471 replies to this topic

[midas]

Lack of Transferrin Receptor 1 in the Heart Causes Lethal Cardiomyopathy and Disruption of Mitophagy in Mice

 

http://dukespace.lib...dle/10161/10522

 

"Mice lacking Tfr1 in the heart died in the second week of life, with cardiomegaly, poor cardiac function, failure of mitochondrial respiration and ineffective mitophagy. The phenotype could only be rescued by aggressive and ongoing iron therapy, but it was ameliorated by either a mutant Tfr1 allele that does not bind transferrin or administration of nicotinamide riboside, an NAD precursor."

 

 

 

 

Lack of Transferrin Receptor 1 in the Heart Causes Lethal Cardiomyopathy and Disruption of Mitophagy in Mice

 

http://dukespace.lib...dle/10161/10522

 

Hadn't seen that one, thanks. Here is another one to slip thru the cracks.

 

 

 

 

Lethal Cardiomyopathy in Mice Lacking Transferrin Receptor in the Heart

http://www.cell.com/...1247(15)01034-7

http://dx.doi.org/10...iom.2015.09.041

 

Access is limited until 2016-02-13T00:00:00Z

 

It appears NAD boosting has other far reaching benefits. Anything that helps keep hearts heathy is a positive indicator for me!  

 

In Brief

Coexisting iron deficiency worsens the prognosis for patients with heart failure. Xu et al. show that the transferrin receptor is essential in the mouse heart, iron is needed continuously to support oxidative phosphorylation, mitophagy is ineffective when iron is insufficient, and nicotinamide riboside benefits mice with cardiac iron deficiency.

 

Summary

"Both iron overload and iron deficiency have been associated with cardiomyopathy and heart failure, but cardiac iron utilization is incompletely understood. We hypothesized that the transferrin receptor (Tfr1) might play a role in cardiac iron uptake and used gene targeting to examine the role of Tfr1 in vivo. Surprisingly, we found that decreased iron, due to inactivation of Tfr1, was associated with severe cardiac consequences. Mice lacking Tfr1 in the heart died in the second week of life and had cardiomegaly, poor cardiac function, failure of mitochondrial respiration, and ineffective mitophagy. The phenotype could only be rescued by aggressive iron therapy, but it was ameliorated by administration of nicotinamide riboside, an NAD precursor. Our findings underscore the importance of both Tfr1 and iron in the heart, and may inform therapy for patients with heart failure." http://www.cell.com/...(15)01034-7.pdf

 

Please cite this article in press as: Xu et al., Lethal Cardiomyopathy in Mice Lacking Transferrin Receptor in the Heart, Cell Reports (2015), http:// dx.doi.org/10.1016/j.celrep.2015.09.023

 

 

Bryan, the NR doesn't seem to be doing your memory any favours....

[Kirito]

how is nicotinamide riboside different from

 

 

http://www.longecity...-23#entry746369

 

[Bryan_S]

how is nicotinamide riboside different from

 

Just for the record Swanson is a fine company that turns out a great product line and I am a customer.

 

That being said; At the current $16.99 retail for thirty 10mg tablets (The price in that link was $16.99 October 11th) Now from the product you quote from Swanson that adds up to only 300mg's for the whole entire package. (10mg times 30)

 

A typical retail bottle of NR is 7.5 grams and it sells for about $46.99. (Our LongeCity Group buy is a much better discount price) Since it appears all NAD extracellular forms are broken down to at least NR or NaR, possibly even simpler precursors (NA/Nam) involving our digestive system, how is NADH giving you value add over NR?

 

Notice how I pause here and give NADH is due because even if its broken down you will still benefit from its residuals. So if you're taking it, that dose is still better than taking nothing.

 

In the end its your money and you should spend it as you see fit but even if NADH could be absorbed unaltered in the digestive tract without degradation, a single 250mg dose of NR is still 25 times higher than one dose of Swanson's NADH product. Even at the current retail price NR is ($46.99 for 7.5 grams) and 250mg of NR retail runs you about $1.57. At Swanson's prices 250mg of NADH would run you approximately $14.16. Do we need to calculate what 7.5 grams of Swanson's NADH would cost? Do you see the disparity, even "if" it was equal per/milligram in NAD boosting potency?

 

Retail NADH .0566 per mg vs NR at .006265 per mg = 9 times the cost of NR. So we could go into the comparison of the molecules and track an oral dose of each but in the end why buy the more expensive NAD booster when a better one has arrived? Swanson see's where this market is going and they have added Nicotinamide Riboside to their product line as well. I'm not forecasting a market shift but they appear to have already hedged their bet's. 

 

I think you just asked this question for sport because weren't you the one who asked me about the potency of a bottle of NR left in a hot car? It looks like you are already taking NR. 

 

Guys most of this is covered in previous posts. Please take the time to look back thru the thread and read the NAD precursor comparisons. I answered this question from a simple cost standpoint because we never did this cost analysis before but there is much more information on this question in the previous posts.

[works4you2]

Wouldn't it be advisable to supplement both together NR + NADH in order to maximize your NAD+ pools?

We know that NR supplementation can only boost NAD+ so much (30% ~ 50% at higher doses), so would that be a good idea to add 5 or 10 mg of NADH to your current NR regime?

[bluemoon]

Elysium said that the results of their 120 person study that presumably started this summer will be out soon -- this fall.  ChromaDex's NR study at U. Boulder Colorado also presumably ended in August, so we can probably expect those results in fall or early winter based on the time earlier studies were conducted and released.

 

Are these the only two studies that results are expected to be put up on their website (at least Elysium's study) in the next few weeks? 

Edited by bluemoon, 11 October 2015 - 03:26 PM.

[Bryan_S]

Elysium said that the results of their 120 person study that presumably started this summer will be out soon -- this fall.  ChromaDex's NR study at U. Boulder Colorado also presumably ended in August, so we can probably expect those results in fall or early winter based on the time earlier studies were conducted and released.

 

Are these the only two studies that results are expected to be put up on their website (at least Elysium's study) in the next few weeks? 

 

I'm expecting news from the University of Copenhagen where their Pharmacokinetic Analysis of Nicotinamide Riboside has been completed. I reached out to the principal investigator and they are still working on their publication. 

 

Wouldn't it be advisable to supplement both together NR + NADH in order to maximize your NAD+ pools?

We know that NR supplementation can only boost NAD+ so much (30% ~ 50% at higher doses), so would that be a good idea to add 5 or 10 mg of NADH to your current NR regime?

 

I know that there are a lot of NADH, (Na) Niacin and (NAM) Nicotinamide users out there. I'm not telling anyone on these paths to discontinue their regiments because even if the more complicated molecules are reduced they will still raise NAD levels to varying degrees. We also just explored the cost of NADH and the minuscule amounts supplied for that money.

 

Just remember as previously posted "So in all we are left with 4 NAD precursors that readily pass the cell membrane unchanged nicotinic acid riboside (NaR), niacin (Na), nicotinamide (Nam) and nicotinamide riboside (NR). What gives NR or NaR (NaR if we could get it) a leg up on the other precursors is the (NMRK1 & NMRK2) nicotinamide riboside kinase 1 or 2 enzymes. These are expressed in varying degrees in different cell types but the point is they convert these 2 precursors directly to NMN which is one step away from NAD. So in effect these 2 precursors cut to the front of the line at the cell membrane (nicotinamide riboside PnuC transporters) and again inside the cell in the NAD salvage cycle."

 

When I go to sleep at night I as one example take nicotinamide, so I'm a NR user by day and a nicotinamide user by night. Now back to NADH, the dietary reference intake established by the Food and Nutrition Board for niacin ranges from 14-18 milligrams niacin daily. Mind you this not a therapeutic NAD boosting dose but a minimum nutritional recommendation. In my estimation a 10 mg tablet of NADH is hardly tipping the scales of NAD boosting if this is your goal but its your money. Also whether the NADH molecule makes it intact thru digestion or at the cell membrane remains doubtful but we can be pretty assured it will be reduced to NR or NaR for cellular uptake in the end regardless.

Edited by Bryan_S, 11 October 2015 - 04:28 PM.

[ironfistx]

I think you just asked this question for sport because weren't you the one who asked me about the potency of a bottle of NR left in a hot car? It looks like you are already taking NR.

Earlier I posted a pic of it but didn't ask, but what do you think of the potency?

[Kirito]

Hopefully not too off-topic, but I found this to be interesting.

 

"Overexpression of the gene pncB enhances significantly the intracellular level of NAD+. The best data were obtained in anaerobic conditions where the increasing of NAD+ was of 13 fold. which are the conditions to be used in a Microbial Fuel Cell (Anode chamber is in anaerobic condition). When Nicotinic acid was added in the medium there was a significant enhancement of NAD+ levels (1,5 fold versus pncB and 3,7 fold versus negative control). Also in Terrific broth condition there was an increasing in the NAD level (2,7 fold versus negative control in the same condition) In the future it will be interesting to measures NAD+ in anaerobic conditions with the presence of high levels of Nicotinic Acid."

 

http://parts.igem.or...rt:BBa_K1604031

[works4you2]

"Overexpression of the gene pncB enhances significantly the intracellular level of NAD+.

So could it be that expression of the gene pncB is the reason why our  NAD+ levels decrease with age?

[Tom Andre F. (ex shinobi)]

Increase the dosage of NR could still be a problem : habit  (that we see with almost ALL dietary supplement: for instance omega 3 krill oil works less and less over time) and the nicotinamide metabolite in the blood (homocysteine ?)

 

The 50% increase in NAD+ for a limited time could also maybe be much higher if we control other factors. For instance I like the way oxaloacetate and beta lapachone. Last study show almost a 2 fold increase: http://www.nature.co...ki2013330a.html

 

 

Also see diagram here: http://www.nature.co...ml#figure-title

 

So the question is : what if we make it a combo ? I think we can play not only to the increase but also on the time NAD+ will remain high and stable

[bluemoon]

Increase the dosage of NR could still be a problem : habit  (that we see with almost ALL dietary supplement: for instance omega 3 krill oil works less and less over time) and the nicotinamide metabolite in the blood (homocysteine ?) ...

 

... So the question is : what if we make it a combo ? I think we can play not only to the increase but also on the time NAD+ will remain high and stable

 

Isn't Elysium taking a combination approach by adding Pterostilbene with NR? Or is that something different?

[midas]

 

Increase the dosage of NR could still be a problem : habit  (that we see with almost ALL dietary supplement: for instance omega 3 krill oil works less and less over time) and the nicotinamide metabolite in the blood (homocysteine ?) ...

 

... So the question is : what if we make it a combo ? I think we can play not only to the increase but also on the time NAD+ will remain high and stable

 

Isn't Elysium taking a combination approach by adding Pterostilbene with NR? Or is that something different?

 

 

The product they do now (Basis, each two softgel serving has 250mg NR and 50mg Pterostilbene) already has Pterostilbene added to it.....

[bluemoon]

 

 

The product they do now (Basis, each two softgel serving has 250mg NR and 50mg Pterostilbene) already has Pterostilbene added to it.....

 

That was my point. Guarente said he thought there might be a synergistic effect between NR and pterostilbene. But is that likely to be different than what Tom Andre F. is referring to? 

[Mr.No]

Not exactly NR but cheaper

http://www.ncbi.nlm....ll-38-3-229.pdf

 

[timbur]

Have others noticed any changes in HDL while taking NR?  In reviewing articles I've saved, it appears that NA raises HDL, but the other NAD+ metabolites don't, or do so minimally. In my latest bloodwork, my HDL is down to 33 from 44 one year ago.  (LDL is down too from 99 to 83.)  I expected my HDL to raise some, since I have been taking NR.  I'm not thinking my NR/NADH/NAM intake is causing any HDL lowering; I expect that is from my sedentary lifestyle and other dietary factors.

[Tom Andre F. (ex shinobi)]

 

 

 

The product they do now (Basis, each two softgel serving has 250mg NR and 50mg Pterostilbene) already has Pterostilbene added to it.....

 

That was my point. Guarente said he thought there might be a synergistic effect between NR and pterostilbene. But is that likely to be different than what Tom Andre F. is referring to? 

 

 

I have lot of trust in pterostilbene, I consider it much better than resveratrol in all points, but its not the synergy i was refering about. For that you need to check the chart I quoted. Anti aging firewall was the first to explain that the gene NQO1 is a master key regulator in the NAD+/NADH ratio. And all the recent study seems to show the same. So I think the NR strategy limit can be outpass using beta-lapachone for exemple
 

[stefan_001]

 

 

 

 

The product they do now (Basis, each two softgel serving has 250mg NR and 50mg Pterostilbene) already has Pterostilbene added to it.....

 

That was my point. Guarente said he thought there might be a synergistic effect between NR and pterostilbene. But is that likely to be different than what Tom Andre F. is referring to? 

 

 

I have lot of trust in pterostilbene, I consider it much better than resveratrol in all points, but its not the synergy i was refering about. For that you need to check the chart I quoted. Anti aging firewall was the first to explain that the gene NQO1 is a master key regulator in the NAD+/NADH ratio. And all the recent study seems to show the same. So I think the NR strategy limit can be outpass using beta-lapachone for exemple
 

 

 

The article you posted earlier does sound interesting:

 

"Several activators of the NQO1 enzyme have been identified, of which β-lapachone (3,4-dihydro-2,2-dimethyl-2H-naphto[1,2-b]pyran-5,6-dione; βL) is the best known.^{27, 28} βL was first isolated from the bark of the lapacho tree and reported to inhibit tumor growth.²⁹ However, recent reports indicate that the enzymatic activation of NQO1 by βL has beneficial effects on several characteristics of metabolic syndromes, for example, prevention of health decline in aged mice, amelioration of obesity or hypertension, prevention of arterial restenosis, and protection against salt-induced renal injury.^{30, 31, 32, 33, 34, 35}"
 

[Tom Andre F. (ex shinobi)]

Yes, I have updated a summary here : http://www.beta-lapa...f-healthy-life/

 

The mitochondria protection of beta lapachone via NAD+ increasis, is well documented

[stefan_001]

Yes, I have updated a summary here : http://www.beta-lapa...f-healthy-life/

 

The mitochondria protection of beta lapachone via NAD+ increasis, is well documented

 

Interesting read. Allthough I am not convinced yet that it is the ratio that matters. Increased abosolute amounts of NAD+ is in my view the most important and it seems beta lapachone could help here. My take it that the increased ratio is somewhat an indication of more absolute amounts of NAD+. Have you tried it? Or have you seen any anecdotal reports of users?

Edited by stefan_001, 13 October 2015 - 07:30 PM.

[TaiChiKid]

 

Bryan_S wrote:

By the way I found this available Postdoc position by searching for the PK study results. I believe this is the same group responsible for "Pharmacokinetic Analysis of Nicotinamide Riboside" See Primary Outcome Measures below. A study publication by the way that has eluded our search so far. I'm awaiting news from this source to help in calculating viable dosing regiments. So if anyone can catch a glimpse of info originating from this lab please post it here!

 

    serum concentrations of metabolites of nicotinamide riboside [ Time Frame: 8 hour, blood samples every 15 min ] [ Designated as safety issue: No ]
    area under the curve for serum nicotinamide riboside [ Time Frame: 8 hours, blood samples every 15 min ] [ Designated as safety issue: No ]
    calculation of halftime of serum nicotinamide riboside [ Time Frame: 8 hours, blood samples every 15 min ] [ Designated as safety issue: No ]
    calculation of C-max of serum nicotinamide riboside [ Time Frame: 8 hours, blood samples every 15 min ] [ Designated as safety issue: No ]
    calculation of t-max of serum nicotinamide riboside [ Time Frame: 8 hours, blood samples every 15 min ] [ Designated as safety issue: No ]

 

Each of those measurements is directly related to an individual's serum half-life for NR which will vary a lot depending on body need, metabolic rate, age, and so forth, but otherwise behaves in the same way as the chain calculation approximates.  The exact amount of NR remaining in serum at any given time is given by Amount( at time t )   ==   A(t) = newDose + A(t-1) * exp -( halfLife * t ).  The amount A decreases continually exponentially and does not 'jump down' by 1/2 after a half-life.  The trick is that the half-life for an individual will vary widely, and hence each of the AUC, CMax, t-max, and the metabolites serum [k]'s.  If you have any two plasma measurements of NR serum levels at given times, you can calculate your own serum half-life.

Edited by TaiChiKid, 13 October 2015 - 09:42 PM.

[caliban]

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[YOLF]

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