiovascular health.
* '''Endothelial Function''': Some studies suggest that TMG might improve endothelial function, thus potentially benefiting cardiovascular health.


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=== Stress Resistance and Cellular Hydration ===
=== Stress Resistance and Cellular Hydration ===
* '''Osmoprotection''': TMG functions as an osmolyte, meaning it helps regulate cellular hydration. This can be particularly beneficial in conditions of cellular stress, helping cells maintain their volume and function.
* '''Osmoprotection''': TMG functions as an osmolyte, meaning it helps regulate cellular hydration. This can be particularly beneficial in conditions of cellular stress, helping cells maintain their volume and function.
* '''Protection against Stressors''': TMG may offer protective effects against certain environmental stressors, potentially aiding in resilience against some forms of oxidative stress.
* '''Protection against Stressors''': TMG may offer protective effects against certain environmental stressors, potentially aiding in resilience against some forms of [[Oxidative Stress|oxidative stress]].


=== Support in Metabolic Processes ===
=== Support in Metabolic Processes ===
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TMG supplementation may cause [[wikipedia:Diarrhea|diarrhea]], bloating, cramps, dyspepsia, [[wikipedia:Nausea|nausea]] or vomiting.<ref name=":02">{{Citation|title=Betaine|date=2012|url=http://www.ncbi.nlm.nih.gov/books/NBK548774/|work=LiverTox: Clinical and Research Information on Drug-Induced Liver Injury|access-date=2023-07-14|place=Bethesda (MD)|publisher=National Institute of Diabetes and Digestive and Kidney Diseases|pmid=31644082}}</ref> Although rare, it can also causes excessive increases in serum methionine concentrations in the brain, which may lead to [[wikipedia:Cerebral_edema|cerebral edema]], a life-threatening condition.<ref name=":02" />
TMG supplementation may cause [[wikipedia:Diarrhea|diarrhea]], bloating, cramps, dyspepsia, [[wikipedia:Nausea|nausea]] or vomiting.<ref name=":02">{{Citation|title=Betaine|date=2012|url=http://www.ncbi.nlm.nih.gov/books/NBK548774/|work=LiverTox: Clinical and Research Information on Drug-Induced Liver Injury|access-date=2023-07-14|place=Bethesda (MD)|publisher=National Institute of Diabetes and Digestive and Kidney Diseases|pmid=31644082}}</ref> Although rare, it can also causes excessive increases in serum methionine concentrations in the brain, which may lead to [[wikipedia:Cerebral_edema|cerebral edema]], a life-threatening condition.<ref name=":02" />


TMG supplementation lowers homocysteine but also raises [[wikipedia:LDL-cholesterol|LDL-cholesterol]] in obese individuals and renal patients.<ref>{{cite journal|vauthors=Olthof MR, van Vliet T, Verhoef P, Zock PL, Katan MB|title=Effect of homocysteine-lowering nutrients on blood lipids: results from four randomised, placebo-controlled studies in healthy humans|journal=PLOS Med.|volume=2|issue=5|pages=e135|year=2005|pmid=15916468|pmc=1140947|doi=10.1371/journal.pmed.0020135}}</ref>
TMG supplementation lowers homocysteine but also raises [[wikipedia:LDL-cholesterol|LDL-cholesterol]] in obese individuals and renal patients.{{#pmid:15916468|pmid15916468}}
 
===Drug and Supplement Interactions===
===Drug and Supplement Interactions===
*'''Anticholinergic Drugs''': TMG might interact with anticholinergic medications, which reduce the effects of acetylcholine, as TMG increases levels of choline, a precursor to acetylcholine.
*'''Anticholinergic Drugs''': TMG might interact with anticholinergic medications, which reduce the effects of acetylcholine, as TMG increases levels of choline, a precursor to acetylcholine.
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*'''Pregnant or Breastfeeding Women''': There is limited research on the safety of TMG supplementation during pregnancy and breastfeeding; thus, consultation with a healthcare professional is advised.
*'''Pregnant or Breastfeeding Women''': There is limited research on the safety of TMG supplementation during pregnancy and breastfeeding; thus, consultation with a healthcare professional is advised.
*'''Pre-existing Health Conditions''': Individuals with pre-existing health conditions, particularly those affecting the liver, should consult a healthcare professional before beginning TMG supplementation.
*'''Pre-existing Health Conditions''': Individuals with pre-existing health conditions, particularly those affecting the liver, should consult a healthcare professional before beginning TMG supplementation.
==Studies==
Protective effects of TMG in experimental animal models, cell culture systems, and clinical studies.
{| class="wikitable"
!Therapeutic Effects of TMG Administration
!Experimental Model
!{{VerticalText|Heart Health and Homocysteine Levels}}
!{{VerticalText|Liver Function and Detoxification}}
!{{VerticalText|Stress Resistance and Cellular Hydration}}
!{{VerticalText|Support in Metabolic Processes}}
!{{VerticalText|Mood and Well-being}}
|-
|Prevents hepatic fat accumulation in ALD
|Male [[Wistar rats]]; [[C57BL/6 mice]]; [[Balb/c mice]]
|
|X
|
|
|
|-
|Preserves/restores hepatic SAM: SAH ratios by regenerating SAM and lowering SAH and homocysteine levels in ALD
|Male [[Wistar rats]]; hepatocytes; male [[C57BL/6 mice]]
| X
|X
|
|
|
|-
|Restores activities of various liver methyltransferases (PEMT, ICMT, PIMT, PRMT) to increase phosphatidylcholine levels, preventing apoptosis and accumulation of damaged proteins, and restoring proteasome activity
|Male [[Wistar rats]]; hepatocytes
|
|X
|
|
|
|-
|Suppresses the synthesis of DGAT2, a rate-limiting enzyme in triglyceride synthesis, by alleviating ERK1/2 inhibition in ALD
|Male [[C57BL/6 mice]]
|
|X
|
|
|
|-
|Upregulates antioxidant defense system and improves oxyradical scavenging activity in ALD
|Male [[Wistar rats]]
|
|X
|X
|
|
|-
|Prevents/attenuates ER stress in ALD
| Male [[C57BL/6 mice]]
|
|X
|X
|
|
|-
| Exerts hepatoprotection by preserving mitochondrial function in ALD
|Male [[Wistar rats]]
|
|X
|
|
|
|-
|Restores the serum adiponectin levels in ALD
|Mice
|
|X
|
|X
|
|-
|Prevents elevations of CD14, TNFα, COX2, GADD45β, LITAF, JAK3, TLR2, TLR4, IL1β, and PDCD4 and NOS2 mRNA levels in alcoholic liver injury
|Male [[Wistar rats]]
|
|X
|
|
|
|-
|Prevents serum ALT and AST activity elevations in models of ALD and MAFLD
|Male [[Wistar rats]]
|
|X
|
|
|
|-
|Reduces liver oxidant stress, inflammation, and apoptosis in MAFLD
| Male [[C57BL/6 mice]]
|
| X
|X
|
|
|-
|Remethylates homocysteine, protecting from oxidant stress and restoring phosphatidylcholine generation in MAFLD
|[[C57BL/6 mice]]
|X
|X
|
|
|
|-
|Stimulates β-oxidation in livers of MCD diet-induced MAFLD
|Male [[Sprague-Dawley rats]]
|
|X
|
|X
|
|-
|Alleviates steatosis and increases autophagosomes numbers in mouse livers with MAFLD
| Male [[C57BL/6 mice]]; rats
|
|X
|
|X
|
|-
|Enhances the conversion of existing WAT to brown adipose tissue through stimulating mitochondrial biogenesis in MAFLD
| Mice
|
|X
|
|X
|
|-
|Alleviates ROS-induced mitochondrial respiratory chain dysfunction in MAFLD
|Male [[Sprague-Dawley rats]]
|
|X
|X
|X
|
|-
|Attenuates different grades of steatosis, inflammation, and fibrosis in MAFLD patients
|Human trials
|
|X
|
|X
|
|-
|Prevents adipose tissue dysfunction in ALD
| Male [[C57BL/6 mice]]
|
|X
|
|X
|
|-
|Reduces the inflammatory adipokines, IL6, TNFα, and leptin in human adipocytes
|Human visceral adipocytes
|
|X
|
|
|X
|-
| Inhibits lipid peroxidation, hepatic inflammation, and expression of transforming growth factor-β1 in liver fibrosis
|Male chicks
|
|X
| X
|
|
|-
|Suppresses alcoholic liver fibrosis
|Rats
|
|X
|X
|
|
|-
|Prevents the formation of Mallory–Denk bodies through epigenetic means by attenuating the decrease of MAT1A, SAHH, BHMT, and AMD1 expression
|Male [[C3H mice]]
|
|X
|
|
|
|-
|Reverses the inhibitory effects of acetaldehyde on IFN signaling and decreases de-methylation of STAT1 by JMJD6
|HCV-infected Huh7.5 CYP2E1 (+) cells and human hepatocytes
|
|X
|X
|
|
|-
|Enhances expression of PPARα and elevates fatty acid catabolism
|Male [[C57BL/6 mice|C57BL/6]] and [[ApoE−/− mice]]
|
|X
|
|X
|
|-
|Inhibits lipogenic activity in liver by activation of AMPK
|[[ApoE−/− mice]]; Male [[C57BL/6 mice]]
|
|X
|
|X
|
|-
|Regulates colonic fluid balance
|Rats
|
|
|
|X
|X
|-
|Improves intestinal barrier function and maintains the gut microbiota
|Porcine epithelial cells; Caco-2 cells; rat small intestinal cell line IEC-18
|
|
|
|X
|X
|-
|Activates GI digestive enzymes and ameliorates intestinal morphology and microbiota dysbiosis
|Male [[Sprague Dawley rats]]
|
|
|
|X
|X
|-
|Attenuates alcoholic-induced pancreatic steatosis
|Male [[Wistar rats]]
|
|X
|
|X
|
|-
|Associated with resilience to anhedonia and prevention of stress-related psychiatric disorders
|Male [[C57BL/6 mice]]
|
|
|X
|
|X
|-
|Treats asthma-induced oxidative stress, thus improving airway function of lung tissue
|[[BALB/C mice]]
|
|
|X
|
|
|-
|Protects against cadmium nephrotoxicity
|Male [[Wistar rats]]
|
|X
|X
|
|
|-
|Protects against isoprenaline-induced myocardial dysfunction
|Male [[Wistar rats]]
|X
|
|
|
|
|-
|Anti-nociceptive and sedative role via interactions with opioidergic and GABA receptors
|Male albino mice
|
|
|X
|
|X
|-
|Normalizes fetal growth and reduces adiposity of progeny from obese mice
|[[C57BL/6J mice]]
|
|
|
|X
|
|-
|Anti-cancer effect in alcohol-associated breast cancer cell growth and development
|Breast adenocarcinoma cell line (MCF-7)
|
|X
|
|
|
|-
|Reduces rectal temperature in broiler chickens
|Chickens
|
|
|X
|
|
|-
|Improves post-natal lamb survival
|Lambs
|
|
|X
|X
|
|}
==See also==
==See also==


*[[Wikipedia:Trimethylglycine|Wikipedia article]]
*{{SeeWikipedia|Trimethylglycine|}}


==References==
==References==
<references />
<references />
[[Category:Orally Consumable Longevity Molecules]]
[[Category:Orally Consumable Longevity Compounds]]
[[Category:Antioxidant Compounds]]
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