Inquiry Regarding Rapa, Metformin, Acarbose, and Their Alignment with My Conditions

Supplements
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#21

You’re taking quite a big stack of supplements. I would carefully add additional drugs/supplements one-by-one and test them if they meet your target goals

  • LDL 115 mg/dL would be considered on a higher side (if you consider PESA study where the safer levels appears to be under 60 mg/dL). Many people on this forum (including myself) take Rosovastatin 5mg, and to get additional lipid lowering effect (without needing to bump up statin dose), you could add Ezetimibe 10mg, and if necessary Bempedoic acid 180mg as well. You could add one or two of these, take them for a couple of weeks, and test your LDL-c or Apo(B) levels (which are cheap tests to do) and see what sort of lipid lowering effect you get, and then titrate accordingly. Psyllium husk (if you can tolerate fibre) can also offer a small lipid loweing effect

  • Note that Berberine that you’re taking also has a small lipid lowering effect. I would suggest dihydroberberine (instead of regular berberine) due to better absorption, and smaller 1/5th dosage will do the same job, and much less chances of developing liver toxicity (in theory, I haven’t tested that).

  • For rapamycin, I suggest starting with a very low dose (1mg or 2mg per week) and gradually work your way up to your target dose (the popular range for people this forum is roughly 5mg-8mg). Look out for any side effects. There are many blogs on this forum to get started.

  • You haven’t shared any info on your metabolic parameters (like fasting insulin and HBA1C). I assume you want to include metformin and acarbose for generally longevity effects. For some people, these drugs can mitigate the potential hyperglycaemic response (which may be a benovalent response) to taking rapamycin. But in my case, rapa doesn’t seem to affect my glucose parameters. In your case, as a very active individual following a good diet, you may want to decide if you really need these drugs

  • Given your methylation is impaired (which is the case with me as well, heterozygous for MTHFR A1298C), some of the methylation support supplements you’re taking makes sense. E.g. L-methylfolate, TMG, Alpha-GPC

  • I agree with the comment already mentioned on this page that Glycine + NAC as precursors to glutathione (indirect effect), may be a better option compared to taking glutathione (direct effect), so that the body can regulate and produce enough glutathione on a supply-demand basis. In addition, oral gluathione brands are generally poorly absorbed

  • Urolithin-A: The science for this doesn’t appear to be very strong. Some people anecdotally claim benefits, but it is hard to tell. Also very expensive

  • In terms of some of the other supplements you’re taking (such as plant phenols and antioxidants), there is mixed opinion as to whether they are needed / move the needle. E.g. CoQ10, Vitamin C, Bacopa, probiotics, etc. But if they’re helping with your conditions, then well and good.

In general, keep an eye on liver enzymes and kidney function tests (both cheap tests) when you’re taking a lot of drugs and supplements.

Just my 2 cents

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#22

@snax444 You took the words right out of my mouth. Excellent post! :slight_smile:

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#23

Hello, and thanks for your generous insights—I really appreciate it!

  • LDL: I’m not doing too well—my levels have been hovering between 115 and 121 in my last two tests, despite berberine (I didn’t know about the dihydro form, I will look into that!), omega-3, exercise, and a solid diet. I’ve been discussing pharmacological options with my doctor, but so far, I’ve only managed to get prescribed ezetimibe, which I doubt will be enough to reach ~70. He proposed a statin, but I’ve read here that they affect desmosterol and are not recommended for APOE4 carriers. I’d much rather follow your suggestion of BA + ezetimibe (NEXLIZET) - thanks a lot for that! Now I just need to convince him…

  • HbA1c: Currently at 5.5%. Fasting glucose ranges from 84 on a good day to 100 on a bad one. I hit 199 after a 200g carb meal, which pushed me to start metformin 4x/week based on the info I found here. I’m happy with the results and think I can optimize my A1c at ~5% or lower. I’ll test again soon. It also seems beneficial for improving leaky gut, and I kind of feel it.

  • Methylation: This is an ongoing battle. A few months ago, my homocysteine was at 14 (range 4-15.40), and I managed to bring it down to 11.8 by increasing TMG to 1g. Now I’m upping it to 2g, hoping to get below 10 and closer to 9. My folate was at 14.9 (range: 4.6–18.7) and B12 at 357 (range: 191–663). I think I could increase B12 a bit and want to switch to hydroxocobalamin, which seems optimal for MTHFR and COMT. How are you managing your homocysteine and related markers with MTHFR?

  • Rapamycin: I’ve been tempted for a while but I am unsure how I’ll handle my lipids—especially given my genetic predisposition to diabetes, and also my glucose…

  • Glutathione: My GPX levels came back low (21.2, reference range: 76–904). Poor oral absorption is a real issue, and I can’t get the recommended suppository shipped to Italy. I might move to Tationil injections for a quicker boost, though they require some prep. Waiting on my latest test results - I’ve recently switched from liposomal glutathione to S-acetyl-glutathione. I take glycine and NAC daily, but they don’t seem to be enough on their own.

  • Antioxidants: I’m now looking for a more structured cycle for some of them. My NRF2 is at 301, suggesting solid antioxidant activity, but I’m still unsure how to balance oxidative stress without interfering with necessary redox processes. The doctor who suggested the NRF2 test was happy with the result.

  • Brain: I feel the effects of my brain stack strongly, which benefits my work as a scholar, and I hope it helps keep APOE4 risks at bay. (I don’t use all the brain stack compounds daily, btw). My psilocybin microdosing protocol has been particularly enjoyable and efficient, I think I forgot to mention it in my OP.

  • Urolithin: It works really well for me - I feel the effects quite potently and take it every other day (500mg–1g). It also benefits my gut. It’s a bit pricey, but I get it from Aeternum, so it’s not too crazy in the end.

  • Liver enzymes: They’re right in optimal range atm - so, looks like I’m ready to abuse some more drugs now :laughing:

Thanks again for your time and insights—I always appreciate the collective brainpower circulating in this community! Looking forward to sharing more :heart:

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#24

What do you feel “potently”? I have been wondering about urolithin A. Even if it works the subjective feeling from it would be hard to predict: increased mitophagy might feel like tiredness but then post recovery with healthier mitochondria might feel like the opposite. But if you take it every day, I couldn’t begin to guess at how it works or how you might feel. I would think it should be used in pulses to let the body recover. Or maybe the effect is so small that it doesn’t require a separate recovery phase. But you feel it “potently” so I’m intrigued.

#25

@emanuele, thats a good update. Its good to see that you’re tracking things and also tuning in on how your body is feeling / responding.

You may want to check this new video, just released by Matt Kaeberlien one day ago (# The Effects of Rapamycin on APOE4 Carriers & Brain Function) https://www.youtube.com/watch?v=b76K5PU3rfE

On LDL, 100-180 mg/dL is like the population average I suppose. Most people will be in that range, in the absense of lipid lowering drugs. If you’re in the camp that believes that lower the better, then a combination of drugs will be necessary. Ezetimibe alone will not move the needle much. Psyllium husk, berberine, fish oil, exercise, garlic, etc will not move the needle much either. Yes, Bempedoic Acid + Ezetimibe would be a good experiement. In my case, normal hovers around 100-120. With Rosovastatin 5mg alone, I get it down to 75. With Bempedoic acid + Ezetimibe, I get it down to 75. With all 3 together, I get it down to under 50. Thats just me (not everyone responds the same way). Many people on this forum source drugs from India (very inexpensive generic drugs, and relatively good quality profile, depending on the brand/source). If you can get your hands on PCSK9i, that can also be a good 2-week experiment.

Ok, if you intend to drop HBA1C from 5.5 down to 5, then adding metformin makes sense. High level of consistent activity should also bring down HBA1C, however, in your case, it looks like you’re at the maximum threshold of exercise already. In addition, although new research shows that Intermittent Fasting does not provide any additional benefit beyond that of caloric restriction, in my case it does seem to provide additional benefit (which is reduction of Fasting Insulin), especially if you’re doing early TRE (Time Restricted Eating). Another note is that since HBA1C & Fasting Glucose are not perfect markers, you can consider testing for Fasting Insulin as well (Homa-IR appears to be a better indicator of glucose homeostatis, compared to fasting glucose alone). Mario Kratz (https://www.youtube.com/@nourishedbyscience) is a fantastic unbiased resource on all things related to glucose homeostatis / insulin sensitivity. Highly recommend watching / reading his content.

On Methylation, Chris Masterjohn PHD is the best resource, he goes into great detail. My homocysteine has been consistent around 5. Note that not everyone does well on mega-dosing methyl-folate. Likewise, too much TMG (beyond 4mg/day) appears to increase LDL. You normally find a combination of methyl donors, i.e. methylated B-vitamins + TMG on the market. B2 + B6 + MethylFolate + MethylCobalamin + TMG. Its good to experiment the dosage that you feel better (i.e. achieving lower homocysteine, without getting side effects like anxiety or brain fog from mega-dosing). Another/parallel strategy is to provide the body with the output of methylation, i.e. creatine and phosphatidyl choline, these two are the major end products of methylation. So, the theory is that if you supplement the body with these, then your methylation (MTHFR gene) doesn’t need to work as hard. Lastly, on some days when i’m consuming liver or fish roe or several egg yolks, I don’t bother to take methyl support supplements, because I know I’m getting enough from food. One final note: heavy exercise (which you appear to do) can also deplete methyl donors.

On Urolithin A, SiimLand has done some research (https://www.youtube.com/watch?v=CP2BFwUV6-I). In your case, I suspect that you’re getting a bulk of the benefits (mitophagy, mitochondrial biogenesis & other adaptations) from your exercise regimen, rather than Urolithin A alone, but I could be completely wrong.

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#26

Hello, when I take Urolithin A, I feel an immediate boost in energy and mental clarity. It also works very well after a heavy gym session, significantly speeding up recovery. I’m still unsure whether it’s best taken with or without food. Currently, I’m taking it with food, as this seems to be the more recommended approach, despite its alleged effects should synergize well with a fasting window, (yet absorption on an empty stomach is more of an issue). I’m on a day-on/day-off schedule…

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#27

This is a rather damning exposé. It is consistent with every expert I’ve had on WiseAthletes who I asked about urolithin A…all said the research doesn’t back the claims.

I would never pay such a high price for these dubious benefits but I will try it when I can find a cheaper source someday.

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#28

I’ve just watched the video—it’s interesting, definitely a deceiving campaign. Still, I don’t think it makes much sense to compare Urolithin A or any other supplements to the benefits of exercising (which would probably beat them all). Neither do I think people should take Urolithin A to increase performance at the gym, as there’s clearly better stuff for that (e.g., creatine). I have no skin in the game, but I can’t deny my phenomenological experience, which is positive despite the price being a bit of a rip-off. I have to say that my body is generally quite sensitive to molecules, so there’s that too…

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#29

@snax444 Thanks for your additional feedback, I’m going to check all the references soon…homocysteine below 5 with MTHFR sounds very impressive to me!