Longevity and Vitamin U

We age and die as a result of our body accumulating oxidative damage. For example, smoking creates oxygen radicals that damage lung cells. This damage reduces the function of these cells and when enough cells have been damaged or die, lung tissue fails to function and we die from lung failure. 

The best way to live your healthiest life is to reduce future oxidative damage as much as possible. The key to doing this is to restore and maintain high glutathione levels. Glutathione is the main antioxidant in your body that quenches the radicals that damage cells. 

Healthy glutathione levels have been associated with longevity. Studies have shown that centenarians have similar glutathione levels to that of young people. In contrast, people who die at a younger age almost always have a low level of glutathione, which almost certainly contributes to the degenerate condition. 

Can glutathione levels be restored? Evidence suggests they can. Studies on middle age people showed that taking supplements restored their glutathione levels to that of their younger counterparts in 24 weeks.  Studies on mice taking similar supplements found those who received supplements lived 24% longer than those who didn't. Furthermore, biochemical markers of good health improved with supplementation suggesting restoring these biochemical markers is probably a useful predictor of lifespan. 

Does this mean humans taking supplements that restore glutathione levels will live longer lives? As humans aren't mice, we can't extrapolate this data to human longevity, but the results so far are promising.

What's the best way to restore glutathione levels? Glutathione is made up of cysteine, glycine and glutamic acid. In these studies, NAC and glycine are the two amino acids that improved health and longevity in mice and improved health biochemical markers in people (roughly 7 g per day in people). Note that NAC and glycine levels were low in these middle aged people whereas glutamic acid levels were normal, and that NAC is converted into cysteine before becoming a component of glutathione.

Can Vitamin U be substituted for NAC? Quite possibly, although this has not been tested directly. Vitamin U is an amino acid (S-methylmethionine) that is produced naturally by all flowering plants and is found in all produce, especially stalky and cruciferous vegetables. Vitamin U is integrated into the human body by specific enzymes in the liver and kidney. One advantage of taking Vitamin U over NAC is that these enzymes in the liver and kidney specifically regulate the integration of Vitamin U, converting it into cysteine-->glutathione when needed without any of the potential side effects of NAC dosing.

Note that while restoring glutathione levels will minimize further damage from oxidative stress, it won't directly reverse existing damage. However, restoring healthy glutathione levels will allow your body's natural repair systems to heal your body the best they can. 

https://pubmed.ncbi.nlm.nih.gov/21795440/

https://pubmed.ncbi.nlm.nih.gov/35268089/

https://pubmed.ncbi.nlm.nih.gov/12486409/

Vitamin U is metabolized by the enzyme BHMT2

Summary - BHMT2 is the enzyme that catalyzes the assimilation of Vitamin U into our body. Made at high levels in the liver and kidneys, BHMT2 catalyzes the transfer of a methyl group from Vitamin U to homocysteine. This reaction plays an important role in the maintenance of healthy glutathione levels by contributing to an optimal methylation state, which drives existing and newly-formed homocysteine into the transsulfuration pathway and towards glutathione synthesis.

Vitamin U is a nutrient that is ubiquitous and abundant in vegetables and fruit. It is a noted dietary mucin secretagogue that has been shown to play an important role in healing and preventing peptic ulcers. It appears that Vitamin U interacts directly with the cells lining the stomach and induces secretion through a non-receptor mediated mechanism, different to that used by other secretagogues (more). 

Vitamin U doesn't just interact with the stomach. In fact, much of Vitamin U is absorbed by the small intestine and taken to the liver where it is metabolized. It is assimilated into our body via the methionine cycle (more). The enzyme that is responsible for Vitamin U assimilation is BHMT2 (Betaine Homocysteine Methyl Transferase 2). BHMT2 catalyzes the transfer of a methyl group from Vitamin U to homocysteine to produce two molecules of methionine. These products enter the methionine cycle where they donate methyl groups to form the universal methyl donor SAM and eventually are converted back into homocysteine. The fate of homocysteine is determined by the methylation status in the cell. A low SAM:SAH ratio results in homocysteine awaiting the appearance of new methyl donors in the form of Vitamin U, betaine and methyl folate for reentry into the methionine cycle. A high SAM:SAH ratio results in homocysteine entering the transsulfuration pathway, eventually forming cysteine and glutathione.

BHMT2 is well-expressed in the liver and kidneys (top 5% of proteins in these organs by abundance) (more) and is expressed at low levels in many other tissues throughout our body (more). 

High expression kidney, liver

Moderate expression thyroid, adrenal, pancreas, gallbladder, ovaries, rectum

Low expression nasopharynx, bronchus, stomach, duodenum, small intestine, colon, testis, epididymis, prostate, endometrium, fallopian tubes, heart muscle, skeletal muscle

Examples

BHMT2 is expressed at low, but measurable levels in the gastric glands. Not expressed in the gastric pits or muscle layer (more). 

BHMT2 is expressed at moderate levels in the thyroid gland (more).

BHMT2 is expressed at moderate levels in the mucosa lining the gallbladder (more).

BHMT2 is expressed at high levels in the renal tubules, but not in the renal glomeruli (more).

BHMT2 is expressed at high levels in hepatocytes, but not in bile duct cells (more).

To what extent these antibody stains indicate function of BHMT2 remains an open question. If the low expression of BHMT2 in the stomach is actually responsible for the protection afforded by Vitamin U, then the similar levels of expression in other tissues may indicate that Vitamin U has a physiological function in those tissues too. However, this remains to be scientifically investigated and does not constitute medical advice.

How was BHMT2 discovered?

Around 1940, scientists at the Lankenau Hospital Research Institute in Philadelphia were investigating the effects of oxidation on the uptake and metabolism of proteins. Gerrit Toennies was a chemist focusing on making forms of methionine and cysteine that had undergone oxidation to varying degrees. Mary Bennett fed these oxidized amino acids to rats to further our understanding of how animals use sulfur amino acids. They found that when the milk protein casein was chemically oxidized, it was no longer a viable source of protein for rats. Most proteins are made up of 20 types of amino acids. The scientists discovered that methionine and tryptophan were the two types of amino acid that were irreversibly oxidized (more).

During these studies, Toennies made a methionine derivative that was a little different. By reacting methionine with methyl iodide, methionine was methylated at the sulfur again, converting the sulfur into a sulfonium. Bennett fed this methionine sulfonium to rats in place of methionine. For 5 days, the rats did not grow. On the 6th day, the rats suddenly started growing at the same rate as the control rats being fed methionine (more).

What happened to the rats? Bennett suggested that the rats "may have developed a special mechanism for taking care of the extra methyl group" that allowed the sulfonium to be converted into methionine. This special mechanism was probably an enzyme that at that time had yet to be discovered. In 1959, Shapiro and Yphantis revealed that the liver expresses an enzyme that converts Vitamin U into methionine by methyl transfer to homocysteine (more). The gene encoding this activity was characterized in 2000 by Chadwick and named BHMT2 due to its resemblance to another liver enzyme BHMT1 (more). It was shown by the Garrow lab in 2008 that purified BHMT2 enzyme catalyzed the reaction between Vitamin U and homocysteine (more). 

It was hypothesized by Toennies that sulfoniums could have a biological role and it was speculated that methylmethionine sulfonium could exist naturally. In 1954, this hypothesis was confirmed by McRorie and others, extracting this compound from cabbage. Interestingly, the latter linked the chemical properties of their newly-discovered compound with those of a recently-discovered Vitamin U, and proposed that this compound was a source of methionine as well as a methyl donor (more). 

Does expression of BHMT2 depend on the presence of Vitamin U? From the studies of Bennett, it would seem that a lack of methionine might induce BHMT2 expression in rats rather than the presence of Vitamin U. For comparison, expression of the related enzyme BHMT1 in rat liver is induced 4-fold when methionine levels are low/choline normal and an additional 2-fold in the presence of betaine (more). However, not much research has gone into addressing BHMT2 expression, especially in humans. 

Vitamin U and acne, dandruff and eczema

Acne, dandruff and eczema are skin conditions the origins of which are often idiosyncratic and mysterious. However, one characteristic shared by all three conditions is low glutathione levels. Glutathione is by far the most important antioxidant in the human body, yet we absorb little of it from our food- that's why our body makes it. 

There are three main causes of low glutathione - 

1. A medical condition that drains large amounts of glutathione

2. A genetic block that prevents the biosynthesis or regeneration of glutathione

3. Not enough glutathione precursors in our diet

Identifying the root cause of your skin condition is an important first step in the healing process. However, this is easier said than done. Often we just don't know why these conditions happen. Sometimes they can break out suddenly and worsen quickly, particularly under stress. At other times, symptoms can persist chronically for years.

Irrespective of the root cause, restoring your glutathione levels is a vital part of this rebalancing act. Glutathione is a tripeptide comprised of cysteine, glutamate and glycine. Of these amino acids, cysteine is most commonly in short supply. If glutathione levels are low due to dietary factors, it is usually due to a shortage of cysteine. Cysteine is found in protein, especially that derived from animals. Cysteine is also made from methionine, again abundant in animal proteins. These sulfur amino acids are also plentiful in grain proteins. However, some people find that meat/dairy/grain are inflammatory for other reasons like hormones or allergens. 

Vitamin U is S-methylmethionine, a soluble nutrient abundant in vegetables and fruit that is converted into methionine by the enzyme BHMT2. There have not been any direct studies into whether Vitamin U has any effect on these three conditions, whether taken internally in the diet or as a supplement, or when applied topically as an active component of a lotion. However, taking Vitamin U can help restore glutathione levels which are low in the tissues affected by acne, dandruff and eczema, so it is quite likely that increasing your intake of Vitamin U will help with these conditions, especially in combination with the identification and removal of triggers of these conditions in you. 

A glass of freshly-made vegetable juice every day is an excellent way to boost your Vitamin U intake along with a slew of vitamins and minerals essential for good skin health.

Vitamin U - A possible natural alternative to N-acetylcysteine (NAC)

The current coronavirus pandemic has changed our lives forever. One of the hallmarks of coronavirus (COVID-19) infection is acute oxidative stress, and as a consequence, life-threatening damage to the endothelial cells lining our blood vessels. It has been proposed that to counter this oxidative stress one may take N-acetylcysteine (NAC) as part of an array of treatment options that may allay this frightening illness.

Dr Roger Seheult 

https://www.youtube.com/watch?v=Dr_6w-WPr0w

https://www.youtube.com/watch?v=kK-DNyKnb5c

Dr Chris Martenson 

https://youtu.be/lIkXmAI6A0olist=PLRgTUN1zz_oeQpnJxpeaEkFimDeepqyWf&t=1494

N-acetylcysteine (NAC) is a popular supplement invented in the 1960s used primarily to optimize glutathione levels. It is normally used in hospitals in emergency situations to treat overdoses of acetaminophen (e.g. Tylenol), which results in an acute and deadly shortage of glutathione in the liver. When acetaminophen is taken as directed, it is safely metabolized by the liver enzymatically. A small amount is oxidized to form N-acetyl-p-benzoquinone imine (NAPQI), which is highly toxic. NAPQI is detoxified in the liver by conjugation with glutathione. However, in overdoses of acetaminophen, NAPQI levels rise dramatically as the regular detoxification processes are overwhelmed. The liver literally cannot regenerate glutathione fast enough to quench the toxic NAPQI. Extensive liver damage and death often ensues. NAC helps by being quickly converted into cysteine, which enables the production of fresh glutathione.

NAC is also sold as a dietary supplement as a means of optimizing glutathione levels on an everyday basis. Glutathione is the master antioxidant in the human body, responsible for detoxifying compounds in the liver as well as reacting with reactive oxygen species that are harmful in large amounts. Glutathione differs significantly to other antioxidants (such as Vitamin C) in that it is made by humans. Our body makes glutathione from three amino acids - glutamate, cysteine and glycine. Levels can get low when our diet is short of these amino acids. The rate-limiting amino acid is usually cysteine, which the body can obtain from the diet following the digestion of protein, and also enzymatically from methionine. When cysteine levels in the diet are inadequate, glutathione levels in the body become inadequate, resulting in general inflammation. Most chronic illnesses are characterized as having low glutathione levels and restoring glutathione levels may help reduce inflammation, if not actually reverse the underlying problem. 

Vitamin U (S-methylmethionine) is a naturally abundant nutrient found in vegetables and fruits, especially cruciferous (e.g. cabbage, kale) and stalky vegetables (e.g. celery, asparagus). Like NAC, one of the functions of Vitamin U is to facilitate glutathione biosynthesis via its conversion to cysteine. Its use as an alternative to NAC in the treatment of acetaminophen overdose has been proposed and remains under investigation. One of the advantages of Vitamin U is that unlike NAC, Vitamin U is already found in many of the foods available in the fresh market, and is therefore unlikely to cause side effects. 

While Vitamin U should not be used in an emergency situation as its efficacy has not been tested, Vitamin U may serve as an alternative to NAC by those looking for a natural choice to boost their glutathione levels and restore their redox balance on an everyday basis. 

It should be emphasized that any possible overdose of paracetamol/acetaminophen should be treated at a hospital by a doctor and not self-treated with NAC or Vitamin U. 

References

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2798828/

https://www.webmd.com/vitamins-supplements/ingredientmono-1018-N-ACETYL+CYSTEINE.aspx?activeIngredientId=101