#61

An older study about natural mTOR inhibitors the study demonstrated that the amino acids that inhibited mTOR signaling and IgE-mediated mast cell activation-
histidine,
lysine,
threonine

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#62

Later study Exposure to the Amino Acids Histidine, Lysine, and Threonine Reduces mTOR Activity and Affects Neurodevelopment in a Human Cerebral Organoid Model - PMC confirms that an increased levels of the amino acids histidine, lysine, and threonine inhibits mTOR activity- so could this be a new natural mTOR inhibition stack?

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#63

I have read that magnesium L-threonate is a magnesium complex with magnesium and the amino acid L-threonine. And that Threonine is dominant part of the complex. Anyone that knows more about the chemistry?

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#64

I was adding it to my coffee every morning (two cups of strong coffee with 7g collagen and 3g glycine each, to which I added 1tsp dark cacao: I attached images of the label into the other cacao thread). But given in that thread others had rightly pointed out that the active polyphenols we desire from cacao require us to eat 50g per day (2oz seems too much per day), Iā€™m not sure my 2tsp daily was actually doing anything. Yes it tasted good, but not that much better. So I stopped ā€” no need for complications. Did I make the correct choice?

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#65

For phytonutrients, a wide variety is my goal. I donā€™t eat cacao everyday but itā€™s on my list. I also add as many spices as I can. No silver bullets or ā€œsuperfoodsā€ is my assumption.

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#66

I eat chocolate cuz it tastes good. Any benefit to health is just a bonus.

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#67

IMO its nice to have things that benefit health that also taste good. Sadly my local supermarket no longer has mint dark chocolate, but I can live with eating a small amount of 85% cocoa chocolate. That does taste good.

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#69

Hello, could you briefly give me a clue, on the idea of why zero supplements on the day 5 and 6 of rapa?

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#70

A few reasons based on no hard data. (1) fewer interactions between drugs seems like a good thing unless I specifically want an interaction, such as Metformin (I do take metformin during the part of the week of my rapa dose). (2) less chemical stress on my body. While I am taking too many chemicals (which I hope to change soon), I reduce the stress on my body by giving my body a break from nearly all non food exogenous chemicals. (3) it helps my addictive tendencies. It is actually hard to stop taking my supplements. My mind races around thinking of all the reasons I should take them. Iā€™m much better with none than ā€œmoderationā€.

Iā€™m open to other ideas but that is my reasoning at the moment. I am working on podcasts to get into this topic further.

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#71

Olafurpal:

Late reply, been on a work binge:

Thank you for your illuminating replies concerning curcumin, which I choose to accept. So I may restart curcumin, with a 4-hour time gap to my main mTOR inhibitor, as per John HenningĀ“s advice.

Below are in-vivo studies on three other substances, with the dosages highlighted. Do you have the time to comment about interaction risks with rapamycin/other mTOR inhibitors? The dosages are may be high, but mTOR inhibition appear to be central to their impact on the rodents, at least for the first two.

Coenzyme Q10 Ameliorates Pancreatic Fibrosis via the ROS-Triggered mTOR Signaling Pathway - PubMed (nih.gov) . CoQ10 was administered for 4 weeks. Isolated primary PSCs from C57BL/6 mice were treated with 100 Ī¼ M CoQ10 for 72 h

Melatonin and Rapamycin Attenuate Isoflurane-Induced Cognitive Impairment Through Inhibition of Neuroinflammation by Suppressing the mTOR Signaling in the Hippocampus of Aged Mice - PMC (nih.gov) ā€œā€¦.male C57BL/6 miceā€¦ā€¦.received 1 mg/kg/day mTOR inhibitor rapamycin solution or 10 mg/kg/day melatonin solution, respectively, intraperitoneally at 5:00 p.m. for 14 days consecutivelyā€.

Quercetin Alleviates Neuropathic Pain in the Rat CCI Model by Mediating AMPK/MAPK Pathway - PMC (nih.gov) CCI+ que group (30, 60, 120 mg/kg) (Note: inhibition of mTOR is not directly mentioned, but the article states that AMPK activation leads to mTOR inhibition which is known to (often) be the case).

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#72

Has the combination of Metformin and Rapamycin been studied?

#73

Yes - a little:

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#74

@John_Hemming On the topic of the importance of mitochondrial health, hereā€™s a thought experiment that just occurred to me to see the energy expenditure of the body for doing nothing (i.e., just maintenance). This is simplistic, but how would you make it better?

Okay, to drive home the point that the body is doing a lot just to stay alive and repair stuff. And, any problem with ATP production by the mitochondria would interfere with this demand for energy even if enough food was consumed or enough fuel storage was in place or if autophagy was functioning well. The issue at hand is the mitochondriaā€™s capacity to turn non-ATP fuel (fatty acids, glucose, lactate, ketone bodies, etc.) into ATP needed by the cellsā€¦ cells die without a continuous flow of ATP, and cells (and organs) have the ability to down regulate processes that canā€™t be fueled. If i designed the system, I would prioritize surviving for the next few seconds or minutes over surviving for the next decade or two (especially for a 60 year old).

For context:
1000 kcal per hour is an all out, kick your butt level of intensity that can only be done by very fit people. I am not confident I could do this today. Most exercise I do is between 200 - 700 kcal over 45 min to 90 minutes. This is the energy my body needs to move my 200 lbs body around vigorously for around an hour. Call it 400 kcal per hour. That is what 400 kcals buys

Letā€™s see what the body needs every 24 hours just to do regular maintenance (including the stuff needed for healthspan and lifespan). For simplicity, letā€™s ignore the energy cost of digesting food. Iā€™m also going to ignore the low energy usage of fidgeting and using the toilet, for simplicity sake. Iā€™m also going to ignore the energy needed to do extra repair and adaptation from exercise.

25 kcal per KG body weight is a rough estimate of BMRā€¦energy cost for keeping the body alive. Letā€™s say that amount includes the commonly referred to 30% used by the brain for thinking. An 80kg person would need 2000 kcal x (1-30%)= 1400 kcal to power all the body ā€œstay aliveā€ processes.

1400 kcal just to stay alive. Call it 60 kcals per hour every hour every day. Yes, 60<400, but that is a comparison of how hard I can exercise in an hour vs. doing nothing. I would have guessed a 100x difference, not a 7x.

Eating more wonā€™t help. I need to keep vast hoards of healthy mitochondria powering my repair and maintenance processes to have a healthy body for a long time.

What did this rough sketch leave out or get wrong?

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#75

It is a good perspective, but we need to work out the dimensions.

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#76

I donā€™t have time to look into this in deetail, but in short, I think the problem with these studies you linked to on CoQ10, melatonin and quercetin is basically similar in that in all cases the doses you get from supplementing them is not high enough to have a significant effect on mTOR in vivo. The CoQ10 study was in vitro, the melatonin study used a very high dose given intraperitoneally and quercetin is metabolized to a large extent in the intestines and liver so all these are unlikely to reach concentrations as high as those found to effect mTOR after ingesting them at reasonable doses.

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#77

My uninformed guess is that eating a moderate to higher protein diet and reducing mToR using Rapa and possibly other means is the best of both worlds. My reasoning: the best guess as to why low protein diets correlate/cause longevity is via mToR per se. So we want lower mToR. But we also know protein has a lot of benefits, eg satiety/caloric control (from meat per se) and promoting higher muscle mass and strength, which is why Attia and Stanfield are so stoked on it. You might argue that the mechanism by which that happens is protein causing elevated mToR per se. However, mToR being the sine que non for muscle mass/strength is refuted by the clinical evidence of Rapamycin for prevention of sarcopenia and the large amount of anecdotal evidence of people on Rapamycin who have been gaining more muscle since they started it. Iā€™ve yet to see a single anecdote of anyone reporting that they believe Rapa is inhibiting their muscle or strength building efforts.

The reason Iā€™m posting this in this thread is bc we have been discussing combo therapies, and Iā€™m treating the amount of protein consumption and Rapa as a combo therapy.

Would love to hear opposing ideas.

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#78

These are timing issues. When you eat food it is processed and the impact on different cells varies. The Rapamycin cycle depends upon its half life that varies between people, but is thought to be about 60 hours.

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#79

I think there are multiple other reasons - skim some of the papers about protein or amino acid restriction and you can get a sense.

For instance another growth vs repair signaling aspect of protein is its impact via insulin increases. See eg the first two posts here

Insulin and aging ā€“ a disappointing relationship (Paper)?

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#80

Thanks! Although I donā€™t have the knowledge to fully follow through on your reasoning, what you say seems reasonable. I will continue with several of those supplements, but to be safe will discard some, going more for intermittent dosing.

I wonā€™t burden you with studies on the remaining supplements, except if I find an indication of high enough effects on mTOR concentration in vivo at reasonable doses.

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#81

Related to this topic: Peter Attiaā€™s supplements he takes.

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