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NAC, IGF-1, and mTOR

nac mtor igf-1

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#1 mealz13

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Posted 17 March 2015 - 07:40 PM


Hi all,

 

  I recently posted about an anti-anxiety regimen in the mental health forum, but decided to take this quick question here.  I have been practicing calorie restriction and methionine/cysteine restriction and would like to know if keeping NAC in my anti-anxiety stack would off set some of my progress.  Namely, does NAC directly (or indirectly) increase cysteine in the body?  Would this have negative effects on mTOR?  I have read some studies that by glutathione production it actually inhibits mTOR, but this doesn't make sense to me?  I take about 1.2 grams x2 daily, and if it turns out that it actually increases cysteine in the body and has negative effects on mTOR I will cut down to 600mg, although it would be too bad because it helps me a lot.  Also I found a couple studies showing it increases IGF-1, which I also don't want.  Thanks for reading.



#2 Kalliste

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Posted 18 March 2015 - 07:03 PM

Fasting is partially mediated by mitochondrial ROS production. You are probably better of not using NAC while fasting.



#3 Monkey_Boy

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Posted 24 March 2015 - 03:36 AM

I was also worried about NAC and its effects on methionine/cysteine restriction. I now believe NAC actully reduces methionine.

 

Methionine and homocysteine are in equilibrium in a methylation cycle. Dietary methionine is converted to homocysteine by SAMe.

A percentage of homocysteine is converted back into methionine in the folate cycle(by b12 and folate).  The remainder of the homocysteine is converted to cysteine by B6 and serine. Cysteine leaves the system as glutatione(GHS), taurine and sulphate. Homocysteine is a very bad thing to have in circulation. Converting it back to methionine is one solution but temporary since it evenually converts back. The best way to clear homocysteine is change it to cysteine and then GHS. I think the goal of dietary cysteine restriction is to reduce homocysteine by creating a need for more serum cysteine and encourage homocysteine to convert. One of the goals of methionine restriction is to reduce homocysteine.

 

This is where NAC comes in. NAC breaks homocysteine loose from its carrier protein. Some of the NAC mixes with the homocysteine and gets excreated in urine. The rest of the homocysteine gets converted to taurine, GHS and sulphate. Supplementing with NAC reduces methione, reduces homecysteine and increases GHS. All good things.

 

Lastly, NAC can cross the blood brain barrier. There it increases neural glutathione(GHS), reduces the release of glutamate and inhibits glutamate receptors. This is why it is used to reduce anxiety.

 

I haven't found and information(yet) about NAC and mTOR but its interesting enough that I'll keep looking. I don't think NAC increases system cysteine in any meaningful way. The acetyl- group on NAC hinders its metabolism as cysteine and so does not contribute much to the distribution of cysteine in the body.

 

 


Edited by Monkey_Boy, 24 March 2015 - 03:38 AM.

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#4 Darryl

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Posted 24 March 2015 - 04:27 AM

Seems counterproductive with respect to methionine restriction. Cysteine supplementation appears to reverse benefits of MetR in leanness and mitochondrial ROS production, while N-acetylcysteine supplementation reverses MetR effects on leanness (and I'm willing to bet, would abrogate mitochondrial ROS benefits as well)

 

Elshorbagy, A. K., Valdivia-Garcia, M., Mattocks, D. A., Plummer, J. D., Smith, A. D., Drevon, C. A., ... & Perrone, C. E. (2011). Cysteine supplementation reverses methionine restriction effects on rat adiposity: significance of stearoyl-coenzyme A desaturaseJournal of lipid research,52(1), 104-112.

Perrone, C. E., Mattocks, D. A., Plummer, J. D., Chittur, S. V., Mohney, R., Vignola, K., ... & Orentreich, N. (2012). Genomic and metabolic responses to methionine-restricted and methionine-restricted, cysteine-supplemented diets in Fischer 344 rat inguinal adipose tissue, liver and quadriceps muscleJournal of nutrigenetics and nutrigenomics5(3), 132.

Elshorbagy, A. K., Valdivia-Garcia, M., Mattocks, D. A., Plummer, J. D., Orentreich, D. S., Orentreich, N., ... & Perrone, C. E. (2013). Effect of taurine and N-acetylcysteine on methionine restriction-mediated adiposity resistance.Metabolism62(4), 509-517.

Gomez, A., Gomez, J., Torres, M. L., Naudi, A., Mota-Martorell, N., Pamplona, R., & Barja, G. (2015). Cysteine dietary supplementation reverses the decrease in mitochondrial ROS production at complex I induced by methionine restrictionJournal of Bioenergetics and Biomembranes, 1-10.

 

Notably, some of these researchers found fasting plasma total cysteine independently associated with BMI, with the highest quartile associated with a five-fold greater risk of childhood obesity. Rats fed more cysteine are fatter and more insulin resistant.

 

Elshorbagy, A. K., Valdivia-Garcia, M., Graham, I. M., Reis, R. P., Luis, A. S., Smith, A. D., & Refsum, H. (2012). The association of fasting plasma sulfur-containing compounds with BMI, serum lipids and apolipoproteinsNutrition, Metabolism and Cardiovascular Diseases22(12), 1031-1038.

Elshorbagy, A. K., Valdivia-Garcia, M., Refsum, H., & Butte, N. (2012). The association of cysteine with obesity, inflammatory cytokines and insulin resistance in Hispanic children and adolescentsPloS one7(9), e44166

Elshorbagy, A. K., Church, C., Valdivia-Garcia, M., Smith, A. D., Refsum, H., & Cox, R. (2012). Dietary cystine level affects metabolic rate and glycaemic control in adult miceThe Journal of nutritional biochemistry23(4), 332-340.


Edited by Darryl, 24 March 2015 - 04:44 AM.

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#5 Monkey_Boy

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Posted 24 March 2015 - 02:48 PM

You make some excellent points. It is arguable whether using NAC increases system cysteine. The acetyl- group in NAC hinders its metabolism as cysteine and limits its first pass distribution as cysteine to the body. NAC operates by kicking homocysteine(Hcy) loose from its binding protein. Some of the Hcy is cleared without conversion to cysteine. Cysteine that is created is reduced by conversion to GSH, taurine and sulfates. Adding glycine and serine to assist this conversion would lower cysteine further.

 

Reducing Hcy and methionine are positives in themselves and reduce the pool of precursors for cysteine production. Since some Hcy is cleared without conversion to cysteine and NAC is not immediately metabolized as cysteine, both the immediate and equilibrium increase in systemic cysteine is limited. It is certainly worth finding where the final balance is struck.

 

Arguably, the reduction of methionine should reduce mitochondrial ROS.

The effect of NAC on mTOR  and IGF-1 would also be worth knowing.

-------------------------------

N -Acetyl-cysteine reduces homocysteine plasma levels after single intravenous administration by increasing thiols urinary excretion.

Ventura P1, Panini R, Pasini MC, Scarpetta G, Salvioli G.

 

Metabolism of N-acetyl-L-cysteine. Some structural requirements for the deacetylation and consequences for the oral bioavailability .

Sjödin K, et al     Biochem Pharmacol. (1989)

 

N-acetylcysteine in psychiatry: current therapeutic evidence and potential mechanisms of action . J Dean O, Giorlando F, Berk M         Psychiatry Neurosci. (2011)


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#6 Monkey_Boy

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Posted 26 March 2015 - 03:18 AM

Note that 1800mg day is a high dose for long term use, close to or at max non-toxic dosages.

800mg/m2/day is the max long term dose from one study I saw and I wont take that much myself.

 

--------------------------

Urinary and plasma homocysteine and cysteine levels during prolonged oral N-acetylcysteine therapy.
Ventura P, Panini R, Abbati G, Marchetti G, Salvioli G.

Department of Internal Medicine, Chair of Internal Medicine II, University of Modena and Reggio Emilia, Modena, Italy.


Acute administration of N-acetylcysteine (NAC) may induce alterations in plasma and urinary levels of homocysteine (Hcy) and cysteine (Cys). We studied the effects of continuous oral NAC therapy on different Hcy and Cys plasma and urinary forms in 40 healthy subjects assigned to three groups (groups A: n = 13, no therapy; group B: n = 14, NAC 600 mg/day, and group C: n = 14, NAC 1,800 mg/day) for 1 month (T(1)). After a 1-month washout period without therapy (T(2)), all subjects were treated with oral NAC (1,800 mg/day) for 2 months and (T(3) and T(4)) reassessed monthly for plasma and urinary thiols. The treated subjects showed a significant decrease in plasma total Hcy and a slight increase in total Cys levels; the alterations of different forms of plasma thiols suggested an NAC-induced increase in disulfide forms and an increase in urinary Hcy and Cys excretion as disulfide forms. The effects appeared to be dose dependent, being more marked in subjects treated with higher dosages. This approach may be important, as an association or alternative therapy in hyperhomocysteinemic conditions of poor responses to vitamins. Copyright 2003 S. Karger AG, Basel


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#7 Monkey_Boy

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Posted 31 March 2015 - 10:16 PM

Apologies and pardon my OCD but I’m going to do one more post on this subject.

 

First, here is the dosing study I mentioned above.

Vol. 4, 245-251, April/May 1995

Cancer Epidemiology, Biomarkers & Prevention 245

Pharmacokinetic and Pharmacodynamic Studies of N-Acetylcysteine, a Potential Chemopreventive Agent during a Phase I Trial”

L. Pendyala2 and P. J. Creaven

 

They found that 800 mg/m2/day is the maximum constant dose without side effects in all subjects and that no increase in Cysteine(Cys) was found at that dose.  The other studies that I found reporting increased Cys after NAC were using larger doses. (This study also found that at a lower dose of 400 mg/m2/day not all subjects saw an increase of Glutatione(GHS).)

 

Second,mTOR.

I found lots of studies where increased GHS decreased mTOR.  One Lupus study was testing NAC to stop T-cells from going rogue by the decrease in mTOR.  They are easy to find, so no citations.

 

Third IGF-1.

I found this study in PubMed using oral glutamine(GLN) instead of NAC.

 

Effect of glutamine on glutathione, IGF-I, and TGF-beta 1.

Johnson AT1, Kaufmann YC, Luo S, Todorova V, Klimberg VS.

 

They state “GSH is counter-regulatory to IGF-I”

also

“Oral GLN increased significantly blood, breast tissue, and gut mucosa levels of GSH in both DMBA and control groups in comparison with the control groups not treated with GLN. At the same time, the levels of blood IGF-I and TGF-beta 1 decreased significantly”

 

The several websites I found claiming the opposite (GHS increases IGF-1), all looked to be selling something.

 

I think increasing GHS decreases mTOR and likely IGF-1. I also think NAC can be used to do this without increasing Cysteine. I’m currently supplementing with NAC and R-Alpha Lipoic Acid to increase my GHS levels.  I also constantly tinker, based on new information. Since cysteine increases body fat,  I might stop for a month or two and monitor my fat ratio.


Edited by Monkey_Boy, 31 March 2015 - 10:17 PM.

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#8 mealz13

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Posted 03 April 2015 - 10:32 PM

Thanks all for responding.  I think I will still supplement but at a lower dose than I originally planned; I'm hoping I will still get the desired effect for anxiety  :wacko:



#9 monoracer33

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Posted 03 May 2018 - 08:46 AM

I was also worried about NAC and its effects on methionine/cysteine restriction. I now believe NAC actully reduces methionine.

 

Methionine and homocysteine are in equilibrium in a methylation cycle. Dietary methionine is converted to homocysteine by SAMe.

A percentage of homocysteine is converted back into methionine in the folate cycle(by b12 and folate).  The remainder of the homocysteine is converted to cysteine by B6 and serine. Cysteine leaves the system as glutatione(GHS), taurine and sulphate. Homocysteine is a very bad thing to have in circulation. Converting it back to methionine is one solution but temporary since it evenually converts back. The best way to clear homocysteine is change it to cysteine and then GHS. I think the goal of dietary cysteine restriction is to reduce homocysteine by creating a need for more serum cysteine and encourage homocysteine to convert. One of the goals of methionine restriction is to reduce homocysteine.

 

This is where NAC comes in. NAC breaks homocysteine loose from its carrier protein. Some of the NAC mixes with the homocysteine and gets excreated in urine. The rest of the homocysteine gets converted to taurine, GHS and sulphate. Supplementing with NAC reduces methione, reduces homecysteine and increases GHS. All good things.

 

Lastly, NAC can cross the blood brain barrier. There it increases neural glutathione(GHS), reduces the release of glutamate and inhibits glutamate receptors. This is why it is used to reduce anxiety.

 

I haven't found and information(yet) about NAC and mTOR but its interesting enough that I'll keep looking. I don't think NAC increases system cysteine in any meaningful way. The acetyl- group on NAC hinders its metabolism as cysteine and so does not contribute much to the distribution of cysteine in the body.

This is very informative. I really want to use NAC to reduce my anxiety and high homocysteine levels as well as to increase GSH. I do have CBS/BHMT hetero mutations and am concerned about taking anything high in sulphur. Any advise?



#10 John250

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Posted 01 June 2018 - 06:03 PM

I use 500mg NAC 2x/day and just got bloodwork for Methylmalonic Acid, MMA and Homocysteine to see if my b12 was effected.

Methylmalonic Acid result 3.6 range 1.6-29.7
MMA Normalized result 1.6 range 0.4-2.5
Homocysteine result 4.6 range 0-15

I was not using any B 12 supplements but I just started methyl B 12 5000mcg from Jarrows

Edited by John250, 01 June 2018 - 06:03 PM.






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