Some tweets for Professor Nir “Mr Metformin / Mr Tame trial” Barziai in response to above
NirBarzilaiMD (@Nir Barzilai) Tweeted: These examples shown here tie the aging-related disease of COVID-19 to the hallmarks of aging, particularly the declining immune system. This is because metformin does more that just treat the hallmark of metabolic dysregulation 6/7
I am wary of higher doses of metformin, but I do have some doubts about my doubts.
It’s commonly said that metformin is a mitochondrial toxin. I find that simple description to be unsatisfactory. What I’d like to know is when is it helpful and when is it not? How does it affect mitophagy / mitochondrial fusion? Why does it intefere with exercise? And so on. I should probably do another literature search to understand this better. But I don’t seem to hear any podcast hosts or guests going into more detail yet.
Berberine is an HDAC inhibitor which is a good reason to take it. I started on Berberine because I could not easily get metformin (that was before I got rapamycin) and I concluded that Berberine was a reasonable alternative to metformin.
However, in around June 2022 I concluded that I should be looking particularly for “natural medicines” that have good research evidence for their benefits that are also HDAC inhibitors because they have a considerable track record on side effects and HDAC inhibition (mild) was a good objective.
Hence Berberine is one of my primary quartet (Berberine, Curcumin, Pterostilbene and Quercetin). At the moment I am running an increased citrate testing cycle where I am not doing other things, but in a while I will increase HDAC inhibition and also reintroduce some of my mitochondrial improvement techniques. I want, however, at least one other baseline blood test (probably next week).
As part of the HDAC inhibition testing I have now about 20 different molecules divided into 5 quartets (because otherwise testing would be far too stretched out) to test.
I have concluded (provisionally) that HDAC inhibition works synergistically with citrate supplementation, but has slightly different effects in terms of gene expression. This may link to which Classes of HDAC are inhibited, but again testing for this gets really really complicated and as far as I am concerned my objective is to improve my health and as long as I am doing that I am happy.
It is better to discuss this on the citrate protocol thread, but it is important to mix up the cations (Magnesium, Potassium, Sodium). If you take Magnesium Citrate you need to know how much citrate is in the supplement which can be calculated from the amount of magnesium. However, as you won’t notice much with citrate until you are taking at least 2g of citrate a day (ideally spread out a bit as it has a half life of 30 mins or so) you need to be careful to balance out Magnesium, Potassium and Sodium levels. (ie take some Mg Citrate, K Citrate and some Na Citrate)
Citrate assists cells in generating cytosolic ROS which is used as a tool to fight infection hence it helps with things like clearing warts and lumps, but this has the effect that it can kick off some inflammation when it fights things. Hence you need to gradually increase supplementation. I have been using it for over a year so when I am on low supplementation that is still 10g a day, but people have to build up to this slowly.
If people start with say 1g per day for a couple of weeks without problems then it should be possible to increase to 2g. However, you need to make sure your kidney function is up to the levels of supplementation that I take (that’s not because of the citrate, but the cations). Hence it may be worth talking to a medical professional and none of this is medical advice.
I am currently running a higher level so I had 5g of citrate at 7.30am, 5g at 8.15am and will have 5g at about 9am. I will then have a bit more (not decided yet) and end with 5g at noon. This will allow my cells to calm down so it won’t impact on sleep. I think, however, it would be dangerous to start with this.
I buy my citrate in a powdered form and mix it up in a glass of water with or without some cordial.
I have the molecular mass equivalent of Magnesium Citrate Tribasic Mg3(C6H5O7)2
(which is probably what you have, but not certainly what you have) as being 451.1 and that of the three Magnesium ions as being 72.915 which makes it 16% of the total. Hence 400g of Magnesium should be 2.475 g of Mg(3) Citrate(2) and that should be 2g of Citrate.
However, that is the anhydrous variety. Hence your weight may be something different.
The main thing is to start small, but not expect anything much to happen until you get above about 4g.
When I was on holiday (which in the end was about 5 weeks as when I returned home I stayed on the reduced protocol) I limited myself to 10g of Citrate (per day). One thing I noticed was that the skin on my elbows which had become smooth became slightly rough again. I think that has now shifted to being more smooth given that I have increased supplement levels to 20g and higher. (today will probably be 30g by the time I get to noon I am currently on 15g).
My plan is to try to isolate out the effects of varying citrate levels without doing much about HDAC, mitochondrial improvements or indeed acetate.
Acetate can feed through ACCS2 which has a curious, but unsurprising, inhibition from acetylation. Hence that can also be synergistic in limited circumstances.
I find the superficial cosmetic things useful because they are a way of tracking changes that are mainly internal and harder therefore to measure.
If you are going to take grams of sodium it is best to also take some but a lesser amount of potassium and if you want to take large amounts of citrate then inevitably you take large amounts of the cations. Hence if you don’t balance them out you may cause metabolic problems with overdosing on any one of the cations.
I don’t expect anyone to take as much citrate as I do, but in the end I have taken about 40g so far today (but will stop now). That means something like 15-18g of cations. I have not tried just taking that as magnesium (say), but I think that might be an overdose.
I measure the levels of sodium, potassium, magnesium and calcium in my blood. As far as I am concerned the citrate supplementation does have a noticeable effect on those, but does not push them out of the normal range.
Hence I think there is a risk if you don’t balance out the cations. However, I have not experimented to see what happens if an unbalanced use of cations occurred. The only lifespan model organisim test done using citrate was on drosophila where they used sodium only, but I don’t personally think that is a good idea.
However, I may be over worrying.
Incidentally I have just measured my blood pressure it is 114/77 with a heart rate of 67. Where it would be if I had only used Sodium Citrate I don’t know, but I am not going to find out experimentally.
I took 1,000 mg daily, 500 mg morning and night, for decades with no ill effects noted.
Now, I only take 500 mg on the days I take rapamycin. The main ill effect with most people on high doses of metformin is gastric disturbances.
But, if you need it for glucose control it is still the first line of meds most doctors prescribe.
The two drugs have overlapping but not identical effects. I take both at different times to get a combined benefit without taking a larger dose of each. I included one paper that speaks to the combined effect.
1.5 M died from diarrheal diseases in 2019. It’s easy to mess up hydration and if something else happens at the same time, someone might get hospitalized, etc…
edit: oh I thought you wondered if it’s a problem to have diarrhea.
Wow! An A1c of 5.8 is a perfect reason to give metformin! And/or acarbose - no reason you can’t go both if needed. It’s sad how often good doctors withhold safe, effective medications out of fear or lack of knowledge.
In the US the usual “consensus medical establishment” wears blinders;
Review the paper;
“Metformin; a review of its history and future: from lilac to longevity”
If you have not seen, review the older Nir Barzilai interview by Attia, Yes it is long 2 hours and 45 minutes. Make notes as you watch
#35 – Nir Barzilai, M.D.: How to tame aging
Your doctor/physician works for you{you are the boss/employer, paying] if they will not do what you want fire the person and hire a nother doctor/physician.
Why do people tolerate doctors/physicians who will not do what you want?
Well, one reason is they’ve gone to medical school and I have not. What I want them to do may not make sense for my goals.
Of course, there is the issue that most doctors don’t have a focus on longevity and prevention and are not up on the literature. And this is a systemic issue because the reward structure (payment for services) encourages them to focus on what they get paid most for; addressing disease.
Yes. Unfortunately my personal (and my family’s) experience with few exceptions is that primary care doctors are technicians who are very good at a narrow slice of what I need. I’ve given up on the regular medical system for my preventive medicine. But I do want expert medical advice sometimes, so I’m very pleased that capitalism has found a gap in the regulatory barriers. I suppose that gap also creates opportunities for abuse, so I’ll have to be careful.
