I fall asleep easily. It is the sleep after the morning pee that needs some help.
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Agreed, tumor decline is greater on melatonin alone. No dispute there, like I said. But the text of the authors is what I misunderstood. This is what they said, that made me conclude that there is no tumor reduction if melatonin and glycine are combined.
Melatonin and glycine alone significantly reduced the tumor volume by 63.2% (p = 0.002) and 43% (p = 0.044) over time, respectively, while tumor volume increased by 8.7% in the controls. Moreover, treatment with melatonin and glycine alone reduced the tumor proliferation index. Most interestingly, the combination therapy did not have any influence on the above-mentioned tumor parameters.
I thought it meant no tumor reduction from the combo. But their numbers show the following:
3.3. Change in Tumor Volume
We observed an 8.7% (−17.5; 40.9) increased tumor volume in the control group and a 63.2% (−3.1; 71.1) decreased tumor volume in melatonin, 43% (−12.6; 70.1) in glycine, and 47.7% (−116.9; 60.6) in combined supplementation with melatonin and glycine at day 8 vs. day 14.
So I summarized that as:
a decrease in tumor volume of
63.2% for melatonin,
43% for glycine; and
47.7% for the combo.
Based on the numbers, II take the sentence “Most interestingly, the combination therapy did not have any influence on the above-mentioned tumor parameters” to mean the combo did not provide synergistic effects, such that it did not improve over melatonin alone, or only marginally improved over glycine alone. They actually state that in their conclusion.
the combined supplementation with these nontoxic substances did not yield additive effects.
But there is a 47.7 reduction in tumor volume by the combo (in rats). So I opined above, that I am happy with that, but want to chase the other benefits of glycine, shown in human studies. So I am willing to forego the additional benefit (in rats) of melatonin alone (63% versus 47.7%).
The sample size is too small
The rats were randomly assigned to either sham groups (n = 10/group) or experimental groups (CRLM; n = 15/group).
to make any conclusions, except
This study suggests an inhibitory function for melatonin and glycine alone in the case of CRLM growth by acting as natural antiangiogenic molecules, with a following angiogenesis-dependent cancer proliferation and immunomodulation. In spite of the fact that dietary melatonin and glycine given separately exert anticancer effects, the combined supplementation with these nontoxic substances did not yield additive effects. To explain these findings, further investigations are warranted.
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NAC is the one thing I’d worry about taking with mTOR downregulators. Not because it’s a mTOR upregulator (cysteine which it is metabolised to is actually an inhibitor or mTOR) but because it’s a powerful antioxidant with a relatively long half life.
It’s been shown to repress the cellular oxidative stress glucosamine and Ashwagandha cause from mTOR downregulation. In doing so it inhibits the protective response of the cells that is likely the key piece of the lifespan enhancement puzzle. In one mouse trial it completely nullified the lifespan gains glucosamine gave.
Well it’s not the only one I’d avoid. Leucine too. I don’t think anyone takes that as a supplement for longevity unless I’m mistaken though.
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Leucine is part of most protein sources.
Yes I just mean as a supplement. I know It’s the most abundant amino acid (and pretty important). Fortunately it’s got a very short half life so isn’t much of an issue TBH. I just wouldn’t take a capsule of it at the same time as glucosamine for example.
Very interesting. When you talk about the relatively long half life. Do you mean the half of the glutathione increase following NAC? Or the half-life of nac itself?
I assume the former is the relevant one?
I guess my overarching question is: can we cycle nac+glycine and rapamycin, and if so how long a break in nac plus glycine prior to “rapamycin day”?
NAC itself. I don’t think glutathione is the factor here. NAC on its own is a free radical scavenger in the blood before it’s broken down. Its half life is approx 6 hours after an oral dose so not very long but long enough to counteract a lot of the effects of shorter mTOR inhibitors like glucosamine, astaxanthin and ashwagandha for example. Rapamycin of course lasts forever so less of an issue.
Glycine half life is super short so I wouldn’t worry about that at all. It’s not clear it has any nullifying effect either. Rapamycin lasts so long it’s hard not get some overlap with NAC unless you take NAC only like 1/2 days a week. If you choose shorter term mTOR inhibitors you can take stuff 3 times a day with not too much overlap of half-lives. I want to start astaxanthin but am worried it might do the same thing to glucosamine (which IMO is the molecule we have the most evidence for geroprotection in humans for) that NAC does. Going to try space out Ashwagandha, glucosamine, astaxanthin and NAC. Taurine, glycine, etc I don’t care too much when I take because they’re metabolised in minutes.
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Upon further reading I’m less concerned about astaxanthin now. It’s an antioxidant but not an autophagy inhibitor. In fact it’s the opposite. NAC really is the only supplement I take that is an autophagy inhibitor. Need to time it well.
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I believe you are right with your concern. Thanks for sharing. I agree that we need to be very careful with NAC. I wonder if we can say something about the doses? Would eg. 300 mg NAC a day be safe? But what a pity, as the other trials in favor of GlyNAC are so promising!
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Interesting papers but… The dose makes the poison…:
- The 2020 Taiwanese study on OA says “Moreover, because data on the dose and administration forms of oral NAC (e.g., oral granule or oral effervescent tablet) were not available in the NHIRD, the dose-response relationship could not be determined.”.
- Also, this study is weird because they don’t say the reason why people take NAC. Maybe they think they can cure OA with it, in that case it’s obvious that these people have more OA.
- The 2019 French study on lung adenocarcinoma says 40 mM, that’s 6.5 g FOR A NEWBORN MOUSE! Given even before birth: “A group of pregnant females received N-acetyl-L-cysteine (MilliporeSigma) dissolved at 40 mM directly in the drinking water. Newborns continued drinking NAC after weaning, until the age of 4 months (young group) or 12–18 months (aged group).” That’s 1 kg per day for an adult human?! Or did I make a mistake?
- The 2015 Swedish study about melanoma: I don’t have access to it, but this paper (Effect of N-Acetylcysteine on Cisplatin Toxicity: A Review of the Literature 2023) citing it says: “There is controversy surrounding the involvement of antioxidants and ROS in cancer. Epidemiological studies on synthetic antioxidant supplementation are inconclusive and contradictory due to the antioxidant versus prooxidative properties of antioxidants and the involvement of antioxidants in intracellular signaling and redox regulation, which modulate proliferation, apoptosis, and gene expression.”
So it’s might not be as bad as it sounds…
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The latest study from May 2023 on the effects of GLYNAC on cognitive function.
The key findings of this study are that (1) compared to young mice, old mice have (a) cognitive impairment, (b) brain abnormalities with GSH deficiency, elevated OxS, impaired mitochondrial function, abnormal mitophagy and autophagy, diminished glucose transporters/uptake, elevated inflammation and higher genomic damage; (c) low brain neurotrophic factors (BDNF, GDNF and NGF); and (2) supplementing old mice with GlyNAC improved/reversed these brain defects, and improved cognition.
Glycine and NAC have a positive correlation to improved cognitive function. The Blue (Y) group is young mice. The Red (OC) and Green (OG) are old mice. OC is control. OG is old mice receiving GLYNAC. Pre is before receiving GLYNAC. Post is after. As you can see, GLYNAC reduced errors and helped mice navigate the maze almost as well as a young mouse!
The old-control mice had 69% (p < 0.001) lower total-GSH concentrations, and 75% (p < 0.05) lower reduced-GSH concentrations compared to young mice. Compared to old-control mice, the GlyNAC supplemented old mice had 156% higher total-GSH concentrations (p < 0.01) and 204% higher reduced-GSH concentrations (p < 0.001), and these results were not statistically different from values in young mice. There were no differences in oxidized glutathione concentrations (GSSG) between the three groups (Figure 3, Table 1).
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I’m sceptical of all of this research coming out of Baylor. Pretty much all the positive longevity studies on glyNAC are from that team and guess what? They have a patent on glyNAC. Hoping the ITP tests it.
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I’m aware that the ITP has tested glycine. It’s NAC I’m concerned about though. Lots of evidence it counteracts the mTOR inhibition benefits of rapa, glucosamine and Ashwagandha.
My father and I have been taking glycine and NAC for over a year. My father’s Glutathione levels are 945 which is amazing for his age. His levels are higher than most twenty somethings. Based on our blood work, it appears to work as promised. There is other literature available from other sources as well regarding the effects of glutathione.
There probably isn’t too much research into glycine and NAC due to both being inexpensive and readily available amino acids. But that doesn’t mean it doesn’t work.
Raising glutathione is one thing. It doing anything beneficial to people without any deficiency or morbidity is another. Further, it blocking the autophagic effects of rapamycin is again another question altogether.
I’d be happy to read any research outside of Baylor you can share as I have a lot of it and would love a reason to start taking it again.
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You can reference Dr. Patel’s advice on Glutathione. He is not associated with Baylor but he’s another researcher in this space. His RCT on glutathione is in progress but was delayed by COVID. Taking Glycine and NAC is the best way to raise Glutathione (GSH), so this is all interrelated.
Key points:
- When you have a disease (diabetes, hyperlipidemia, COVID, cancer, etc…), your glutathione levels decrease.
- If they decrease too much you can get cytokine storms and other harmful effects.
- Glutathione production decreases at age 30.
- Glutathione demand does not decrease and even gets larger with age.
- Senescent cells create a greater demand for glutathione.
- Glutathione production can be increased by taking Cysteine, Glycine along with NAD.
- Direct glutathione supplements are a bit sketchy right now so best to take the precursors in 6. above.
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Thanks, I’ll check it out. I do note he’s also got a patent on a topical cream however. History has made me very wary of anyone trying to sell anything in the longevity space.
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I apologize for not following up with my experience. I have continued 100mg NACET daily for this entire time, along with 6g glycine, and a few other things I add and drop (12mg astraxanthin, 5000 IU vit D, 1mg finasteride, and 400mg Mg; 5g creatine now stopped due to taste and inconvenience but probably starting again). My “sore knees have gone away and caused likely that I started heavy lifting centered around deadlifts and not NAC. I occasionally get other soreness related to heavy deadlifts in different part of my legs (such as ligaments, muscles), but not being stupid and allowing time to recover and heal seems to work for me. So for me, I’m not sure NAC is an issue.
As part of this, I don’t look like a “muscle guy” ( cue @Agetron and @desertshores on the body building stage) and I’m not trying to become “big” (or “ripped” as the gen x-ers say, or “swol” as the Millennials say or “swol bruh’ as the gen z-ers say) — just “solid”, “athletic” and “healthy” looking (and actually healthy) — but in less than one year in December I reached my goal of squatting 2x my body weight (335 lbs in 2x 2 reps). It’s not Wolverine or Captain America levels, but for me that’s a huge improvement; there was a small crowd of people gathered around our small gym, mostly because there were a lot of plates for that gym and I really don’t look like a body builder, so that was pretty funny.
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If you haven’t tried a boswellia serrata supplement you should give it a try.
Oddly, it has a special affinity for reducing knee pain.
Boswellia Serrata Extract offers several health benefits, including:
Reduction of Inflammation and Pain:
Contains boswellic acids with anti-inflammatory properties.
Reduces knee and joint pain.
Clinical studies indicate effectiveness in reducing pain and improving symptoms in osteoarthritis and rheumatoid arthritis patients.
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Sadly it seems herbal supplements and I do not mix. I’ve developed allergies from most of them.