Creatine, Rapamycin and mTOR c1 (and the aging brain)

OK do I have this right: Creatine upregulates mTOR c1. It may have neuro-protective effects (among other benefits. Rapamycin downregulates mTOR c-1. It may have neuro protective effects. But if one pushes go and the other pushes stop, do they cancel each other out? Anyone here taking both? or concerned about this issue?
I do understand that everything is a tradeoff. Me personally: I want to minimize the possibility of neuro degeneration. I care much more about that than increasing longevity. I do not have the APOE4 gene but I do have family history,
Please let me have your thoughts . . .

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Lots of speculation here, but it seems reasonable to think that it’s not that mtor is straight up bad, but it’s that chronically elevated mtor is bad. With age, mTor becomes chronically elevated rather than pulsed as it is in youth and there is no opportunity for cells to repair and clear because the growth program is constantly elevated.

Again we’re flying blind here but I don’t think creatine would necessarily be bad and could probanly work into a weekly rapamycin cycle, just probably not taken at the same time.

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There are IMO arguments to cycle various things in various ways. One in some ways is an anabolic/catabolic cycle. Rapamycin would be part of the catabolic.

There is, however, a complexity in that you need the genome to function fully to enable autophagy hence there is an argument for supplementing for gene expression for a period of time during the catabolic phase.

I am currently juggling in my mind whether to use creatine at the same time as AMPK activators. To cover all bases it might be worth having a more complex cycling.

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Yes - it seems best to alternate. There have also been discussions on this topic in the past: Rapamycin and creatine (Counter-productive?) - #4 by DeStrider

related: Creatine for new user - #3 by JazzMann

Search on Pubmed on creatine and mTORC1 for more info:

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How on earth do you ‘alternate’?

Everything I’ve read about creatine says you need a loading dose. Just how would ‘alternating’ work, and be effective?

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Take 5g/day for like for ever of load with 20g/day for about a week then take 5g/day, it doesn’t really really matter in the long rung unless you need to perform in 2 weeks

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Exercise is also neuroprotective and activates mTOR in the brain and muscle, but lowers in the liver and fat. It’s possible that it’s this selectivity that is protective. That’s why personally I think proper diet and exercise is >>>>>>>> rapamycin.

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“Creatine is a compound that comes from three amino acids (glycine, L-arginine, and L-methionine ). Creatine is found mostly in your body’s muscles as well as in the brain. Most people get creatine through seafood and red meat — though at levels far below those found in synthetically made creatine supplements. The body’s liver, pancreas and kidneys also can make about 1 gram of creatine per day.”

“Your body stores creatine as phosphocreatine primarily in your muscles, where it’s used for energy.”

“Recent studies have shed light on potential mechanisms by which creatine supplementation may impact the Akt/mTOR pathway. These mechanisms provide insights into the molecular pathways through which creatine supplementation may influence muscle protein synthesis and hypertrophy.

One proposed mechanism involves the upregulation of insulin-like growth factor 1 (IGF-1) expression. Creatine supplementation has been shown to enhance IGF-1 signaling, which can activate the Akt/mTOR pathway and promote muscle protein synthesis [16]. IGF-1 is a potent growth factor that stimulates muscle growth and regulates protein synthesis. By increasing IGF-1 expression or signaling, creatine supplementation may amplify Akt/mTOR pathway activation, leading to enhanced muscle protein synthesis and hypertrophy.

Another potential mechanism involves the modulation of intracellular energy status and ATP availability. Creatine supplementation increases intramuscular creatine and phosphocreatine (PCr) levels, which can enhance cellular energy reserves [34]. This increased energy availability may positively impact the activation of mTOR and its downstream targets involved in protein synthesis. Adequate ATP levels are necessary for optimal mTOR signaling, and by maintaining higher ATP levels, creatine supplementation may support the sustained activation of the Akt/mTOR pathway and promote muscle protein synthesis.

These proposed mechanisms highlight the multifaceted effects of creatine supplementation on the Akt/mTOR pathway. By influencing IGF-1 expression and signaling, as well as intracellular energy status, creatine supplementation may provide a favorable environment for the activation of the Akt/mTOR pathway and subsequent muscle protein synthesis and hypertrophy.”

Sounds like a supplement to take off-cycle with rapa.

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FWIW I’ve used Creatine for many years. It was not the first supplement I tried to help - prepare and partake in - endurance training and events, but it’s certainly one of the most trusted.

I don’t compete anymore but I do HIIT training every Monday, Wednesday and Friday and take creatine 90 minutes before training only on these days.

For the last two years, I’ve been taking Rapa and settled on 6mg a week for four weeks and I cycle off for two or three weeks.

My comprise for the conundrum of Creatine and Rapa together, is to take Rapa post HIIT training on Friday.

My reasoning: Creatine has a relatively short half-life of 3 hours. It’s largely gone by noon on Friday when I take 6mg Rapa (63 hour half-life). I have no more Creatine until Monday morning HIIT training. This gives Rapa about 60 hours all to itself.

There are many unknowns about what we are all doing with self- biohacking but this works for me. I think I’m getting the benefit of both Rapa and Creatine and I’m feeling healthy, fit and happy.

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Just don’t take creatine on the day you take rapamycin. (assuming you are not a daily dosing with rapamycin)

“Creatine has a relatively short half-life of 2.5–3 hours, meaning that after this time, the concentration of creatine in the body will be reduced by 50%. To maintain elevated plasma levels, small oral doses should be taken every 3–6 hours throughout the day”

Though, I do wonder who wins the tug of war if taken at the same time.

As for loading, there is some controversy surrounding this. Personally, I just double the dose the next day. I take creatine because I am not an athlete and I am trying to avoid sarcopenia.

“But creatine supplements are rarely essential for athletes since your body actually produces creatine on its own and it can also easily be obtained through a diet of whole foods. More specifically, creatine is produced in your liver, kidneys, and pancreas, then stored as phosphocreatine in your muscles.Feb 1, 2022”

“Your body makes creatine from three key amino acids: glycine, arginine, and methionine. And while red meat and salmon are great sources for amino acids and creatine, vegetarian-friendly eggs provide a massive amount of these amino acids as well.”

Maybe, just eat an egg the next day?

Do Athletes Really Need Creatine Supplements? | U.S. Anti-Doping Agency (USADA).

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Is it only about the three hour half-life of ingested creatine, or does the above matter?

By taking creatine, one seeks to increase these stores. Would not those stores also act against rapa effect? If yes, then I don’t see where just stopping for a day would accomplish much.

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True. And, stopping creatine for a day wouldn’t hurt your efforts to be stronger either.

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Until we have an accurate and easy way to measure mTORC1, we won’t know.
But since rapamycin seems to be working for those in the forum with a lot more muscle than me, maybe creatine in the muscle doesn’t matter.

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Just my subjective view:

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I am questioning the wisdom of using creatine with rapamycin. I am using 8mg of rapamycin weekly and cycling. My reason to use it is longevity. If i get the benefits of muscle strength retention it’s a plus.
I tried to order from forveda but they did not list rapamycin or sirolimus.

Is Joseph related to jim lavelle the pharmacist /nutritionist?

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No. Jim Lavalle is Italian. Joseph Lavelle is Irish. Jim was a guest on the WiseAthletes podcast…we had fun with the name similarities.

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Refined carbohydrates, like white flour, white rice, and sugars can raise IGF-1 levels , because they cause rapid increases in insulin levels, leading to increases in IGF-1 signaling.
Higher blood levels of IGF-I (Insulin-like Growth Factor), in older men was associated with increased risk of cancer death.

So Creatine raising IGF is good but sugars raising IGF is bad ?
This is the problem with taking things to the extreme like KETO diet or wearing CGM and avoiding any insulin spikes. Occasional spikes from fruit or occasional sweets may be actually warranted for health.

BCAA’s, Creatine and glycemic foods can activate mTOR.
Exercise is a selective mTOR activator.
Rapa is a mTOR inhibitor.
Other factors to lesser degree and undiscovered.

This is why it’s nearly impossible to figure the proper lifestyle based on molecular biology, we don’t know enough.

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In the end it come down to genomic function. This require cycling.

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What are your Ampk activators?