Methionine/Cysteine restriction increases longetivity AND energy expenditure
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Interesting study In humans,showing increase of FGF21 6-fold after seven days. Diet was 9% protein , 71% carbs, 20% fat.
Anybody interested in this diet, should listen to the first 15 minutes of this pod with ray. dropped some gems.
He mentions mTOR inhibition as the major MoA of MR, which I have only sparingly seen mentioned in the studies.
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This is the 30 year old study that a lot of people have mentioned. In which there was a 43% increase in life span in rats.
The researchers make some obervations that are hard to reconcile with some parts of the bioenergetic viewpoint.
They measured GSH and GSSG levels and they were through the roof. In old mice GSH was 278% higher than in old control mice. Now GSSG did not change, meaning the GSH/GSSG ratio increased a lot.
Since the GSH/GSSG ratio is a proxy for the NAD/NADH ratio and for how oxidized the organism is, the mice should be in an extremely reductive state- yet they lived a lot longer and are healthy.The only place where GSH decreases was the liver and kidneys.
They also found that these changes were present as early as 2 months into the diet. While other research suggests that it might take 2-4 weeks for those changes to happen. I'm not sure if those changes would also occur on an intermittent approach, but I read there was a study on that, I just havent found it yet.
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@Mauritio said in Methionine/Cysteine restriction increases longetivity AND energy expenditure:
Thanks.
I was tryign low fat, low protein yesterday as well.
And I feel like restricting two macro-nutrients is too much. not sure if I could handle that long term. If almost all you eat is carbs, you probably run into satiety problems down the road. Carbs just arent that filling IME. But maybe it would get easier over time, as the animal studies show a shift in substrate utilization towards carbohaydrate oxidation, so maybe the cravings are transitory.I have noticed I don''t crave fatty foods as much when I take pyrucet. I'm thinking the more you increase glucose oxidation, the less you fatty foods tasty. However I'm not sure the same can be said about protein.
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Something interesting about all this to me is that before I recognized that I was hypothyroid, I ate a plant based diet, (heavy on fruits, but a fair amount of rice and potatoes) and ate a couple cheeseburgers once a week. Like vegan except for one day a week. I had previously been vegetarian exclusively for about 10 years, (which probably contributed to my hypothyroidism as I in no way avoided PUFAs, and did not consume dairy).
During that period when I first re-introduced beef once a week I have never been healthier. It actually still stands out in my mind as a time when I was incredibly well. I would imagine that I never got more than 75 grams of protein in a day, (6 days a week) and the majority of that would have been from plants, (squash, potatoes, bread, various fruits, some beans). I’m willing to bet with some very modest changes I could probably replicate that diet and fall into methionine restriction pretty easily.
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@Mulloch94 said in Methionine/Cysteine restriction increases longetivity AND energy expenditure:
@Mauritio said in Methionine/Cysteine restriction increases longetivity AND energy expenditure:
Thanks.
I was tryign low fat, low protein yesterday as well.
And I feel like restricting two macro-nutrients is too much. not sure if I could handle that long term. If almost all you eat is carbs, you probably run into satiety problems down the road. Carbs just arent that filling IME. But maybe it would get easier over time, as the animal studies show a shift in substrate utilization towards carbohaydrate oxidation, so maybe the cravings are transitory.I have noticed I don''t crave fatty foods as much when I take pyrucet. I'm thinking the more you increase glucose oxidation, the less you fatty foods tasty. However I'm not sure the same can be said about protein.
It might be true. Im on day 3 and I crave protein slightly less than on day one, certainly not more. The studies show that when you restrict protein, you increase carb and fat oxidation. Fat actually more than carb.
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@evan-hinkle said in Methionine/Cysteine restriction increases longetivity AND energy expenditure:
Something interesting about all this to me is that before I recognized that I was hypothyroid, I ate a plant based diet, (heavy on fruits, but a fair amount of rice and potatoes) and ate a couple cheeseburgers once a week. Like vegan except for one day a week. I had previously been vegetarian exclusively for about 10 years, (which probably contributed to my hypothyroidism as I in no way avoided PUFAs, and did not consume dairy).
During that period when I first re-introduced beef once a week I have never been healthier. It actually still stands out in my mind as a time when I was incredibly well. I would imagine that I never got more than 75 grams of protein in a day, (6 days a week) and the majority of that would have been from plants, (squash, potatoes, bread, various fruits, some beans). I’m willing to bet with some very modest changes I could probably replicate that diet and fall into methionine restriction pretty easily.
You mention you increased your protein and got healthier, how is that related to the protein restriction discussed in this thread? Wouldnt that be an argument against it?
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@Mauritio nah, too many factors. I was eating a pufa laiden vegan diet with a ton of indigestible “foods.” I think the very low protein of one meat based meal a week in combination with a whole food vegetarian diet would probably be a great option.
From this model I went carnivore and incorporated block fasting and one meal a day, (information I didn’t share). So increasing protein to that degree very certainly did not help, (it’s kinda relative right?) I’m looking at the one meat meal a week plus whole food vegetarian, (not dogmatic) as a potential “easy” diet to achieve methionine restriction. Sorry for any confusion.
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@evan-hinkle Ok, thanks.
Dare to think.
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Does anybody know the study where they showed that eating low protein 3 times a week, bascially gave the same benefits on longevity as doing it full time? I ve seen that mentioned but havent found the actual study. That is the last thing on that whole topic that Im really interested in.
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I mean in a lot of these studies restricting protein really means increasing carbs at its expense by quite a significant margin.
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@Mauritio said in Methionine/Cysteine restriction increases longetivity AND energy expenditure:
Does anybody know the study where they showed that eating low protein 3 times a week, bascially gave the same benefits on longevity as doing it full time? I ve seen that mentioned but havent found the actual study. That is the last thing on that whole topic that Im really interested in.
Apart from what's already in this topic mentioning 3 days of restriction (protein in general), there's this one about intermittent methionine restriction/IMR (3 days of restriction).
To the best of our knowledge, we show for the first time that IMR confers to male and female mice the beneficial metabolic effects previously reported for continuous MR. That is, as compared with control-fed mice, animals undergoing the more stringent of two IMR regimens (IMR2) benefit from reduced adipose tissue accumulation, protection against hepatosteatosis, improved glucose homeostasis, and altered circulating levels of IGF-1, FGF-21, leptin, and adiponectin. Despite a much shorter interventional period than continuous MR (only 3 days per week), not only is IMR capable of producing similar health benefits, but other aspects of this intervention are actually superior to classical MR.
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@TexugoDoMel
Thanks! Thats the one I meant.
The results arent as encouriging as I hoped, but still good.They had two Intermittent methionine restricion (IMR) groups, both of them were fed 3 days of a methionine restricted diet followed by a low methionine diet for 4 days in case of IMR1 and a no methionine diet in case of IMR2. They had a continuously methionine restricted diet as a control group
In terms of health effects only IMR2 was really capable of keeping up with continous MR. IMR1 had benefits but not quite as much.
Unforuntely its not really possible for people to have a no methionine diet.
Plus, none of the groups ate any cysteine. And only 0.02% in the diet is able to remove the benefits of MR. So Im increasingly worried about cysteine, since in most of the animals studies on MR, it is 0, which is hard to replicate in humans.
<img src="https://onlinelibrary.wiley.com/cms/asset/5bc56635-0d01-43e0-baf4-fa08c37470ab/acel13629-fig-0001-m.png" alt="Details are in the caption following the image"/>
So continous MR does seem to be quite a bit superior to intermitten MR ,which can also be seen by the other data on liver and hormones in the study.
The longer you restrict methionine, the better.An interesting finding of the study was that alternating high and low methionine days had a similar effect as the 3-4 approach, which underlines the flexibility of this diet.
So if you feel have a good week ,you can have a high protein day once a week and if you have bad week 4 times a week and still get a lot of benefits.<img src="https://onlinelibrary.wiley.com/cms/asset/5bc56635-0d01-43e0-baf4-fa08c37470ab/acel13629-fig-0001-m.png" alt="Details are in the caption following the image"/>Dare to think.
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Cool thread. I’ve been experimenting with high carb/low fat/lowish protein(one protein meal a day probably around 50-60g but haven’t measured). A few things I’ve found:
-to do a low protein/high sucrose diet and still get daily requirements of nutrients, it seems to either require sugar/honey consumption with some nutrient dense foods like milk/liver/meat or copious ripe fruit with some vegetables. For me, I’ve never found the fruit to be great quality in my area so I’ve been trying the former strategy.
-For the sugar diet(not sure what else to call it lol), I’ve found that my gut is exceedingly happy and I’m definitely losing fat. I haven’t noticed any muscle loss, but it is early(2 weeks ish). I also weight lift a few days a week so might have an effect.
-Ive also found that this diet definitely needs more copper/liver consumption. I generally notice I need more copper if I start having histamine reactions to food(copper supplementing relieves this). I don’t tend to eat liver so I’ve been supplementing with 2mg copper daily
-Stabilizing blood sugar is definitely hard with this. I’ve found it has gotten better over time(hopefully it keeps getting even better), but I have to eat often and I find a tiny bit of fat(I use like a quarter teaspoon of higher fat cocoa powder)with the carbs can help prolong satiety.
-I have one meal a day of higher fat and protein for dinner. Definitely have some cravings for it, but that only seems natural as it is the most nutrient dense meal of the day.
-Will update as I go, but this is how I’ve been approaching it so far. -
What Ive been hinting at before: the presence of cysteine restriction in the MR animal studies , but the absence of cysteine restriction in the way we do it and the human studies.
Maybe calling it methionine restriction is misleading and it should be called cysteine restriction!
The authors show that the weight loss benefits require cysteine restricion, not mehionine restricion. So by not restricting cysteine we might not be getting the full benefits."Decreasing the dietary intake of methionine exerts robust anti-adiposity effects in rodents but modest effects in humans. Since cysteine can be synthesized from methionine, animal diets are formulated by decreasing methionine and eliminating cysteine. Such diets exert both methionine restriction (MR) and cysteine restriction (CR), that is, sulfur amino acid restriction (SAAR). Contrarily, SAAR diets formulated for human consumption included cysteine, and thus might have exerted only MR."
This study shows that taurine (another sulfur amino acid) increases the benefits of MR even further. "
NAC on the other removed the benefits of MR.
Just like a small amount of cysteine removed almost all the benefits of MR in this study.
Dare to think.
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@Mauritio said in Methionine/Cysteine restriction increases longetivity AND energy expenditure:
Another interesting find of the above mentioned study is that Cysteine restriction (CR) and not MR, increases a protein called PECK-M by 5-10 times.
This protein has many pro metabolic benefits.
In fact one of the most interesting studies I've ever posted was on transgenic mice that had genetically increased levels of that protein. The benefits of that sound similar to MR/CR, which suggests that many of the benefits of it are due to an increase in PECK-M.These were some of the benefits of over expressing PECK-M in mice:
"The mice were 7-10 times more active !! Beeing able to run 5km at once (a mouse!) They were consuming more food while having less body fat ,which indicates a high metabolism. And they lived almost 2 years longer than normal mice ( normal mice live 2-3 years at max) so they DOUBLED their LIFESPAN !"
That's what I wrote in 2018.These mice also had an extended reproduction window, which is quite interesting because in some experiments life extension comes at the cost of lower reproductive health. So they lived a lot longer and were healthier overall. I've never seen more research on that over the years, yet I've never seen a more robust increase in lifespan in mice in any study.
Edit: just saw that the in the mice they over expressed the mitochondrial and not the cytosolic form of PECK, but i guess their effects are similar
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M Mulloch94 referenced this topic on
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So I can’t help but think that the way to go here might be more about appropriate amino acid supplementation vs restricting the sulphur aminos. I know for instance BCAAs help with tryptophan, but is there anything that “opposes” cysteine? I’ve been looking through pubmed, but nothing as of yet. I did find a few interesting studies however:
https://pubmed.ncbi.nlm.nih.gov/38181033/
Here the expectation was that cystine, (the oxidized form of cysteine) restriction would increase gut permeability, but they found the opposite to be true, and a slight increase in the intestinal mucus lining was observed.
So as my goal is to develop a “reasonable” diet low in these sulfuric aminos, a diet consisting of primarily fruit/juice three days a week remains, (only in my opinion) a relatively simple lifestyle modification, (and possibly sustainable as a result). So my question now is, much like the thread in the old forum about MAP aminos for, (unironically, people with compromised digestion-as low stomach acid and poor enzyme production are very likely lead to poor protein digestion and the inability to break protein down into the aminos needed: hypothyroidism) what if there were an appropriate combination of aminos to add to a three day a week fruit/juice diet? If extra care were taken to select aminos that specifically opposed methionine or cysteine, is it possible that they would further improve the high carb, protein restricted fruit and juice diet?
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@Mauritio said in Methionine/Cysteine restriction increases longetivity AND energy expenditure:
@TexugoDoMel
Thanks! Thats the one I meant.
The results arent as encouriging as I hoped, but still good.They had two Intermittent methionine restricion (IMR) groups, both of them were fed 3 days of a methionine restricted diet followed by a low methionine diet for 4 days in case of IMR1 and a no methionine diet in case of IMR2. They had a continuously methionine restricted diet as a control group
In terms of health effects only IMR2 was really capable of keeping up with continous MR. IMR1 had benefits but not quite as much.
Unforuntely its not really possible for people to have a no methionine diet.
Plus, none of the groups ate any cysteine. And only 0.02% in the diet is able to remove the benefits of MR. So Im increasingly worried about cysteine, since in most of the animals studies on MR, it is 0, which is hard to replicate in humans.  <img src="https://onlinelibrary.wiley.com/cms/asset/5bc56635-0d01-43e0-baf4-fa08c37470ab/acel13629-fig-0001-m.png" alt="Details are in the caption following the image"/>So continous MR does seem to be quite a bit superior to intermitten MR ,which can also be seen by the other data on liver and hormones in the study.
The longer you restrict methionine, the better.An interesting finding of the study was that alternating high and low methionine days had a similar effect as the 3-4 approach, which underlines the flexibility of this diet.
So if you feel have a good week ,you can have a high protein day once a week and if you have bad week 4 times a week and still get a lot of benefits.<img src="https://onlinelibrary.wiley.com/cms/asset/5bc56635-0d01-43e0-baf4-fa08c37470ab/acel13629-fig-0001-m.png" alt="Details are in the caption following the image"/>Considering:
Control - Total methionine availability: 0.86%
MR(continuous) - Total methionine availability: 0.12%
IMR1(4 days 0.86% and 3 days 0.12%) - Total methionine availability: 0.54%
IMR2 and IMR2-A(4 days 0.86% and 3 days 0%) - Total methionine availability: 0.49%And this study in which glycine mimics some of the effects of methionine restriction:
https://faseb.onlinelibrary.wiley.com/doi/abs/10.1096/fasebj.25.1_supplement.528.2I see it differently, especially considering Travis' content from the old forum.
If the goal is to limit methionine in this intermittent style, just eliminating meat and eggs would make it very difficult for you to reach 0.86% on "high methionine days", even with a little meat (unless you overdo it). Most days, even though I like milk and low-fat fish, I don't even reach 0.4% methionine while maintaining more than 1g/kg of protein. So I imagine that on restriction days the effects would be similar even if you didn't consume 0%, but tried to keep it as close to 0 as possible.
Travis said that the reason for restricting methionine is because the amount of methionine reflects the amount of polyamines, which are responsible for proliferation/growth and are generally up-regulated in cancers. I even remember him commenting on a study that just adding polyamines in the presence of stem cells made them differentiate into adipocytes, since polyamines also up-regulate enzymes such as fatty acid synthase, PPAR-gamma, etc.
He also mentioned a way of limiting the use of methionine to create polyamines through substrate competition, which happens when you ingest selenomethionine (supplement or food). The body does not distinguish between methionine and selenomethionine, but selenomethionine cannot be used to create polyamines.
So, in my opinion, the closest thing to simulating studies like this one, even if we don't reach 0% on restriction days, would be:
1- On non-restriction days still restrict consumption of meat and eggs in general so as never to reach 0.86% methionine.
2- On restriction days try to keep as close as possible to 0% methionine, so focusing on fruit and vegetables, tubers and some fats for satiety would be best. To help even more on these days, supplement glycine and selenomethionine (brassicas, such as kale, have a higher concentration of selenomethionine, or take supplements).
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@TexugoDoMel
Good points!
I haven't even calculated the percentage of methionine that I consume. I only went by total protein amount and tried to limit high methionine/Cysteine foods. So it might well be that I'm quite below 0.86% although the "magic number" where benefits appear is around 0.17-0.2% of methionine.BUT: all of that is with 0% Cysteine and that's the issue. As outlined in the posts above if we want to replicate these studies using 0 percent Cysteine, the best we can do is to lower methionine even further, so to mimic a 0.12% methionine + 0% Cysteine diet we have to consume less than 0.12% methionine ,because we do not consume 0% Cysteine and methionine can be converted to Cysteine. I'm not sure how much less we would have to consume, but it might be quite a bit.
I didn't know Travis made comments on protein restrictions, although I vaguely recall that he used to it pretty little protein.
Peat also said that eating muscle meat (which is high in methionine and cysteine) mimics a state of stress in the body, since these are the amino acids that are freed up and metabolized when your body burns your own muscles for energy, in times of starvation.Counterintuitively MR can actually increase polyamine production, maybe that accounts for specific polyamines:
"Similarly, MetR can increase the production of polyamines such as spermidine, which are involved in autophagy."Another way to lower methionine is to decrease its intestinal absorption.
Interestingly long time MR decreases intestinal absorption.
Taurine, arginine and lysine also lower its absorption. So taking taurine at the same time as a high protein meal might be good idea.
Glycine also lowers its absorption. Although it's more true to say that methionine lowers glycines absorption , IIRC up to 86% !"...l-Met uptake is very potently inhibited by l-arginine, l-citrulline, l-lysine and l-isoleucine in the rat intestine 53. "
"Taurine supplementation has also been suggested to reduce Met absorption 55..."
"The rate of absorption of methionine increased in the jejunum after a restricted dietary Intake, a high-protein diet or a high-methionhe diet, but decreased after long-term protein deprivation. Short-term dietary restriction had a similar effect on methionine absorption in jejunum and ileum, though less pronounced in the latter. The rate of absorption of dimethionine was less influenced by dietary changes than that of methionine."
- Effect of dietary changes on intestinal absorption of
L-methionine and L-methionyl-L-methionine in the rat
Dare to think.
- Effect of dietary changes on intestinal absorption of
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@TexugoDoMel said in Methionine/Cysteine restriction increases longetivity AND energy expenditure:
And this study in which glycine mimics some of the effects of methionine restriction:
https://faseb.onlinelibrary.wiley.com/doi/abs/10.1096/fasebj.25.1_supplement.528.2That's an interesting study. 28% increase in life span is pretty good! And that's without restricting methionine. Although 8/12% glycine in the diet is a huge amount that's like 50g of glycine or 150g of gelatin. Not sure how the lower amounts of glycine did.
But I suspect that if you reduce methionine further your glycine requirement might go down as well.
In any case glycine seems to increase the MR benefits.Here is another study on the same type of rats that also used 8% glycine and it only increased lifespan by about 5% .
Dare to think.
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Here's a recent human trial that put obese people on a 8 week low methionine, low cysteine diet. The results are relatively unimpressive. Not sure why . Maybe the amount of M+C was too high (2g/day)?
"Both groups lost weight during the intervention. On average, the SAAR group lost 1.14 kg more body weight compared to controls after 8 weeks (β 95% CI − 1.14 (− 2.04, − 0.25) kg, p = 0.013). No conclusive differences between groups were observed for body fat %."
https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-023-04833-wOn the other hand here is a human study where a similar amount of M+C was shown to be beneficial. The lowest amount came down to 1500-2000mg of cysteine+methionine per day.
Major takeaway for me is: cysteine does matter.
The weight loss in the group lowest in cysteine was 3 times as much as in the group lowest in methionine.Overall a good study design, which kind of corroborates the animal studies, showing that weight loss seems to be dependent on low cysteine, but only low methionine has some benefits as well.
Also the only diet that increased body temp significantly was the diet lowest in cysteine. The low methionine diets were ineffective or even slightly reduced body temp.
https://www.sciencedirect.com/science/article/pii/S1279770723003184#fig1
