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NMN supplementation reverses cerebrovascular endothelial dysfunction and improves cognitive function in aged mice.

nmn endothelial dysfunction animal study cerebrovascular

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#1 Fredrik

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Posted 15 April 2019 - 11:38 AM


Highlights

 

  • Nicotinamide mononucleotide (NMN) supplementation reverses aging-induced cerebrovascular endothelial dysfunction and improves neurovascular coupling responses in 24-month-old C57BL/6 mice.

  • NMN treatment restores NAD+ levels, improves mitochondrial energetics and attenuates mitochondrial oxidative stress in aged cerebromicrovascular endothelial cells.

  • Rescue of neurovascular coupling responses associates with improved cognitive performance in NMN treated aged mice.

 

 

"Adjustment of cerebral blood flow (CBF) to neuronal activity via neurovascular coupling (NVC) has an essential role in maintenance of healthy cognitive function.

 

In aging increased oxidative stress and cerebromicrovascular endothelial dysfunction impair NVC, contributing to cognitive decline.

 

There is increasing evidence showing that a decrease in NAD+ availability with age plays a critical role in a range of age-related cellular impairments but its role in impaired NVC responses remains unexplored.

 

The present study was designed to test the hypothesis that restoring NAD+ concentration may exert beneficial effects on NVC responses in aging.

 

To test this hypothesis 24-month-old C57BL/6 mice were treated with nicotinamide mononucleotide (NMN), a key NAD+ intermediate, for 2 weeks. NVC was assessed by measuring CBF responses (laser Doppler flowmetry) evoked by contralateral whisker stimulation. We found that NVC responses were significantly impaired in aged mice.

 

NMN supplementation rescued NVC responses by increasing endothelial NO-mediated vasodilation, which was associated with significantly improved spatial working memory and gait coordination.

 

These findings are paralleled by the sirtuin-dependent protective effects of NMN on mitochondrial production of reactive oxygen species and mitochondrial bioenergetics in cultured cerebromicrovascular endothelial cells derived from aged animals.

 

Thus, a decrease in NAD+ availability contributes to age-related cerebromicrovascular dysfunction, exacerbating cognitive decline. The cerebromicrovascular protective effects of NMN highlight the preventive and therapeutic potential of NAD+ intermediates as effective interventions in patients at risk for vascular cognitive impairment (VCI)."

 

https://www.scienced...21323171930240X


Edited by Fredrik, 15 April 2019 - 11:40 AM.

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#2 Harkijn

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Posted 15 April 2019 - 04:30 PM

Another confirmation of the power of NMN. As for our many doubts about oral availability of precursors this study does not help. The mice were injected.


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#3 able

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Posted 16 April 2019 - 02:41 AM

Another confirmation of the power of NMN. As for our many doubts about oral availability of precursors this study does not help. The mice were injected.

 

Yes, and the dosage was huge - 500 mg/kg bodyweight, by IP injection.

 

Any idea why some research uses IV and others use IP?



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#4 Daniel Cooper

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Posted 16 April 2019 - 03:55 PM

IP is just easier with mice.



#5 able

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Posted 05 June 2019 - 06:32 PM

I’m surprised this wasn’t posted yet, as it seemed pretty impressive to me.

 

https://www.scienced...5sVMcL6gM#bib67

 

It looks like 2 weeks of NMN completely restores NAD+ to same level as young mice.  Not just in liver, or blood, but in TISSUE (chart F).

 
 

1-s2.0-S221323171930240X-gr1.jpg

 

I can’t recall - did any previous research with NMN or NR show complete restoration in tissue?

 

ABN sent out an email about this  and has a nice review here.

 

 

This study – published in June 2019 – found that decreased NAD+ resulted in diminished cerebral blood flow (CBF) and cognitive decline.

 

Supplying 24-month-old mice with NMN for 2 weeks restored NAD+ levels and renewed growth of endothelial cells, resulting in increased cerebral blood flow and reversed cognitive decline to that of the 3-month-old control mice.

 

According to this study NMN supplementation:

 

  • Reverses age-induced cerebrovascular endothelial dysfunction and improves NVC responses in old mice.
  • Restores NAD+ mitochondrial energetics and reduces mtROS in aged cerebromicrovascular endothelial cells.
  • Rescues cognitive performance
  • Likely applies to treatment of Alzheimer’s disease.

Edited by able, 05 June 2019 - 06:34 PM.

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#6 Fredrik

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Posted 05 June 2019 - 08:21 PM

Wasn´t posted yet? Oh, I posted it 15 April and you even commented on it. We all need to boost our cerebral blood flow from time to time. Lots of things to read and digest  ;). I´m voting your post as "informative" since it was more fun to read with graph inserted.

 

https://www.longecit...n-in-aged-mice/


Edited by Fredrik, 05 June 2019 - 08:29 PM.

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#7 able

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Posted 05 June 2019 - 08:37 PM

Wasn´t posted yet? Oh, I posted it 15 April and you even commented on it. We all need to boost our cerebral blood flow from time to time. Lots of things to read and digest  ;). I´m voting your post as "informative" since it was more fun to read with graph inserted.

 

https://www.longecit...n-in-aged-mice/

 

hah, right.  Informative as it shows what age does to memory!  Can't believe I forgot - guess I didn't pay enough attention before.

 

I didn't quite grasp the impressive results from reading the wonkish writing you posted from the research.

 

It basically restored NAD+ levels, blood flow, and cognition to that of the young mice.

 

Clearly my memory sucks.   Did any prior research show completely restrored NAD+ levels  in tissue?

 

 


Edited by able, 05 June 2019 - 08:43 PM.

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#8 Michael

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Posted 06 June 2019 - 02:03 AM

First: unless anyone raises a cogent objection, I'm going to merge this into Fredrik's earlier thread.
 

It looks like 2 weeks of NMN completely restores NAD+ to same level as young mice.  Not just in liver, or blood, but in TISSUE (chart F).
 
I can’t recall - did any previous research with NMN or NR show complete restoration in tissue?


A couple of reasons to curb your enthusiasm ;) . First, this was i.p. injected NMN, which partially bypasses the liver, and was also the typical 500 mg/kg; this is not going to reflect what anyone gets from oral administration of a few hundred milligrams (absent any advantage from any still-unproven superiority of sublingual NMN).

 

Second, when they say "tissue," I'm guessing you're imagining tissues all over the body — skeletal muscle, brain, cardiac muscle, etc. But as you can see from the description of Figure 1(F) (what you refer to as "chart F"), this was actually only in aortic endothelium — ie, the layer of the blood vessel closest to the blood flow, and in a vessel adjacent to where they were sticking the needle. It would be surprising if there wasn't a very robust increase in "tissue" NAD+ under those conditions.


Edited by Michael, 06 June 2019 - 02:04 AM.

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#9 able

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Posted 08 June 2019 - 03:43 AM

It seems this research was published in 2 different places, a month apart, with different titles and some changes in authors.  Partly why I thought it was not posted yet (along with old age memory)

 

 

 

Nicotinamide mononucleotide (NMN) supplementation rescues cerebromicrovascular endothelial function and neurovascular coupling responses and improves cognitive function in aged mice.

 

and

Nicotinamide mononucleotide (NMN) treatment attenuates oxidative stress and rescues angiogenic capacity in aged cerebromicrovascular endothelial cells: a potential mechanism for the prevention of vascular cognitive impairment

 

Good point about the NAD+ increase in aorta - not quite the same as an organ.

 

I do still think the near total restoration in cognitive function is quite impressive and hopeful.

 

They just need to figure out more effective delivery methods to get similar results in humans.

 

 



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#10 brosci

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Posted 14 June 2019 - 03:07 PM

If the goal is to support heart health, does the latest research point to NMN or NR as being superior?


Edited by brosci, 14 June 2019 - 03:08 PM.


#11 Fredrik

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Posted 14 June 2019 - 03:20 PM

If the goal is to support heart health, does the latest research point to NMN or NR as being superior?

 

I don´t think anyone knows yet.

 

NMN is just NR with an added unnecessary phosphate group that the body will cleave anyway.

 

NMN may be more stable on the shelf than NR (if so the phosphate group may have some use after all). Maybe. I stored my NR in the fridge as the patents described increased degradation with higher temperatures and David A Sinclair later said this in one of his lectures.

 

NR has a head start with more human clinical trials than NMN. At least one NR study is looking at heart health.

 

David A Sinclair says that both NR and NMN increased lifespan (unpublished) in his lab and that they have very similar metabolic effects and that they increase endurance in animals.

 

We´ll see in the coming years when human data will be available ^^


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#12 Daniel Cooper

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Posted 14 June 2019 - 03:29 PM

I think the only advantage I see to NMN is that it isn't locked up by a Chromadex patent on the preferable synthesis route, and therefore might one day be cheaper (although I think the currently used synthesis route for NMN is more expensive than Chromadex's patented NR synthesis).

 

 

 



#13 brosci

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Posted 14 June 2019 - 07:47 PM

I've seen ribose used for heart & mitochondrial health, and I've read NR is part ribose (my understanding of these compounds is very limited.) Does this offer any additional benefits for the NR form?



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#14 able

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Posted 14 June 2019 - 08:11 PM

I don´t think anyone knows yet.

 

NMN is just NR with an added unnecessary phosphate group that the body will cleave anyway.

 

NMN may be more stable on the shelf than NR (if so the phosphate group may have some use after all). Maybe. I stored my NR in the fridge as the patents described increased degradation with higher temperatures and David A Sinclair later said this in one of his lectures.

 

NR has a head start with more human clinical trials than NMN. At least one NR study is looking at heart health.

 

David A Sinclair says that both NR and NMN increased lifespan (unpublished) in his lab and that they have very similar metabolic effects and that they increase endurance in animals.

 

We´ll see in the coming years when human data will be available ^^

 

I agree it seems likely they have similar metabolic effect.

 

NMN has a possible advantage that some unspecified amount of oral supplements can utliize the slc12a8 enzyme to transport directly to NAD+ in the intestines.  NR cannot.  But it is likely a very small amount.

 

NR is perhaps able to enter most cells more quicky, but is extremely unstable in bloodstream.

 

NMN is much more stable in the bloodstream.  According to Liu, both are metabolized in the liver and excreted as NAM.  If correct, neither really makes it to the blood in significant quantity.  

 

if Liu is not entirely accurate and some does make it to blood, they might have some different metabolic effect.  

 

I would agree that I don't believe anyone really knows which is "better".


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