Methionine/Cysteine restriction increases longetivity AND energy expenditure
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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
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@Mauritio said in Methionine/Cysteine restriction increases longetivity AND energy expenditure:
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.
You mentioned that 0.02% cysteine would already abolish these effects of MR, I think I missed it, I couldn't find the info. I found 0.5% and the minimum I found similar to what you said was 0.2%.
The intermittent restriction I mentioned I did a long time ago, I think my calculations at the time didn't even reach 0.1% cysteine (I think it was close to 0.07%? I don't remember).
That'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.
The aim is not to ingest the same amount, but to potentiate MR with a higher dose of glycine since it is impossible to simulate without a diet similar to the one in the laboratory.
There seem to be some studies on BCAA restriction having similar effects in relation to FGF21, there's even a study mentioning the relationship between BCAA and methionine
I didn't know about taurine, some people say that aspirin also blocks some of the absorption of methionine but I've never seen anything about it.
M and CysR+glycine+selenomethionine+taurine still seems to be the closest way to simulate these studies.
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@TexugoDoMel said in Methionine/Cysteine restriction increases longetivity AND energy expenditure:
You mentioned that 0.02% cysteine would already abolish these effects of MR, I think I missed it, I couldn't find the info. I found 0.5% and the minimum I found similar to what you said was 0.2%.
Sorry , I meant 0.2% ! Thanks for the correction .
@TexugoDoMel said in Methionine/Cysteine restriction increases longetivity AND energy expenditure:
The intermittent restriction I mentioned I did a long time ago, I think my calculations at the time didn't even reach 0.1% cysteine (I think it was close to 0.07%? I don't remember).
Interesting , I'll do the calculation on that soon, too.
@TexugoDoMel said in Methionine/Cysteine restriction increases longetivity AND energy expenditure:
There seem to be some studies on BCAA restriction having similar effects in relation to FGF21, there's even a study mentioning the relationship between BCAA and methionine
I didn't know about taurine, some people say that aspirin also blocks some of the absorption of methionine but I've never seen anything about it.
M and CysR+glycine+selenomethionine+taurine still seems to be the closest way to simulate these studies.
Interesting so even more amino acids to avoid. Tryptophan, Cysteine, Methionine, BCAAs.
Glutamine and aspartic acid are other candidates,too.Peat was wondering about histidine as well.
"Histidine is another amino acid precursor to a mediator of inflammation, histamine; would the restriction of histidine in the diet have a longevity promoting effect, too?"
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"The few studies that have been done indicate that the requirements for tryptophan and cysteine become very low in adulthood."
'Histidine is another amino acid precursor to a mediator of inflammation, histamine; would the restriction of histidine in the diet have a longevity promoting effect, too?"
"When only the muscle meats are eaten, the amino acid balance entering our blood stream is the same as that produced by extreme stress, when cortisol excess causes our muscles to be broken down to provide energy and material for repair."
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Both methionine and cysteine are used by the body to grow hair. I wonder if going very low would result in hair loss. How are the met/cys-restricted rodents looking in terms of fur?
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@TexugoDoMel said in Methionine/Cysteine restriction increases longetivity AND energy expenditure:
The intermittent restriction I mentioned I did a long time ago, I think my calculations at the time didn't even reach 0.1% cysteine (I think it was close to 0.07%? I don't remember).
I calculated the amounts I eat at the moment and it comes down to both aorund 600mg of methionine and cysteine, which is exactly 0.12% of a 2000kcal diet, so Im spot on.
You could also use the 10.4mg/kg/d of the above mentioned human study, which was the most effective dose, which would give most people around 600-1000mg of cysteine and methionine per day each.
I have no idea how you would get to 0.07% , because this is definitely me trying. Like I only eat around 15g of cheese per day as a treat lol.
What saves me diet wise is ice cream. I found some flavors with less than 2g of protein per 100g and one even 0.8g/100g. Meat cravings are going down, but it does get tiresome to almost only eat sweet stuff.
Dare to think.
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@revenant
I found this study showing that a methionine-choline deficient diet led to hair loss in mice and methionine was able to restore it.However i coud not find a mention in any of the other studies the mice/rats experiencing hair loss.
I think in the douzens of studies that have been done on MR over the years, they would have noticed and mentioned hair loss as a side effect.
In longevity studies they often include pictures, so it should be easy to verify this ...
unfortunately I couldn't find the concentration of methionine in the study below.Personally I can say that at the beginning I experienced a lot less hair loss, then I did one high protein day and ever since that hair loss is back to normal / not better. Not sure why...
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@Mauritio said in Methionine/Cysteine restriction increases longetivity AND energy expenditure:
@TexugoDoMel said in Methionine/Cysteine restriction increases longetivity AND energy expenditure:
The intermittent restriction I mentioned I did a long time ago, I think my calculations at the time didn't even reach 0.1% cysteine (I think it was close to 0.07%? I don't remember).
I calculated the amounts I eat at the moment and it comes down to both aorund 600mg of methionine and cysteine, which is exactly 0.12% of a 2000kcal diet, so Im spot on.
You could also use the 10.4mg/kg/d of the above mentioned human study, which was the most effective dose, which would give most people around 600-1000mg of cysteine and methionine per day each.
I have no idea how you would get to 0.07% , because this is definitely me trying. Like I only eat around 15g of cheese per day as a treat lol.
What saves me diet wise is ice cream. I found some flavors with less than 2g of protein per 100g and one even 0.8g/100g. Meat cravings are going down, but it does get tiresome to almost only eat sweet stuff.
Fruit, lots of potatoes, coconut, butter, rice, a bit of sugar... I don't have many cravings and I like potatoes a lot, so it's easy for me to stick to them, even on workout days.
But I haven't done continuous MR for a long time, I prefer intermittent MR, even if it's not as efficient, because I don't need to lose weight.
The only difference is that my calories are almost twice as much as yours hence the impact on the percentage
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@TexugoDoMel cool, potatoes really are a great food. Surprisingly low in C+M .
Do you notice a shift when you are doing C+M restriction? For me there's a noticable difference it's just hard to put the finger on what it is.
What cycle are you doing ATM? -
Here is another very interesting mouse study on MR/CR.
Mice on MR were resistant to weight gain, hepatic steatosis and insulin resistance on a high fat diet, despite the mouse strain being especially susceptible to obesity. And despite the fact that the mice were eating more and had better absorption of food.
Their hormone levels were altered. FGF21 was increased 16 fold. And leptin was decreased by 95%, so the mice were really leptin and thus insulin sensitive.
As can be seen in the image below, SCD1 decreased a lot. SCD1 converts saturated fatt acids into unsaturated fatty acids. So through restricting methionine you indirectly lower PUFA in your body. High SCD1 is also implicated in all kinds of diseases, so lowering it will be healthy overall.
As usually mice on MR show lower bone density . And
"...levels of the collagen degradation marker, CTX-1, were significantly higher in the MR animals on HFD by 83%..." . So it seems like their body was trying to get more collagen from their bones , possibly as a reaction to the low protein consumption overall. Which leads me to speculate that you could prevent the bone loss through a generous dietary supply of collagen/ gelatin . -
@Mauritio FWIW I notice that the methionine content of the cheeses correlates pretty well with the protein content.
https://fitaudit.com/categories/mlk/protein -
@annis good point. That makes sense and is more practical.
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@revenant said in Methionine/Cysteine restriction increases longetivity AND energy expenditure:
Both methionine and cysteine are used by the body to grow hair. I wonder if going very low would result in hair loss. How are the met/cys-restricted rodents looking in terms of fur?
These last days since your message I have noticed a lot more hairs in my sink and I couldn't attribute it to anything else than my diet change.
So today i had the first normal protein day for the first time in like 10 days. And I already notice less hair loss, so there seems to to be a connection.
I did not eat a lot more protein, so maybe there is a dose resembling a compromise between minimal hair loss and maximal metabolic benefits.
The intermittent approach might help out here as well.I also seem to be have lost my desire for meat or at least it decreased. In the last 10 years there wasn't a week where I didn't eat meat, probably not even 3 days in a row. But now I don't crave it much anymore, even a good boar bratwurst didn't seem so appealing to me anymore. I still crave milk protein though .
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Another reason to supplement taurine on MR.
Not only does it lower methionine absorption, but it is drastically reduced in livers on MR."Thus, MR caused a 20-fold downregulation of taurine in WT and an 11-fold downregulation in LmnaG609G/G609G livers..."
Another thing that i personally noticed is that MR seems to have an effect on bile. This study shows that bile acids are changed, for example cholic acid is drastically increased.
The enzyme Cyp39a1 was increased on MR, which is an alternative pathway for bile acid synthesis, suggesting that the primary pathways are downregulated somehow .
Another interesting observation was that MR decreased hair loss in a model of accelerated aging mice.
"Despite their reduced size (Figure 6A), Zmpste24−/− MR mice had a 21% increase in median survival and an almost 28% increase in maximal survival (Figures 6B and S6A) and showed a healthier aspect, mostly apparent by a reduced loss of hair and improved atrophy of hindlimbs (Figures 6C and S6B)."
