The mitochondrial NAD+ transporter SLC25A51 is a fasting-induced gene
metabolismjournal.com
metabolismjournal.com
My chemistry and biology knowledge are fairly limited, but I di like to understand things and so started looking into this and found [1]. For my level of knowledge I feel it gave a great balance between what I could understand whilst also showing how incredibly complex human chemistry is.
There is currently a related discussion here in "A physical wiring diagram for the human immune system" / https://news.ycombinator.com/item?id=32381790 but the link to biochemical-pathways.com is way over my head.
I found that BBC link useful and thought others may do as it's related but simple.
[1] https://www.bbc.co.uk/bitesize/guides/z2vbb9q/revision/1
I suspect taking ciprofloxacin 8 years ago caused metabolic myopathy in me as well because of its known deleterious effects on mtdna and oxidative stress well established in research, but doctors have never been helpful at even going in that direction. I had a loss of 35% VO2 max in the first year alone afterward.
As that was progressing slowly we went privately to see a consultant neurologist; he examined her and looking at things like jaw strength concluded it was metabolic myopathy related to a problem with the muscle cells and phosphate. He said he'd only seen it a couple of times before and it's very rare and not surprising it hadn't been picked up earlier. We're now going in for muscle tests, DNA tests, and all sorts to try and identify what is wrong and how/if it can be fixed.
The thought is her osteoporosis was likely caused by the cells leaching nutrients from the bones as they couldn't get them normally, that has been stabilised by traditional Alendronic acid, calcium, and Vit.D.
This is not how it works. When a cell has a metabolic defect, it is unable to use much of the substrates readily available in the blood stream (glucose, lipids). And of course such a cell cannot "leach" nutrients from the surrounds as its substrate absorption ability is seriously diminished.
I suppose there is another process going on. It is an old good inflammation - in this case, an autoimmune reaction of the body to its own metabolically subpar cells. When such a "metabolic" inflammation occurs, it tends to target blood vessels of all sizes, causing the gradual dysfunction of their endothelium. With time, this induces a state similar to disseminated intravascular coagulation, although in a much milder form. This causes chronic problems with blood flow due to micro-clotting, which in turn affects nutrients delivery. This induces foci of tissue hypoxia, furtherly aggravating mitochondrial dysfunction at those areas. The immune system senses that and tries to "fix" it by inducing even more inflammation, but everything this does is causes such foci to spread even further. This is never a static process and it cannot be stopped without medications, causing a gradual quality decline of patient's life through months/years.
Sometimes it affects bigger arteries and veins, causing more pronounced defects such as thrombophlebitis. But in any way, bone tissue needs nutrients delivered by the blood flow as well and when it is compromised on either level, bones start to degenerate. You can now see the whole picture of how a mitochondrial disease can induce such a seemingly unrelated condition as osteoporosis.
Besides the bones, it can affect any organ in the body, especially those having high demands in energy (ATP), such as nervous system, liver, heart, muscles. Сhances are that your wife may have some other manifestations as well, especially neurological ones.
The condition can be managed and even cured if the mitochondrial dysfunction is not caused by a genetic defect. If you are interested in details then let me know and I will provide the framework for a protocol.
Looking online we're not seeing any lumpy thrombophlebitis, but there is a possibility marks on the legs are similar to what seems to be referred to as Superficial Thrombophlebitis. I don't recall any of the doctors mentioning that but perhaps that's not something they are too worried about at this stage.
> causing a gradual quality decline of patient's life through months/years.
She's currently getting noticeably worse over a few weeks, including breathing, and we are doing what we can to expedite the diagnosis and hopeful treatment.
> If you are interested in details then let me know and I will provide the framework for a protocol.
Yes please, that's very kind and I am interested in trying to understand what's going on within my bounds.
Please pay attention to lactate levels in her blood work. Difficulties with breathing tell me that she may have episodes of lactic acidosis, actually I'm pretty sure she has given the other manifestations. This also means that she is B1 and/or B12 deficient.
Please note that the correct blood test for B1 deficiency is the test for transketolase activity which is rare and quite expensive. Not those quantitative B1 tests that show literally nothing. This may be a gotcha for lots of people with actual B1 deficiency but whose B1 quantitative levels are ok. This is a typical situation of concern for a condition known as mitochondrial dysfunction. The most widely-known cause of induced mitochondrial dysfunction is malnutrition, see Beriberi. Another common cause is the episodes of hypoxia or ischemia.
The B12 deficiency can be detected quite easily in the widely accessible blood work. It leads to anemia and may induce mitochondrial dysfunction as well.
Once mitochondrial dysfunction is induced there is no way out without the medical intervention.
Here is the framework of a treatment for a patient with induced mitochondrial dysfunction:
a) Slightly suppress the inflammation
b) Slightly anti-coagulate the blood
c) Fix the induced condition (osteoporosis)
d) Fix other induced conditions. Heart, liver are most-commonly affected, a close attention should be paid to them.
e) Gradually repair the damage of mitochondrial apparatus while reducing tissue hypoxia
All these actions should be undertaken in parallel, not one by one.
And here is a practical example of how I would treat her, for reference:
1. CoQ-10 60 mg + Alpha-lipoic acid 60 mg, should be taken at least 30 minutes before the first meal, daily.
2. Multivitamin*** + B1** (Thiamine Chloride, HCL) 250 mg + Benfotiamine 300 mg + Magnesium 100 mg + D3* 5000 I.U. + K2 MK7 100 mcg, right after the first meal, daily.
3. B3 (Nicothinamide Riboside or Nicothinamide) 100 mg, on an empty stomach between the first and second meals, daily.
4. Aspirin 300-500 mg or Ibuprofen 400 mg (but not both) right after the second meal, once in 2-4 days.
These medicals represent a so-called mitochondrial cocktail with an addition of NSAID.
Osteoporosis may require additional calcium supplementations.
Besides the medicals, the diet correction is obligatory. Lower the consumed sugar levels to less than 50 grams per day. Exclude the foods with glycemic index >= 50 from the everyday diet. There should be 3 meals: morning, day, evening. Do not overeat and do not be hungry. Prioritize quality fat products to hydrocarbonates (look at ketogenic diets for inspiration). Recommended everyday products: milk, eggs, meat, tomatoes, cucumbers, peppers, paprika, avocado, fatty fumed/salted fish (salmon, trout), black rice (not brown and not white!), barley porridge, cheese. Totally exclude tea and coffee. Avoid processed foods as they are poor in nutrients and may contain things like MSG which would cause neurotoxicity in patients with mitochondrial dysfunction.
Besides the medicals and diet, a life style corrections should be made. Everyday relaxed 45+ minutes walks are obligatory, but be sure that you have no bone pains in your feet. If you do, supplement with calcium and ensure that the specific pains go away before starting new physical activity sessions. Worries and responsibilities should be left behind. It is recommended to take at least 2 weeks sabbatical and devote it to the health.
Treatment progress control: after the first paradoxical reactions a patient should start to feel considerably better, and should continue to do that week after week. Sometimes there will be bitter regressions, but the overall course of treatment should be positive.
Blood work to pay attention to: lactic acid, transketolase, glucose, A1c, HOMA-IR, triglycerides, low-density lipoprotein (LDL), gamma-glutamyl transferase (GGT) and other hepatic markers. Be sure to exclude anemia. The closer the blood work to the norm, the better the person will feel.
* Periodically check the D3 levels in blood work to not become higher than normal, if it is then exclude D3 and K2 MK7.
** Therapeutical doses of B1 vitamin and vitamins in general may cause strong paradoxical reactions. Paradoxical reaction is when a patient perceives an imaginary worsening despite the fact that his condition is being improved. This means that the very first vitamin doses should be very small, just the tiniest pieces of a tablet, you can scrape them with a knife. Then the doses should be gradually increased to the recommended levels [1].
*** Multivitamin should contain Manganese. For example [2].
This protocol is for reference only and works better when it is adjusted to the conditions of a particular patient. The treatment takes months and sometimes years, depending on the age of the condition.
[1] https://www.hormonesmatter.com/refeeding-syndrome-thiamine-d...
We'll keep all this in mind, I appreciate all the information as it helps putting the whole picture together. Cheers.
There is a more widespread test similar to lactate called bicarbonate blood test. It allows you to determine the overall blood acidity level, so you will be able to capture the acidosis/alkalosis of any nature, not only caused by lactate.
It is best to perform the test at the very same moment when the shortness of breath is being experienced.
[1] https://www.hormonesmatter.com/with-thiamine-paradox-symptom...
P.S. If you want to chat write to: alex -at- zodiac.herald.icu
Yeah it's really weird that when doctors profit from pathologically over-prescribing antibiotics, they're hesitant to consider the long term effects of doing so.
It's almost as if "It is difficult to get a man to understand something, when his salary depends on his not understanding it".
Really, really strange.
This is effectively stating the mechanism for utilizing these is shown to be linked to fasting.
The efficacies are already proven. A new study which accounts for the activation of the gene and utilization of the supplements will likely show a major therapeutic potential or life extension therapy
Here’s a snippet from WebMD:
> While there is some evidence that suggests NADH supplements might reduce blood pressure, lower cholesterol, help chronic fatigue syndrome by providing energy, and increase nerve signals for people with Parkinson's disease, there isn't enough information to know for sure how or if these supplements work.
I can't speak to any of their claims but the company is legitimate.
Nope, doctors just give old people vitD because they are deficient and also old people die.
People have are hard time utilizing statistics that actually retain context.
In fact, that may be the biggest problem in medicine today.
"Proven" is a strong word unless those are RCTs, or at least, natural experiments. Otherwise the causation issues should be obvious.
Related, incorrect birth certificates explain most cases of long-lived humans: https://www.biorxiv.org/content/10.1101/704080v1
Those are more likely in poor regions, which is why those supposed supercentenarians don't take supplements, smoke and eat red meat.
Why bother with the unproven, uncertain outcomes of a (commercial) supplement when you can undertake a proven and broadly beneficial action ?
I think fasting alone has already been shown to be beneficial and not harmful, and I don't see enough proof that the supplement doesn't cause some harm from hot-rodding something, but I'm nobody. So, perhaps it's true that supplement alone is of little value, fasting alone is good, and fasting plus supplement is better.
Found this on the first Google search: https://www.nmn.com/topic
Are they selling something, sure, but the studies are all linked.
The wide research interest alone should be some indication of the promise these compounds hold
Do some people just not have Slc25a51? Does this matter?
Is this supposed to be some kind of longevity insight?
I'm not a doctor or a researcher etc. Just a guy who likes to watch these things play out and barely understands what I hear :)
Did you mean Peter Attia?
In other words, you will die literally from exhaustion.
Insufficient intake of this vitamin causes the disease named pellagra (which was frequent at people who ate almost only corn, i.e. maize, with too little of other vegetable or animal food).
This study appears to show that fasting is related to inducing the gene Slc25a51 and improving those factors.
I guess this contributes to the body of science around the potential health benefits of fasting.
What would be scummy would be some pharmaceutical company discovering this, not releasing the information, and trying to develop (or worse, failing to develop) a drug on their own after internal research that was never released to the world.
Anyone have an idea?
https://www.frontiersin.org/articles/10.3389/fendo.2021.6492... Literally no one talks about this in mice metabolic research. I would not be surprised if a huge majority of mouse researchers in diabetes are unaware.
Part of our message is basically what you just said. We have multiple examples of genes where mutations cause diabetes in humans but don't in mice.
The other one we have is the fact that human pancreatic beta cell lines in labs don't even 100% act like human pancreatic beta cells in humans.
https://www.understandinganimalresearch.org.uk/news/nine-out...
But to be fair, there's a huge failure rate for pharmaceutical drugs in general.
Fasting in mice turns on SIRT3 which requires NAD+ and this newly discovered gene SLC25A51 is involved in transporting NAD+ to SIRT3. There's plenty of data that shows mice can live 30% longer when calorie-restricted due to sirtuins being activated..
Anyone who's ever listed to Dr. David Sinclair speak about longevity, he almost always talks about how NAD+ is possibly the most important chemical in the human body, since we'd be "dead in 30 seconds" without it.
Sirtuins are the longevity genes that are activated when organisms are under duress, which can be simulated by fasting. Your body doesn't know when you're going to eat again, so the sirtuins get activated.
I wouldn't be surprised if researchers and labs are looking for ways to activate SLC25A51 chemically to get the NAD+ flowing to SIRT3 without requiring fasting.
You can listen to David Sinclair and Rhonda Patrick get into the details of how all of this works: https://www.foundmyfitness.com/episodes/david-sinclair
Sinclair, IMHO, is all protein and zero enzyme and that is his problem. Without enough zinc NMNAT will not function and will slow the SIRT cycle. And increasing SIRT activity by shoving NAD in the cell with out zinc will end up depleting zinc.
It was disappointing to hear David Sinclair makes his own resveratrol… can’t get it
To what end ?
Fasting would be cheaper, easier and less time-consuming and would include all of the related, broad-spectrum effects that we also believe fasting may produce.
I guess if you're a pharma investor or existing, entrenched player it makes sense to go that direction.
As a consumer, however, I wonder why (pills that might convey a subset of the benefits of fasting) would be interesting in any way.
Because fasting is hard?
We share 97% of our genes with mice. Our organ systems and metabolic pathways are extremely similar. Our homeostatic mechanisms are nearly identical.
Some mouse models don't carry over to us, to be sure. But the reality is that most do. Do we know for a fact that this paper applies to us? No. But it significantly updates our priors. And that's always noteworthy.
For example, fasting for several hours in mice and in humans are completely different things (a human would have to fast for days to get similar results).
There's plenty more on Google, including the interaction between an MTHFR mutation and NAD supplementation.
I'm a geneticist and I still read that as a curse word ...