Glycine is an MTORC1 Activator

I find it interesting that Glycine promotes longevity and protects against sarcopenia by activating MTORC1. Rapamycin seems to neutralize some of the effects of Glycine, although Rapamycin seems to overrule Glycine. Yet, when Rapamycin levels wane, Glycine’s benefits can kick in. Seems that alternating between the two (or just constantly dosing Glycine) would have a beneficial effect. Or better yet, Glycine + NAC. Based on this data, I will stop taking NAC on the immediate days after dosing with Rapamycin.
Thoughts?

The non-essential amino acid glycine is often considered biologically neutral, and not required for the regulation of protein synthesis under normal healthy conditions. However, reduced intracellular levels of glycine have been reported in older individuals (1) and in mouse models of diabetes and muscular dystrophy (2, 3), suggesting that either glycine metabolism is increased during these conditions, or tissue demand exceeds dietary intake. Our observations in several mouse models of muscle wasting showed that supplementation with glycine preserved muscle mass and metabolic function in a range of conditions where the anabolic response to nutrition was altered (46). Glycine administration attenuated skeletal muscle wasting and loss of physical function in a mouse model of cancer cachexia, which was associated with a reduction in protein breakdown and skeletal muscle markers of inflammation and ROS (4). In a mouse model of acute (LPS-induced) inflammation, glycine administration preserved the skeletal muscle anabolic response to leucine, through upregulation of mTORC1 signaling and preservation of protein synthesis. Glycine can affect cell homeostasis via glycine receptor mediated signaling and via its metabolism (7). Indeed, previous reports have linked glycine receptor-mediated signaling, via its scaffolding protein gephyrin, to mTORC1 activation in other tissues (8). In the in vivo LPS model we also showed a reduction in oxidative stress (DHE) but not mRNA expression of pro-inflammatory cytokines and chemokines in skeletal muscle (6). Dietary glycine supplementation in a mouse model of caloric restriction reduced adiposity (whole-body and epididymal fat mass) and preserved lean mass and muscle mass (5). Together, these data revealed a positive effect of glycine treatment on skeletal muscle protein metabolism, mass and function during muscle wasting conditions. However, it is currently unclear whether the beneficial effects of glycine on skeletal muscle are entirely the result of inflammatory cell inactivation, or whether glycine has muscle cell-specific effects. We tested the hypothesis that glycine would directly attenuate myotube wasting in an mTORC1-dependent manner.

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I know that rapamycin does not inhibit MTOR equally in all tissue type/organs. Peter Attia supplements with creatine and protein every day. I do also. I don’t think rapamycin counteracts the impact of either in muscle tissue.

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A review of the healthy longevity methods of glycine supplementation.

Highlights
• The simple amino acid glycine extends lifespan in worms, mice, and rats.
• Glycine also improves aspects of health in mammalian models of age-related disease.
• Glycine is the acceptor for GNMT, an enzyme responsible for methionine clearance.
• GNMT also converts glycine to sarcosine, an autophagy-inducing metabolite.
• Glycine may prolong life by inducing autophagy and mimicking methionine restriction.

Abstract
The restriction of calories, branched-chain amino acids, and methionine have all been shown to extend lifespan in model organisms. Recently, glycine was found to boost longevity in genetically heterogenous mice. This simple amino acid similarly extends lifespan in rats and improves health in mammalian models of age-related disease. While compelling data indicate that glycine is a pro-longevity molecule, divergent mechanisms may underlie its effects on aging. Glycine is abundant in collagen, a building block for glutathione, a precursor to creatine, and an acceptor for the enzyme glycine N-methyltransferase (GNMT). A review of the literature strongly implicates GNMT, which clears methionine from the body by taking a methyl group from S-adenosyl-L-methionine and methylating glycine to form sarcosine. In flies, Gnmt is required for reduced insulin/insulin-like growth factor 1 signaling and dietary restriction to fully extend lifespan. The geroprotector spermidine requires Gnmt to upregulate autophagy genes and boost longevity. Moreover, the overexpression of Gnmt is sufficient to extend lifespan and reduce methionine levels. Sarcosine, or methylglycine, declines with age in multiple species and is capable of inducing autophagy both in vitro and in vivo. Taken all together, existing evidence suggests that glycine prolongs life by mimicking methionine restriction and activating autophagy.

Open access:

Glycine and aging: Evidence and mechanisms
Adiv A. Johnson, Trinna L. Cuellar
https://doi.org/10.1016/j.arr.2023.101922

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Perhaps why Glycine is helpful in healthy longevity?

Study: “The amount of glycine available from synthesis & diet may fall significantly short of the amount needed for all metabolic uses, including collagen synthesis by about 10 g per day for a 70 kg human”.

Published: 03 December 2009

A weak link in metabolism: the metabolic capacity for glycine biosynthesis does not satisfy the need for collagen synthesis

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As suggested before, every cell has mTOR. Question is which mTOR is activated or suppressed.

Rapa is also not entirely positive:

[quote]
We demonstrate that chronic mTORC1 inhibition with rapamycin is overwhelmingly, but not entirely, positive for aging mouse skeletal muscle, while genetic, muscle fiber-specific activation of mTORC1 is sufficient to induce molecular signatures of sarcopenia[/quote]
https://www.nature.com/articles/s41467-020-18140-1

From DeStrider’s quote:

So what is Gephyrin?
https://www.nature.com/articles/nrn3670

So I will continue my treatment. And btw I take Rapa only >4 hours prior and before other supplements.
In most cases it is:
In the morning Glycine & NAC
In the evening Rapa

I just make sure they don’t interact.

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I take lots of Glycine daily (11 g Collagen + 2 tbsps) along with 1.6 g NAC daily even on days when I take Rapamycin. I think it’s important to keep the glycine intake as it is used for other things such as clearing glutamate and methionine and producing GSH - even if it may be at cross-purposes with Rapamycin.

Does anyone think there may be an issue with taking GlyNAC + Rapa?

I think I’ll ask Dr. Miller about this.

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I like glycine. Paradoxically it improves sleep and lessens daytime sleepiness. For me it actually works on reducing daytime sleepiness.

"Glycine improved subjective sleep quality and sleep efficacy (sleep time/in-bed time), and shortened PSG latency both to sleep onset and to slow wave sleep without changes in the sleep architecture. Glycine lessened daytime sleepiness and improved performance of
memory recognition tasks

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Has anyone noticed potential acceleration of knee arthritis from NAC suggested in a Chinese research paper? (Referenced Below) I ask because obviously we all want to minimize our “one step back” in the supplement/longevity/healthspan treatments we are pursuing. I definitely feel my knees are more sore over the past six months, but I don’t know if it is from:
o. lifting heavy weights (squats and deadlifts at 1.5x body weight) 3x per week,
o. from stair climbing (I do roughly 60-100 flights 3-4x per week — only up — but I don’t think this is it),
o. from taking NACET at 100mg daily (which could be as much as 2g equivalent of NAC, although likely lower) as part of GlyNAC,
o. or just “old age”…

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Glycine helps to fall asleep and therefore is better at pm hours. Rapa is usually administered in the morning as it increases energy. It’s beneficial to exercise after taking Rapa. How do you sleep with your reverse schedule for both?

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I also take glycine at night for better sleeping. It improved my deep sleep stage much. If I wake up at night, I would empty 1 capsule of glycine under my tongue and easily fall asleep again.

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desertshores, dose and brand of glycine you taking?

I am taking the NOW brand from Amazon. I take 6 grams a day with 2 grams of NAC.

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Never heared that before.

First of all, I fall asleep very quickly so I do not need any help and I also do not feel any difference on Rapa days.

Glycine may help you fall asleep if taken before bedtime. But that doesn’t mean it will make you tired or something.
For example: Trimethylglycine helps you to build muscles and it’s normally administrered after (or before) resistence training. I’ve not heared anything about other atheletes getting tired after they take it.

BTW there is also evidence that proteins will improve the quality of your sleep. I’m not sure if Glycine has a beneficial effect that goes beyond. But I’m not really into that data. I’ve tested taking proteins before going to bed because I do excercise a lot. For me it’s just pointless.

In case of Rapa: I don’t think that it will increase any energy levels shortly (if I am wrong, please feel free to correct me =) ).
Normally I do not excercise on Rapa days. But that’s just a coincidence.
The real reason why I do not take Rapa in the morning is just that I don’t think that two whole Grapefruits are that yummy for breakfast. :wink:

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Díaz-Flores et al administered 15-g glycine daily (5 g, 3 times daily) to patients with metabolic syndrome. Despite fasting glucose rising significantly from 101 mg/dL to 114 mg/dL (P =0.001), glycated hemoglobin fell from 7.81% to 6.45% (P =0.0001); the increase in fasting glucose in these patients might be explained by a stimulatory effect of glycine on glucagon secretion.45 Glycine supplementation was also associated with significant reductions in systolic blood pressure and plasma markers of oxidative stress.45 Importantly, when 5-g glycine was administered along with 25-g glucose in an oral glucose tolerance test, the subsequent increase in plasma glucose was notably blunted compared to the response to glucose alone. Because the glycine had relatively little impact on insulin secretion, the authors hypothesized that glycine was promoting intestinal production of an unknown hormone capable of boosting insulin sensitivity.44 When patients with type 2 diabetes were administered 5-g glycine 4 times daily for 6 months in an uncontrolled clinical trial, glycated hemoglobin fell from 9.6% to 6.9% (P <0.05); a favorable impact of glycine on oral glucose tolerance and on protein glycation might have collaborated in producing this benefit.46 A reduction of glycated hemoglobin in glycine-treated diabetic rats has also been reported.47 In rats with streptozotocin-induced diabetes, a favorable effect on certain diabetes complications (ie, glomerulosclerosis, cataracts, and microaneurysms of the retinal arteries) has been found.48-50

Mark F. McCarty is coowner and science director of a nutraceutical company that sells a product containing glycine. James H. O’Keefe is the chief medical officer and founder of CardioTabs, a nutraceutical company. James J. DiNicolantonio has no conflicts of interest to disclose .

The studies cited, however, do not indicate conflicts of interest.

M Díaz-Flores, M Cruz, G Duran-Reyes, C Munguia-Miranda, H Loza-Rodríguez
Canadian journal of physiology and pharmacology, 2013•cdnsciencepub.com

MC Gannon, JA Nuttall, FQ Nuttall
The American journal of clinical nutrition, 2002

Effect of glycine on hemoglobin glycation in diabetic patients
Guillermo Carvajal Sandoval, Roberto Medina Santillan, Enedina Juarez, Gustavo Ramos Martlnez, Maria Elena Carvajal Juärez
Escuela Superior de Medicina (ESM)

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I actually have started to take rapa literally 10 minutes before bedtime. This seems to work best for me as when i used to take in the morning I would stay awake till late the first night. Now when I take right before bed it does not interrupt my sleep the night i take, and even the next day/night my sleep seems ok. Plus, for some unknown reason to me my complexion was way better in the morning after the night I took RAPA. It was so noticeable that I even had a girl at work make a comment to the effect of “did you do something to your face”, and I said what do you mean. They go well somehow you look younger, to which I replied nah but it could be because I had a nice dream about you, and maybe that made me younger lol. I will continue doing it this way.

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BTW, I also started taking a 500mg metformin the morning after RAPA and have stopped all other supplements for first two days. I consider those two days as cycling days for other supps.

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If you have cancer you should avoid glycine.

Glycine fuels cancer cells

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Upon review of current literature, I am eliminating my NAC and glycine supplements. The reason is primarily, but not only, age-related. I find it useful to shorten my stack by eliminating supplements I do not love.

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I believe that’s an older study. The more recent data showed it was serine and not glycine. They are both involved in the same cycle.

Here’s an article on dietary restriction of amino acids for fighting cancer from 2020.

The leading substrates consumed in cancer cells included glucose and AAs, such as tryptophan, tyrosine, phenylalanine, lysine, valine, methionine, serine, threonine, isoleucine, leucine and glutamine [6].

IMHO, these are the ones to look out for. Glycine reduces glutamine.

Glycine restriction and supplement

Although glycine might be important for rapid cancer cell proliferation by supporting de novo purine nucleotide biosynthesis [6], glycine restriction alone didn’t have the same detrimental effect on cancer cells as serine starvation, which might be explained by the inter-conversion between serine and glycine in one-carbon metabolism by serine hydroxymethyl transferase (SHMT) [7, 16, 17], especially the mitochondrial glycine synthesis enzyme SHMT2 [6]. Interestingly, the consumption and release profiles of the NCI-60 cancer cell lines demonstrated that glycine among AAs had the most heterogeneous pattern either consumed or released, whereas serine showed relatively homogenous consumption [[6](Dietary restriction of amino acids for Cancer therapy - PMC)]. Beyond the potential role of glycine restriction in blocking the rapid growth of certain cancer cells, the dietary supplement of glycine was also reported to inhibit the growth of certain types of tumors, such as liver tumors [29] and melanoma tumors [30]. Therefore, the heterogeneous metabolism of glycine in cancer cells might account for its paradoxical effects.

What this states is that glycine starvation had no effect on cancer unlike serine. So it didn’t matter how much glycine was present for the cancer. Glycine promotes some cancers and defends against others. It’s more of a cancer profile modulator. However, if you are genetically predisposed to some of the cancers glycine is bad for, you may want to stop taking glycine and the reverse is also true.

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I have seen that study. It is cautionary. But it was done on cell lines.

Below is a study on pancreatic cancer.

Conclusion. The risk of pancreatic cancer was reduced by more than 70% in individuals with elevated levels of glycine and serine in serum collected, on average, more than 10 years prior to cancer diagnosis in a prospectively designed case-control study. These novel findings support a protective role of serine and glycine against the development of pancreatic cancer in humans that might have an implication for cancer prevention.

Glycine also reduces tumor volume in colorectal cancer.

Conclusion

Data of this study clearly demonstrates that glycine nicely decreases tumor volume. Underlying mechanisms most likely include a significantly decreased MVD in tumors. Glycine has additive indirect anti-tumor effects if given together with FOLFOX. While anti-angiogenic properties of glycine are not toxic in contrast to the clinically established drugs clinical trials are warranted to assess its value in the human settin

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