#597

That is largely irrelevant to aging in fully developed adults that are not producing much new elastin at all. A main thing that needs to be done here to reverse aging is to fix the damaged elastin not to create new one. Creating more new elastin would be a bottleneck for its regeneration if the body were actively removing old elastin and replacing it with new elastin in adulthood, but the studies on the half-life of elastin show that that is not really happening in the first place.

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#598

While I appreciate your attempts to improve your health with this method, this is all largely speculation. You have little idea if your experiments are actually increasing your acetyl-CoA levels. The body is so complicated and there could be great number of reasons for your subjective effects that have nothing to do with acetyl-CoA. Have you seen any clinical trials in which oral consumption of citrate led to increased acetyl-CoA in some cells of the body?

Steve is far closer to correct here. There may be some new elastin formed during aging, but it is not much, and clearly not enough to keep the tissues rejuvenated. Trying to stimulate creation of new elastin is mostly a dead end because the body just doesn’t regenerate much of it in the first place. The half-life of elastin in humans is remarkably long, or around 74 years! Marked longevity of human lung parenchymal elastic fibers deduced from prevalence of D-aspartate and nuclear weapons-related radiocarbon - PubMed

This is a massive oversimplification of aging.

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#599

Any idea how to fix that damaged elastin?

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#600

Unfortunately it’s a very hard problem to solve and there is nothing I’m aware of that can significantly fix it. AGE breaking compounds will likely help, but we don’t have any effective AGE breaker drugs so how much of a difference that will make remains to be seen.

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#601

Again my friends:

we are back at: replacement is a (or the) solution… and one that does not need us to be able to understand, repair, reverse or rejuvenate.

#602

Have you tried Fenofibrate yet? That’s supposed to specifically lower ApoB, Trigs, LDL and even VLDL. It can also raise HDL.

It’s only in worms but it has also shown longevity benefits:
https://pmc.ncbi.nlm.nih.gov/articles/PMC3651519/

It’s also dirt cheap from India, I paid $20 per 100 tablets. I started it in January and am due a lipid panel next month so we’ll see.

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#603

The pathways on acetyl-CoA are well established.

#604

Let me know how your trial with fenofibrate goes. It’ll be interesting to see how your lipids have changed!

#605

I think it is a useful process to try to identify mechanistic patterns.

#606

Yes but these pathways are tightly regulated depending on things such as the energy demands of the cells. So it’s not like pushing more citrate into the cells is going to necessarily lead to increased production of acteyl-CoA. Have you seen any studies showing that increased citrate ingestion or even direct intravenous infusion of citrate increases acetyl-CoA levels in vivo?

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#607

Agreed. I really don’t know much about elastin, other than university courses on extracellular matrix. But it seems that your options are:

  1. Replace it with tissue engineered material. Since elastin is so integrated into tissues, surrounded by cells, presumably you just need to replace the entire tissue.

  2. Induce your fibroblasts and smooth muscle cells to start producing elastin again. I don’t think that small molecules or gene overexpression would work. But maybe something like the temporary reprogramming to revert those cells to a fetal-like stage would have a change.

  3. Some sort of enzymatic-based remodelling, breaking down and removing the old dysfunctional stuff.

All of that seems very sci-fi right now. I suspect for some of us it might be too late, but maybe future generations can solve this problem.

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#608

The results that i get are in conformance with the mechanistic hypothesis. This also fits with one in vitro experiment, but there are not that many experiments in this area. I do understand the feedback systems.

#609

What results are you talking about, and why would they necessarily be caused by increased acetyl-CoA rather than any number of other things that could also result in subjective or measurable results? Could you please link to the in vitro experiment you refer to?

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#610

I don’t know what his “bi-weekly” really is. Biweekly can mean either occurring every two weeks or occurring twice a week, though it is most commonly understood to mean every two weeks. Which is how I dose, 6mg 1 hr. after taking 12 oz of GFJ every 2 wks.

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#611

What Bryan Johnson was referring to by bi-weekly is almost certainly ever other week. IIRC there was a time when he took 6 mg one week, 12 mg the next and then repeat.

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#612

I will aim to find the link later.

The results are mainly from my experimentation that I presented in a poster at the British Society for Research on Aging conference in September 2024 on which this web page is based.

https://citrate.science/2024poster/poster.html

I think of note and quite consistent is the rapid wound repair. Every week I have a blood draw and depending on citrate dosing and timing around the venepuncture it repairs in different timescales. One of the phlebotomists has asked me for some citrate because she is having an operation and wishes to repair as quickly.

Another thing that I am aware of is now my body is rebuilding. For instance the skin on my feet has been restructuring.

Now when you look at the research on the links between acetyl-CoA and gene expression it is clear that this is a possible mechanistic consequence. I don’t know what alternate approach would work.

There is a lot of research on citrate transport in and out of various cells which I have in a limited way summarised on the web page above. There is also research on ACLY. I am not the only person that thinks that the way cells recognise a high power availability is the cytosolic level of acetyl-CoA.

There is not that much research on citrate supplementation although there is a lot of experience with human beings using citrate in a medical environment normally in terms of blood transfusions and dialysis.

There is a drosophila result on citrate

I happen to think that they got the mechanism wrong.

In the end rapid wound repair is I think a good test of whether or not I am managing to change some of the key pathways of aging. I am not the only person to think that:

Impairment of wound healing is also linked with the aging process of skin, leading to a prolonged and impaired wound healing process. Thus, instead of the skin healing rapidly, it can progress a to chronic state that will increase the susceptibility of having wound infection and scarring.

This (and the restructuring of other skin) is in fact an example of maintenance and repair of the Extra Cellular Matrix which has rightly been discussed in another topic.

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#613

This paper is perhaps the key one that made me start looking at the links between the various acetyl-CoA pathways and gene expression.

https://www.nature.com/articles/s43587-021-00105-8

In this case acetate supplementation was used to directly affect acetyl-CoA levels. Acetate is metabolised by the ACSS2 (acyl-CoA synthetase) enzyme to acetyl-CoA. However, that particular pathway is one subject to homeostasis at a cellular level. Hence I use citrate which is subject to homeostasis in blood serum rather than the cytosol.

Strikingly, restoring cytosolic acetyl-CoA levels either by exogenous CiC expression or via acetate supplementation, remodels the chromatin landscape and rescues the osteogenesis defects of aged mesenchymal stem cells.

Arguably this gives a mechanism by which acetate supplementation can have a minor effect. I do a lot of indirect acetate supplementation, but it is citrate that has very obvious and very clear effects.

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#614

Thanks for the links. That mouse study is very interesting. The 1% dietary citrate, that was effective for some parameters, is equivalent to ingestion of about 5 g of citrate for a 70 kg adult human. How much citrate are you ingesting?

The fact that it had some beneficial effects on the mice is interesting, regardless of what caused those effects. It’s hard to say from the study whether the effects resulted from citrate uptake and increased production of acetyl-CoA increase or something else. The liver gene expression (see figure 4 o in the study) seems to have changed towards lower lipogenesis, which is the opposite to what one would expect with increased citrate, but the mice also lost weight, and that might explain lots of the benefits. It’s annoying when compounds result in weight loss because then it’s often hard to determine to what extent weight loss was a cause of the benefits rather than other effects of the compounds.

#615

So this is soomething you have seen several times after varying the dose of citrate so you are highly confident it’s the citrate having this effect, regardless of how it’s doing it?

The transport seems to be tightly regulated, as it should be with such substances that play a role in energy production. I expect it would be hard to bypass that by merely ingesting citrate. If that were possible to significant extent then I would expect to see some studies showing that exogenous citrate increases ATP production in cells. Have you seen any studies that show that citrate can increase ATP production?

#616

A lot of your questions are answered on this web page
https://citrate.science/2024poster/poster.html

If that were possible to significant extent then I would expect to see some studies showing that exogenous citrate increases ATP production in cells. Have you seen any studies that show that citrate can increase ATP production?

I don’t understand your reasoning for this. I personally would not expect exogenous citrate to increase ATP production.

There is a flow of ATP and citrate from the mitochondria. There are also transport proteins.

The levels of citrate in the body are managed in blood serum not the cell. This is important because acts as one of a number of mechanisms of blending the efficiency of cells effectively averaging out the biological age of individual cells.