Stem cell exhaustion is a well-established hallmark of the aging process1. Bone marrow mesenchymal stem cells (MSCs) have been shown to play an important role in aging due to their ability to regenerate bone by giving rise to adipocytes, chondrocytes and osteoblasts2,3,4. However, aged MSCs show decreased capacity to differentiate into osteogenic and chondrogenic lineages. This feature has been linked to increased fat content in the bone marrow upon aging, and concomitantly higher risk of osteoporosis and fractures5,6.
I think citrate fixes this. I mean lots of citrate taken a number of times during the day.
A bit more from the paper:
Discussion
In the present study we focused on the flux of acetyl-CoA from mitochondria to the nucleus, and we investigated how age-associated changes in the flow of acetyl-CoA affect stem cell function. The data presented here suggest a model (Fig. 6e) whereby aging-driven changes in chromatin structure lead to the transcriptional alterations that are responsible for the decreased osteogenic potential of aged MSCs. We show that, upon aging, there is a shift in the subcellular localization of acetyl-CoA, which affects the epigenetic landscape. In particular, aged MSCs exhibit compartmentalized acetyl-CoA localization in the mitochondria, as a result of enhanced MDV-lysosomal degradation of CiC. Strikingly, restoring histone acetylation, and thus chromatin plasticity, is sufficient to improve the impaired osteogenic capacity of aged MSCs, highlighting the fundamental role of CiC in the regulation of the metabolism–chromatin–osteogenesis axis.
The CiC aka the tricarboxylate transport protein or Citrate Carrier gene SLC25A1 transfers citrate from the mitochondria to the cytosol. However, if you eat citrate a little bit gets in the cytosol of cells that are short of citrate. (not much, most is burnt by the liver)
It looks like rapamycin might be good for mature bone health.
The above research found that reducing a downstream product of Notch signaling strengthened the bone, while https://www.nature.com/articles/ncomms10533
found that increased autophagy [which is something rapamycin induces] degrades Notch.
autophagy impacts stem cell differentiation by degrading Notch1
I have two interviews coming up with bone health specialists. This topic came up from audience members who discovered they had osteoporosis despite being active, life long athletes. There are many misconceptions about bone health. It’s more like muscle health than I expected.
Any questions I should ask in the interviews? I have a MD and a functional doc coming up very soon.
There is a paper that demonstrates that Osteoporosis occurs because of a problem with protein SLC25A1 in the mitochondrial membrane. This results in holding back citrate from the cytosol. Hence there is not enough acetyl-CoA in the nucleus to enable ostoblasts to differentiate properly. Hence you get an imbalance where osteoclasts are created, but osteoblasts are not. Hence the bones are broken down and weakened, but not rebuilt adequately.
Normally bones go through a process of renewal with osteoclasts and osteoblasts in balance.
Citrate supplementation fixes this (as it does sarcopenia), but the people you are interviewing may not know about that.
@John_Hemming Id bet you are right that this is not front and center for a clinician. But I’ll explore emerging ideas and research.
Based on my prep work, I believe the main idea for me is to think of bone health as a function of overall health. It isn’t just or even mainly about “impact” to stress bones and calcium in the diet. Poor gut health, chronic inflammation in the body, caloric restriction…all can lead over time to bone loss. If you didn’t start with strong bones in your 20s (were not active as a kid, always dieting, etc) you are set up for problems later. Catabolism for muscle is catabolism for bones.
Osteoporosis itself is because the osteoblasts end up as a form of adipocyte. However, good bone growth depends on a number of things. (if there is enough acetyl-CoA to ensure that osteoblasts differentiate properly).
“Use it or lose it” very much part of how bodies work. If there are no strains then bones don’t grow as strongly.
Nutrients - calcium and protein really
Micronutrients - vitamin D, oddly enough menaquinone-4 is useful here for carboxylating osteocalcin (the gla complex) - the usual ones magnesium, phosphorous, and potassium.
The point about osteoporosis and differentiation is this is driven by broader health as it is the general senescent cells that drive SASP (particularly IL-10) that causes the reduction in SLC25A1 which means the cells don’t differentate.
Hence exogenous citrate rescues this.
SLC25A1 is also known as the mitochondrial citrate carrier.
You can probably use a Janus Kinase inhibitor to have a similar effect as it prevents IL-10 from reducing NF kappa B. I am not a fan of JK inhibitors.
I take 5g in a spoon mixed with water and possibly some cordial for taste although I don’t mind drinking it without flavouring. My next door neighbour who is a hospital A&E consultant has tried it and finds it a bit salty for his taste.
Today I have had 3 5g spoon fulls, one at 7am, one at 2pm and one with chia seeds in a mixed berry drink (no banana) at noon. I also had some capsules for breakfast at 9am. (hence a total of about 20g)
My experience in initially ramping up (remember I could find no records of anyone else trying high dose citrate so I was initially quite cautious and I think I was right to be careful because of the impact on cytosolic ROS) was that it was 2g per day that started having some effects.
To be honest I don’t see that much of a downside and I am not quite sure what the best maintenance dose is.
It is important to remember that there is always citrate in the blood at perhaps 50-100 microMolar concentration.
The issue as to whether there is a linear dose response curve is complex. The liver has a special citrate transport that takes citrate out of the cells and to some extent alternative splicing is managed by acetyl-CoA levels. Also at some point you might get non-enzymatic acetylation which could lead to hyperacetylation. However, I don’t think it is possible with the doses I have taken which go to 75g to achieve this.
I don’t think there will be much of a response really until you hit 2g. Again from there depends upon the burden of senescence (which should be kicked into the cell cycle by the acetyl-CoA levels going up)…
Its a hard one. I think it comes down to cautious experimentation combined with measurement and keeping detailed records.
For someone who wants to go all in and you don’t have to worry about compliance, what would a complete, comprehensive protocol look like to improve bone mass, health and strength in the second half of their life?
What are their thoughts on using vibration plates? Especially if combined with resistance exercise while standing or sitting on it (I’ve eg done squats, deadlifts and back rows when I borrowed my mother’s plate and it worked out very well logistically).
Here is an example of the vibration place her doctor recommended: LifePro Rumblex Plus 4D Vibration Plate Exercise Machine -Triple Motor Oscillation,Linear, Pulsation+3D/4D Motion Vibration Platform |Whole Body Viberation Machine for Weight Loss & Shaping. Amazon.com
Can you ask them about the latest research / findings re: role of vibration at various frequencies in “waking up” bone marrow stem cells and nudging them towards becoming osteoblasts instead of fat cells?
Do you mind telling us what you are taking for ditrate supplementation? It seems to come in several varieties, potassium, sodium, calcium & boron. Do you do some of each?
I am offering a small amount of coached biohacking on this for a few people if you wish me to do that. On the other hand you can simply read the details on the post I have linked to.