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

Discussion in 'Other Health News and Research' started by anne_likes_red, Jan 1, 2014.

  1. anne_likes_red

    anne_likes_red Senior Member

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  2. heapsreal

    heapsreal iherb 10% discount code OPA989,

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    Can u gives us your run down on it. Too much for my brain.
    Interested in the sert gene as it can improve insulin sensitivity and leptin sensitivity etc
     
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  3. anne_likes_red

    anne_likes_red Senior Member

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    Hi Heaps, I haven't got into the nitty gritty of the pseudohypoxia part of it yet (that consequence is news to me) but the bottom line I think is the need to improve nad*/nadh ratio.
    HBOT if administered 'correctly' can do this I believe.
    The simplest way may be to burn very long chain fatty acids as a primary fuel, rather than sugar/carbs. My understanding is that will shift the ratio positively as well as cut down free radicals.

    Sirt is super interesting! It's stimulated by endurance exercise, cold exposure, fasting, fat burning (plus some plant compounds such as resveratrol)....and yes improves insulin and leptin sensitivity, at least at the liver level.

    Re the paper:
    Highlights
    • A specific decline in mitochondrially encoded genes occurs during aging in muscle
    • Nuclear NAD+ levels regulate mitochondrial homeostasis independently of PGC-1α/β
    • Declining NAD+ during aging causes pseudohypoxia, which disrupts OXPHOS function
    • Raising nuclear NAD+ in old mice reverses pseudohypoxia and metabolic dysfunction

    Summary:
    Ever since eukaryotes subsumed the bacterial ancestor of mitochondria, the nuclear and mitochondrial genomes have had to closely coordinate their activities, as each encode different subunits of the oxidative phosphorylation (OXPHOS) system. Mitochondrial dysfunction is a hallmark of aging, but its causes are debated. We show that, during aging, there is a specific loss of mitochondrial, but not nuclear, encoded OXPHOS subunits. We trace the cause to an alternate PGC-1α/β-independent pathway of nuclear-mitochondrial communication that is induced by a decline in nuclear NAD+ and the accumulation of HIF-1α under normoxic conditions, with parallels to Warburg reprogramming. Deleting SIRT1 accelerates this process, whereas raising NAD+ levels in old mice restores mitochondrial function to that of a young mouse in a SIRT1-dependent manner. Thus, a pseudohypoxic state that disrupts PGC-1α/β-independent nuclear-mitochondrial communication contributes to the decline in mitochondrial function with age, a process that is apparently reversible.

    Hope that's helpful. (Remember it's a mouse study.)

    Anne.

    PS Happy New Year. Hope 2014 is a good one!! :D
     
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  4. alex3619

    alex3619 Senior Member

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    I am still reading the article. Resveratrol is of interest as a possible herb to be converted to a drug due to a claim it activates SIRT1 and so extends lifespan. So far I think pharma has been unsuccessful in turning this into a drug, and there is some doubt about how bioavailable the herb is as most is possibly destroyed in the stomach.

    PS The reason for aging they are focused on is that parts of the molecules needed for energy production are made by the mitochondria, but the mitochondria make less of them as we age, shifting the cells toward anaerobic metabolism. The nuclear encoded enzyme components are fine, but the mitochondria cannot keep up. They look at SIRT1 and NAD+ as beneficial, but it occurs to me than mitochondrial proliferation may be a key factor here.
     
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  5. alex3619

    alex3619 Senior Member

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    Think of the cell this way. Its a factory with two assembly lines, and those lines feed into an energy making plant. Both lines work fine when they are new, but as they get older the M line (for mitochondria) slows down. Now the N line (for nucleus) keeps making its components on time, but there are not enough M line components to finish the product, and so an inefficient product or insufficient product is shipped to energy production, and energy production has to find other ways to function as a substitute.
     
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  6. alex3619

    alex3619 Senior Member

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    Stabilized HIF-1 alpha appears to do the damage, stopping the mitochondria from making messenger RNA and hence proteins needed for proper energy production. This can happen from oxidative stress. So controlling oxidative stress inside the cell and especially mitochondria is critical. Its implied that stabilization means damaged and so not able to function, but I am still unclear on this. What they seem to be showing though is that something other than oxidative stress might be a major factor.

    A gene called c-Myc is a big part of the process, and helps HIF-1 alpha to induce mitochondrial mRNA activation.

    SIRT1 works by some kind of activation of HIF-1alpha, and this depends on c-Myc. This whole process appears to depend on NAD+, which is one of the activating factors for SIRT1.

    All of this appears to work because a substance called AMPK acts as a switch, increasing mitochondrial mRNA production, though I am not sure I am interpreting this right.

    So anything that boosts NAD+ might be good, including metabolic precursors that get turned into NAD+.

    In mice, under artificial conditions, the process is reversible.


    In summary:

    NAD+ -> SIRT1 -> HIF-1 alpha -> higher AMPK (still unsure about this) -> increased mitochondrial mRNA -> more assembled oxidative phosphorylation complexes -> higher capacity for using oxygen and fuel to make energy.

    Figure N on p1635 is their diagramatic summary.


    Abbreviations/Acronyms/Key terms

    CR = Calorie Restriction
    NMN = Nicotinamide Mononucleotide

    I wonder what would happen if resveratrol and NADH were taken together? What if this were accompanied by a high protein diet and occasional fasts? They indicate a high fat diet would be bad though.
    Background Reading

    http://en.wikipedia.org/wiki/Sirtuin_1

    http://en.wikipedia.org/wiki/Nicotinamide_adenine_dinucleotide

    On NMN: http://www.cell.com/cell-metabolism/abstract/S1550-4131(11)00346-9?script=true This paper also confirms a high fat diet in humans causes an issue here.

    NMN might be available as coenzymated vitamin B3, I am looking into this. However B3 (particularly as niacinamide) alone may be all that is needed. Alcohols can seriously deplete B3 however, which might be an additional reason why we cannot tolerate alcohol. NADH may have a simialar effect, though I would perhaps be inclined to look at combining B3 and NADH, and so utilize two different paths to NAD. NAD can also be bought as a supplment, iHerb sells it though it is currently out of stock.

    But here is the downside to using nicotinamide or regular B3: http://www.sciencedaily.com/releases/2009/12/091222105449.htm

    Niacin can be dangerous if you are diabetic, and due to possible hypoxia in ME this might apply to most of us.. But see this:

    http://news.wustl.edu/news/Pages/4169.aspx
    [My bolding]

    Does this mean we need to be sure we get NAD and not NADH? Possibly.

    All is not lost however. http://www.nutrimedlogic.com/r-alpha-lipoic-acid-diabetes.html

    (Caveat: this is a press release by a commercial company.)
    So taking niacinamide, NADH and R-Alpha Lipoic acid in combination might work, but getting the ratios and doses right could be a serious problem.
     
    Last edited: Jan 1, 2014
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  7. alex3619

    alex3619 Senior Member

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    Just a thought, but in ME could oxidative stress in the brain (hypothalamus), trigger poor protein regulation of two key proteins in the liver (made in the brain though, I think, I forget their names just now), induce poor fat regulation, fool the liver into thinking we have too much energy, and trigger stabilizatoin of HIF-1 alpha, knocking out a key role in mitochondrial DNA influence on energy production?
     
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  8. MeSci

    MeSci ME/CFS since 1995; activity level 6

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    This relates to rodents, I believe. Rodents are overwhelmingly herbivorous, so their natural diet will be low in fat, I believe (it should be possible to check this).

    In my view dietary studies in non-human animals are some of the worst at predicting effects in humans, due to the large differences in natural diet and digestive processes.
     
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  9. anne_likes_red

    anne_likes_red Senior Member

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    Hmmm yes high fat mouse chow diets - if not oxidised seed oils - is usually lard, soy and sucrose (nice!) and used to induce stress and inflammation....and obesity I guess?
    I wasn't regarding this as a dietary study so much!

    Thanks for your summarising Alex. I wonder if NMA will be available as a supplement anytime soon? It's one of those 'useful' things boosted by endurance exercise (gah!) and seems to further enhance the activity of SIRT...

    ETA I read more carefully above. Make sure you update if you hear about a supplement. I think it may have been approved as a food additive, and there's some interest in it from the anti-aging enthusiasts. Is enthusiasts the right word? If I had a younger brain I might come up with a better word....:rolleyes:

    @heapsreal re SIRT: I had this paper bookmarked. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3527007/
    ...No need to read the whole thing but glancing down at the red sub headings seems to suggest it's a useful path to be looking down...not specifically for PWME of course...it has relevance for many modern (and ever increasing) illnesses. Anne.
     
    Last edited: Jan 1, 2014
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  10. anne_likes_red

    anne_likes_red Senior Member

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    Alex said:
    I've been getting that message pretty consistently the past couple of years in my reading.
    ...That is by no means to say I've been reading the best sources!! :p

    I have been reading about Mito proliferation today...thanks for the lead on that.
    Anne.
     
  11. alex3619

    alex3619 Senior Member

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    On burning fat, most of the research showing harm is based on a high fat high carb diet. For many years now there has been concern that high fat and high carb are not compatible. So a high protein, higher fat, low carb diet may have a different response. This is worth looking into if you want to investigate eating more fat. Fat and carbs are metabolically incompatible at high levels.
     
  12. alex3619

    alex3619 Senior Member

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    http://ajpendo.physiology.org/content/303/3/E308

    I wonder if we have a very poor NAD/NADH ratio during exercise, with prolonged recovery, leading to secondary signalling changes?
     
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  13. Radio

    Radio *****

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    I wonder if we have a very poor NAD/NADH ratio during exercise, with prolonged recovery, leading to secondary signalling changes?
    Loss of ATP energy production, induces by anaerobic metabolism generating lactic acid and restricting blood flow and NO production, BH-4 could be a factor as well...
     
  14. Radio

    Radio *****

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    So taking niacinamide, NADH and R-Alpha Lipoic acid in combination might work, but getting the ratios and doses right could be a serious problem.

    R-Alpha acid can be very powerful even at lose dose, This way mercury is not an issue and NADH to NAD recycling is improved. This is a great way to generating more ATP.
     
    Last edited: Jan 5, 2014
  15. alex3619

    alex3619 Senior Member

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    Low NAD is also a cause of shifting to anaerobic metabolism.
     
  16. Radio

    Radio *****

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    One of the main problems with fibromyalgia is the lactic acid build up and the restricted blood flow in the muscles. I'm glad to see others who understand that NAD is a factor...
     
    Last edited: Jan 1, 2014
  17. alex3619

    alex3619 Senior Member

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    Which according to Julia Newton also occurs in CFS (possibly ME), though it is not known if restricted blood flow is the cause, other factors may be involved.
     
  18. alex3619

    alex3619 Senior Member

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    Here is a question that is worth asking I think. I suspect methylation and similar issues are only risk factors for ME, not a true cause though perhaps contributing, and we know many with long term ME have these issues. How about those who recovered from ME, or garden variety post viral fatigue? Do they have methylation issues etc.? If they don't it would be good to know this. Methylation and similar issues might not only increase risk of getting ME, they might increase the risk of not recovering. I suspect this is highly likely, but data would be nice.

    Say my mantra with me again: We Need More Research.
     
  19. Radio

    Radio *****

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    I have thought about this and i am convinced there is a viral component, What happens when you lose your methylation? You can't make RNA, DNA, and phospholipids to repair and maintain the system. Where do the viruses live? Viruses hide in fat to escape immune system detection. When we loses are protective fats, The immune system see the viruses, Booooom! The domino effect is CFS/ME. The root cause in my opinion has always been a methylation problem that triggers a massive fatty acid, phospholipids, sphingomyelin deficiencies, that activates the immune system and damage the mitochondria as the mast-cell explodes in a sea of viral infections.
     
    Last edited: Jan 5, 2014
  20. dannybex

    dannybex Senior Member

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    Can someone please explain the quinolinic acid part of all of this? It's my understanding that QA is exitotoxic (sp) and/or neurotoxic, and high levels have been found in ME/CFS, parkinson's, MS, etc. My levels were high on an OAT test last spring……….Thanks Anne for starting the thread. :)
     

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