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Declining NAD+ Induces a Pseudohypoxic State Disrupting Nuclear-Mitochondrial Communication...

brenda

Senior Member
Messages
2,263
Location
UK
@alex3619 many thanks, very interesting. My vitD levels are:

Total Vitamin D
Status:
(25-hydroxyvitamin D3
ADEQUATE
: 64.6 nmol/L,
Interpretive Guide:
: 67.4 nmol/L
25-hydroxyvitamin D 2
: 2.8 nmol/L)

Is this 1,25?

I gave up dairy over 6 months ago and eat bone broth..

Is phosphorus the same as phosphate? I have 1780 (250-500) on a hair analysis.

Serum inorganic phosphate 1.24 (08-1.5). Very high alkaline phosphatase. That's all I can find. I have vitamin A deficiency symptoms.
 
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Radio

Senior Member
Messages
453
@alex3619 many thanks, very interesting. My vitD levels are:

Total Vitamin D
Status:
(25-hydroxyvitamin D3
ADEQUATE
: 64.6 nmol/L,
Interpretive Guide:
: 67.4 nmol/L
25-hydroxyvitamin D 2
: 2.8 nmol/L)

Is this 1,25?

I gave up dairy over 6 months ago and eat bone broth..

Is phosphorus the same as phosphate? I have 1780 (250-500) on a hair analysis.

Serum inorganic phosphate 1.24 (08-1.5). Very high alkaline phosphatase. That's all I can find. I have vitamin A deficiency symptoms.
A combination of low phosphate diet and insufficient vitamin D appeared to be to blame, though there were implications that something genetic was involved.
You do have the +/+ VDR Taq polymorphism, I would look into K-2, vitamin D-3, NAD support. The High alkaline phosphatase can be related to a intracellular magnesium deficiency. Have you been tested for H-pylori?
 
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anne_likes_red

Senior Member
Messages
1,103
I still have some fibromyalgia stiffness and will be supplementing with this...
N ( R ) Niagen Nicotinamide Riboside

Please make sure to update your progress with this! :)
I'm not surprised to see such supplements hitting the market. Thanks for the heads up on that one.

Fibro muscle stiffness and some cognitive issues are my remaining sticky symptoms after improvement in other areas....including exercise capacity, PEM, restorative sleep.
 

Radio

Senior Member
Messages
453
Please make sure to update your progress with this! :)
I'm not surprised to see such supplements hitting the market. Thanks for the heads up on that one.

Fibro muscle stiffness and some cognitive issues are my remaining sticky symptoms after improvement in other areas....including exercise capacity, PEM, restorative sleep.

Hey Anne , Thanks....I will keep you updated on my protocol progress...I have found that a-lot of my cognitive issues are mast-cell food related. The Low Histamine Chef diet really help in my recovery. ;)
 
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alex3619

Senior Member
Messages
13,810
Location
Logan, Queensland, Australia
@alex3619 many thanks, very interesting. My vitD levels are:

Total Vitamin D
Status:
(25-hydroxyvitamin D3
ADEQUATE
: 64.6 nmol/L,
Interpretive Guide:
: 67.4 nmol/L
25-hydroxyvitamin D 2
: 2.8 nmol/L)

Is this 1,25?

I gave up dairy over 6 months ago and eat bone broth..

Is phosphorus the same as phosphate? I have 1780 (250-500) on a hair analysis.

Serum inorganic phosphate 1.24 (08-1.5). Very high alkaline phosphatase. That's all I can find. I have vitamin A deficiency symptoms.

The vitamin D you had measured is inactive vitamin D. 1,25 is active vitamin D.

Phosphate is the primary form of phosphorous in the body. Phosphate is phosphorous bound to four oxygen atoms. Serum levels are not reliable if you have intracellular phosphate deficiency. I am not sure about hair analysis for this.

Alkaline phosphatase does not tell you much about phosphate levels, but it does tell you a bit about liver function and gut detox issues.

This level of vitamin D is not apparently consistent with phosphate deficiency, but its very hard to be sure. In addition the serum phosphate does not fit with the kind of phosphate deficiency I was talking about, though 0.8-0.9 would if you had that result.

Doh, I just remembered the name of the condition, it was called Phosphate Diabetes because they excrete too much phosphate in the urine.
 

brenda

Senior Member
Messages
2,263
Location
UK
@alex3619

Thanks. I will get my active d level done. I have raised liver enzymes. My doc says she won't investigate the high AP because l have had it for a long time. That's the NHS for you.
 

brenda

Senior Member
Messages
2,263
Location
UK
Thanks Alex

I have been checking out the UK labs and they all seem to do the 25 OH D test and a few say that it is the most accurate one??
 

alex3619

Senior Member
Messages
13,810
Location
Logan, Queensland, Australia
Thanks Alex

I have been checking out the UK labs and they all seem to do the 25 OH D test and a few say that it is the most accurate one??

Its the cheapest and easiest one. In many cases its so inaccurate as to be useless. Its routinely found to be misleading in ME or any inflammatory condition.

This is the active form of vitamin D: http://en.wikipedia.org/wiki/Calcitriol
 

brenda

Senior Member
Messages
2,263
Location
UK
@alex3619 Thanks. I understand now. I checked my 25OHD twice, at the start of summer and at the end. It went up 3 points which surprised me as, for a change, there was plenty of sunshine and I made sure I had exposure often. But then I read that I was at the higher end of normal. It seems to me that those with low 25OHD tend to have high 1,25, so a problem with storage which I assume is sometimes due to VDR Taq ++ blocking receptors? but mine is getting into storage. So its less likely I have high but I agree with you that is worth getting it done and will continue to look for a lab.
 

Lou

Senior Member
Messages
582
Location
southeast US
@nandixon , regarding nicotinamide riboside said, "I felt no effects whatsoever..."

Did you take the supplement as recommended, upon awaking, before a meal?
 

nandixon

Senior Member
Messages
1,092
@nandixon , regarding nicotinamide riboside said, "I felt no effects whatsoever..."

Did you take the supplement as recommended, upon awaking, before a meal?

Yes, I did. I tried:

One capsule before breakfast;
Two capsules before breakfast;
Two capsules before breakfast and two capsules before lunch;
Four capsules before breakfast; and
Four capsules before breakfast sublingually.

I never felt anything, except perhaps a negative/unwell feeling after the sublingual dose.

Just to mention that I also don't feel any effect at all from ribose. Perhaps people who experience some benefit from ribose might also find nicotinamide riboside helpful. It's just a guess though.
 

Radio

Senior Member
Messages
453
Yes, I did. I tried:

One capsule before breakfast;
Two capsules before breakfast;
Two capsules before breakfast and two capsules before lunch;
Four capsules before breakfast; and
Four capsules before breakfast sublingually.

I never felt anything, except perhaps a negative/unwell feeling after the sublingual dose.

Just to mention that I also don't feel any effect at all from ribose. Perhaps people who experience some benefit from ribose might also find nicotinamide riboside helpful. It's just a guess though.

Interesting...It's possible you may have massive mitochondria damage an the nicotinamide riboside is not being absorbed into the cells. I needed to repair my leaky mitochondria with phospholipids replacement therapy... before i benefited from any supplements.
 
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nandixon

Senior Member
Messages
1,092
Interesting...It's possible you may have massive mitochondria damage an the nicotinamide riboside is not being absorbed into the cells. I needed to repair my leaky mitochondria with phospholipids replacement therapy... before i benefited from any supplements.

Thanks! I did actually order some NT Factor* late last week and it's supposed to arrive later today, so I'll see if it makes a difference.

*(I ordered this one: http://www.iherb.com/Nutricology-NT-Factor-EnergyLipids-Chewables-60-Chewable-Tablets/49283)
 

anne_likes_red

Senior Member
Messages
1,103
There's a post on the excellent Anti-Aging Firewalls blog about the paper.
It's By James P Watson with editorial assistance from Vince Giuliano. Here: http://www.anti-agingfirewalls.com/...list-of-things-i-learned-about-aging-in-2013/
In my opinion, this was the “Top Anti-aging Story” of 2013 – The story of how mitochondrial dysfunction is not due to intrinsic mitochondrial degeneration (i.e. the Free Radical Theory of Aging or the Wear and Tear theory) but due to inadequate expression of mitochondrial encoded genes which are controlled by cell nuclear factors. Specifically, when nuclear levels of NAD are low, a sequence of events occurs in the cell nucleus that ultimately results in a lack of adequate expression of mitochondrial DNA genes that are required for Complex I, III, and IV in mitochondrial electron transport. In this scenario, the nuclear-encoded proteins required for mitochondrial electron transport chain are still expressed, but the proteins whose genes are encoded only by mitochondrial DNA are not expressed. Thus, mitochondrial electron transport cannot occur and cells develop a metabolic picture which is typical in cancer, which is called the Warburg effect. With Warburg-type metabolism, cells do not generate ATP from the mitochondria and instead, become dependent on cytoplasmic generation of ATP via aerobic glycolysis.

The primary driver of this “metabolic reprogramming” is the transcription factor, Hypoxia Inducing Factor 1 alpha (HIF-1α), which normally only activates Warburg-type metabolism when oxygen levels are low. Unfortunately, when nuclear NAD+ levels are low, HIF-1α is stabilized and is not degraded by VHL as would normally be the case. As a result, cells are “metabolically reprogrammed” to use aerobic glycolysis in the presence of normal oxygen. HIF-1α inhibits a chain of events that ultimately results in a reduced expression of the mitochondrial transcription factor, TFAM, which normally migrates from the cell nucleus to the mitochondria to stimulate mitochondrial DNA replication. As a result, mitochondrial encoded genes are expressed. When HIF-1α inhibits TFAM, this does not occur. The nuclear encoded mitochondrial proteins are still created via the transcription factor Nrf1, but because TFAM is suppressed by HIF-1α no mitochondrial-encoded protein components of the electron transport chain are expressed. This results in mitochondria that cannot make ATP but still have defective electron transport chains that “run in reverse”. This “reverse electron transport” results in the production of uncontrolled amounts of free radicals from the mitochondria, which then create the “Universal Signature of Aging” which is mitochondrial dysfunction with high free radical production. All of these events can be traced back to inadequate NAD+ in the nucleus. Without adequate NAD+ in the nucleus, SIRT1 cannot function, since NAD+ is a mandatory co-factor for all of the Sirtuins. What David Sinclair and colleagues from both Harvard and Australia showed in a landmark publication late in 2013 was that supplementation with an NAD+ precursor could reverse this mitochondrial dysfunction and “Warburg-like” metabolic state in mice in one week. Sinclair and associates used an NAD+ precursor called NMN, but previous work showed that another NAD+ precursor could also work, Nicotinamide Riboside (NR). NMN is only one step away from NAD+, but is difficult to make and is very expensive. NR is two steps away from NAD+, but is much easier to make, is much less expensive, and is already available for sale under the proprietary name, Niagen. To date, no studies in humans have replicated the findings from Sinclair’s mice studies. Until these are done, we must “hold our breath”. However, in Sinclair’s studies, all of the mitochondrial dysfunction seen in aging mouse skeletal muscle was reversed (with the exception of muscle strength).

In summary, deficiency of NAD+ in the nucleus of muscle cells produces a state of “pseudohypoxia”, where there is adequate oxygen but high levels of HIF-1α. This results in the inhibition of the mitochondrial transcription factor, TFAM, which inhibits the expression of mtDNA. As a result, mitochondria do not produce the proteins encoded in mitochondrial DNA that are required for “forward electron transport” and ATP production. “Reverse electron transport” occurs and high levels of free radicals are produced, giving the exact picture of aging. In this picture cells are dependent on aerobic glycolysis in the cytoplasm and cannot burn fat. They develop the exact metabolic picture of cancer, called the Warburg effect. The mitochondrial dysfunction and this Warburg-type metabolism are fully reversible with the supplementation of NAD+ precursors.

Anne.
 

Star-Anise

Senior Member
Messages
218
Hi everyone, I'm just starting my journey with figuring out how to address what I think is mitochondrial dysfunction.
Over the years I have made great gains in energy through balancing my gut, supporting my adrenals, and introducing methylation protocols.
However, currently I'm having still problems with creating and sustaining energy, despite the major gains I have had in correcting brain fog, & building my stamina/and reserve.
My body seems to rely heavily on anaerobic metabolism, and when I try to work my cardiovascular system - i.e. heart pumping, my blood sugars seem to crash.
I have been experimenting with acetyl-l-carninitine & carnitine fumarate which seem to cause an energy crash, unless I take miniscule amounts.
I have been trying to introduce Co-enzyme Q10 - and have had mixed results, maybe increased fatigue too.
Introduction of adenosyl B12 seems to have helped my gut, as I have been able to introduce a bunch of new foods, but I have also gained 5lbs since I introduced it, and I'm not convinced it's all muscle. My clothes are definitely fitting tighter.
I have been experimenting with upping my methylfolate to address maybe shortage in methylfolate & it seems to help with water weight.

My questions:
a) Where is best place in your experience to get OAT?
b) Has anyone had any success with mitochondrial test through Dr. Myhill?
c) @Radio Can you tell me more, or direct me to a link that can tell me more about leaky mitochondria?

Over the years I have done pretty good with figuring stuff out, but this stuff is way over my head. Unfortunately I think it is where I'm having my problems. I think I want to get some tests to better inform me about where to start, and any advice/direction anyone here could provide would be so very much appreciated.:)
S
 

Radio

Senior Member
Messages
453
Hi everyone, I'm just starting my journey with figuring out how to address what I think is mitochondrial dysfunction.

My questions:
a) Where is best place in your experience to get OAT?
b) Has anyone had any success with mitochondrial test through Dr. Myhill?
c) @Radio Can you tell me more, or direct me to a link that can tell me more about leaky mitochondria?
S
Reverse Mitochondrial Damage 101
http://forums.phoenixrising.me/index.php?threads/how-to-we-fix-the-leaky-mitochondria.28175/
 
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