Would Trimethylglycine(Betaine) also help in this scenario? I assume it does not fix the the ATIC issue but could correct the high homocysteine. Thank you for great information!
A dose-response RCT by Olthof et al. (Journal of Nutrition, 2003, n=76) showed that 6 weeks of daily betaine reduced fasting homocysteine by 12% at 1.5 g, 15% at 3 g, and 20% at 6 g compared to placebo. Stacked with folinic acid and methylcobalamin in the context of MOTS-c use, the three compounds cover the recycling pathway from every available angle (unless there are more!!??). Very good catch, I'll definitely be adding this to my list of recommendations.
Awesome article as always! I was one of those supplementing with methylfolate to (unsuccessfully) overcome the fatigue issues. Will buy the other two supplements now. Thanks!
I have the MTHFR gene and take high levels of a prescription product, EB-C3. My homocysteine level is low. My naturalpath said I could take Mots-c. Now I'm confused and paid $240 for the 40mg vial and was prescribed 0.5ml 3x a week. I usually take the EB-C3 daily. I'm confused with all of this. help. please.
I can't even find leucovorin for sale in my country. It's available via Amazon but the 15 mg tablets are like 13 € each. Almost 400 € for a month's supply. LOL!
iHerb sells folinic acid supplements but the doses are like 800 mcg, a far cry from the recommended 5-15 mg. I don't think I'll be stuffing my face with 20 of these losenges at once.
I tend to have high homocysteine levels. I took my first MOTS-C dose and felt awful. I’m going to add the two supplements you suggested, but I’m still a little nervous about my homocysteine.
Re-reading this article and graphs, I focused on how MOTS-c blocks ATIC, which in turn causes AICAR to accumulate. Just realized that many peptide vendors sell AICAR (one example has 50mg per vial). Would taking AICAR directly instead of MOTS-c prevent this whole issue, causing fat burning without blocking ATIC and having to take leucovorin and methylcobalamin? If so, any idea on dosage for AICAR? From what I’ve read, starting dosage is 10-20mg per day, titrating to 50mg/day depending on tolerance.
On paper, skipping straight to AICAR looks like a great alternative. You get the AMPK activation without MOTS-c needing to block ATIC and disrupt the folate cycle to get there. The problem is that AICAR is an extremely blunt instrument and MOTS-c is a surgical (in comparison, anyways). MOTS-c acts catalytically on the folate-methionine cycle at low concentrations, causing AICAR to accumulate endogenously in the tissues where MOTS-c naturally distributes (primarily skeletal muscle and metabolic tissue), and the folate disruption that comes along for the ride can be managed with leucovorin and methylcobalamin.
Exogenous AICAR has none of that selectivity. It floods every tissue equally through systemic distribution, activating AMPK in muscle (where you want it) and in cardiac tissue and the brain (where excessive activation carries neurodegenerative and cardiotoxic risk at higher exposures).
As far as dosing, cardiac surgery trials ran 42 mg/kg intravenously, roughly 3 grams for an average adult, and the mouse endurance data that made AICAR famous used the human equivalent of 35 grams. I'm not sure if a few milligrams subcutaneously may cross the activation threshold at all, and from the anecdotes I have read, everything points to MOTS-C just being better.
Have you read otherwise? Is AICAR still something you'd explore? If I'm missing anything, please let me know!
In fact, I asked Grok yesterday after I posted this and it gave me a very similar answer. Just wanted to hear it from someone who knows what he’s talking about. Thanks!
Would Trimethylglycine(Betaine) also help in this scenario? I assume it does not fix the the ATIC issue but could correct the high homocysteine. Thank you for great information!
A dose-response RCT by Olthof et al. (Journal of Nutrition, 2003, n=76) showed that 6 weeks of daily betaine reduced fasting homocysteine by 12% at 1.5 g, 15% at 3 g, and 20% at 6 g compared to placebo. Stacked with folinic acid and methylcobalamin in the context of MOTS-c use, the three compounds cover the recycling pathway from every available angle (unless there are more!!??). Very good catch, I'll definitely be adding this to my list of recommendations.
Nice tip. I will try that route because it's easier to get than a prescription med.
I was about to post the same idea
Awesome article as always! I was one of those supplementing with methylfolate to (unsuccessfully) overcome the fatigue issues. Will buy the other two supplements now. Thanks!
Would OTC Folinic acid work if you don’t have access to a Leucovorin Rx?
I have the MTHFR gene and take high levels of a prescription product, EB-C3. My homocysteine level is low. My naturalpath said I could take Mots-c. Now I'm confused and paid $240 for the 40mg vial and was prescribed 0.5ml 3x a week. I usually take the EB-C3 daily. I'm confused with all of this. help. please.
I can't even find leucovorin for sale in my country. It's available via Amazon but the 15 mg tablets are like 13 € each. Almost 400 € for a month's supply. LOL!
iHerb sells folinic acid supplements but the doses are like 800 mcg, a far cry from the recommended 5-15 mg. I don't think I'll be stuffing my face with 20 of these losenges at once.
I tend to have high homocysteine levels. I took my first MOTS-C dose and felt awful. I’m going to add the two supplements you suggested, but I’m still a little nervous about my homocysteine.
Very interesting… For someone who was only wanting to take a one off 10mg over 4 weeks- could they get away without supplementing with these 2 things?
Would you recommend it to someone who is not working out consistently?
Re-reading this article and graphs, I focused on how MOTS-c blocks ATIC, which in turn causes AICAR to accumulate. Just realized that many peptide vendors sell AICAR (one example has 50mg per vial). Would taking AICAR directly instead of MOTS-c prevent this whole issue, causing fat burning without blocking ATIC and having to take leucovorin and methylcobalamin? If so, any idea on dosage for AICAR? From what I’ve read, starting dosage is 10-20mg per day, titrating to 50mg/day depending on tolerance.
On paper, skipping straight to AICAR looks like a great alternative. You get the AMPK activation without MOTS-c needing to block ATIC and disrupt the folate cycle to get there. The problem is that AICAR is an extremely blunt instrument and MOTS-c is a surgical (in comparison, anyways). MOTS-c acts catalytically on the folate-methionine cycle at low concentrations, causing AICAR to accumulate endogenously in the tissues where MOTS-c naturally distributes (primarily skeletal muscle and metabolic tissue), and the folate disruption that comes along for the ride can be managed with leucovorin and methylcobalamin.
Exogenous AICAR has none of that selectivity. It floods every tissue equally through systemic distribution, activating AMPK in muscle (where you want it) and in cardiac tissue and the brain (where excessive activation carries neurodegenerative and cardiotoxic risk at higher exposures).
As far as dosing, cardiac surgery trials ran 42 mg/kg intravenously, roughly 3 grams for an average adult, and the mouse endurance data that made AICAR famous used the human equivalent of 35 grams. I'm not sure if a few milligrams subcutaneously may cross the activation threshold at all, and from the anecdotes I have read, everything points to MOTS-C just being better.
Have you read otherwise? Is AICAR still something you'd explore? If I'm missing anything, please let me know!
In fact, I asked Grok yesterday after I posted this and it gave me a very similar answer. Just wanted to hear it from someone who knows what he’s talking about. Thanks!