NAD+ for mitochondria

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SammyJo
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Re: NAD+ for mitochondria

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I tried Niagen for 3 months and Basis for 2 months. Neither of these nicotinamide riboside products made any change to energy level. I was trying to see if it could do anything like a B vitamin that does give me a tremendous energy boost.

Since 2014 I've been using niacin ER as a sublingual to induce a flush and increase mobility.
600-800 mg niacin is what I take as sublingual to generate a flush, which allows to go from wheelchair only to walking with walker up to 100 ft. Exercise for 60 min (peddling, core strength, arm weights). Stiffness is gone from legs.
If you try this start small with 50 mg and work your way up. Use a pill crusher, put the power under tongue. It's very intense, so be careful. You will get used to it eventually, but at first it is an uncomfortable, itchy sunburn feeling.

Managed to time the flush right last week and blew back my neuro's hair when I jumped up and headed down the hall with a walker for 50 feet. The doc kept saying "I've never heard of this"

The clinical pharmacist suggested Prozac as a vasodilator (that's why Raynaud's patients use it). It does have 2 MS trials but they reported MRIs, not mobility results.

So have I found a way to unlock the NAD fire hose, or is it vasodilation, and the oxygen allows better mobility?

So is it
A) As a precursor to NADH, niacin provides electrons for ATP synthesis that fuels mitochondria & energy.
per http://nootropicsexpert.com/vitamin-b3-niacin/

“Any condition associated with poor mitochondrial function, such as chronic fatigue syndrome… may well benefit from niacinamide supplementation.”

But can NAD+ create such a dramatic energy increase in just 20 minutes, enough to get me walking?

Or is it
B) The mechanism and mitigation of niacin-induced flushing
Niacin activates the arachidonic acid cascade to induce vasodilatation. Niacin activates the G-protein coupled receptor 109A (GPR109A) to increase cAMP and releases arachidonic acid from cell membranes. Arachidonic acid is metabolised to produce prostaglandins, ...
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2779993/

There is some historical info on the flush effect. Richard Brickner's original paper "Phenomenon of relief by flush in multiple sclerosis" from the 1950's, they mainly used Amyl Nitrite, CO2 and histamine phosphate USP to achieve the flush, but they did occasionally use Nicotinic Acid. I found a paper that summarized all the subsequent work done in this direction, but the authors dismiss it because it was observational reports; controlled studies weren't as common in the 1950's. Also they seemed to building a case towards the end argument that expanding veins to treat CCSVI was pointless.

'On the historical succession of vessel-based therapies in the treatment of multiple sclerosis'
https://www.academia.edu/attachments/45 ... ?s=regpath
Last edited by SammyJo on Sun Aug 27, 2017 8:41 pm, edited 1 time in total.
RRMS '95 SPMS '02 | CCSVI 10/09 | Adult stem cells 2012 | http://www.patientsforstemcells.org/
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NHE
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Re: NAD+ for mitochondria

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Several years ago I was in the ER due to chest cramps. They gave me a nitroglycerin tablet which is a strong vasodilator. My brain loved that stuff. I just started talking and talking. Note that these chest cramps weren't due to the NR (I wasn't taking it at that time), they were likely due to elevated homocysteine which was an early sign of my folate and B12 deficiencies. Unfortunately, homocysteine wasn't tested at that time even though I was symptomatic.
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SammyJo
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Re: NAD+ for mitochondria

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NHE, do yo think the vasodilation from the nitro patch enlivened you with oxygen?
RRMS '95 SPMS '02 | CCSVI 10/09 | Adult stem cells 2012 | http://www.patientsforstemcells.org/
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Re: NAD+ for mitochondria

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SammyJo wrote:NHE, do yo think the vasodilation from the nitro patch enlivened you with oxygen?
Yes, I think that the vasodilation got blood flowing more efficiently in my brain. Nitroglycerin is usually prescribed to heart failure patients. I've read that long-term use of nitroglycerin can interfere with the body's own vasodilation process through endothelial nitric oxide synthase, eNOS. In a sense, one can become dependent on it. It was an interesting experiment, but I don't know if I could I could talk a doctor into a prescription. By the way, the nitro was in the form of a small sublingual tablet about 4 mm or so in diameter. It was pretty fast acting. I've done some preliminary research into natural vasodilators, but haven't yet found something for a more permanent solution. Though, over the summer I like to eat fresh cherries and watermelon and find that it helps with my blood pressure.
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NHE
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Re: NAD+ for mitochondria

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Lower mitochondrial NAD+/NADH ratio is associated with cellular senescence.


Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype.
Cell Metab. 2016 Feb 9;23(2):303-14.

Cellular senescence permanently arrests cell proliferation, often accompanied by a multi-faceted senescence-associated secretory phenotype (SASP). Loss of mitochondrial function can drive age-related declines in the function of many post-mitotic tissues, but little is known about how mitochondrial dysfunction affects mitotic tissues. We show here that several manipulations that compromise mitochondrial function in proliferating human cells induce a senescence growth arrest with a modified SASP that lacks the IL-1-dependent inflammatory arm. Cells that underwent mitochondrial dysfunction-associated senescence (MiDAS) had lower NAD+/NADH ratios, which caused both the growth arrest and prevented the IL-1-associated SASP through AMPK-mediated p53 activation. Progeroid mice that rapidly accrue mtDNA mutations accumulated senescent cells with a MiDAS SASP in vivo, which suppressed adipogenesis and stimulated keratinocyte differentiation in cell culture. Our data identify a distinct senescence response and provide a mechanism by which mitochondrial dysfunction can drive aging phenotypes.

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Re: NAD+ for mitochondria

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Nicotinamide riboside rescues angiotensin II-induced cerebral small vessel disease in mice
CNS Neurosci Ther. 2020 Apr;26(4):438-447.


Aims: Hypertension is a leading cause of cerebral small vessel disease (CSVD). Currently, treatments for CSVD are limited. Nicotinamide riboside (NR) can protect against vascular injury and cognitive impairment in neurodegenerative diseases. In this study, the protective effects of NR against angiotensin - (Ang -)-induced CSVD were evaluated.

Methods: To explore the effects of NR in CSVD, C57BL/6 mice were infused with Ang -, and NR was added to the food of the mice for 28 days. Then, short-term memory, blood-brain barrier (BBB) integrity, and endothelial function were detected. Arteriole injury and glial activation were also evaluated.

Results: Our data showed that mice infused with Ang - exhibited decreased short-term memory function and BBB leakage due to decreased claudin-5 expression and increased caveolae-mediated endocytosis after 28 days. Furthermore, Ang - decreased the expression of α-smooth muscle actin (α-SMA) and increased the expression of proliferating cell nuclear antigen (PCNA) in arterioles and decreased the expression of neurofilament 200 (NF200) and myelin basic protein (MBP) in the white matter. These CSVD-related damages induced by Ang - were inhibited by NR administration. Moreover, NR administration significantly reduced glial activation around the vessels.

Conclusion: Our results indicated that NR administration alleviated Ang --induced CSVD by protecting BBB integrity, vascular remodeling, neuroinflammation, and white matter injury (WMI)-associated cognitive impairment.

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Re: NAD+ for mitochondria

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Restoring nuclear entry of Sirtuin 2 in oligodendrocyte progenitor cells promotes remyelination during ageing

Nat Commun. 2022 Mar 9;13(1):1225.


The age-dependent decline in remyelination potential of the central nervous system during ageing is associated with a declined differentiation capacity of oligodendrocyte progenitor cells (OPCs). The molecular players that can enhance OPC differentiation or rejuvenate OPCs are unclear. Here we show that, in mouse OPCs, nuclear entry of SIRT2 is impaired and NAD+ levels are reduced during ageing. When we supplement β-nicotinamide mononucleotide (β-NMN), an NAD+ precursor, nuclear entry of SIRT2 in OPCs, OPC differentiation, and remyelination were rescued in aged animals. We show that the effects on myelination are mediated via the NAD+-SIRT2-H3K18Ac-ID4 axis, and SIRT2 is required for rejuvenating OPCs. Our results show that SIRT2 and NAD+ levels rescue the aged OPC differentiation potential to levels comparable to young age, providing potential targets to enhance remyelination during ageing.

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Re: NAD+ for mitochondria

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Amazon Announces a New NMN Product Regulation on the Site
https://healthnews.com/longevity/longev ... -the-site/

Starting March 13th, 2023, Amazon stated it would require further documentation from all nicotinamide mononucleotide (NMN) suppliers if they wanted to continue selling their product on the site. They must show proof that they have been approved by the U.S. Food and Drug Administration (FDA) for over-the-counter sales.

Key takeaways:
  • Amazon has announced about an upcoming NMN product regulation starting on March 13, 2023.

  • NMN suppliers will have to show proof of FDA approval to remain on the site.

  • Failure to reinstate products as requested will result in the removal of remaining inventory.
The letter comes in reference to an FDA decision announced in October 2022 that reclassified NMN as a drug or drug ingredient, requiring FDA approval for its sale. The change was triggered after Metro International Biotech submitted a form of proprietary NMN they developed to the FDA for investigation as an investigational new drug (IND) in July 2022.

According to the FDA, once a drug has been submitted for such studies, it can no longer be sold as a dietary supplement and must require FDA approval prior to being marketed.

Found in all life forms, NMN is a molecule commonly used in dietary supplements for its anti-aging potential. It is believed to increase the levels of nicotinamide adenine dinucleotide (NAD+), a compound that plays a crucial role in repairing and protecting DNA and promoting optimal mitochondrial health and cellular energy. However, as we age, NAD+ levels tend to decline.

Amazon requirements for suppliers

NMN suppliers have just a few weeks left to plan their next steps. Amazon listed three supporting documents that suppliers will have to provide in order to reinstate their products:
  1. Upload the ingredient list for the product to the product detail page.

  2. Upload labeling with a National Drug Code (NDC) clearly present and legible.

  3. Request a reinstatement through their standard seller appeal process.
If brands do not apply for reinstatement and have any remaining inventory of these products in Amazon fulfillment centers after March 13, 2023, they will need to create a removal order for return or disposal of their remaining inventory.

If they don’t submit a removal order within 30 days of receiving a removal notice, Amazon may dispose of that inventory in accordance with its Service Terms and Legal Policies.

How suppliers are responding?

ProHealth wrote in a statement that they received the letter from Amazon, but “haven’t received any communication from the FDA, and we plan to continue to sell NMN until the FDA tells us that we have to stop.”

This wasn’t the first time Amazon has taken action to remove a popular dietary supplement that the FDA deemed inappropriate for use in natural products.

In May 2021, Amazon also removed NAC (N-acetyl-L-cysteine) from its platform, which resulted in a lawsuit filed by the Natural Products Association against the FDA in a U.S. District Court in Maryland seeking a permanent injunction against the FDA’s retroactive exclusion of NAC from dietary supplements.

The ruling is yet to be determined, and the lawsuit remains pending. In the meantime, however, in August 2022, the FDA announced its plans “to exercise enforcement discretion”, so NAC supplements were reinstated on Amazon.

"We believe this story will eventually end up as the earlier skirmish over NAC, and NMN will be returning to Amazon, but it is not assured. It is possible the FDA will decide to fight harder this time and stop all sales from every platform."
- Renue By Science, NMN brand

You might be unable to buy NMN supplements from some suppliers on Amazon starting March 13th, 2023. However, you will still be able to make purchases from retailers like Hello100 directly.

Disclaimer:

As of October 11, 2022, beta-nicotinamide mononucleotide (Β-NMN) is under an investigation as a potential new drug by the FDA, meaning that it might lose its dietary supplement status. However, retailers haven’t officially received a warning letter and continue with distribution of the NMN products.

[Apparently, the powers that be at Amazon never took organic chemistry. Beta-NMN has a different molecular structure than NMN.]
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