Methionine/Cysteine restriction increases longetivity AND energy expenditure

[Ecstatic_Hamster]

@Mauritio Sarcosine seems to be a mixed bag.

https://febs.onlinelibrary.wiley.com/doi/full/10.1002/1878-0261.12439

DNA hypermethylation is one of the most common epigenetic modifications in prostate cancer (PCa). Several studies have delineated sarcosine as a PCa oncometabolite that increases the migration of malignant prostate cells while decreasing their doubling time. Here, we show that incubation of prostate cells with sarcosine elicited the upregulation of sarcosine N-demethylation enzymes, sarcosine dehydrogenase and pipecolic acid oxidase. This process was accompanied by a considerable increase in the production of the major methyl-donor S-adenosylmethionine (SAMe), together with an elevation of cellular methylation potential. Global DNA methylation analyses revealed increases in methylated CpG islands in distinct prostate cell lines incubated with sarcosine, but not in cells of nonprostate origin. This phenomenon was further associated with marked upregulation of DNA methyltransferases (Dnmts). Epigenetic changes were recapitulated through blunting of Dnmts using the hypomethylating agent 5-azacytidine, which was able to inhibit sarcosine-induced migration of prostate cells. Moreover, spatial mapping revealed concomitant increases in sarcosine, SAMe and Dnmt1 in histologically confirmed malignant prostate tissue, but not in adjacent or nonmalignant tissue, which is in line with the obtained in vitro data. In summary, we show here for the first time that sarcosine acts as an epigenetic modifier of prostate cells and that this may contribute to its oncometabolic role.

[Mauritio]

@Ecstatic_Hamster Im not sure about this one.. Here are 2 studies showing no or very little correlation to cancer. And even if they did, correlation ≠ causation. Sarcosine might be an endogenous anti-tumour factor and that could be the reason it' s high.it reduces methionine levels and strongly increases glycine's effects, both causes an anti-tumour effect. And i'm not sure these effects are taken into acc­ount in the in-vitro studies.

"Median sarcosine content in tissue was about 7% higher in matched malignant vs nonmalignant samples, which was significantly. Sarcosine values were not associated with tumor stage (pT2 vs pT3), tumor grade (Gleason score less than 7 vs 7 or greater) or biochemical recurrence. The lack of metastatic tissue samples was a study limitation."
https://pubmed.ncbi.nlm.nih.gov/21168877/

Serum sarcosine is not a marker for prostate cancer
pubmed.ncbi.nlm.nih.gov/20233752/

Here's a good explanation:
https://www.nature.com/articles/nrurol.2011.33

[Mauritio]

This study shows that sarcosine lowers brain serotonin, while increasing GABA.

I took 500mg today. It was quite nice. My mood increased and my muscles looked fuller , also my skin and hair looked better . As if I had taken a big dose of collagen.
So far so good. It wasn't too exciting but it also wasn't sedating so actually a nice balance.

"Pretreatment of sarcosine (600 mg/kg, i.p.) non-significantly improved learning and memory deficits induced by non-competitive NMDA receptor antagonist MK-801, significantly increased the GABA and decreased the 5-HT levels (p<0.05)."
https://pubmed.ncbi.nlm.nih.gov/25710578/

[Ecstatic_Hamster]

@Mauritio said in Methionine/Cysteine restriction increases longetivity AND energy expenditure:

This study shows that sarcosine lowers brain serotonin, while increasing GABA.

I took 500mg today. It was quite nice. My mood increased and my muscles looked fuller , also my skin and hair looked better . As if I had taken a big dose of collagen.
So far so good. It wasn't too exciting but it also wasn't sedating so actually a nice balance.

"Pretreatment of sarcosine (600 mg/kg, i.p.) non-significantly improved learning and memory deficits induced by non-competitive NMDA receptor antagonist MK-801, significantly increased the GABA and decreased the 5-HT levels (p<0.05)."
https://pubmed.ncbi.nlm.nih.gov/25710578/

thank you -- great find.

[Kat]

This post is deleted!

[Mauritio]

T3 blocks mTOR.

"T3 also decreased amino acid levels, and in conjunction with SIRT1 activation, decreased MTOR activity to stimulate autophagy"
https://pubmed.ncbi.nlm.nih.gov/30209975/

[albion]

This post is deleted!

[albion]

@LucH said in Methionine/Cysteine restriction increases longetivity AND energy expenditure:

Selenium administration resulted in a marked decrease in the activity levels of the liver succinate dehydrogenase, malate dehydrogenase, and lactate dehydrogenase while pyruvate dehydrogenase increased significantly.
2) http://www.hc-sc.gc.ca/ewh-semt/pubs/water-eau/selenium/index-fra.php

Here's what the link says:

"In addition, organic and inorganic forms of selenium can interact with sulfur of sulfhydryl groups, groups having a crucial role in proteins and other molecules, such as glutathione (Spallholz, 1997). This interaction may also lead to the formation of reactive intermediate compounds, such as selenosulfides and methylselenide, which react with other thiols to decrease glutathione both in vitro and in vivo in animals, then a production of superoxide anion and hydrogen peroxide (Spallholz, 1997; Nogueira and Rocha, 2011; Zhang and Spallholz, 2011). Selenium therefore inhibits enzymes containing thiol, such as methionine adenosyltransferase, succinate dehydrogenase, lactate dehydrogenase and NADP+-isocitrate dehydrogenase (Mézes and Balogh, 2009). The decrease in the amount of antioxidant proteins containing thiol can also result in an indirect production of reactive oxygen derivatives (Mézes and Balogh, 2009). The increase in reactive oxygen derivatives can induce a cascade of events, including lipid peroxidation, DNA damage and a loss of membrane integrity and permeability (e.g. organelet membrane), leading to the release of lysosomal enzymes and tissue necrosis (Mézes and Balogh, 2009)."

"According to another theory on the mechanism of toxicity, high concentrations of selenium would lead to the replacement of sulfur by selenium (Letavayová et al., 2006). For example, selenium could be responsible for the absence of sulfur in amino acids, for example in the sulfhydryl groups of glutathione, crucial groups participating in antioxidant defense (Pickrell and Oehme, 2002). This type of replacement can inhibit protein synthesis and the activity of DNA-repairing proteins."

I'm skeptical. Selenium in physiological doses seems to increase, not decrease, Glutathione activity.

I don't like this part, though:

"It has been hypothesized that the increased risk of diabetes resulting from a high selenium intake is caused by excessive antioxidant activity (Steinbrenner, 2011). The latter would result in the elimination of hydrogen peroxide, which normally acts as an intermediate (second messenger) in the mechanism of insulin secretion by the pancreas and in the transmission of signals after the binding of insulin to its receptor. This is why the high concentrations of antioxidants induced by selenium may have reduced insulin sensitivity."

[LucH]

@albion said in Methionine/Cysteine restriction increases longetivity AND energy expenditure:

I'm skeptical. Selenium in physiological doses seems to increase, not decrease, Glutathione activity.

I don't like this part, though:

"It has been hypothesized that the increased risk of diabetes resulting from a high selenium intake is caused by excessive antioxidant activity (Steinbrenner, 2011).

1. 55 mcg Se are required. more in case of detox (thiol pathway) 200 mcg.
   Exceptionally 400 mcg at the beginning of poison attack. So, not as usual / prolonged dose.
   The problem is to agree on physiological needs.
2. And yes, if selenium takes the place of bonds devoted to sulfur, we are going to have problems. It's a question of time and amount.
   If you get problems with sulfur, you'll get problem with methylation. Havoc in view. I can give a link if desired (Excess oxalate => sulfur needed => methylation problem => Havoc).
3. Never heard that too much of a good thing is bad?
   Selenium has also an anti-oxidant activity.
   I haven't explored the action deeply on insulin secretion / sensitivity but in the word antioxidant, there is the prefix anti-. Would be better to see further *1
   But you aren't going to suffer from excess if you take 100 mcg Se in cure or 3 times a week.
   I'm not trying to convince you - since you didn't justify / explain your point of view.

*1 For other readers (SE AND INSULIN RESISTANCE)
This study says Se role is controversial in DT2.
While Se supplementation is not associated with a risk of T2DM in individuals with low concentrations or in individuals maintaining the recommended nutritional dose, excessive long-term Se exposure has been shown to increase the risk of T2DM due to excessive GPx1 activity[64] and a consequent impairment of insulin sensitivity[57] (Figure 1).
World J Diabetes. 2023 Mar 15;14(3):147–158. doi: 10.4239/wjd.v14.i3.147

57. https://pmc.ncbi.nlm.nih.gov/articles/PMC10075028/#B57
    -,
    ref64 DOI: 10.1055/s-0043-119544

[albion]

@LucH Yes it seems dosage matters a lot with selenium. This tracks with personal experience as well—euphoria on initial dosing, then a slight "film" over consciousness develops if repeated over >4 days consecutively.

[serotoninskeptic]

@Mauritio Look into @anabology's posts on FGF21 and the "honey diet." The idea is intermittent protein restriction from morning until dinner eating just fruit, sugar, honey etc. Then meeting your protein requirements at dinner, getting like 1g-1.2g/kg of protein total. Tons of people are getting great results from it including myself. You can read more on his X account and longestlevers.com.

[Mauritio]

@Serotoninskeptic thanks! That's basically what I've been doing for a while now. I posted a study showing benefts of MR after Just 6h! So if you only eat signifi­cant amounts of protein in the evening you have an18h window of "benefits". Intermittent protein fasting.

I feel bad for the normal person they've just adapted to high protein being healthy and now this...

[serotoninskeptic]

@Mauritio Nice, yeah i think this is definitely the most effective and safest way to go about restricting protein. Instead of restricting total protein very low like Ray did in his later years you can instead have periods of fasting from protein while still meeting your protein requirements overall.

[Ecstatic_Hamster]

We’re taking a 200 µg dose every other day be reasonable? It’s difficult to get anything but 200 µg dose.

[Mauritio]

That's what I ve been suspecting. There is a threshold for the benefits. There is a subjective switch that I feel when Im on MR.
This implies that until the threshold there is no harm and after the threshold the harm increases disproportionetly from consuming excess methionine. That is the problem with the intermittent approach @Serotoninskeptic . I think it is a good idea to limit protein to one meal mostly, but overall protein intake shouldnt exceed 40-70g for most people. Thats at least my current opinion.

This is from Peats last Newsletter. His last gift to us.

"There is a threshold effect in exposure to
the harmful amino acids, and this involves a
very sensitive system for detecting their concentration, apparently involving the actin filament network throughout the body. Above
the threshold concentration, methionine
activates mTOR. Increased mTOR shortens
life-span and increases the processes of aging.
Increased fat in the diet increases mTOR,
adding to the effects of amino acids. "

"The way these regulators of energy and
aging interact is holistic, and it’s necessary to
understand that organisms make generaliza￾tions about their problems. Things that inhibit
mTOR will increase adaptation and organiza￾tion with expansion of the time horizon, while
things that activate it (methionine, estrogen,
radiation) will accelerate cell growth and
inflammation and activate terminal processes.
Progesterone and estrogen relate to the degree
of mTOR activity through the body as a
whole, not just through a series of receptor
intermediates."

[serotoninskeptic]

@Mauritio Yeah this makes sense. Also in the later years of his life Ray clarified that 100g+ would only be useful for an active young person with a 4-5k calorie metabolism. So, the needs decrease with aging as well as with slower metabolism, and activity level. Someone like me who is young in my 20s and active, lifting weights and maintaining at 3.5k-4k calories. I might need close to 100g or more but intuitively I tend to be around 80-100g and don't really go over that. Im still able to build muscle on this amount.

[Mauritio]

@Serotoninskeptic yes! He never gave out a recommendation to eat just 50g of protein. It's context specific.
For someone like you it might indeed be necessary to get more than 70g of protein.
I intuitively eat 60-80g if I don't restrict myself.
But I feel like the "threshold" is lower for me. I only feel the switch when I'm around 40-50g per day.

[serotoninskeptic]

@Mauritio Yeah I even noticed a huge boost in metabolism and overall energy going from eating 150-200g down to around only 80-100g and increasing my carb intake even further. Most muscle building benefits stagnate around 1g/kg or 1.2g/kg of body weight.

[Mauritio]

@Serotoninskeptic And muscle building isn't everything, maybe one can build a little more muscle on a way higher P-diet, but at what cost?

[Mauritio]

@Serotoninskeptic said in Methionine/Cysteine restriction increases longetivity AND energy expenditure:

@Mauritio Look into @anabology's posts on FGF21 and the "honey diet." The idea is intermittent protein restriction from morning until dinner eating just fruit, sugar, honey etc. Then meeting your protein requirements at dinner, getting like 1g-1.2g/kg of protein total. Tons of people are getting great results from it including myself. You can read more on his X account and longestlevers.com.

I finally had some time to look into it and I'm on board with most of it. But are you really eating massive amounts of protein with little to no carbs? Sounds like a recipe for high cortisol especially so close to bedtime (no carbs for the next 8h).
I think if you kept carb intake throughout the day that would be a better idea.