Methionine- Restricted Diet… Who needs it?

Methionine is an essential amino acid — one of the building blocks of protein that cannot be produced by the human body so must come from our food. It is one of two sulfur-containing amino acids (the other is cysteine). Methionine is an intermediary in the synthesis of cysteine, carnitine, taurine, and other compounds. It protects liver cells, and helps to prevent lipid peroxidation, and possibly atherosclerosis and elevated cholesterol. Although methionine is essential to human life, some people benefit by limiting, but not eliminating methionine in their diets. For such individuals a methionine-restricted diet may be advised.

Should I be on a methionine-restricted diet?

Some individuals need to restrict methionine due to inherited disorders that affect methionine metabolism. There is growing interest in methionine restricted diets for those who are unaffected by these genetic metabolic disorders. Evidence suggests that such diets could enhance longevity and help to prevent or treat certain chronic health conditions. The most common indications for a methionine-restricted diet are:

i) MTHFR variants. MTHFR gene mutations can lead to elevated homocysteine. Methionine restriction is commonly recommended to help reduce homocysteine accumulation.

ii) Cancer. While human studies are sparse, there is some evidence that cancer cells grow less robustly, and sometimes undergo apoptosis (cell death) when deprived of methionine.

iii) Depression. High methionine intakes can elevate homocysteine levels and risk of depression.

iv) Lifespan extension. Low methionine diets increase metabolic flexibility and overall insulin sensitivity and improve lipid metabolism while decreasing systemic inflammation.

v) Insulin resistance. Methionine restriction has been shown to reduce adiposity and improve insulin sensitivity.

vi) Homocystinuria. This inherited disorder of metabolism often requires a low methionine diet.

If methionine-restriction may help kill cancer cells and increase longevity, shouldn’t everyone be on a methionine-restricted diet?

We don’t know for sure, but it is an option for those who are interested in employing a novel dietary strategy for disease risk reduction. While severe methionine restriction is rarely advised, a moderate methionine restriction may be beneficial. The most concentrated methionine sources are animal products such as meat, poultry and fish. You will see from the table below that the eating pattern that is lowest in methionine is a purely plant-based diet or vegan diet. Other vegetarian or near-vegetarian diets are lower in methionine than omnivores diets, but not as low as vegan diets. For most people, simply eating a plant-based diet is likely sufficient for reducing methionine intake. Those with metabolic disorders or other conditions that may warrant methionine restriction can further restrict methionine by limiting high methionine plant-based foods.

If a methionine restricted diet is indicated for me, how much methionine should I be eating each day?

The RDA (recommended dietary allowance) for methionine + cysteine (adults 19 yrs+) is 19 mg/kg/day, while the EAR (estimated average requirement) is 15 mg/kg/day. People should not dip too much below these levels as they represent the lower end of what is needed for human health. Methionine-restricted diets allow 800-1200 mg methionine per day for most adults. For methionine alone, 15 mg/kg is thought to be a reasonable lower limit. So, if a therapeutic, methionine-restricted diet is indicated for you, multiply your healthy body weight by 15 to find a level of methionine intake that is appropriate. Let’s say your healthy body weight is 60 kg, you would need 900 mg methionine per day.

Are there any downsides to severely restricting methionine?

Absolutely. There is some evidence that a lack of methionine could reduce levels of S-Adenosylmethionine or SAM-e increasing risk of depression. A lack of methionine has also been linked to senile graying of hair. When you restrict methionine you are naturally restricting protein, at least to some degree.  Ensuring sufficient protein is essential to health. Protein is necessary for building, strengthening and repairing body tissues, for making antibodies, hormones, enzymes and other compounds that are critical to every body process.  A lack of protein can result in muscle loss, increased risk of bone fractures and undesirable changes in hair and skin. Seniors tend to absorb protein less efficiently, so they may need to consume 15-25% more protein than other adults in order to absorb the same amount. So while methionine restriction can be beneficial, it is important that we meet our needs for methionine, and for protein.

METHIONINE IN COMMON FOODS

(SOURCE: THE USDA NUTRIENT DATABASE RELEASE 28)

NOTES:

1. These figures in this table were sourced from the USDA National Nutrient Database for Standard Reference Release 28. http://ndb.nal.usda.gov/ndb/nutrients/index
2. The chart is set up using food groups (e.g. vegetables, fruits, legumes, etc.). Within each group, you will notice a variety of colors which represent different categories of methionine concentration (see key that precedes the chart). Within each color category, foods appear in alphabetical order.

Selected References

Cavuoto P, Fenech MF. A review of methionine dependency and the role of methionine restriction in cancer growth control and life-span extension. Cancer Treat Rev. 2012 Oct;38(6):726-36.

Durando X, Thivat E, Gimbergues P, Cellarier E, Abrial C, Dib M, Tacca O, Chollet P. [Methionine dependency of cancer cells: a new therapeutic approach?].  Bull Cancer. 2008 Jan;95(1):69-76.

Hasek BE, Stewart LK, Henagan TM, Boudreau A, Lenard NR, Black C, Shin J, Huypens P, Malloy VL, Plaisance EP, Krajcik RA, Orentreich N, Gettys TW. Dietary  methionine restriction enhances metabolic flexibility and increases uncoupled respiration in both fed and fasted states. Am J Physiol Regul Integr Comp Physiol. 2010 Sep;299(3):R728-39.

Orgeron ML, Stone KP, Wanders D, Cortez CC, Van NT, Gettys TW. The impact of dietary methionine restriction on biomarkers of metabolic health. Prog Mol Biol Transl Sci. 2014;121:351-76.

Patil YN, Dille KN, Burk DH, Cortez CC, Gettys TW. Cellular and molecular remodeling of inguinal adipose tissue mitochondria by dietary methionine restriction. J Nutr Biochem. 2015 Nov;26(11):1235-47.

Plaisance EP, Greenway FL, Boudreau A, Hill KL, Johnson WD, Krajcik RA, Perrone CE, Orentreich N, Cefalu WT, Gettys TW. Dietary methionine restriction increases fat oxidation in obese adults with metabolic syndrome. J Clin Endocrinol Metab. 2011 May;96(5):E836-40.

Tapia-Rojas C, Lindsay CB, Montecinos-Oliva C, Arrazola MS, Retamales RM, Bunout D, Hirsch S, Inestrosa NC. Is L-methionine a trigger factor for Alzheimer’s-like neurodegeneration?: Changes in A? oligomers, tau phosphorylation, synaptic proteins, Wnt signaling and behavioral impairment in wild-type mice. Mol Neurodegener. 2015 Nov 21;10(1):62.

Trimmer EE. Methylenetetrahydrofolate reductase: biochemical characterization  and medical significance. Curr Pharm Des. 2013;19(14):2574-93.

Wanders D, Burk DH, Cortez CC, Van NT, Stone KP, Baker M, Mendoza T, Mynatt RL, Gettys TW. UCP1 is an essential mediator of the effects of methionine restriction on energy balance but not insulin sensitivity. FASEB J. 2015 Jun;29(6):2603-15.