Methionine restriction has been known for decades in longevity research. But less methionine is not necessarily better and it’s often worse.

I was prompted to write this post because of my vegetarian diet post. Some people were assuming that methionine is something that needs to be reduced in the diet in order to be optimally healthy.

Like almost everything else in biology, the levels that are optimal for one person are suboptimal for another.

This post is meant to clarify the pros and cons of methionine and clarify who should be taking higher or lower levels.

Methionine Restriction and Longevity

There is scientific evidence that restricting methionine consumption can increase lifespans in some animals [1].

A 2005 study showed methionine restriction without calorie restriction extends mouse lifespan [2].

Several studies showed that methionine restriction also inhibits aging-related disease processes in mice [34] and inhibits colon cancer in rats [5].

In rats, methionine supplementation in the diet specifically increases mitochondrial ROS production and mitochondrial DNA oxidative damage in rat liver mitochondria offering a plausible mechanism for its liver toxicity [6].

Methionine and Genetics

There are a few genes that can affect the amount of dietary methionine you want to get.

The MTHFR gene is one significant gene that affects the conversion of homocysteine to methionine. If you have a poor functioning gene (as I do), you will require more folate. If you don’t get adequate folate, you will have higher homocysteine and lower methionine.

Low methionine intake was significantly associated with an increased risk of Colorectal Tumor in MTHFR 677 (AA) individuals compared to people with low intake and the normal genotype [7].

The MTRR gene and MTR gene convert homocysteine to methionine (see related SNPs) and if they are not functioning well, you may have higher levels of homocysteine and lower methionine

 

Why Methionine is Important and Who Has a Larger Need

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 a fatty liver, anemia and lost two-thirds of their body weight over 5 weeks [8, 9].

Methionine is only one of two amino acids that provide sulfur for the body, which is required to sulfate many compounds.

Methionine (in the form of SAM-e) and Cysteine (in the form of NAC) are commonly taken as supplements and I recommend reading my posts on these to understand how they can be beneficial.

Methionine converts to cysteine, so supplementing with cysteine reduces the requirements for methionine [10].

Dietary methionine alone is capable of providing all the necessary body sulfur (except thiamin and biotin) [10].

1) Helps Detox

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

Sulfur helps produce glutathione, which is critical for proper antioxidant function [10].

Tylenol requires sulfate for its excretion and it’s often given in high doses to alleviate pain (4 gm/day, as recommended on the label). This equivalent dosage in rats causes a depletion of sulfate, which can be corrected by methionine supplementation [10].

Tylenol was more toxic and was eliminated more slowly in animals deficient in sulfates [10].

2) Increases Glutathione

Cysteine and methionine are not stored in the body.

When you have a deficiency in sulfur amino acids such as methionine, glutathione levels suffer more than more critical processes such as protein synthesis [10].

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) [11].

Glutathione levels are lower in a large number of diseases and following certain medications, which can be reversed by taking methionine [10].

Methionine and sulfur should be able to spare losses of Glutathione associated with dietary deficiencies, increased utilization due to disease or altered immune function [10].

Under conditions of low methionine, synthesis of sulfate and Glutathione will be reduced, which is likely to negatively influence the function of the immune system and of the antioxidant defense mechanisms [10].

Animals undergoing methionine restriction live under sterile and perfect conditions, as opposed to humans.

3) Is Important For Gut Health

Methionine is often found in the same foods with cysteine

There is some evidence that dietary methionine (and cysteine) is important to ensure the health of the intestine and immune function during development and in inflammatory states [12].

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, improved villus height and area and crypt depth, and a higher number of goblet cells [12].

Benefits of methionine for gut health:

A precursor for GSH, taurine, and cysteine

• Reduces intestinal oxidative stress

• Intestinal structure

• Increases goblet cells and proliferating crypt cells

4) Helps The Immune System

Methionine is important to the immune system [13, 14] and methylation (it’s the precursor to SAM) [15, 7].

For the immune system, methionine increases glutathione, taurine, CD4+ and CD8+ cells [14].

5) Helps Methylation

Methionine is important for methylation (it’s the precursor to SAM) [15, 7].

Many people who don’t methylate well enough would do better with higher intakes of methionine.

However, it’s not clear exactly what effects methionine has on methylation.

Methionine supplementation has the potential to induce relevant changes in methylation and expression of genes.

It remains to be determined whether high Methionine intakes have a greater tendency to induce DNA hyper- or hypomethylation.

Methionine can be helpful and harmful in different situations and further research is needed to clarify exactly which genes are affected by this [15].

6) Can Help The Joints

Sulfates/sulfur is critical for glycosaminoglycan synthesis, which is important for cartilage [10].

One study concludes that a “significant proportion of the population that included disproportionally the aged, may not be receiving sufficient sulfur and that these dietary supplements [glucosamine/chondroitin sulfate], were very likely exhibiting their pharmacological actions by supplying sulfur [16].

In order to increase growth, chicken diets are always supplemented with methionine/cysteine [10].

7) Helps Produce Compounds That Help The Heart and Cells

Methionine is an intermediate in the biosynthesis of cysteine, carnitine, taurine, lecithin, phosphatidylcholine, and other phospholipids. Improper conversion of methionine can lead to atherosclerosis [17].

8) Helps Fertility

Methionine restriction causes lower fertility [1819].

9) Is More Important Under Inflammatory Conditions

Under inflammatory conditions and oxidative stress, the requirement for sulfur amino acids such as methionine goes up, in part because of increase glutathione needs and sulfur excretion [14].

The immune system also uses up methionine when it’s stimulated in pigs [20].

Observations in experimental animals and patients indicate that antioxidant defenses become depleted during infection and after injury. For example, in mice infected with influenza virus, there was a 45% decrease in the GSH contents of blood [21].

Substantial decreases in Glutathione occur in:

  • Asymptomatic HIV infection [22]
  • Elective abdominal operations [23]
  • Hepatitis C [24]
  • Ulcerative colitis [24]
  • Cancer [24]
  • Cirrhosis [24]
  • Sepsis [25]

Under conditions of a glutathione deficiency, a sublethal dose of TNF became lethal [26].

10) Can Help Epigenetics Under 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.

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 [27].

11) Is Protective Against Lupus

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.

Reducing the methionine and choline content of the diet increased lupus disease severity in genetically susceptible mice [28].

12) Depletion Can Cause Greying of Hair

Loss of methionine has been linked to senile greying of hair. Its deficit leads to a buildup of hydrogen peroxide in hair follicles and a gradual loss of hair color [29].

13) Venous Thrombosis

Low fasting methionine concentrations are a risk factor for recurrent venous thrombosis [30].

Methionine in the Diet

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

Most fruits, vegetables, and beans are low in methionine.

Compared to fish eaters and meat eaters, vegans have the lowest intake of methionine [3132].

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 [10].

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 may be 2 or 3 times higher [33].

One study by Tuttle et al. 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 [34].

Average Intake

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

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” [10].

Many older people could turn out to be outright deficient (group X) [10].

The figure below compares the sulfur amino acid intake in g/day to the accepted RDA (1989), twice the RDA values accepted to provide greater safety to a large population, and to values arrived to for older individuals by the VA study of Tuttle et al.

Average sulfur amino acid intake associated with the consumption of a variety of typical diets [35]:

GroupSAA (g/day)
IHigh-protein6.8
IIHigh-protein low-calorie5.0
IIIOriental-American4.8
IVAverage balanced4.3
VFast-food4.1
VIDieter3.5
VIILacto-ovo-vegetarian3.0
VIII“health conscious diet2.6
IXVegan2.3
Xelderly people (75 yr old)1.8

1743-7075-4-24-4

How Much Methionine is Too Much?

A “loading dose” of methionine (0.1 g/kg) has been given, and the resultant acute increase in plasma homocysteine has been used as an index of the susceptibility to cardiovascular disease.

A 10-fold larger dose, given mistakenly, resulted in death. 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 [36].

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 [36].

In infants, methionine intakes of 2 – 5 times normal resulted in impaired growth and extremely high plasma methionine levels, but no adverse long-term consequences were observed [37].

The Case Against Methionine Restriction

Methionine restriction has been known for decades in animal longevity research [38].

If restricting methionine can make animals live longer, then why don’t we try to do it?

Fallacies About Methionine Restriction

There are three fallacies that you should be careful about when it comes to drawing conclusions about your optimal methionine level.

  1. If restricting methionine increases maximum lifespan, then restricting it is not necessarily optimally healthy.
  2. If excess methionine is bad, then restricting it doesn’t mean it’s 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 has what’s called a biphasic response. If you get too little or too much, it’ll cause a lot of problems. You need to get a balanced amount, and that level will be different for everyone.

1) Longevity Research Doesn’t Apply

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

The issue with methionine restriction is the amount that you’d have to lower methionine for it be beneficial for longevity is not practical for other purposes.

It’s not that much different than lowering free radicals by not breathing. It’s not practical in the long run because of the side effects.

Methionine is important to the immune system. If you take less methionine over the long run, you may become susceptible to chronic infections and that can cause many problems.

Animals in longevity studies are in sterile environments and if they live longer in a sterile environment, it doesn’t mean they will in the real world.

A lot of things that cause longevity are bad for specific people. Lowering IGF-1 can be good for longevity, but for some people, higher levels are much better for their biology. Same with methionine.

2) Methionine Doesn’t Raise Homocysteine

Some say that methionine is bad because it raises homocysteine and elevated homocysteine is associated with negative health outcomes and we know the role of methionine as a precursor to homocysteine.

The problem is that fluctuations in dietary methionine intake do not alter blood homocysteine concentrations [3940].

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
[R, 41, 4042].

Vegetarians, who have lower methionine intake, actually have higher homocysteine levels because of lower B12 [43].

Also, other factors can balance methionine-induced homocysteine in meat eaters (assuming it did raise homocysteine, which it doesn’t).

For example, glycine and serine balance the negative effects of high dose methionine on homocysteine [44].

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 adding just 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 [18].

This led the researchers to determine that methionine “acts in combination with one or more other essential amino acids to shorten lifespan” [1819].

Who Should Be Careful With a Higher Methionine Diet

Schizophrenics

In animals, high levels of methionine are 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. A lower GABAergic function is a cause of schizophrenia [45].

People Deficient in B Vitamins

If you have a high methionine intake, special attention should be paid to folic acid and vitamins B-6 and B-12 under these circumstances [14].

My Conclusions About Methionine Restriction

It’s not practical in the long run because of the side effects.

I don’t believe the studies about methionine restriction relate to humans because in the real world people don’t die from too much methionine. Other things go wrong first and not getting enough, however, can be problematic to some people, even if it potentially helps them in another way (assuming that lower levels are somewhat beneficial in some ways).

Methionine may be analogous to IGF-1: it can possibly be good for longevity, but it’ll worsen performance and it could worsen autoimmunity.

Supplementary: Why a Higher Protein Diet is Important For Your Gut

Studies have established convincing evidence 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.

These amino acids each have unique properties that include, maintaining the integrity, growth, and function of the intestine, as well as normalizing inflammatory cytokine secretion and improving T-lymphocyte numbers, specific T cell functions, and the secretion of IgA by lamina propria cells [46].

Most of my clients do better with a higher protein diet, and this is, in part, because a higher protein diet is needed when people have gut problems [46].

I made the mistake of believing the vegan myths that lower protein is healthier for everyone (it might be for some people, but certainly not me).

Summary of the role of amino acids in GALT and the intestine [47]:

Amino acidFunctions
Glutamine
• Oxidative substrate for immune cells and IECs
• A precursor for glutamate/GSH
• Intestinal growth, structure, and function (young animals and disease states)
• Supports proliferative rates and reduces apoptosis of IECs
• Protects against E.coli/LPS-induced damage to the intestinal structure and barrier function
• Lowers inflammatory and increases immunoregulatory cytokine production
• Improves the proliferative responses of IELs and MLN cells
• Intestinal IgA levels

• Increases lymphocyte numbers in PP, lamina propria, and IELs
Glutamate
• Oxidative substrate for immune cells and IECs
• A precursor for GSH and other amino acids (i.e. arginine)
• Intestinal growth, structure, and function
• Acts as Immunotransmitter between dendritic cells and T-cells*

• Facilitates T-cell proliferation and Th1 and proinflammatory cytokine production
Arginine
• Precursor for NO and glutamate in IECs and immune cells
• Intestinal growth, structure, and function
• Supports microvasculature of intestinal mucosa
• Increases expression of HSP70 to protect the intestinal mucosa
• Protects against E.coli/LPS-induced damage to the intestinal structure and barrier function
• Facilitates neutrophil and macrophage killing through iNOS-mediated NO production
• Increases intestinal IgA levels
• Lowers inflammatory cytokine levels in the intestine

• Increases T-lymphocytes in lamina propria, PPs, intraepithelial spaces
Methionine &Cysteine
• Precursor for GSH, taurine, and cysteine
• Reduces intestinal oxidative stress
• Intestinal structure
• Increases goblet cells and proliferating crypt cells

• Protects against DSS-induced intestinal damage (colitis model) by lowering inflammation, crypt damage, and intestinal permeability.
Threonine
• Mucin synthesis
• Intestinal structure and function
• Intestinal IgA levels

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