Eating less helps you live longer, but eating less is hard. One line of experiment suggests that eating less of just one protein component, methionine, is sufficient to extend life span, perhaps as effectively as though less calories were being consumed. It’s an intriguing idea, though the research is fraught with contradictions, and to separate methionine from other protein components is not easy or cheap.
It was first reported in 1993 that rats subjected to a diet restricted in methionine (MR) enjoyed comparable life spans to rats that were on caloric restriction (CR). In the first experiments, methionine was reduced to ⅕ its normal level in the diet, and growth of the rats was severely stunted.
What is methionine?
Proteins are the workhorse chemicals of the body, macromolecules consisting of folded chains of sometimes tens of thousands of amino acid molecules strung together. There are 20 amino acids to choose from*, and the particular sequence of amino acids in the chain determines how the protein will fold up (“tertiary structure”), and thus what shape it will have, and how it will function in the body.
When we eat protein, it is “someone else’s” long chain protein molecules that we ingest. The particular form that the protein takes was useful to the plant or animal that we’ve eaten, but not to us, so our digestion breaks down the protein into the component amino acids, and then rebuilds the protein chains we need from these “recycled” pieces. Of the 20 amino acids, our bodies rely exclusively on the foods we eat to get 8 of them, the “eight essential amino acids” made famous by Frances Moore Lappé 40 years ago. The other 12 we can manufacture for ourselves.
Methionine is one of these eight essential amino acids, and one of just two that include the element sulfur.
Costs and Benefits
Various rodents fed on a low-methionine diet have been observed to live longer. In some of these experiments, food intake was strictly controlled to assure that the MR animals and the controls received the same total calories. [ref]
Oxidative damage from the mitochondria is a hallmark of aging, and this has been noted to decrease reliably with methionine restriction. [ref] The authors of this article “conclude that methionine is the only dietary factor responsible for the decrease in mitochondrial ROS production and oxidative stress, and likely for part of the longevity extension effect, occurring in CR.” In other words, the only reason that caloric restriction extends life span is that the body gets less methionine in the process. This may be an extreme, if tenable position. I don’t believe that an experiment has yet been done in which rodents are fed a diet that is both high in methionine and low in calories.
Methionine restriction lowers cancer rates, and has been proposed as a cancer treatment, logically enough since it limits cell growth.
The Start Codon
Here’s a clue about why methionine is special. The instructions for making proteins is coded into DNA, via the genetic code, which specifies words of 3 DNA letters, each corresponding to one of the 20 amino acids. The genetic code also contains “punctuation”, instructions to start and stop. The “start codon” is also the word for methionine. Every chain of amino acids that the body constructs begins with methionine.
No methionine – no protein synthesis. A shortage of methionine means that the body is inhibited in making every kind of protein. I remarked a few months back that more genes are expressed (more proteins synthesized) as the body grows older. Perhaps methionine restriction is putting a brake on this production of extra proteins that are not produced when we’re young, and that contribute to aging.
Paradoxes
SAMe is a supplement I take. The “Me” in SAMe is for “methionine”, which is part of the chemical formula. SAMe promotes methylation of DNA, which decreases gene expression, which (theoretically) extends life by a similar mechanism to methionine restriction. Go figure.
Methionine is a necessary ingredient for the body to synthesize glutathione, “the mother of all anti-oxidants” and a longevity factor. And yet, less methionine has been associated with more glutathione.
Toward a Practical Diet
We can’t live entirely without methionine – the body would not be able to make any proteins at all. Restricting methionine is likely to have impacts on growth, health, and wellbeing that are as yet unstudied in humans. “rats fed a diet without methionine developed steatohepatitis (fatty liver), anemia and lost two thirds of their body weight over 5 weeks.” (Wikipediia) In one experiment where methionine was severely restricted but not eliminated entirely, ⅕ of the mice died, and the other ⅘ went on to live longer than control mice.
A separate issue is how to accomplish methionine restriction in practice. Proteins that we eat consist of chains of amino acids with all 20 mixed in. Even if you chew your food very carefully, you can’t just spit out the methionine and swallow the other 19. So methionine restriction in practice involves eating foods that are low in methionine. Though all protein has methionine, some protein sources are much lower in methionine than others. I compiled the following table from data available at USDA Nutirtion refrence site.
|
Food (100g) |
% Methionine |
Calories |
fat g |
carb g |
protein g |
cal fr fat |
cal fr carb |
cal fr protein |
|
Frozen Peas |
0.47% |
52 |
0.38 |
9.02 |
3.5 |
6.37% |
67.93% |
25.70% |
|
Almonds 100g |
0.86% |
597 |
52.83 |
19.29 |
22.09 |
74.22% |
12.18% |
13.60% |
|
Lentils |
0.93% |
116 |
0.38 |
20.13 |
9.02 |
2.84% |
67.62% |
29.54% |
|
Mung Beans |
1.05% |
105 |
0.38 |
19.15 |
7.02 |
3.15% |
71.35% |
25.50% |
|
Split peas |
1.07% |
118 |
0.39 |
21.1 |
8.34 |
2.88% |
70.10% |
27.02% |
|
Peanuts 100g |
1.22% |
585 |
49.66 |
21.51 |
23.68 |
70.26% |
15.06% |
14.68% |
|
Tofu 100g |
1.32% |
145 |
8.72 |
4.27 |
15.78 |
38.37% |
31.21% |
30.43% |
|
Chick Peas 100g |
1.36% |
164 |
2.59 |
27.42 |
8.86 |
24.77% |
38.09% |
37.14% |
|
Walnuts |
1.50% |
654 |
65.21 |
13.71 |
15.23 |
83.55% |
7.90% |
8.55% |
|
Black beans |
1.59% |
130 |
0.35 |
24.35 |
8.18 |
2.35% |
73.56% |
24.09% |
|
Cashews |
1.60% |
576 |
46.35 |
32.69 |
15.31 |
68.41% |
21.69% |
9.90% |
|
Broccoli 100g |
1.61% |
35 |
0.41 |
3.88 |
2.38 |
16.25% |
42.40% |
41.34% |
|
Wheat Gluten 100g |
1.65% |
370 |
1.85 |
13.79 |
75.16 |
2.70% |
49.27% |
48.04% |
|
Boiled peas |
1.91% |
84 |
0.22 |
15.63 |
5.36 |
2.29% |
73.22% |
24.48% |
|
Wheat Germ 100g |
2.01% |
382 |
10.7 |
49.6 |
29.1 |
23.39% |
48.73% |
27.88% |
|
2% Milk 100g |
2.39% |
50 |
1.97 |
4.68 |
3.3 |
40.21% |
30.27% |
29.52% |
|
Roast Beef |
2.68% |
163 |
4.1 |
0 |
29.59 |
24.02% |
0.00% |
75.98% |
|
Chicken |
2.72% |
300 |
20.97 |
0 |
25.95 |
64.84% |
0.00% |
35.16% |
|
Eggs |
2.95% |
142 |
9.9 |
0.76 |
12.53 |
62.93% |
2.17% |
34.90% |
|
Salmon 100g |
3.07% |
182 |
8.13 |
0 |
25.44 |
26.47% |
37.23% |
36.30% |
|
Tuna |
3.07% |
139 |
1.22 |
0 |
29.97 |
8.50% |
0.00% |
91.50% |
|
Sardines 100g |
3.07% |
208 |
11.45 |
0 |
24.62 |
34.38% |
33.23% |
32.39% |
|
Egg white 100g |
3.39% |
52 |
0.17 |
0.73 |
10.9 |
3.22% |
6.22% |
90.56% |
|
Brazil nuts |
6.50% |
656 |
66.43 |
12.27 |
14.32 |
84.93% |
7.05% |
8.02% |
You can see that all animal sources (including milk and especially eggs) are high in methionine. So an MR diet is a vegan diet, not just any vegan diet, but a subset of vegan protein sources. There appear to be no general rules. For example, almonds are a good source of low-methionine protein, but Brazil nuts are terrible. Lentils are first-rate, soy beans not so good, and wheat germ is poison.
The table also makes clear that even a strict vegan diet (free of Brazil nuts) would only reduce methionine intake by about 1/2. Extrapolating from the rodent experiments, we may need to reduce by ~ 3/4 before crossing a threshold where benefits kick in.
(Note incidentally that CR is not like this. There is no threshold for caloric restriction. Eating less increases life span quite smoothly. You get a little benefit from eating a little less, and a lot of benefit from eating a lot less.)
A long shot idea
Glycine is the simplest of the 20 amino acids. (It is literally just an amine group linked to an acid group, NH2CH2COOH.) It was reported at an experimental biology conference two years ago that increasing glycine has similar effects to decreasing methionine in the diet, showing life extension and some of the same metabolic benefits in rats. To my knowledge, this has not yet been written up in a peer-reviewed journal. I’ve written to the author, and will add a comment below this post if I hear anything.
Bottom line
The number of experiments that have been done with methionine restriction is tiny compared to caloric restriction. There is no data at all, that I am aware of, for humans on a methionine-restricted diet. It’s an intriguing idea, and I’m guessing that more study of methionine restriction will yield interesting insights into aging. I don’t think we know enough yet to consider adopting MR as an aid to long-term health, especially since severe restriction is likely to have side-effects, and mild restriction is is likely to be ineffective.
_______
*not to be confused with the nucleic acids that make up DNA. There are only 4 of those.
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Very intriguing study; animal proteins and Brazil nut avoidance should do the trick!!!
If you check Google Scholar for “methionine and atherosclerosis” you’ll find that methionine is very much implicated in cardiovascular disease. In fact, methionine can be used to induce atherosclerosis reliably in rabbits. Methionine is converted by the transmethylation/transsulfuration pathway to homocysteine, which accelerates lipid peroxidation. (Homocysteine has long been a known marker in human cardiovascular disease.) Probably the only reliable way to reduce dietary methionine is to eat a very-low-protein diet and supplement it with a methionine-knockout amino-acid mix. (In other words, buy the individual amino acids minus Met, and combine them into a no-Met mixture; take the resulting mix as a supplement.)
Great post.
Thanks for the article. The benefit from reducing this amino acid from my diet by trying to adopt such a limited/restrictive diet is still speculative. And the cost of trying to do so just isn’t worth the effort.
Shortage of another amino acid, tryptophan, also supposedly has life extending properties: http://raypeat.com/articles/aging/tryptophan-serotonin-aging.shtml
5:2 fasting with around 600 calories for males on fasting days has shown favorable outcome on the documentary eat fast and live longer from bbc.
Extending it to every other day, or alternate day fasting with a very low protein high calorie food such as macadamia nuts. Should result in vast methionine restriction at least on alternate days, combined with a few grams of glycine(assuming its clearance of methionine works) should be effective in theory.
Moderate calorie intake on nonfasting days would result in an overall calorie restriction over a 2 day period. So one’d get CR(calorie restriction) as backup to the MR(methionine restriction).
Is your table correct? It says:
Frozen Peas 0.47%
Boiled peas 1.91%.
If I can’t trust what you tell me about peas, can I trust other lines in the table?
Thanks for excellent article anyway!
I noticed the same contradiction, and that’s why I included both entries. Data is from USDA on-line guide to nutrients in food, and I agree it raises suspicion about reliability of this source.
http://ndb.nal.usda.gov/
Also, one needs to consider taking C60 (bucky balls) in olive oil, as an antioxidant; and resveratrol as an up regulator of sirtuin and repair genes.
What can you tell us about rapomycin as a longevity compound?
The short version is: strong version it extends life in mammals, but the expectation is that it suppresses the immune system to an extent that will make you vulnerable to cold, flu, and more serious diseases. Companies are working on separating the two functions to create a rapamycin sister that has more of the good effect, less of the bad.
Sam e supplementation as it is a kind of methionine makes me nervous since I am one of the one in three that has genetic issues with folic acid. Anyway, I am taking it along with b12 and methylated folic acid and glycine. I will test my homocysteine levels in a few months. As a part of this I am reducing methionine in my diet, but not becoming vegan.
Vegan is not too difficult to do, as long as you don’t make a religion out of it. For example, little chicken in chicken noodle soup won’t be enough to make any difference. I used to think meat was necessary; but when I went vegan, I found my gains from weight lifting continued up just as though I were still a carnivore. Vegan also saves a lot of money at the grocery store. Cheers.
But Jerry – wasn’t that just the point of the article? If you don’t do it “religiously” there’s no benefit. In practice, you either have to cut protein so far back that you look like one of those African children with a bloated stomach, or else you have to eat synthetic food that is reconstituted from amino acids minus methionine.
Ethylene, a plant hormone derived from methionine is involved in plant senescence. It is a gas which is soluble in the fatty layer in cell membranes. Has it been overlooked in animal tissue? It would be interesting to check to see if there is any ethylene present in senescent animal cells. It would also be interesting to see what affect it would have on animal cells. Would it cause senescence?
Any update from on that “glycine may lower methionine” line of research? Thanks for your interesting post.
As of July, 2015, I haven’t heard anything, and a Google Scholar search doesn’t come up with any account of research on glycine supplementation.
Link for glycine supplementation that has similar effect to methionine restriction in rats: http://www.fasebj.org/cgi/content/meeting_abstract/25/1_MeetingAbstracts/528.2
It is the conversion of methionine to homocysteine that actually does the oxidative damage. Getting enough B vitamins helps convert or restore the damaging homocysteine to its original form. Homocysteine has been associated with stroke MI, Alzheimer’s RA and a host of bad health consequences. Restricting methionine intake is a radical, last ditch way to reduce homocysteine levels. (this can be measured by a blood test but your insurance probably won’t pay for it)
That’s an interesting hypothesis, and biochemically plausible. Counting against it, it’s my understanding that methionine restriction doesn’t kick in until methionine levels are super-low. Can you refer me to any papers on this theory?
– Josh
I’m not sure if this answers your question, but regarding your comment about Methionine restriction, this study found that 60% restriction got you most of the benefits (taken from Summary). However, this is from the viewpoint of reduced mitochondrial free radical generation and damage, as opposed to lifespan from reading the body (since 35% of normal levels only increased lifespan by 7% vs 42% for those rats given only 20% of controlled levels, which supports your argument that the most severe restriction is necessary for most of the ls gain).
http://www.benbest.com/calories/Meth.html
This is the first I heard about the negatives of Methionine. I am glad to have stumbled across this info, but I use SAMe regularly to boost my mood. To the point where I almost feel addicted to it. I have a high PSA number so I have been studying causes of Prostate Cancer. I have not been diagnosed with PC, but I do have an enlarged Prostate BPH. I have also just found a link between cancer (prostate) and high Methionine levels. http://nutritionfacts.org/video/starving-cancer-with-methionine-restriction/ Going to stop taking the SAMe and have started becoming a Vegan.
My concerns my forward besides my high PSA number 3.4, is;
1. Fighting depression and mood with out using SAMe
2. Any other side effects of restricting Methioniine
Anyone have any comments, links, or advice for me?
Methionine is the start amino acid of every protein chain. When you restrict methionine, you restrict the production of proteins. In a way, this is a good thing; because at least 3 genes in the human body produce proteins that seem to have no other purpose than to cause aging. That is also probably how resveratrol (which up regulates Sirt1 gene) works when its Sirt1 protein deacetylates histones, causing them to tighten up around the DNA chain and prevent genes from activating. Nevertheless, I personally like to lift weights to grow bigger muscles; and I found restricting Methionine, by restricting protein in my diet, interfered with my weight lifting progress; I quit getting stronger. So it is not a good thing, if you are trying to build a bigger stronger body; otherwise, you may be better off restricting Methionine. Going vegan is probably the easiest way to cut back on protein, and thereby cut back on Methionine.
Whereas meat and other animal protein also has very large amounts of MET, my way to still maintain muscle and health but cutting out much animal met and animal fat) is to make a smoothie from soy isolate powder and drink it maybe 3 times a day, and try to eat as much vegetation as possible to make my daily calorie goal. Lots of protein is to help counteract sarcopenia, suffered to various degrees by persons over 65. I’m 81.
24g Soy isolate powder: 90 cal, 20g protein, 302mg MET
100g Roast beef: 163 cal, 30g protein, 974 mg MET
I wonder if eating foods with a good balance of methionine and glycine would work. I believe eggs have lots of methionine AND lots of glycine. Perhaps the glycine in the egg would “cancel out” any negative effects of the methionine in the egg. This is, of course, assuming that the idea about taking glycine having the same effect as lowering methionine intake is true.
Maybe as long as you eat enough glycine-rich foods, you could get the same outcome as you would get if you removed the methionine foods.
I am a vegetarian and have methionine deficiency. I didn’t know I was getting a fatty liver from not eating enough protein. it also made my gallbladder develop sludge. Maybe lower methionine is good for people who eat a lot of animal products but very low methionine is NOT good. Digestion does not work well without it. I think people should figure out how much they need based on body weight and strive to eat that amount.
Is there anything that might bind Met and take out of the loop? I was alarmed at Brazil nuts since I try to eat one everyday for the selenium.
I maybe do a form of methionine restriction – I eat little protein and mostly lupin beans + fasts + glycine and it really does something, when I eat anything with a lot of methionine, I feel much different. (Lupin has even less methionine for protein than lentils and almonds, macadamia nuts are even better if I remember correctly).
Creatine supplementation helped me feel good on MR, maybe a mechanism with SAMe.
BTW I recommend this tool https://nodetools.myfooddata.com/nutrient-ratio-tool/ – to look for foods with desired ratios – you can make more useful tables than in the article (e.g. protein / methionine)
This is interesting — I had been under the impression that methionine restriction in humans was both impractical to arrange because of limited food options and also that it would not be good for sense of well-being.