232 replies to this topic

[Chris Edited]

My own n1 personal experience:

 

For the past two years I've been eating a low protein vegan diet and I am also a regular user of topical tazarotene. Last night I took 10g glycine before bed and applied tazarotene as usual. Upon waking up I discovered a very significant increase in skin exfoliation. I was worried for some time that I was not responding to tazarotene since I hardly ever peel following use. However what I saw this morning was dramatic, I didn't even know that my face was capable was shedding that much skin. 

 

My hypothesis is that glycine supplementation satisfied my skins requirement for collagen production. The paper by Meléndez-Hevia E et al. (2009), which Darryl referenced seems to support this.  

 

Did you have to gradually elevate your L-Gl;ycine dose to get to 10g?

 

Even 3 g has a  heavy tranquilizing effect on me leaving me feeling rather uncomfortably sedated.. actually allowed a lucid dream the first night I took 3 g before going to bed but I  am not so tranqued during the day with  around 2 g .

 

 

Edited by Chris Edited, 26 June 2015 - 04:10 PM.

[Kevnzworld]

I noticed that Glycine is included in the NIH's ITP study, cohort 10 begun in 2014 so we should know more in a year or two given the mice started supplementation at nine months

Cohort 10: C2014
Compound Concentration in food Age at treatment initiation
Supplemental glycine
80,000 ppm
9 months

https://www.nia.nih....mpounds-testing

[Phoenicis]

 

My own n1 personal experience:

 

For the past two years I've been eating a low protein vegan diet and I am also a regular user of topical tazarotene. Last night I took 10g glycine before bed and applied tazarotene as usual. Upon waking up I discovered a very significant increase in skin exfoliation. I was worried for some time that I was not responding to tazarotene since I hardly ever peel following use. However what I saw this morning was dramatic, I didn't even know that my face was capable was shedding that much skin. 

 

My hypothesis is that glycine supplementation satisfied my skins requirement for collagen production. The paper by Meléndez-Hevia E et al. (2009), which Darryl referenced seems to support this.  

 

Did you have to gradually elevate your L-Gl;ycine dose to get to 10g?

 

Even 3 g has a  heavy tranquilizing effect on me leaving me feeling rather uncomfortably sedated.. actually allowed a lucid dream the first night I took 3 g before going to bed but I  am not so tranqued during the day with  around 2 g .

 

 

I actually didn't titrate my dose gradually, since I really wanted to see whether 10g would produce any effects. In hindsight I'll probably need to take it for a much longer period to make out any changes. The first night I didn't notice any sedation, but yesterday I took another 10g during the day and felt tired in the evening and upon waking up this morning. I did however notice positive improvement in my mood.

 

I've been reading through some studies on glycine and growth hormone ("GH") since I'm trying to find the optimal dose for MR. It looks like the stimulatory effects on GH are dose dependant.

• Kasai, K. (1980) et al. Glycine stimulated growth hormone release in man. Acta Endocrinol (Copenh). 1980 ;93(3):283-6:

Found a significant increase in GH -

4g - 0.05 P

8g - less than 0.001 P

 

The most prfound increase was after

12g - less than 0.001P

 

I also found an anomaly in:

• Brind, J. et al. (2011). Dietary glycine supplementation mimics lifespan extension by dietary methionine restriction in Fisher 344 rats. FASEB Journal;25:528.2

I was unable to locate a full text copy of this article, however the abstract does note something significant. Glycine supplemented rats showed a decrease in fasting glucose, insulin, IGF-1, and triglycerides. However glycine supplemented rats did not show the same increase in apidonectin as seen in MR rats.

 

So overall this sounds ok, but I think it is essentail to narrow down on the correct dose. I wonder why apdonectin was was not increased in the glycine groups, could an increase in GH be intereferng with some of the benefits? Perhaps a better approach would be to combine MR with lower doses of glycine.

 

As Junnilav, RK et al. (2013) point out, increases in GH are normally accompanied by increases in IGF-1 levels. See:

• Junnilav, RK et al. (2013). The GH/IGF-1 axis in ageing and longevity.Nat Rev Endocrinol. 2013 Jun;9(6):366-76.

A few other points to note, Junnilav, RK et al. (2013) state that lower GH/IGF-1 levels are associated with increased longevity in mice. Another study by Cheng, C. et al. (2014) showed that the beneficial effects of prolonged fasting on stem cell regeneration are blocked  by IGF-1/PKA. See:

• Cheng, C. et al. (2014). Prolonged Fasting Reduces IGF-1/PKA to Promote Hematopoietic-Stem-Cell-Based Regeneration and Reverse Immunosuppression. Cell Stem Cell. Volume 14, Issue 6, p810–823.

On the other hand we know that older individuals (over 60 years) have only low levels of GH (Junnilav, RK et al. (2013)), so perhaps we could ask whether higher doses of glycine would be appropriate for them. That hypothesis seems to be supported by findings of this study:

• Levine, M. et al. (2014). Low Protein Intake Is Associated with a Major Reduction in IGF-1, Cancer, and Overall Mortality in the 65 and Younger but Not Older Population

I was a little worried about a link between cancer and glycine after coming accross some studies indicating that glycine restricition may be useful for cancer patients. However this recent study appears to show that glycine does not support cancer cell proliferation, wheras serine does:

• Labuschagne, C. et al. (2014). Serine, but not glycine, supports one-carbon metabolism and proliferation of cancer cells. Cell Rep. 2014 May 22;7(4)

As a guy in my 20s eating a vegan low methioine diet, I think I'll go with 3g glycine before bed. I believe the increase in GH is dose dependant, so I'm aiming for a low dose that will increase the efficiency of MR.

 

I am now curious as to whether arginine is sufficinetly available in both vegan and omnivore diets and what effect its supplementation has on the GH IGF-1 axis, as well as creatine biosynthesis. As mentioined in my first post, Tang et al. (2015) show that the AAR and creatine biosynthesis can be interrupted by low levels of glycine and arginine.

Edited by Phoenicis, 27 June 2015 - 03:08 PM.

[Phoenicis]

I think I may have found some information that explains the decrease in IGF-1 levels in Brind, J. et al. (2011)'s glycine supplemented rats. It appears that glycine stimulates glucogen production, but this effect is opoposed by also ingesting glucose:

• Gannon, M. et al. (2002). The metabolic response to ingested glycine. Am J Clin Nutr. vol. 76 no. 6 1302-1307

It should also be noted that Brind, J et al. (2011) noted decreases in glucose and insulin, wheras Gannon, M. et al. (2002) found that glycine supplementation increased insulin modestly, but not glucose. Glycine also delayed increases in insulin after glucose administration and modestly lowered the overall amount of insulin. Gannon, M. et al (2002) note that glycine accelarated glucose clearance.

 

This study is very interesting:

• McCarty, MF. (1999).Vegan proteins may reduce risk ofcancer, obesity, and cardiovasculardisease by promoting increased glucagon activity. Medical Hypotheses(1999)53(6), 459–485

McCarty, MF. (1999). argues that increased glucagon production has insulin sensitizing properties. Essentally he argues that glucagon has the following impact on the liver:

1. increased CaMP activity and PKA
2. suppression of anabolic activities
3. increased fatty acid oxidation, ketone production
4. upregulation of IGFBP-1, which sequesters unbound insulin like growth factor (IGF-1) and blocks its activity.

While reductions in IGF-1 sounds good, inductions of CaMP and PKA would seem bad, since Cheng, C. et al. (2014) seem to show that the beneficial effects of prolonged fasting on stem cell regeneration are blocked by PKA, as well as IGF-1. Nonetheless increased glucagen could explain why Brind, J. et al. (2011)'s glycine supplemented rats had low IGF-1 levels.

 

The question that remains for me is how much glycine is best for making MR more efficient, while not stimulating GH and PKA excessively? It also appears that glucose should be avoided, as this would according to Gannon, M. et al. (2002) attenuate glucogen production.

 

 

Edited by Phoenicis, 27 June 2015 - 04:17 PM.

[Saintless]

Apparently drinking chamomile tea can increase urinary glycine levels. Chamomile decreases risk of death for MA women. Apologies in advance for being slightly off topic on the 2^nd study.

 

 

“Drinking the tea also was associated with an increase in urinary levels of glycine….Levels of both hippurate and glycine remained elevated for up to two weeks after the study participants stopped drinking the tea.”

 

http://www.scienceda...50104112140.htm

 

“The data showed that consuming chamomile was associated with a 29 percent decreased risk of death from all causes among women compared with nonusers, even after adjusting for demographics, health conditions and health behaviors. This effect was not present in men.”

"The reason for a difference in our reported findings between Hispanic women and men is not clear, although women were shown to be more frequent users of chamomile than men,"

http://www.scienceda...50520160312.htm

[Phoenicis]

Coming back to the orginal study that inspired this post:

• Hashizume O. et al. (2015): Epigenetic regulation of the nuclear-coded GCAT and SHMT2 genes confers human age-associated mitochondrial respiration defects.Nature Scientific Reports 5, Article number:10434.

I did find another study that could shed further light on (Pai, JP. et al. (2015) findings:

• Pai, JP. et al. (2015). Glycine decarboxylase deficiency causesneural tube defects and features of non-ketotic hyperglycinemia in mice. Nature Communications. 6:6388.

Pai, JP. et al. (2015). found that mice deficient in glycine dehydrogenase ("GLDC") in their mitochondria develop a disease called "non-ketotic hyperglycinemia (NKH)". GLDC is responsible for decarboxylating glycine and donating a one-carbon unit into one carbon metabolism (Pai, JP. et al. (2015)). The interesting theme that seems to be emerging here is epigenetics. One carbon metabolism plays an important role in the methylation cycle and DNA methylation.(Pai, JP. et al. (2015) While mutations like those studied by Pai, JP. et al. (2015) seem to be quite rare, they could also demonstrate the important role for dietary gycine in maintaining one carbon metabolism and DNA methylation. For example, Pai, JP. et al. (2015) show that GLDC mutants have "abnormal tissue folate profiles". The researcher say that this effect is likely explained by disturbances in one carbon metabolism, where folic acid cannot be efficiently converted in 5MTF folate (Pai, JP. et al. (2015)). Since the majority of the population seem to be concuming foods fortified with folic acid, rather than 5MTF folate, this could be an issue. To further complicate things we also know that MTHFR gene mutations are present in some individuals, who would be especially vulnerable.

 

Hashizume O. et al. (2015) seem to show that GLDC was downregulated in the mRNA of elderly subject, resulting in respiration defects. NKH, as examined by Pai, JP. et al. (2015) results in impaired nucleotide synthesis and at least one other study has linked this trait to impaired mitochondrial respiration.[1] While this could be a stretch, one might speculate that low glycine levels and GLDC mutations could have some simularities.

 

The thing that most interests me is the fact that the methylation cycle appears to be strongly affected by glycine; both as a one-carbon donator and as an essential element in creatine biosythesis (Tang et al. (2015)). These effects appear to be opposite in nature, since glycine can both promote methylation via one carbon metabolism (Hashizume O. et al. (2015)) and mediate SAM reductions via creatine biosynthesis (Tang et al. (2015)). I am beginning to sound like broken record player, but I wonder what effects, if any, folate (5mtf), methyl-b12 and b6 have on methioine restriction.

 

[1] Gatterman, N. et al. (2004), Severe impairment of nucleotide synthesis through inhibition of mitochondrial respiration. Nucleosides Nucleotides Nucleic Acids. 2004 Oct;23(8-9):1275-9.)

 

 

 

 

 

 

 

Edited by Phoenicis, 28 June 2015 - 10:57 PM.

[Phoenicis]

Apparently drinking chamomile tea can increase urinary glycine levels. Chamomile decreases risk of death for MA women. Apologies in advance for being slightly off topic on the 2^nd study.

 

 

“Drinking the tea also was associated with an increase in urinary levels of glycine….Levels of both hippurate and glycine remained elevated for up to two weeks after the study participants stopped drinking the tea.”

 

http://www.scienceda...50104112140.htm

 

“The data showed that consuming chamomile was associated with a 29 percent decreased risk of death from all causes among women compared with nonusers, even after adjusting for demographics, health conditions and health behaviors. This effect was not present in men.”

"The reason for a difference in our reported findings between Hispanic women and men is not clear, although women were shown to be more frequent users of chamomile than men,"

http://www.scienceda...50520160312.htm

 

The researchers seem to point to glycine as a beneficial AA for these woman, I wonder if chamomile upregulates glycine biosynthesis. It is said to have sedatory effects as well!

Edited by Phoenicis, 28 June 2015 - 10:49 PM.

[larrgus]

If you are interested go to youtube and search for glycine and inflammation. There is a 3 part video of a doctor who talks about

glycine, methionine and inflammation. According to him 8 grams is the best dose and he said that the reason for too much inflammation

is because people lack glycine because they do not eat whole meat anymore only the muscle but no cartilage and because of this they lack

glycine. He also talks about glycine and heart diseases. It sounds as if glycine is a miracle substance which fixes all kinds of issues caused

by inflammation.

[ClarkSims]

I think I found a major problem with extrapolating the results of the Hashizume study to diet recommendations for humans.

 

From the study: "Glycine (140 μM) was included in the medium for 10 days before the estimation of O

2

consumption rates."   http://www.nature.com/srep/2015/150522/srep10434/extref/srep10434-s1.pdf

 

the baseline concentration of glycine in human plasma is about 220 micro molar. After supplimentation it goes to 900 micro molar. http://ajcn.nutrition.org/content/76/6/1302.full

 

After the ingestion of glycine, the plasma glycine concentration increased from a baseline of 217 ± 21 μmol/L to a peak of 909 ± 106 μmol/L at 40 min, after which it decreased toward the fasting baseline. At the end of the study, however, the plasma glycine concentration was still elevated (414 μmol/L).

 

So if 140 micro molar solutions of glycine improved mitochondrial health, we would all have healthy mitochondria.

 

*sigh*

 

I was so hopeful when I read the study, I think this undermines the premise.

 

Does anyone have any thoughts?

[Phoenicis]

It probably depends upon whether one's seeking reduced homocysteine, effective methionine restriction, or other benefits. In Fukada SI et al 2008, the control rats consumed 0.8% (wt/wt) Met diets, while those with experimental hyperhomocysteinemia consumed 1.8% Met, so between 0.8% and 1.8% (range likely depends on other amino acid intake), the ability to regulate Hcy was overwhelmed. Supplemental intake of 2.5% glycine or serine (beyond the 1.8% Gly + Ser in the base diet) largely eliminated the Hcy elevation. For supplementation to reduce Hcy, perhaps 2 or 3:1 supplemental glycine/excess dietary methionine (wt/wt) is a useful target. On the other hand, Brind J et al. 2011 found roughly 28% lifespan extension with 8% Gly in a 0.43% Met diet (18:1), but didn't think their 4% Gly diet (9:1) results were worth mentioning in their poster abstract.

 

My own decision to opt for 1 heaping tsp (~6 g) is influenced mostly by Meléndez-Hevia E et al. 2009, which calculated a daily glycine deficit of –8.5 to –10 g/day. My supplementation is in the context of a barely methionine adequate lower-protein vegan diet (I'd shift to higher protein if I were 65+ yo).

 

Hey Darryl, any chance you elaborate on how one would calculate excess methioine? I also found a paper about creatine biosynthesis that references Meléndez-Hevia E et al. (2009):

• Brosnan, JT. et al. (2011).The metabolic burden of creatine synthesis. Amino Acids;40(5):1325-31.

The paper essentially agrees with Melendez-Hevia E et al. (2009)'s finding that glycine biosynthesis may not be adequate to maintain sufficient levels for creatine biosynthesis, especially in vegans. I wonder if glycine supplementation would help to main higher levels with creatine supplements? One could imagine that MR would make methioine availability a bottleneck in creatine sythesis. I did read that creatine supplementation shuts down biosynthesis, but cant remember where.

 

I think I found a major problem with extrapolating the results of the Hashizume study to diet recommendations for humans.

 

From the study: "Glycine (140 μM) was included in the medium for 10 days before the estimation of O

2

consumption rates."   http://www.nature.com/srep/2015/150522/srep10434/extref/srep10434-s1.pdf

 

the baseline concentration of glycine in human plasma is about 220 micro molar. After supplimentation it goes to 900 micro molar. http://ajcn.nutrition.org/content/76/6/1302.full

 

After the ingestion of glycine, the plasma glycine concentration increased from a baseline of 217 ± 21 μmol/L to a peak of 909 ± 106 μmol/L at 40 min, after which it decreased toward the fasting baseline. At the end of the study, however, the plasma glycine concentration was still elevated (414 μmol/L).

 

So if 140 micro molar solutions of glycine improved mitochondrial health, we would all have healthy mitochondria.

 

*sigh*

 

I was so hopeful when I read the study, I think this undermines the premise.

 

Does anyone have any thoughts?

 

Thats a good point, but I wonder how transferable plasma concentration would be to those in organs and muscle? I also found this slightly dissapointing study about amino acid acid supplements done on worms:

• Edwards, C et al. (2015). Mechanisms of amino acid-mediated lifespan extension in Caenorhabditis elegans. BMC Genetics 2015, 16:8

I honestly dont understand the results of that study since glycine actuallly shorten worm lifespand, whereas serine, proline, and tryptophan extended it. But given the positive studies on glycine, this simply does not make sense to me. I recently read a really interesting open access review on fasting that clearly states that tryptophan restriction also extends life:

• Longo VD and Mattson MP (2014). Fasting: molecular mechanisms and clinical applications.Cell Metab. 2014 Feb 4;19(2):181-92.

Edited by Phoenicis, 02 July 2015 - 08:02 PM.

[Darryl]

Hey Darryl, any chance you elaborate on how one would calculate excess methioine? 

 

I wonder if glycine supplementation would help to main higher levels with creatine supplements? One could imagine that MR would make methioine availability a bottleneck in creatine sythesis. I did read that creatine supplementation shuts down biosynthesis, but cant remember where.

 

I use the WHO's estimated requirement:

 

10 mg/kg/d methionine: 

15 mg/kg/d methionine + cysteine

 

The later makes more sense, dietary cysteine spares methionine requirements. My diet as an omnivore was around 250-300% of requirements, my current vegan diet is around 150%. Unless one is consuming a lot of refined / junk food, its rather difficult to achieve methionine restriction, but methionine moderation is possible.

 

 

 

Creatine biosynthesis is:

In kidney: L-arginine + glycine → ornithine + guanidinoacetate

In liver: guanidinoacetate + SAM → creatine + SAH

 

If the later reaction were the rate limiting one, methionine restriction would indeed reduce circulating SAM and throughput to creatine. However

 

Stead LM et al. 2001. Methylation demand and homocysteine metabolism: effects of dietary provision of creatine and guanidinoacetate. American Journal of Physiology-Endocrinology And Metabolism, 281(5), E1095-E1100.

The principal regulatory site, and rate-limiting step, in the creatine biosynthetic pathway is the L-arginine:glycine amidinotransferase reaction. Creatine exerts feedback repression onL-arginine:glycine amidinotransferase at the pretranslational level, an example of end-product repression

 

(edit: remarkably) the methylation of guanidinoacetate to creatine via guanidinoacetate methyltransferase consumes more SAM than all other methylation reactions combined

 

So, glycine supplementation will not do much to increase creatine (its end-product regulated), nor will methionine restriction effect creatine synthesis (the 1st reaction is rate limiting, not the 2nd reaction that consumes SAM), and exogenous creatine will shut down biosynthesis (by repressing the expression of the 1st reaction's enzyme, so within a couple days).

 

Edited by Darryl, 03 July 2015 - 01:00 AM.

[Skyguy2005]

Low methionine foods include Ginkgo Biloba nuts, almonds, macadamia nuts, mushrooms, dark chocolate, soy/tofu/etc, beans, lentils.

 

0.1% Methionine can't be that difficult.

[Darryl]

One can design a weird diet with insufficient methionine, depending or low-protein density (by calorie) foods like high fat nuts or cassava. However, of the foods you suggest, only macadamia nuts have methionine density low enough dilute dietary methionine to restriction. 

 

g Met in 2000 kcal (WHO requirement for 60 kg adult: 0.60 g)

ginkgo nuts     0.76

almonds         0.54

macadamia nuts  0.06

white mushrooms 2.82

tofu            2.79

black beans     2.02

lentils         1.33

cassava         0.14

 

I do however believe attention to dietary amino acid ratios might achieve "effective" methionine moderation or restriction. For those who buy into the idea of using excess glycine to mimic methionine restriction, one can consider the glycine/methionine ratio of foods, or better, the (glycine+serine)/(methionine+cysteine) ratio, as serine and glycine readily interconvert, and cysteine spares methionine requirements. Among foods with reasonable protein density, here are typical (G+S)/(M+C) ratios: legumes (4.1), nuts (3.0), mollusks (2.8), grains (2.5), tubers (2.4), red meat, poultry (2.4), dairy, pork (2.3), fish (2.1). Among "supplemental" proteins, gelatin reigns: gelatin (36.0), soy (3.4), pea (3.2), casein (2.1), egg whites, whey (1.8). There's nothing comparable among plant proteins to gelatin. the closest are ginko nuts (6.6) and almonds (6.3), while buckwheat (4.3) is notably high for a grain.

 

 

Edited by Darryl, 04 July 2015 - 07:56 PM.

[sthira]

I have to say -- and I know this is n=1 anecdotal -- but I'm noticing nice things about glycine. I'm taking about fifteen-grams a day, and I'm a vegan, so maybe I'm filling in some previously unknown dietary deficiency. Maybe it's placebo -- but I've never really noticed much with supplements, like, ever, including my flirtations with fads I've fallen for -- resveratrol, c60oo for two years, NR, some others.

Glycine? I'm sleeping better, sleeping more soundly, awakening more refreshed, which is really very nice. I also seriously stress my body daily in ballet and crazy contortionist acro type stuff, and recovery time is, um, shorter? I've less aches and pains in my overworked feet, toes, ankles, shins, calves. Some of these troubles have seriously diminished... I'm quite close to my body, and I'm knocking on wood and hoping not to jinx myself here with this little glycine testamony. My tendonitis issues aren't as severe? I've overflexible limbs -- joints, bones -- and sometimes I pull in too deeply, and suffer. Especially under the influence of high adrenaline when my body limits are forgotten in the immediate moment, and I get lost the in the joys of motion, then must repay the debt later. Now I seem to be extending farther, deeper, finding more rotation in joints previously plateaued, and I'm just sorta feeling stronger and more flexible overall. Maybe it was a dietary deficiency for me, the vegan -- but the change is noticeable.

I've been nursing a torn medial meniscus for a few years, the avascular thing won't heal on its own, despite stem cell injections, PRP, heavy quad rehabbing, massage, a shit ton of new age bullshit, it just won't heal. I've noticed no knee issue relief from my 15-g glycine supplementation, but it's a little exciting to wonder if maybe my torn white-zone cartilage will cut me a break, regrow something in that overused crack other than poor ole pathetic scar tissue.

Edited by sthira, 04 July 2015 - 08:12 PM.

[Phoenicis]

 

Hey Darryl, any chance you elaborate on how one would calculate excess methioine? 

 

I wonder if glycine supplementation would help to main higher levels with creatine supplements? One could imagine that MR would make methioine availability a bottleneck in creatine sythesis. I did read that creatine supplementation shuts down biosynthesis, but cant remember where.

 

I use the WHO's estimated requirement:

 

10 mg/kg/d methionine: 

15 mg/kg/d methionine + cysteine

 

The later makes more sense, dietary cysteine spares methionine requirements. My diet as an omnivore was around 250-300% of requirements, my current vegan diet is around 150%. Unless one is consuming a lot of refined / junk food, its rather difficult to achieve methionine restriction, but methionine moderation is possible.

 

 

 

Creatine biosynthesis is:

In kidney: L-arginine + glycine → ornithine + guanidinoacetate

In liver: guanidinoacetate + SAM → creatine + SAH

 

If the later reaction were the rate limiting one, methionine restriction would indeed reduce circulating SAM and throughput to creatine. However

 

Stead LM et al. 2001. Methylation demand and homocysteine metabolism: effects of dietary provision of creatine and guanidinoacetate. American Journal of Physiology-Endocrinology And Metabolism, 281(5), E1095-E1100.

The principal regulatory site, and rate-limiting step, in the creatine biosynthetic pathway is the L-arginine:glycine amidinotransferase reaction. Creatine exerts feedback repression onL-arginine:glycine amidinotransferase at the pretranslational level, an example of end-product repression

 

(edit: remarkably) the methylation of guanidinoacetate to creatine via guanidinoacetate methyltransferase consumes more SAM than all other methylation reactions combined

 

So, glycine supplementation will not do much to increase creatine (its end-product regulated), nor will methionine restriction effect creatine synthesis (the 1st reaction is rate limiting, not the 2nd reaction that consumes SAM), and exogenous creatine will shut down biosynthesis (by repressing the expression of the 1st reaction's enzyme, so within a couple days).

 

 

According to my calculations I consume anywhere from 1.4g Meth+Cys on a low protein vegan diet, to 1.7g Meth+Cys on tofu + falafel days. According to the WHO a 65kg male only requires 1g, so I think on average I may be looking at .55g excess Meth+Cys. Wouldn't supplementing 3g glycine therefore give roughly a 5:1 gycine:(excess)meth+cys ratio; just from my supplemented glycine?

 

One more question, since creatine metabolism is "end-product regulated", do you think that a sufficient supply of glycine (should I be worried about arginine?) would allow the body to adequately biosynthesize creatine? I'd rather not supplement creatine if that would interfere with methioine restriction. Apparently creatine loss is about 2g/day for a 70kg male (80% less in womenz) and vegan men can biosynthesize 14mmol/day (womenz =11mmol)[1] Notably both showed reduced creatine levels,[1] but I wonder what impact glycine supplementation could have on increasing synthesis?

 

I'm hoping there is no significant interaction betweeen methionine "moderation" and conservatively supplementing carnitine and beta-analine. It definitely appears that restriction is going to be difficult, but even so at least one study has shown that vegans have lower IGF-1 levels than folks practicing "severe" caloric restriction.[2] Maybe since plant protein is also less bioavailble, that accounts for part of the difference?[3]

 

I find that Chinese cooking makes being vegan easier, for cooking I like this book on Amazon and I also go to some of the better restaraunts here in my city.

 

I also found a study showing glycine to be neuroprotective:

• Selin, A. et al. (2012). Mechanism Underlying the Protective Effect of Glycine in Energetic Disturbances in Brain Tissues under Hypoxic Conditions. Bulletin of Experimental Biology and Medicine. Volume 153, Issue 1, pp 44-47

References:

 

[1] Brosnan, JT. et al. (2011).The metabolic burden of creatine synthesis. Amino Acids;40(5):1325-31.

[2] Fontana, L. et al. (2008). Long-term effects of calorie or protein restriction on serum IGF-1 and IGFBP-3 concentration in humans. Aging Cell. 2008 Oct; 7(5): 681–687.

[3] McCarty, MF. et al. (2009).The low-methionine content of vegan diets may make methionine restriction feasible as a life extension strategy. Med Hypotheses. 2009 Feb;72(2):125-8

Edited by Phoenicis, 06 July 2015 - 06:35 PM.

[Darryl]

 

 

on average I may be looking at .55g excess Meth+Cys. Wouldn't supplementing 3g Glycine therefore give roughly a 5:1 Gycine:(excess)Meth+Cys ratio, just from my supplemented glycine?

 

One more question, since creatine metabolism is "end-product regulated", do you think that a sufficient supply of glycine (should I be worried about arginine?) would allow the body to adequately biosynthesize creatine? I'd rather not supplement creatine if that would interfere with methioine restriction. Apparently creatine loss is about 2g/day for a 70kg male (80% less in womenz).[1] Apparently vegan men can biosynthesize 14mmol/day (womenz =11mmol) and both show reduced creatine levels.[1] I wonder what impact glycine supplementation could have?

 

I'm hoping there is no significant interaction betweeen methioine moderation and conservatively supplementing carnitine and beta-analine.    

 

0.55 g excess M+C is similar to my results.

 

3 g G in excess of requirements might be 5:1 for excess M+C, however the calculated G deficit of -8.5 to -10 g G/d from Meléndez-Hevia et al. 2009 suggests most lower dose G will be consumed in collagen turnover.

 

We just don't know what a meaningful dose of G for effective methionine restriction/moderation would be. The Brind et al. 2011 poster abstract used an 18:1 G:M to achieve "effective" methionine restriction, which suggests something like 15+ g supplemental G in low-protein diets like ours. While there are 1 year followups of very high psychotherapeutic 60g G/d in the literature, evidence that really high G supplementation is generally safe, and doesn't cause depletion of other nutrients, is scarce.  

 

As glycine conjugation is important in excretion of other compounds in my supplement regimen (nicotinic acid & salicylate), I've aimed at the <10 g range suggested by Meléndez-Hevia et al. 2009, and juggled my other supplements (taken at breakfast and late afternoon), with glycine at bedtime to prevent unwanted interference.

 

As for arginine, there's this study where L-arginine and glycine supplementation increased tissue creatine in "traumatized" rats, but I haven't encountered human studies on creatine precursors and tissue levels. I suspect the study that might determine L-arginine sufficiency wouldn't look at creatine, but would instead focus on polyamine concentration, sperm count, and motility in semen, as there are a few studies that indicate L-arginine supplementation improves these in both animals and humans (though with followups showing no effect).

 

Carnitine synthesis does consume SAM at protein methylase III, but its a really minor sink: I'm matching omnivore intakes of carnitine at 100 mg/d. The methionine transmethylation cycle for SAM production is so central that if we were to budge its throughput much, we'd be very sick. My sense is at best methionine restriction might result in slight undermethylation, with the major longevity effects from reduced excess methionine/higher H₂S/reduced mitochondrial potential/reduced mitochondrial ROS production. 

 

I personally supplement creatine at approximately omnivore intakes (500 mg/d), as tissue levels are lower in vegetarians and one study found cognitive improvements with supplementation (only in vegetarians). Thanks to demand from bodybuilders, its cheap at this dose. The carninutrient amino derivatives (creatine, β-alanine, taurine, carnitine) are all well downstream, via irreversible reactions, from more central metabolic cycles, so supplementing at conservative/omnivore intakes seems unlikely to have much effect on more central amino balances.

Edited by Darryl, 06 July 2015 - 07:20 PM.

[Phoenicis]

I found one interesting study on oral guanidinoacetic acid (normally synthesized from glycine +argine in the kidney):

• Ostojic, S. et al. (2014). Dose–response effects of oral guanidinoacetic acid on serum creatine, homocysteine and vitamins levels. European Journal of Nutrition, Volume 53, Issue 8, pp 1637-1643

Very interesting, it does note increased creatine levels and no depletion of b vitamins!

 

I also like these studies showing that glycine can increase endogenous glutathione synthesis (I think Darryl already pointed out the latter):

• Sekhar, RV et al. (2011). Deficient synthesis of glutathione underlies oxidative stress in aging and can be corrected by dietary cysteine and glycine supplementation. Am J Clin Nutr. 2011 Sep;94(3):847-53
• Ruiz-Ramírez, A. et al. (2014). Glycine restores glutathione and protects against oxidative stress in vascular tissue from sucrose-fed rats.Clin Sci (Lond). 2014 Jan 1;126(1):19-29

Edited by Phoenicis, 08 July 2015 - 12:57 PM.

[Phoenicis]

According to my calculations Sekhar, RV et al. (2011) used 90mg/kg doses of glycine for the elevations in glutathione. For me that would work out to about 6.5g.

 

I'm thinking that this should also be a useful cysteine sink:

 

L-glutamine + L-cysteine (gamma-glutamylcysteine synthetase) -> L-glutamylcysteine + L-glycine (glutathione synthase) -> reduced glutathione

Edited by Phoenicis, 08 July 2015 - 03:22 PM.

[Phoenicis]

According to Ostojic S. and Vojvodic-Ostojic A. (2015), guanidinoacetic acid ("GAA") raises creatine significantly:

 

1.2g - 80% increase in Cr

2.4g - 116% increase in Cr

4.8g - 293% increase in Cr

 

See:

• Ostojic S. and Vojvodic-Ostojic A. (2015). Single-dose oral guanidinoacetic acid exhibits dose-dependent pharmacokinetics in healthy volunteers.Nutr Res. 2015 Mar;35(3):198-205

 

Edited by Phoenicis, 08 July 2015 - 06:29 PM.

[Brett Black]

I noticed that Glycine is included in the NIH's ITP study, cohort 10 begun in 2014 so we should know more in a year or two given the mice started supplementation at nine months

Cohort 10: C2014
Compound Concentration in food Age at treatment initiation
Supplemental glycine
80,000 ppm
9 months

https://www.nia.nih....mpounds-testing

The following website(which sells a product containing glycine) claims that the inclusion of gycine in the ITP study was due to their application to the NIA, and they quote the rationale they gave for testing it:
 

http://www.proglyta....ation-mice.html

Last September, I submitted an application to the NIA’s Interventional Testing Program (ITP). It is like submitting a grant application to the NIH, except that the Sponsor (myself, in this case) does not involve his own institution in the research directly: The entire study is performed at 3 study centers: at the University of Michigan, the University of Texas, and the Jackson Labs in Maine, by NIA-funded scientists, according to the protocol proposed by the sponsor. Every year, the NIA selects up to 5 dietary interventions that are hypothesized to extend the lifespan of the mice and/or delay the onset of age-related diseases. The Sponsor, however, has access to all the data generated, participates in the analysis of the data and is a co-author on resulting published studies.

Of course, the NIA’s decision to run the glycine supplementation experiment does not mean there will results overnight. Even intermediate results on the delay of age/inflammation-related conditions are likely at least two years away, but it’s a great start!

Here is the paragraph—taken straight from my application—which explains my rationale for why it’s a good idea to supplement the diet with glycine:

Physiological role of glycine

As a free amino acid, glycine’s major role appears to be mediated mainly through the glycine receptor, which is a gated chloride channel. Until relatively recently, glycine receptors were thought to be restricted to neurons, as receptors for glycine as an inhibitory neurotransmitter in the central nervous system. Over the last two decades, the same glycine receptor has been identified in a host of other body cell types, especially macrophages from all tissues and endothelial cells (Yamashina et al., 2007). Glycine is thus emerging as essentially a plasma membrane voltage regulator, maintaining the resting potential of cells by keeping these chloride channels sufficiently open to allow the influx of adequate amounts of chloride ion. Thus, cells such as macrophages—the mediators of inflammation—are less prone to activation, a phenomenon which is initiated by cellular depolarization via the opening of calcium channels and the influx of calcium. (Zhong et al., 2003). As most major lifespan-impacting diseases in our society (e.g., cancer, cardiovascular disease, diabetes) seem to stem from some sort of chronic inflammation, it is reasonable to hypothesize that this may be due to widespread low-grade deficiency of glycine in body fluids, and that supplementation with glycine might prevent the onset of many conditions rooted in chronic inflammation and associated with age.

Edited by Brett Black, 10 July 2015 - 04:10 AM.

[Skyguy2005]

 

One can design a weird diet with insufficient methionine, depending or low-protein density (by calorie) foods like high fat nuts or cassava. However, of the foods you suggest, only macadamia nuts have methionine density low enough dilute dietary methionine to restriction. 

 

g Met in 2000 kcal (WHO requirement for 60 kg adult: 0.60 g)

ginkgo nuts     0.76

almonds         0.54

macadamia nuts  0.06

white mushrooms 2.82

tofu            2.79

black beans     2.02

lentils         1.33

cassava         0.14

 

I do however believe attention to dietary amino acid ratios might achieve "effective" methionine moderation or restriction. For those who buy into the idea of using excess glycine to mimic methionine restriction, one can consider the glycine/methionine ratio of foods, or better, the (glycine+serine)/(methionine+cysteine) ratio, as serine and glycine readily interconvert, and cysteine spares methionine requirements. Among foods with reasonable protein density, here are typical (G+S)/(M+C) ratios: legumes (4.1), nuts (3.0), mollusks (2.8), grains (2.5), tubers (2.4), red meat, poultry (2.4), dairy, pork (2.3), fish (2.1). Among "supplemental" proteins, gelatin reigns: gelatin (36.0), soy (3.4), pea (3.2), casein (2.1), egg whites, whey (1.8). There's nothing comparable among plant proteins to gelatin. the closest are ginko nuts (6.6) and almonds (6.3), while buckwheat (4.3) is notably high for a grain.

 

 

 

(1) Dark Chocolate is said to be low in methionine and arginine, according to a paper I read. However I have been unable to find any actual numbers on dark chocolate, cocoa mass, cacao and that sort of thing. Anyone?

 

(2) What does methionine restriction have to do with autophagy. Don't *ALL* amino acids inhibit autophagy? What makes methionine/cysteine restriction special? An explanation of this would be great

 

(3) What about B6/9/12 vitamins? Would taking either more, or less, of these, potentially have any effect on the pathways at hand here?
 

Edited by Skyguy2005, 13 July 2015 - 12:56 AM.

[Darryl]

Dark chocolate, like cacao beans, has relatively little protein content (8% protein by wt, ~6% by kcal). Unsweetened cocoa powder is 20% protein by wt, with a (G+S)/(M+C) ratio of 3.9 - comparable to beans.

 

Methionine restriction does increase autophagy in yeast (at least), one study found elevated autophagy neccesary for its lifespan benefits in yeast.

 

Ruckenstuhl C et al. 2014. Lifespan extension by methionine restriction requires autophagy-dependent vacuolar acidification.PLoS Genet, 10(5), e1004347.

 

There are a number of pathways that may mediate the lifespan benefits of methionine restriction.  Upregulating UCP1, increasing uncoupled respiration and reducing ROS production at mitochondrial complex I, increasing endogenous H₂S production, and inducing FGF21/retrograde response are all candidates. Key mechanistic papers include:

 

Caro P et al. 2009. Forty percent methionine restriction decreases mitochondrial oxygen radical production and leak at complex I during forward electron flow and lowers oxidative damage to proteins and mitochondrial DNA in rat kidney and brain mitochondria. Rejuvenation research, 12(6), 421-434.

Caro P et al. 2009. Effect of 40% restriction of dietary amino acids (except methionine) on mitochondrial oxidative stress and biogenesis, AIF and SIRT1 in rat liver. Biogerontology, 10(5), 579-592.

Hasek BE et al. 2010. Dietary methionine restriction enhances metabolic flexibility and increases uncoupled respiration in both fed and fasted states. American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, 299(3), R728-R739.

Lees EK et al. 2014. Methionine restriction restores a younger metabolic phenotype in adult mice with alterations in fibroblast growth factor 21. Aging cell, 13(5), 817-827.

Hine C & Mitchell JR. 2014. Calorie restriction and methionine restriction in control of endogenous hydrogen sulfide production by the transsulfuration pathway. Experimental gerontology.

Hine C et al. 2015. Endogenous hydrogen sulfide production is essential for dietary restriction benefits. Cell, 160(1), 132-144.

Wanders D et al. 2015. UCP1 is an essential mediator of the effects of methionine restriction on energy balance but not insulin sensitivity. The FASEB Journal, fj-14.

 

The two Caro papers and two Hine papers indicate some pretty unique effects of sulfur amino acid (methionine/cysteine) restriction.

 

Methionine/cysteine restriction is  interesting because it appears to account for all the lifespan benefits of protein restriction, and hence most but not all of the benefits of caloric restriction. Moreover, with a lower protein, lower grain vegan or near vegan diet, its possible to approach a methionine restricted state, though actual restriction would require substantial amounts of very low-protein foods like cassava, wine or added oils. 

 

McCarty MF et al. 2009. The low-methionine content of vegan diets may make methionine restriction feasible as a life extension strategy. Medical hypotheses, 72(2), 125-128.

 

I should also add that methionine restricted diets have been known since the 1940s to largely eliminate spontaneous hepatomas in rats (though its less successful at preventing chemical carcinogenesis or other cancers), and methionine restriction is one of several AA restriction dietary regimens with marked effects on cancer progression (PKU diets have also been tried). This early study I discovered last night showed just how dramatic the effect might be:

 

Silverstone H, & Tannenbaum A. 1951. Proportion of dietary protein and the formation of spontaneous hepatomas in the mouse. Cancer research, 11(6), 442-446.

 

B6, B9, and B12 all play important roles in the methionine tranmethylation cycle (which generates SAM for required methylations, and recycles the byproduct homocysteine back into methionine. Ensuring one's replete in those B vitamins (and betaine/choline as well) can remove bottlenecks that would otherwise cause elevation of homocysteine (which used be considered a cardiovascular risk). The enzymes which clear surpluses in the total Met/SAM/SAH/Hcy pool are glycine N-methyltransferase (GNMT), the primary methyltransferase regulating SAM/SAH balance, and cystathionine β-synthase (CBS), the first step on the transulfuration pathway from homocysteine towards cysteine and glutathione synthesis. GNMT and glutathione synthesis consume glycine, while CBS consumes serine (which equilibrates with glycine through a reversible reaction), so by increasing available glycine, we potentially preempt the negative effects of excess free methionine by keeping the pool at a minimal level.

 

B6, it should be noted, is a cofactor for CBS. B9, however inhibits GNMT activity in some studies. I think there are too many benefits from high folate, and high folate containing foods, to worry about this. Excess glycine works just fine to alleviate experimental hyperhomocysteinaemia induced by excess dietary methionine, and extended mouse lifespan in that to date unreplicated Brind et al 2011 abstract, even when diets are folate replete.

Edited by Darryl, 13 July 2015 - 05:18 AM.

[Skyguy2005]

Does amino acid restriction (all amino acids, not just methionine) not increase autophagy? I saw a study where all amino acids inhibit autophagy (even glycine). Given the prominent role of autophagy, proteasome, and protein tidying-up does this not implicate *protein* restriction, especially methionine and cysteine, as the best strategy to inhbit aging? 

 

I'll try and get this study again. Thanks for the replies btw.

[Skyguy2005]

Oh and doesn't B12 return homocysteine to methionine, while B6 returns it to glutathione? See: http://advances.nutr...nt/2/5/421.full

 

So would more vitamin B6 and somewhat less vitamin B12 be a beneficial thing?

[niner]

Does amino acid restriction (all amino acids, not just methionine) not increase autophagy? I saw a study where all amino acids inhibit autophagy (even glycine). Given the prominent role of autophagy, proteasome, and protein tidying-up does this not implicate *protein* restriction, especially methionine and cysteine, as the best strategy to inhbit aging? 

 

One reason for autophagy is to acquire amino acids from old proteins when they aren't available from diet.  Some amino acids can be synthesized, while the others are called "essential" because it's essential that we get them from diet.  If there is a shortage of any essential AA, I'd expect that to induce autophagy, though perhaps some are better than others.  Autophagy induction is the idea behind Ron Mignery's Protein Cycling Diet, i.e. periods of inadequate protein consumption alternated with sufficiency.  Autophagy has also been suggested as part of the reason that CR extends life.  I would certainly expect Met restriction to induce autophagy, but as Darryl suggests, it looks like there's more to Met than just autophagy.  Regarding your question, protein restriction is one thing that can be done, although that would make it hard to build or maintain muscle mass.  Protein cycling is another, and Met restriction is another.  I don't know of any published evidence that Protein Cycling "works", so I'll call it a hypothesis that makes sense.  Inhibition of aging is only one endpoint to consider; a lot of people are also interested in how they look and feel, which might give the edge to Met restriction or (maybe) Protein Cycling.

[Skyguy2005]

 

Does amino acid restriction (all amino acids, not just methionine) not increase autophagy? I saw a study where all amino acids inhibit autophagy (even glycine). Given the prominent role of autophagy, proteasome, and protein tidying-up does this not implicate *protein* restriction, especially methionine and cysteine, as the best strategy to inhbit aging? 

 

it looks like there's more to Met than just autophagy. 

 

Hang on my friend, I do not have the level of knowledge of you (obviously) (I'm a mathematician ha) , but decrease in feeding (caloric restriction) has to decrease homogeneously the levels of the various proteins being chowed on.

 

What precisely can the extension of life be due to if it is not protein restriction and hence autophagy/proteasome related? It certainly cannot be to do with the protein nature, or ratio, of almonds/beef. They contain about the same amount of protein (although perhaps almonds contain more calories per protein content)

Edited by Skyguy2005, 19 July 2015 - 02:45 AM.

[ClarkSims]

http://www.sciencedi...304416580901415

 

This study concluded not all amino acids inhibit autophagy equally. I couldn't get the full test. I am not clear how many were tested. Neither glycine nor methionine were mentioned.  Of course "isolated rat hepatocytes" might not be a good indicator for an entire human.

 

Does amino acid restriction (all amino acids, not just methionine) not increase autophagy? I saw a study where all amino acids inhibit autophagy (even glycine). Given the prominent role of autophagy, proteasome, and protein tidying-up does this not implicate *protein* restriction, especially methionine and cysteine, as the best strategy to inhbit aging? 

 

I'll try and get this study again. Thanks for the replies btw.

 

[niner]

What precisely can the extension of life be due to if it is not protein restriction and hence autophagy/proteasome related? It certainly cannot be to do with the protein nature, or ratio, of almonds/beef. They contain about the same amount of protein (although perhaps almonds contain more calories per protein content)

 

Not all protein is created equal.  They're all made out of amino acids, but the amino acids are present in different ratios in different proteins, and different amino acids have different effects on health and lifespan.  So in fact, the nature of the protein is very important.  The message of this thread is that sufficient amounts of Gly are a way to get the effects of Met restriction.  We know that Met restriction increases lifespan in experimental animals, but it's hard to restrict Met and eat a normal diet.  Much easier to supplement Gly.

[APBT]

 

http://www.sciencedi...304416580901415

 

This study concluded not all amino acids inhibit autophagy equally. I couldn't get the full test. 

 

 

FULL TEXT OF REFERENCED STUDY:

Attached Files

•  AMINO ACID INHIBITION OF THE AUTOPHAGIC - LYSOSOMAL PATHWAY OF PROTEIN DEGRADATION IN ISOLATED RAT HEPATOCYTES.pdf   913.31KB   13 downloads

[Kevnzworld]

Question in regards to dosing.
On an empty stomach or with food?
I'm taking 2000 Mg's per day in the eve before bed on an empty stomach.