NMN Restores Capillary Density and Blood Flow in Aging Mice

Did they use the mice with faulty NNT gene in this study?

 
As already indicated in the NNT thread, yes: all of their mice — WT, knockout, or transgenic — were NNT mutation-bearing C57Bl/6J mice (see "Experimental Models: Organisms/Strains" in STAR+METHODS.
 

Strange.  I was looking for info on the mice used, and found this chart in the supplementary info.
 
nad-chart-liver-soleus.jpg nad-chart-liver-soleus2.jpg
 
 Seems quite significant that  after 8 weeks of supplementation, liver NAD looks to be over 5x higher in mice receiving NMN.  Soleus looks maybe 50% higher.
 
Isn't that quite a bit higher than some other studies have shown?  What am I missing here?

 
(Specifically, this is supplementary Fig. S6A). Three possible explanations come to mind:
 
First, these are older mice than have been used in nearly all other NAD+ precursor studies. You'd certainly expect on first principles that the relative rise in tissue NAD+ in response to precursor would be greater in older than in younger animals, whatever the final absolute level might be — although surprisingly, the UWash pharmacodynamic study PMID 29211728 seems to suggest the opposite.

Second, you are after all comparing results in different studies with different assay methods: here the investigators used an in-house method, which almost by definition is not what other groups have used. You're always on shaky grounds doing direct comparisons between different studies (cf. MikeDC's initial silliness on this front).

And third, they dosed the animals with NMN via drinking water for 2 months at 400 mg/kg/day, starting at age 18 mo. Most other studies are either for much shorter periods (acute, 1 week) or much longer (12 month) periods. Perhaps there was a progressive build-up over the course of 2 mo that is not captured in shorter studies, but the homeostatic feedback seemingly observed in many other studies after longer periods had not yet kicked in.

I am going to try out Taurine + NAD+ booster (NR in my case) for a while. I would be surprised if I see strong differences but who knows - if the circulation improvement is universal I could imagine that my eyesight would improve somewhat. I am wondering if there is anybody on the board suffering from Hearth Failure and using NR, you may want to consider adding Taurine.

 

Skeletal muscle is not the only tissue that requires adequate
blood flow to maintain function. Heart, liver, bone, and the brain,
for example, are critically dependent on blood flow. It will be
interesting to test whether upregulation of the endothelial
NAD+-H2S pathway improves the vasculature and blood flow
into those tissues as well. If so, precursors to NAD+ and H2S
may not only be effective agents for increasing the recovery
from vessel blockages and enhancing the effects of exercise,
but also for treating the most common of age-related diseases,
if not aging itself.

I have added Taurine to my NR supplementation. Can't tell if there is additional health benefit. 

 
As already indicated in the NNT thread, yes: all of their mice — WT, knockout, or transgenic — were NNT mutation-bearing C57Bl/6J mice (see "Experimental Models: Organisms/Strains" in STAR+METHODS.
 

 
(Specifically, this is supplementary Fig. S6A). Three possible explanations come to mind:
 
First, these are older mice than have been used in nearly all other NAD+ precursor studies. You'd certainly expect on first principles that the relative rise in tissue NAD+ in response to precursor would be greater in older than in younger animals, whatever the final absolute level might be — although surprisingly, the UWash pharmacodynamic study PMID 29211728 seems to suggest the opposite.

 

Second, you are after all comparing results in different studies with different assay methods: here the investigators used an in-house method, which almost by definition is not what other groups have used. You're always on shaky grounds doing direct comparisons between different studies (cf. MikeDC's initial silliness on this front).

 

And third, they dosed the animals with NMN via drinking water for 2 months at 400 mg/kg/day, starting at age 18 mo. Most other studies are either for much shorter periods (acute, 1 week) or much longer (12 month) periods. Perhaps there was a progressive build-up over the course of 2 mo that is not captured in shorter studies, but the homeostatic feedback seemingly observed in many other studies after longer periods had not yet kicked in.

Yes, different studies use different methods, which is why I asked what I was missing  and didn't declare this 500% proves anything.  Perhaps something in their data collection or techniques is questionable that I wouldn't notice.

Your point about homeostasis doesn't seem relevant to me.  Elysium study with much lower dosages in humans shows a clear drop in NAD+ levels from 30-60 days, which everyone assumes is due to homeostasis.  Why would that kick in after 30 days in humans, yet no homeostasis effect at much higher dosages after 60 days in the much shorter lived mice?

Edited by able, 23 April 2018 - 03:54 PM.

Yes, different studies use different methods, which is why I asked what I was missing  and didn't declare this 500% proves anything.  Perhaps something in their data collection or techniques is questionable that I wouldn't notice.

 

Your point about homeostasis doesn't seem relevant to me.  Elysium study with much lower dosages in humans shows a clear drop in NAD+ levels from 30-60 days, which everyone assumes is due to homeostasis.  Why would that kick in after 30 days in humans, yet no homeostasis effect at much higher dosages after 60 days in the much shorter lived mice?

Mice vs humans perhaps? Or I wonder if this is a different kind of homeostasis. If one were to increase dosage post-putative-homeostasis, would we see subsequent similar rise and fall where 2nd trough higher than 1st trough, and by what amount. It could be  activation of downstream NAD consumer that up-regulates over time to some point, leveling off at some level of supplementation? A homeostasis does not necessarily imply an absolute point beyond which supplementation is not useful, correct? It could imply balance between consumers and producers.

Edited by TMNMK, 23 April 2018 - 07:41 PM.

 

Three possible explanations [for the nominally greater boost in tissue NAD+ in this study than others'] come to mind:
 
third, they dosed the animals with NMN via drinking water for 2 months at 400 mg/kg/day, starting at age 18 mo. Most other studies are either for much shorter periods (acute, 1 week) or much longer (12 month) periods. Perhaps there was a progressive build-up over the course of 2 mo that is not captured in shorter studies, but the homeostatic feedback seemingly observed in many other studies after longer periods had not yet kicked in.

Your point about homeostasis doesn't seem relevant to me.  Elysium study with much lower dosages in humans shows a clear drop in NAD+ levels from 30-60 days, which everyone assumes is due to homeostasis.  Why would that kick in after 30 days in humans, yet no homeostasis effect at much higher dosages after 60 days in the much shorter lived mice?

 

Well, who knows? Until you do the study, I'd say it's fraught to just assume a similar absolute (time) or relative (% of LS) time-course between mouse and man. Here, I'll throw out a speculation (I am totally not arguing this — I'm just throwing it out as an example of an hypothesis): maybe part of the reason why humans age ≈10x slower than mice is that we have tighter homeostatic control over our NAD+ levels and/or NAD+:NADH — or, conversely, maybe our slower aging allows us to hold on to better homeostatic control.

Well, who knows? Until you do the study, I'd say it's fraught to just assume a similar absolute (time) or relative (% of LS) time-course between mouse and man. Here, I'll throw out a speculation (I am totally not arguing this — I'm just throwing it out as an example of an hypothesis): maybe part of the reason why humans age ≈10x slower than mice is that we have tighter homeostatic control over our NAD+ levels and/or NAD+:NADH — or, conversely, maybe our slower aging allows us to hold on to better homeostatic control.

Gotcha.  That makes sense, thanks.  

Remember Elysium study with basis has pterostillbene in it. Pterostilbene increases LDL and blood pressure. NR lowers LDL and blood pressure. So maybe the drop was due to

pterostilbene causing more consumption of NAD+

Remember Elysium study with basis has pterostillbene in it. Pterostilbene increases LDL and blood pressure. NR lowers LDL and blood pressure. So maybe the drop was due to

pterostilbene causing more consumption of NAD+

1. Please stop posting the same information simultaneously in parallel threads — especially when the "information" is false.

2.  The claim that "Pterostilbene increases ... blood pressure" is false — or, at least, is contrary to the sole human trial of which I'm aware, which found that In 125 mg PT twice daily lowered both systolic (−7.8 mmHg) and diastolic (−7.3 mmHg) BP, and 100 mg twice daily led to a trend of reduction of SBP and DBP. Do you have evidence to the contrary?

3. Please provide evidence that "NR lowers LDL and blood pressure." There's zero evidence to support an LDL-lowering claim (oh, except your thousands of anonymous anecdotes — right), and contradictory evidence on the latter which may well just turn out to be dueling statistical noise.

1. Please stop posting the same information simultaneously in parallel threads — especially when the "information" is false.

2. The claim that "Pterostilbene increases ... blood pressure" is false — or, at least, is contrary to the sole human trial of which I'm aware, which found that In 125 mg PT twice daily lowered both systolic (−7.8 mmHg) and diastolic (−7.3 mmHg) BP, and 100 mg twice daily led to a trend of reduction of SBP and DBP. Do you have evidence to the contrary?

3. Please provide evidence that "NR lowers LDL and blood pressure." There's zero evidence to support an LDL-lowering claim (oh, except your thousands of anonymous anecdotes — right), and contradictory evidence on the latter which may well just turn out to be dueling statistical noise.

Read the results section. LDL increased 20 point.

https://clinicaltria...870156#outcome2

I asked you about your claim that PT raises BP, not LDL (and your reciprocal claim that NR lowers LDL).
 

Mike's role in this thread is to confuse and distract.  The purpose of the thread is to discuss the study where NMN restores blood flow in aging mice.  NMN is looking better with every passing day and new study.

Also, just to keep things in perspective.  No one is going to defeat aging with any of the nutrient sensing, calorie-restriction strategies, and that includes all sirtuins, mTor and AMPK.  These are NOT the primary hallmarks of aging.  However, they can help us remain much, much healthier until we can get to epigenetic reprogramming, etc. 

That's why I'd love to get some of this stuff somewhat settled so we know when/how to take some of these things, start using them, and then move into even more exciting territory.

Mechanistically, I would think nearly all forms of niacin would lower LDL by inhibit PCSK9 and improving LDL recycling back to the liver.

I did a test 2 years ago w/ NR checking my triglyceride levels and it went like this:

10:30 AM 82 mg/dL upon wake

• Lunch kale veggie shake, sockeye salmon, 6 oz sweet potato, hazel/almond nuts

3:00 PM - run 2.5 miles

4:00 PM - eat dinner

• Sockeye salmon, red cabbage, curried kale, rice/bean mix, blood orange fruit

5:49 PM - 280 mg/dL

5:51 PM - 270 mg/dL

6:00 PM - 375 mg of Nicotinamide Riboside

8:25 PM - 78 mg/dL

10:08 PM - 104 mg/dL

Not the same as LDL cholesterol, of course, but I think a lot of the principles remain the same.  My trigs dropped like a rock 2 hrs later.  I suspect NR is probably unblocking isocitrate dehyodrgenase in the krebs cycle and the mitochondria are being revved up with energy, instead of spewing trigs out into circulation.