Do Methionine Supplementation & Restriction Have Benefits?

Methionine restriction has been known for decades in longevity research, although researchers haven’t found any definite answers. Some say that less methionine is not necessarily better and that it might sometimes be worse. Do they have a point? Let’s take a look at the newest research to clear some of the confusion.

Methionine Restriction and Longevity

The Confusion

Some people assume that methionine is something that needs to be reduced in the diet in order to be optimally healthy.

But like almost everything else in biology, methionine is just not good or bad. We know that it is an essential amino acid – we need to get certain amounts of it from food to be in good health.

On the other hand, people come across some scary dangers of this amino acid searching the internet. From brain damage to heart disease risk, methionine seems to be everything but healthy.

To start with, methionine is considered safe in the amounts people take in with food. It’s also safe when used appropriately in medicinal amounts. Serious dangers occur only with using extremely high doses (orally or intravenously) [1, 2].

This post is meant to clarify the health effects of methionine and whether there are any benefits to higher or lower levels.

Restriction Science

Animal studies suggested that restricting methionine consumption can increase lifespan, but this has never been confirmed in humans [3].

A 2005 study showed methionine restriction without calorie restriction extends mouse lifespan [4].

Several studies found that methionine restriction also inhibits certain aging-related disease processes in mice. But no proper human studies have investigated the effects of methionine on aging-related pathways and diseases in humans [5, 6, 7].

In rats, dietary methionine increases mitochondrial ROS production and DNA oxidative damage the liver. Researchers suspect that this is a plausible mechanism for its liver toxicity in excess, but human data are lacking to confirm this [8].

Methionine and Genetics

There are a few genes that might affect the amount of dietary methionine, but their impact on methionine levels in humans is poorly understood.

The MTR gene coded for the MTR enzyme, which converts homocysteine to methionine (see related SNPs). The MTHFR gene indirectly affects the conversion of homocysteine to methionine, by producing the active form of folate [9].

People that have a poorly functioning gene usually require more folate. Not getting adequate folate may raise homocysteine and lower methionine [10].

Lynch syndrome is a type of inherited cancer syndrome associated with a genetic predisposition to different cancer types. In people with Lynch syndrome, low methionine intake was associated with an increased risk of Colorectal Tumor in MTHFR 677 (AA) individuals compared to people with low intake and the normal genotype [11].

However, no studies have replicated these findings. We also don’t know how they relate to people without Lynch syndrome. Lastly, this study only identified potential associations. It does not provide information about causes [11].

Why Methionine is Important & Who May Need More

An Essential Amino Acid

Since methionine is an essential amino acid, it cannot be entirely removed from animals’ diets without disease or death occurring over time. For example, rats fed a diet without methionine developed fatty liver, anemia and lost two-thirds of their body weight over 5 weeks [12, 13].

Methionine is only one of two amino acids that provide sulfur for the body, which is used to build proteins and sulfate some compounds [14].

Required Intake

The RDA for methionine (combined with cysteine) for adults has been set at 14 mg/Kg of body weight per day.

Therefore a person weighing 70 Kg, independent of age or sex, requires the consumption of around 1.1 g of methionine/cysteine per day [15].

Dietary methionine may be enough to provide all the necessary body sulfur (except thiamin and biotin), according to one scientific review. However, more research is needed to understand just how much our bodies need [15].

Scientists point out that the minimal requirements (RDA) for all the essential amino acids may need to be revised. RDA is estimated based on the amount of amino acids needed to maintain a nitrogen balance, which the body needs to build proteins. But this method doesn’t take sulfur balance into account [15].

The WHO recommendations for methionine/cysteine intake of 13 mg/kg of body weight are in the same range as those suggested by the RDA.

There is a consensus, however, that in diseases and following trauma these values maybe 2 or 3 times higher [16].

One study found that feeding purified amino acid diets containing variable amounts of methionine to older individuals at the VA Hospital required significantly higher levels of methionine than those previously established by the RDA. They all needed more than 2.1 g/day, with some subjects requiring up to 3.0 g/day to remain in positive nitrogen balance [17].

Protein vs. Veggie Intake

High levels of methionine can be found in animal products (eggs, fish, meat) and some nuts and seeds; methionine is also found in grains.

Proteins contain between 3 and 6% of sulfur amino acids. A tiny amount of sulfur comes in the form of so-called inorganic sulfates and other forms of organic sulfur that is found in veggies like garlic, onions, and broccoli [15].

A couple of studies suggest that, compared to fish eaters and meat eaters, vegans have the lowest intake of methionine [18, 19].

Average Intake

Intake of methionine/cysteine measured in 32 individuals ranged between 1.8 and 6.0 g/day (14 and 45 mmol/day) in one study [15].

The figure below compares the sulfur amino acid intake (SAA) in g/day associated with the consumption of a variety of diets [20]:

The authors observed that sulfur amino acids were lower in individuals who tended to be more health conscious and consume no red meat and little animal protein, as well as those consuming “fad diets” [15].

They also pointed out that many older people could turn out to be outright deficient (defined as group X in the study). More human research is needed [15].

What About Supplements?

Methionine (in the form of SAM-e) and Cysteine (in the form of NAC) are relatively popular supplements. However, there’s insufficient evidence to back up their use in most cases.

Some people claim that since methionine converts to cysteine, supplementing with cysteine reduces the requirements for methionine. Although this is possible, there’s no hard proof of it from human studies [15].

Also have in mind that supplements have not been approved by the FDA for medical use. Supplements generally lack solid clinical research. Regulations set manufacturing standards for them but don’t guarantee that they’re safe or effective. Speak with your doctor before supplementing.

Purported Health Benefits of Methionine

Possibly Effective for

Acetaminophen Poisoning

Sulfation is a major pathway for detoxification of pharmacological agents by the liver.

Methionine, taken by mouth, appears to be effective for treating acetaminophen poisoning.

Taking 2.5 grams every 4 hours four times in total was as effective as acetylcysteine in preventing liver damage and death after acetaminophen (Tylenol) overdose. This was the case only if methionine was given within 10 hours of acetaminophen ingestion [21].

Tylenol requires sulfate for its excretion and it’s often given to alleviate pain. High doses of Tylenol depleted sulfate in lab animals, which was corrected by methionine. Tylenol was more toxic and was eliminated more slowly in animals deficient in sulfate [15].

Insufficient Evidence for:

The following purported benefits are only weakly supported by limited, low-quality human studies.

There is insufficient evidence to support the use of methionine for any of the below-listed uses.

Remember to speak with a doctor before taking methionine supplements. Methionine should never be used as a replacement for approved medical therapies.

Joint Support

Sulfates/sulfur is critical for glycosaminoglycan synthesis, which is important for cartilage. However, no clinical studies tested the effects of methionine on joint health [15].

One study concludes that a large portion of the population, especially older people, may not be receiving sufficient sulfur. Dietary supplements such as glucosamine/chondroitin sulfate were proposed to act by supplying sulfur, but human studies haven’t confirmed this mechanism [22].

In the farming industry, chickens are supplemented with methionine/cysteine to increase their growth [15].

Inflammatory Conditions

Scientists suspect that our requirements for sulfur amino acids such as methionine go up under inflammatory conditions and oxidative stress. They hypothesize that this might be, in part, because of increased glutathione needs and sulfur excretion [23].

In experiments on pigs, stimulating the immune system led to increased methionine use [24].

Observations in experimental animals indicate that antioxidant defenses become depleted during infection and after injury. For example, in mice infected with the influenza virus, there was a 45% decrease in the GSH contents of blood [25].

According to limited, small human studies, glutathione may decrease in:

• Asymptomatic HIV infection [26]
• Elective abdominal operations [27]
• Hepatitis C [28]
• Ulcerative colitis [28]
• Cancer [28]
• Cirrhosis [28]
• Sepsis [29]

Still, no studies tested whether methionine supplementation would be beneficial in these cases. It’s also unknown whether a diet higher in methionine can play a role in preventing inflammatory conditions and other states linked with low glutathione. More research is needed.

Lupus

According to two small studies, methionine and other methyl donors – including cysteine, choline, and cofactors such as vitamin B6 – were significantly reduced in Lupus/SLE patients compared to healthy matched controls [30].

However, no clinical trials have yet examined the effectiveness and safety of methionine supplements in lupus patients.

Reducing the methionine and choline content of the diet increased lupus disease severity in genetically-susceptible mice [31].

Venous Thrombosis

In one case-control study of almost 700 people, low fasting methionine concentrations were linked with recurrent venous thrombosis risk. The impact of supplementation on venous health is unknown [32].

Lacking Evidence (Animal Research)

No clinical evidence supports the use of methionine for any of the conditions listed in this section.

Below is a summary of the existing animal and cell-based research, which should guide further investigational efforts. However, the studies listed below should not be interpreted as supportive of any health benefit.

Increasing Glutathione

Cysteine and methionine are not stored in the body. Sulfur helps the body produce glutathione, which is thought to be critical for antioxidant defense [15].

Some scientists have proposed that a deficiency in sulfur amino acids such as methionine might make glutathione levels suffer more than more critical processes such as protein synthesis [15].

Studies suggest that any dietary excess is readily oxidized to sulfate, excreted in the urine (or reabsorbed depending on dietary levels) or stored in the form of glutathione (GSH) [33].

According to limited research, glutathione levels are lower in a large number of diseases and from certain medications. Whether taking methionine can impact this balance is unknown [15].

One hypothesis states that methionine and sulfur should be able to spare losses of glutathione associated with dietary deficiencies and increased utilization due to disease or altered immune function. This has yet to be proven [15].

In animals under conditions of low methionine, synthesis of sulfate and glutathione will be reduced. Researchers believe this is likely to negatively influence the function of the immune system and of the antioxidant defense mechanisms, but human studies are lacking [15].

Also, animals undergoing methionine restriction/low methionine diets live under sterile and perfect conditions, as opposed to humans. Animal’s findings can’t be translated to humans.

Greying of Hair

Loss of methionine has been linked to senile greying of hair. Scientists hypothesize that its deficit leads to a buildup of hydrogen peroxide in hair follicles and a gradual loss of hair color. Human studies are needed [34].

Gut Health

Methionine is often found in the same foods with cysteine. Limited evidence suggests that dietary methionine (and cysteine) may be important to ensure the health of the intestine and immune function during development and in inflammatory states. Large human studies have yet to confirm this and most of the data relies on animal experiments [35].

For example, relative to healthy piglets fed a deficient diet, piglets supplemented with cysteine (0.25 g/kg) and methionine (25 g/kg) had less intestinal oxidative stress. They also had improved villus height and area and crypt depth and a higher number of goblet cells [35].

Scientists think that the following pathways may underlie methionine’s effects on the gut:

• Transformation to GSH, taurine, and cysteine
• Reduction of intestinal oxidative stress
• Affecting intestinal structure, goblet and crypt cells

These mechanisms haven’t been investigated in humans.

Immune Response

Research suggests that methionine may be important to the immune system and methylation [36, 23, 37, 11].

Cellular studies are looking at its immune system impact and whether methionine increases glutathione, taurine, CD4+ and CD8+ cells [23].

Methylation Support

Methionine is involved in methylation as a precursor to SAM-e [37, 11].

Based on this, some people claim that increasing methionine intake is a good idea in poor methylators. However, it’s not clear exactly what effects methionine has on methylation.

Cell studies show that methionine has the potential to induce certain changes in methylation and expression of genes.

It remains to be determined whether high intakes have a greater tendency to induce DNA hyper- or hypomethylation and in which regions. Until then, the impact of methionine supplementation on human health via methylation remains unclear.

Scientists suspect that methionine can be a double-edged sword: helpful in some and harmful in other situations. Further research is needed to clarify exactly which genes and processes are affected by it in humans [37].

Heart Health

Methionine is an intermediate in the biosynthesis of cysteine, carnitine, taurine, lecithin, phosphatidylcholine, and other phospholipids. Scientists are exploring whether improper conversion of methionine can lead to atherosclerosis [38].

Fertility

In animals, methionine restriction causes lower fertility. This hasn’t been tested in humans [39, 40].

Epigenetics & Stressful Conditions

The offspring of stressed rats have epigenetic changes in methylation of the cortisol receptor (GR), which can cause changes in the HPA axis and negatively affect these offspring [41].

Methionine infusion into adult rats reverses the negative epigenetic effects on DNA methylation, nerve growth factor-inducible protein-A binding, the cortisol receptor (GR), and hypothalamic-pituitary-adrenal and behavioral responses to stress [41].

These effects haven’t been investigated in humans.

How Much Methionine is too Much?

Safety

Methionine is considered safe in the amounts people take in with food [1, 2].

It’s also safe when used appropriately in medicinal amounts [1, 2].

Serious dangers have only been reported in people taking extremely high doses (orally or intravenously). Studies suggest that doses over 100 mg/kg should be avoided to prevent severe and potentially lethal brain damage [1, 2].

Similarly, methionine is safe in the amounts found in food and when given medicinally to children. It’s likely unsafe in newborns receiving IV nutrition [42].

Pregnant and breastfeeding women should avoid methionine supplements. Dietary methionine is considered safe.

Toxicology Experiments

A “loading dose” of methionine (100 mg/kg) acutely increased in plasma homocysteine and it has been used as an index of susceptibility to cardiovascular disease. A 10-fold larger dose, given mistakenly, resulted in death [43].

Longer-term studies in adults have indicated no adverse consequences of moderate fluctuations in dietary methionine intake, but intakes higher than 5 times normal resulted in elevated homocysteine levels [43].

Other longer-term studies in adults have indicated no adverse consequences of moderate fluctuations in dietary methionine intake, but intakes higher than 5 times normal resulted in elevated homocysteine levels [43].

In infants, methionine intakes of 2 – 5 times normal resulted in impaired growth and high methionine levels, but no adverse long-term consequences were observed [44].

Additional Precautions

In animals, high levels of methionine were capable of promoting schizophrenia by methylating and stopping the production of the GABRB2 gene, which controls the production of a certain component of the GABA receptor. Lower GABAergic function has been implicated in schizophrenia [45].

The effects of higher methionine intake or supplementation on people with schizophrenia or those are risk are not known.

One study suggests that people who have a high methionine intake should pay attention to maintain an adequate intake of folic acid and vitamins B-6 and B-12 [23].

A Case Against Methionine Restriction?

Methionine restriction has been known for decades in animal longevity research [46].

Some people argue that if restricting methionine can make animals live longer, then why don’t we try to do it? Let’s see what the science says.

Potential Fallacies in Methionine Restriction Research

There are three fallacies that people should be careful about when it comes to drawing conclusions about optimal methionine levels.

1. If restricting methionine increases maximum lifespan, then restricting it is not necessarily optimally healthy.
2. If excess methionine is bad, that doesn’t mean that restricting it is good.
3. If it works in animals to increase lifespan, it doesn’t mean it’ll work in humans because we have a very different environment and somewhat different biology.

A substance like methionine seems to have what’s called a biphasic response. Too little or too much may cause problems. Research suggests that people may need to get a balanced amount. That level may be different for everyone, but large human studies have yet to define it.

1) Longevity Research Doesn’t Equal Optimal Health

After reading longevity research for a while, many people start to realize that it doesn’t apply to humans all that much.

Many substances have longevity-promoting effects in cells or worms. This doesn’t mean that they have any medical value. On the contrary, most approaches that are researched in cells or simple organisms like worms fail to pass further animal studies or clinical trials due to a lack of safety or efficacy.

The issue with methionine restriction is the extent to which you’d have to lower methionine for it be potentially beneficial for longevity in animals is not practical for other purposes. We also can’t translate animal doses to humans.

Some critics say that restricting methionine is not that much different than lowering free radicals by not breathing. They say it’s not practical in the long run because of the possible side effects.

Methionine is important to the immune system. Limited research suggests that lower methionine intake may raise susceptibility to chronic infections in the long run (and that may cause many problems) [47, 3].

Animals in longevity studies are in sterile environments. Lab animals that live longer in a sterile environment may not experience the same in the real world.

Additionally, certain longevity pathways are not necessarily beneficial for all aspects of health. Lowering IGF-1 may be researched for longevity, but increasing levels may be researched for other purposes..

2) Methionine & Homocysteine

Some say that methionine is bad because it raises homocysteine and elevated homocysteine is associated with negative health outcomes. This claim is based on an incorrect interpretation of the fact that methionine is a precursor to homocysteine.

However, studies show that fluctuations in dietary methionine intake do not alter blood homocysteine concentrations [48, 49].

To increase homocysteine, a high dose of pure methionine is required. This dose has been estimated to be equivalent to about 5 times the normal daily intake of methionine [50, 51, 49, 52].

Vegetarians, who have lower methionine intake, actually had higher homocysteine levels because of lower B12 in one study [53].

Also, other factors may balance methionine-induced homocysteine in meat-eaters. For example, glycine and serine are hypothesized to balance the negative effects of high dose methionine on homocysteine. However, this has not been verified in large human studies. More research is needed [54].

Glycine, serine, and B12 are rich in an animal food diet, but not in a vegan diet.

3) Methionine Doesn’t Act Alone

A study published in Nature showed that adding the essential amino acid methionine to the diet of fruit flies under dietary restriction, including restriction of essential amino acids, restored fertility without reducing the longer lifespans that are typical of dietary restriction [39].

This led the researchers to determine that methionine may “act in combination with one or more other essential amino acids” [39, 40].

However, this has yet to be determined in further animal studies and clinical trials.

Supplementary: Higher Protein Diet & Gut Health

Limited studies propose that not only the total protein intake, but the availability of specific dietary amino acids (in particular glutamine, glutamate, and arginine, and perhaps methionine, cysteine, and threonine) are essential to optimizing the immune functions of the intestine and the proximal resident immune cells. Human studies remain to be carried out [55].

These amino acids each seem to have unique properties that include maintaining the integrity, growth, and function of the intestine. Scientists are investigating whether they can normalize inflammatory cytokine secretion and improve T-lymphocyte numbers, specific T cell functions, and the secretion of IgA by lamina propria cells [55].

Summary of the role of amino acids in gut-associated lymphoid tissue (GALT) and the intestine, based on animal and cellular data [56]*:

*None of these mechanisms have been investigated in humans.