2255 replies to this topic

[Black Fox]

I am interested in this relationship mentioned by Nate:

The relationship is more so between straight B3, Niacin and homocysteine.
There was a discussion about it earlier in this thread and I mentioned I'd have mine checked to be sure.

Is there a way for me to search a single thread for a keyword... without resorting to
looking on every page of the thread ?

...
Be mindful that NR along with Niacin raise homocysteine( no wonder why products like Resveracel we including TMG in their formula), you should be a week away from those before getting your blood work...

What is the scientific evidence we have on NR rising homocysteine?

I have been looking at this from time to time w/o finding much beside some anecdotal reports. And as we are on anecdotes, despite 200-300mg supplementation of NR I could not see any effect on my levels while I clearly see it using similar doses of Niacin. Incidentally, I level around 11 mcmol/l despite my B complex supplementation. I am also looking at Cystatin C which measures renal funtion and is correlated to homocysteine. I will re-do a test using an additional 1000 mcg of l-Methylfolate and possibly some extra TMG for some time but I am skeptic as results several years ago were negative. I am not homozygous for MTHFR C677T (rs1801133) and am heterozygous for MTHFR A1298C (rs1801131).

Congrats to Nat for his excellent values!

Sometime ago I scoured the internet for any NR homocysteine connection and found none. My homocysteine levels after six months of taking 400mg of NR daily were unchanged. I think Black Fox may be confusing NR with Niacinamide...
Vast swathes of the population have a poor intestinal absorption of B12 so it's not likely that taking a Bcomplex will help your homocysteine levels. Much more effective: sublingual methylcobalamin.

I wasn't confused, I was talking from the experience. I'm homozygous for MTHFR C677T.

My homocysteine baseline is around 10 uMols/L. No supps!!
While I was talking 1000 mg NR and also supplementing along with a B complex ,TMG and taurine my homocysteine rose to 12 and after a months of "detoxing" on every single supp I switched to 250 mg Niacin along with B complex, TMG and taurine and my homocysteine rose above 16 :(

For al of you out there mega supplementing on NR or Niacing, get yourself tested for MTHFR before jumping on this wagon JMHO
DNA loads the gun but environment pulls the trigger

I'll be addressing my mutation properly shortly with Hydroxycobalamin, L5-MTHF, FOLATE , TMG

I'm also planing to get myself tested for CBS, MAOA, COMT and SUOX

Edited by Black Fox, 14 September 2016 - 07:49 AM.

[Black Fox]

Apologies to everyone in advance as I'm far from being an expert in field of longevity, but I've trying to educate myself through lotta lurking and reading.

As I skimmed the whole Samuel A.J. trammel's papers and the following statements caught my eyes.

"The ability of milk to bind and preserve the integrity of NR makes dairy products potentially good sources of supplementing NR along with, specially non organic sources"

Will it be advisable to chug down a glass of milk along with NR? As we want it to reach our gut as stable as possible , even though I was recommended by HPN's owner Sean Torbati to avoid fats while taking NR.


"Though current data is highly suggestive that NMN utilization requires dephosphorylation by CD73 to NR or hydrolysis to Nam by CD38"

If CD38 is involved in the process of NMN =>>NAM, why does it get outta hand with age? Will it be such a good idea to inhibit it for the long run as we don't know the role that it plays? What about keeping their levels to a youth stage, so it does what it suppose to do?

CD38 has been implicated in the secretion and function of hormones such as oxytocin and ACTH and may modulate maternal and social behavior and also CD38 plays a key role in the mechanism by which the organism fights bacterial infection... And God knows what else...

Cuz some people are supplementing with quercetin and this is being identified as a Sirt 1 inhibitor along with CD38.In fact, SIRT1 and CD38 have several similarities in their enzymatic and catalytical properties.

http://www.ncbi.nlm....les/PMC2883294/

Wouldn't it be better to use. Apigenin over quercetin?http://www.ncbi.nlm....pubmed/23172919


"NMN depends upon CD38, CD73, and NRK"

Will this explain why Sinclair was able to bring the clock back on those old mice's muscles in such short period of time? I'm guessing that old mouse had high levels of CD38

Because according to the paper it shows that NR superior than NMN and yet we have not seen the results of NMN had in such short period of time.

"NR contributed to the intracellular NAD metabolome more rapidly than NMN and increased NAD+ by more than 2 fold after 24 hours, indicating NR is kinetically superior to NMN"

Regarding the discussion between Bryan and Tom, it looks like NR is superior to NA and NAM at hepatic levels even though NA produced the least increase in hepatic NAD+ but also was 4-6 hours faster than NR and Nam in the kinetics of hepatic NAD+ accumulation. They also used NAAD as biomarker to state that NR is superior , but what's the role of NAAD , is it a pool to raise NAD+ over time?

NR is a superior liver precursor to NAD+ compared to Nam and NA and the increase in NAD+ correlated with NAAD... But is it that superior?


Thoughts?

[Nate-2004]

Cuz some people are supplementing with quercetin and this is being identified as a Sirt 1 inhibitor along with CD38.In fact, SIRT1 and CD38 have several similarities in their enzymatic and catalytical properties.

http://www.ncbi.nlm....les/PMC2883294/

Wouldn't it be better to use. Apigenin over quercetin?http://www.ncbi.nlm....pubmed/23172919

 

Wait, what? Quercetin inhibits SIRT1!? Where does it say that? I've been taking both, apigenin at night, quercetin during the day. I'm still not sure what the actual half-life of apigenin is, some say 12 hrs, some say 91. I've been cycling it 3 days on 3 days off.

 

I've read nothing so far about it being a quercetin inhibitor was this in the 200 page deal somewhere? It's not mentioned in the link you posted below that.

[Black Fox]

Cuz some people are supplementing with quercetin and this is being identified as a Sirt 1 inhibitor along with CD38.In fact, SIRT1 and CD38 have several similarities in their enzymatic and catalytical properties.

http://www.ncbi.nlm....les/PMC2883294/

Wouldn't it be better to use. Apigenin over quercetin?http://www.ncbi.nlm....pubmed/23172919

Wait, what? Quercetin inhibits SIRT1!? Where does it say that? I've been taking both, apigenin at night, quercetin during the day. I'm still not sure what the actual half-life of apigenin is, some say 12 hrs, some say 91. I've been cycling it 3 days on 3 days off.

I've read nothing so far about it being a quercetin inhibitor was this in the 200 page deal somewhere? It's not mentioned in the link you posted below that.

it is important to say that it is possible that molecules that inhibit CD38 may also inhibit SIRT1

Chapter 6 , page 13,http://www.ncbi.nlm....les/PMC2883294/

I don't about Apigenin, but it looks it might as well....

Nate, have u gotten any bacteria infections lately?

Edited by Black Fox, 14 September 2016 - 02:09 PM.

[Nate-2004]

it is important to say that it is possible that molecules that inhibit CD38 may also inhibit SIRT1

Chapter 6 , page 13,http://www.ncbi.nlm....les/PMC2883294/

I don't about Apigenin, but it looks it might as well....

Nate, have u gotten any bacteria infections lately?

 

 

I suppose he means any and all CD38 inhibitors and "might" is a key word, seems more of a hypothesis.

 

No infections, I haven't been sick in a couple years now and the one time I was sick within 3 years it lasted a day. 

[Harkijn]

Apologies to everyone in advance as I'm far from being an expert in field of longevity, but I've trying to educate myself through lotta lurking and reading.

As I skimmed the whole Samuel A.J. trammel's papers and the following statements caught my eyes.

"The ability of milk to bind and preserve the integrity of NR makes dairy products potentially good sources of supplementing NR along with, specially non organic sources"

Will it be advisable to chug down a glass of milk along with NR? As we want it to reach our gut as stable as possible , even though I was recommended by HPN's owner Sean Torbati to avoid fats while taking NR.


"Though current data is highly suggestive that NMN utilization requires dephosphorylation by CD73 to NR or hydrolysis to Nam by CD38"

If CD38 is involved in the process of NMN =>>NAM, why does it get outta hand with age? Will it be such a good idea to inhibit it for the long run as we don't know the role that it plays? What about keeping their levels to a youth stage, so it does what it suppose to do?

CD38 has been implicated in the secretion and function of hormones such as oxytocin and ACTH and may modulate maternal and social behavior and also CD38 plays a key role in the mechanism by which the organism fights bacterial infection... And God knows what else...

Cuz some people are supplementing with quercetin and this is being identified as a Sirt 1 inhibitor along with CD38.In fact, SIRT1 and CD38 have several similarities in their enzymatic and catalytical properties.

http://www.ncbi.nlm....les/PMC2883294/

Wouldn't it be better to use. Apigenin over quercetin?http://www.ncbi.nlm....pubmed/23172919


"NMN depends upon CD38, CD73, and NRK"

Will this explain why Sinclair was able to bring the clock back on those old mice's muscles in such short period of time? I'm guessing that old mouse had high levels of CD38

Because according to the paper it shows that NR superior than NMN and yet we have not seen the results of NMN had in such short period of time.

"NR contributed to the intracellular NAD metabolome more rapidly than NMN and increased NAD+ by more than 2 fold after 24 hours, indicating NR is kinetically superior to NMN"

Regarding the discussion between Bryan and Tom, it looks like NR is superior to NA and NAM at hepatic levels even though NA produced the least increase in hepatic NAD+ but also was 4-6 hours faster than NR and Nam in the kinetics of hepatic NAD+ accumulation. They also used NAAD as biomarker to state that NR is superior , but what's the role of NAAD , is it a pool to raise NAD+ over time?

NR is a superior liver precursor to NAD+ compared to Nam and NA and the increase in NAD+ correlated with NAAD... But is it that superior?


Thoughts?

Torbati  advised you to avoid eating fat and NR at the same time. Did he give you a reason for this?Perhaps a reference?

[Bryan_S]

CD38 has been implicated in the secretion and function of hormones such as oxytocin and ACTH and may modulate maternal and social behavior and also CD38 plays a key role in the mechanism by which the organism fights bacterial infection... And God knows what else...

Wouldn't it be better to use. Apigenin over quercetin?http://www.ncbi.nlm....pubmed/23172919

 

I've been taking Apigenin since we first discussed it. On the other hand I jumped on the Senolytics bandwagon (another longevity strategy) and experimented with Quercetin the beginning of last summer.  See: The Common Supplement Quercetin Kills Senescent Cells

For me it seemed to somewhat cancel the NR energy boosting benefits and I felt rundown, I discontinued it after reading this. Potential toxicity of quercetin: So there might be a reason it works as a Senolytic, it interferes with mitochondrial biogenesis. Now this isn't definitive but it might be at odds with what we are trying to do with NR. I'm not wanting to interfere with one one thing to get a benefit in another. So I'm leaning more to the Apigenin side of the road than the Quercetin.

 

We also need CD38, so this is an area needing further study before the proper strategy emerges, which it hasn't. So far I haven't felt any adverse effects from Apigenin but haven't felt any benefits either.

 

Wait, what? Quercetin inhibits SIRT1!? Where does it say that? I've been taking both, apigenin at night, quercetin during the day. I'm still not sure what the actual half-life of apigenin is, some say 12 hrs, some say 91. I've been cycling it 3 days on 3 days off.

 

I've read nothing so far about it being a quercetin inhibitor was this in the 200 page deal somewhere? It's not mentioned in the link you posted below that.

 

 

Nate here is a thread that has gone silent but it still might answer your questions.

[Nate-2004]

I haven't lost the energy that NR gives me one bit since taking quercetin over the last 3 months or so. I realize we need CD38 but I don't think these inhibitors disable it completely given the apparent mechanisms of action in quercetin. Apigenin's mechanism of action is still a bit of a mystery. 

 

The double edged sword of so many of these attempts at solving downstream problems is incredibly frustrating. It's like we're trying to lift the stool we're sitting on. SIRT1 is the goal, NAD+ is the key, and CD38 is the problem, but trying to bring it back down to normal levels (or normal for a 25 year old) defeats the goal? ugh. 

 

These are my thoughts and I suppose a hypothesis, but I had planned to begin cycling quercetin in and out every couple of months or so partly because of cost and partly because I wonder if it's entirely necessary, if indeed its mechanism of action on CD38 is synolitic, to take it continuously. I mean, once senescent cells have been eliminated (the questions of not only whether that's true in vivo but also to what degree) in the endothelium, is it even necessary to take it that often until those cells build up again? How quickly do senescent cells build up? Especially considering it's only targeting those particular senescent cells. I suppose I will redirect my resources back to pterostilbene or resveratrol, if only I could get pterostilbene in bulk.

 

I'd planned to stop taking it for a while this week so we'll see how I feel afterward.

Edited by Nate-2004, 14 September 2016 - 07:05 PM.

[mrlamm]

Would any scientific mind care to comment on this research study: https://jissn.biomed...2970-016-0143-x The NAD+ precursor nicotinamide riboside decreases exercise performance in rats

 

The paper concludes:

 

Chronic administration of the NAD⁺ precursor nicotinamide riboside tended to decrease physical performance in rats. We believe that this finding is important and timely and adds to the expanding literature showing that altering metabolic and redox homeostasis via exogenously administered agents may lead to adverse and not necessarily beneficial or neutral effects.

 

So, thoughts?

[Nate-2004]

Would any scientific mind care to comment on this research study: https://jissn.biomed...2970-016-0143-x The NAD+ precursor nicotinamide riboside decreases exercise performance in rats

 

The paper concludes:

 

Chronic administration of the NAD⁺ precursor nicotinamide riboside tended to decrease physical performance in rats. We believe that this finding is important and timely and adds to the expanding literature showing that altering metabolic and redox homeostasis via exogenously administered agents may lead to adverse and not necessarily beneficial or neutral effects.

 

So, thoughts?

 

This was posted earlier in this thread maybe 6 or 7 pages back, I can't find it, and it was discussed at length.

[rlb373]

 

..... any thoughts?

 

This was posted earlier in this thread maybe 6 or 7 pages back, I can't find it, and it was discussed at length.

 

 

Here's the link #1042 (on page 35) 

 

The Google search: site:longecity.org/forum/topic/82770-nicotinamide-riboside-curated "exercise performance in rats" also turned up hits on page 38

[Nate-2004]

 

 

..... any thoughts?

 

This was posted earlier in this thread maybe 6 or 7 pages back, I can't find it, and it was discussed at length.

 

 

Here's the link #1042 (on page 35) 

 

The Google search: site:longecity.org/forum/topic/82770-nicotinamide-riboside-curated "exercise performance in rats" also turned up hits on page 38

 

 

I think there was an even earlier posting than that, not sure.

Edited by Nate-2004, 16 September 2016 - 05:32 PM.

[Bryan_S]

Regeneration of NAD keeps mouse muscles young

http://science.scien...305/1246.6.full

 

Evidence for a critical role of nitric acid dihydrate Nicotinamide adenine dinucleotide (NAD) metabolism in aging is accumulating. Frederick et al. studied mice with muscle-specific depletion of nicotinamide phosphoribosyltransferase (Nampt), an enzyme needed to restore concentrations of NAD in working muscle. Muscle in young animals tolerated a large reduction in the amount of NAD without obvious loss of function. However, older control animals had decreased muscle concentrations of NAD, which correlated with decreased performance, and these effects were more pronounced in animals lacking Nampt. Restoration of NAD concentrations by feeding older animals nicotinamide riboside partially restored muscle function. Accordingly, overexpression of Nampt in muscle helped prevent the age-dependent decline in muscular function. Thus, maintenance of proper NAD metabolism in muscle appears to be needed for sustained function.

Cell Metab. 10.1016/j.cmet.2016.07.005 (2016).

Edited by Bryan_S, 17 September 2016 - 05:59 AM.
nitric acid dihydrate

[Bryan_S]

Would any scientific mind care to comment on this research study: https://jissn.biomed...2970-016-0143-x The NAD+ precursor nicotinamide riboside decreases exercise performance in rats

 

The paper concludes:

 

Chronic administration of the NAD⁺ precursor nicotinamide riboside tended to decrease physical performance in rats. We believe that this finding is important and timely and adds to the expanding literature showing that altering metabolic and redox homeostasis via exogenously administered agents may lead to adverse and not necessarily beneficial or neutral effects.

 

So, thoughts?

 

We already reviewed this. This was an underfunded study by some Greek graduate students that fly's in the face of a multitude of other studies like the one I just posted. Its not being taken seriously and other than this thread its off the radar.

[Nate-2004]

Regeneration of NAD keeps mouse muscles young

http://science.scien...305/1246.6.full

 

Evidence for a critical role of nitric acid dihydrate Nicotinamide adenine dinucleotide (NAD) metabolism in aging is accumulating. 

 

Wait.... nitric acid dihydrate?!?!?! That's something found in polar stratospheric clouds... That isn't nicotinamide adenine dinucleotide. 

Edited by Bryan_S, 17 September 2016 - 06:00 AM.
source typo corrected

[nikolay]

Guys, a quick question: any evidence if NADH inhibitя sirtuins like NAD does?

[Bryan_S]

Guys, a quick question: any evidence if NADH inhibitя sirtuins like NAD does?

 

The reduced form of NAD+ I don't think is gets far enough to worry about inhibition. https://www.jstage.j...2/52_2_142/_pdf

 

I don't want to be too brutal but its a large fragile molecule and the digestive track is not forgiving. Its also one of the most expensive per gram with pill or capsule dosages in the 10mg range. I've seen one brand claiming 20mg pre capsule. So no direct evidence it inhibits the sirtuin's at these oral dosages and taking enough to test would be extremely expensive.

 

​I've read one article that discussed sirtuin inhibition within the cell but only at high levels which is not the norm.

http://pharmrev.aspe...t/64/1/166.full

 

If it were injected as some NAD+ studies have indicated it would still be broken down into simpler metabolites at the cell membrane to become available within. Here is one study suggesting the fates of several molecules: Comparison of metabolic fates of nicotinamide, NAD+ and NADH administered orally and intraperitoneally; characterization of oral NADH.

 

Here are the salvage paths from an extracellular perspective excluding the digestive track. 

Edited by Bryan_S, 17 September 2016 - 06:02 AM.
format

[Bryan_S]

DNA damage, DNA repair, aging, and neurodegeneration

 

http://perspectivesi...34-976e4af19f0c

 

https://www.research...urodegeneration

[Harkijn]

 

DNA damage, DNA repair, aging, and neurodegeneration

 

http://perspectivesi...34-976e4af19f0c

 

https://www.research...urodegeneration

 

It is interesting or at least for me new that the authors seem to suggest for future consideration that taking NAD+ precursors could be combined with PARP inhibitors. In healthy people.

The role of CD38 in NAD+loss is not even mentioned in this article. Nor is it discussed in a similar one:

https://www.research...cient_disorders

Does CD38 contribute less to NAD+loss than we thought?

[stefan_001]

 

 

DNA damage, DNA repair, aging, and neurodegeneration

 

http://perspectivesi...34-976e4af19f0c

 

https://www.research...urodegeneration

 

It is interesting or at least for me new that the authors seem to suggest for future consideration that taking NAD+ precursors could be combined with PARP inhibitors. In healthy people.

The role of CD38 in NAD+loss is not even mentioned in this article. Nor is it discussed in a similar one:

https://www.research...cient_disorders

Does CD38 contribute less to NAD+loss than we thought?

 

 

The articles seem rather old school to me. Significance of aging due to DNA damage seems overrated to me. Changing methylation patterns that alter DNA function in my view is more impact-full. That disturbs or changes the balance and can give rise to inflamation, CD38 etc.

[Bryan_S]

I don't think anyone would take PARP inhibitors to raise NAD levels. Although if you cut out DNA maintenance NAD levels do rise but at what cost. I think maintaining our chromatin in a youthful configuration with the proper DNA methylation, establishes the framework for long-term epigenetic maintenance. Giving the cell the resources and energy to accomplish this work is step one. If aberrant players such as CD38 can be understood and corrected the whole machine should be self renewing.

[bluemoon]

Here is a recent clip of David Sinclair discussing NAD+ and NMN.

 

It is 23 minutes long and starts at 18:00 or so. We get to see a mouse run after taking NMN for two months, which is just like the resveratrol mouse ten years ago... 

 

[Ohm]

Those mice were injected with NMN.  

 

Is the benefit comparable when regular people are sending NR pills through their GI tract?

[Nate-2004]

Those mice were injected with NMN.  

 

Is the benefit comparable when regular people are sending NR pills through their GI tract?

 

Not only that but it was injected directly into muscle tissue and the only thing tested was muscle performance. I am wondering the same. There is evidence to say that it does increase NAD+ levels.

Edited by Nate-2004, 20 September 2016 - 08:14 PM.

[bluemoon]

At 18:07 Sinclair says that one of the mice running on the treadmill has been drinking NMN in water for a couple of months while the other was not. 

[playground]

At 18:07 Sinclair says that one of the mice running on the treadmill has been drinking NMN in water for a couple of months while the other was not. 

 

I thought we couldn't consume NMN orally. 

Or did i dream that detail ?
 

[Nate-2004]

 

Those mice were injected with NMN.  

 

Is the benefit comparable when regular people are sending NR pills through their GI tract?

 

Not only that but it was injected directly into muscle tissue and the only thing tested was muscle performance. I am wondering the same. There is evidence to say that it does increase NAD+ levels.

 

 

Remind me what the answer to this question was?

 

Regeneration of NAD keeps mouse muscles young

http://science.scien...305/1246.6.full

 

Evidence for a critical role of nitric acid dihydrate Nicotinamide adenine dinucleotide (NAD) metabolism in aging is accumulating. 

 

Wait.... nitric acid dihydrate?!?!?! That's something found in polar stratospheric clouds... That isn't nicotinamide adenine dinucleotide. 

 

 

Did no one think this was strange? 

[Nate-2004]

 

Apologies to everyone in advance as I'm far from being an expert in field of longevity, but I've trying to educate myself through lotta lurking and reading.

As I skimmed the whole Samuel A.J. trammel's papers and the following statements caught my eyes.

"The ability of milk to bind and preserve the integrity of NR makes dairy products potentially good sources of supplementing NR along with, specially non organic sources"

Will it be advisable to chug down a glass of milk along with NR? As we want it to reach our gut as stable as possible , even though I was recommended by HPN's owner Sean Torbati to avoid fats while taking NR.


"Though current data is highly suggestive that NMN utilization requires dephosphorylation by CD73 to NR or hydrolysis to Nam by CD38"

If CD38 is involved in the process of NMN =>>NAM, why does it get outta hand with age? Will it be such a good idea to inhibit it for the long run as we don't know the role that it plays? What about keeping their levels to a youth stage, so it does what it suppose to do?

CD38 has been implicated in the secretion and function of hormones such as oxytocin and ACTH and may modulate maternal and social behavior and also CD38 plays a key role in the mechanism by which the organism fights bacterial infection... And God knows what else...

Cuz some people are supplementing with quercetin and this is being identified as a Sirt 1 inhibitor along with CD38.In fact, SIRT1 and CD38 have several similarities in their enzymatic and catalytical properties.

http://www.ncbi.nlm....les/PMC2883294/

Wouldn't it be better to use. Apigenin over quercetin?http://www.ncbi.nlm....pubmed/23172919


"NMN depends upon CD38, CD73, and NRK"

Will this explain why Sinclair was able to bring the clock back on those old mice's muscles in such short period of time? I'm guessing that old mouse had high levels of CD38

Because according to the paper it shows that NR superior than NMN and yet we have not seen the results of NMN had in such short period of time.

"NR contributed to the intracellular NAD metabolome more rapidly than NMN and increased NAD+ by more than 2 fold after 24 hours, indicating NR is kinetically superior to NMN"

Regarding the discussion between Bryan and Tom, it looks like NR is superior to NA and NAM at hepatic levels even though NA produced the least increase in hepatic NAD+ but also was 4-6 hours faster than NR and Nam in the kinetics of hepatic NAD+ accumulation. They also used NAAD as biomarker to state that NR is superior , but what's the role of NAAD , is it a pool to raise NAD+ over time?

NR is a superior liver precursor to NAD+ compared to Nam and NA and the increase in NAD+ correlated with NAAD... But is it that superior?


Thoughts?

Torbati  advised you to avoid eating fat and NR at the same time. Did he give you a reason for this?Perhaps a reference?

 

 

Would love to know the answer to this one.

[Bryan_S]

Normalization of NAD+ Redox Balance as a Therapy for Heart Failure

Chi Fung Lee, Juan D. Chavez, Lorena Garcia-Menendez, Yongseon Choi, Nathan D. Roe, Ying Ann Chiao, John S. Edgar, Young Ah Goo, David R. Goodlett, James E. Bruce and Rong Tian

 http://dx.doi.org/10...NAHA.116.022495

 

Published: September 20, 2016

 

http://circ.ahajourn...134/12/883.full

 

Abstract

 

Background: Impairments of mitochondrial function in the heart are linked intricately to the development of heart failure, but there is no therapy for mitochondrial dysfunction.

 

Methods: We assessed the reduced/oxidized ratio of nicotinamide adenine dinucleotide (NADH/NAD+ ratio) and protein acetylation in the failing heart. Proteome and acetylome analyses were followed by docking calculation, mutagenesis, and mitochondrial calcium uptake assays to determine the functional role of specific acetylation sites. The therapeutic effects of normalizing mitochondrial protein acetylation by expanding the NAD+ pool also were tested.

 

Results: Increased NADH/NAD+ and protein hyperacetylation, previously observed in genetic models of defective mitochondrial function, also are present in human failing hearts as well as in mouse hearts with pathologic hypertrophy. Elevation of NAD+ levels by stimulating the NAD+ salvage pathway suppressed mitochondrial protein hyperacetylation and cardiac hypertrophy, and improved cardiac function in responses to stresses. Acetylome analysis identified a subpopulation of mitochondrial proteins that was sensitive to changes in the NADH/NAD+ ratio. Hyperacetylation of mitochondrial malate-aspartate shuttle proteins impaired the transport and oxidation of cytosolic NADH in the mitochondria, resulting in altered cytosolic redox state and energy deficiency. Furthermore, acetylation of oligomycin-sensitive conferring protein at lysine-70 in adenosine triphosphate synthase complex promoted its interaction with cyclophilin D, and sensitized the opening of mitochondrial permeability transition pore. Both could be alleviated by normalizing the NAD+ redox balance either genetically or pharmacologically.

 

Conclusions: We show that mitochondrial protein hyperacetylation due to NAD+ redox imbalance contributes to the pathologic remodeling of the heart via 2 distinct mechanisms. Our preclinical data demonstrate a clear benefit of normalizing NADH/NAD+ imbalance in the failing hearts. These findings have a high translational potential as the pharmacologic strategy of increasing NAD+ precursors are feasible in humans.

 

"The strategy represents a novel therapeutic approach that targets the modification of protein functions consequent of mitochondrial dysfunction. Indeed, the NAD+ precursors such as NMN or nicotinamide riboside have yielded beneficial outcomes in animal models of diabetes mellitus,38 obesity,39 and aging.40 By comparing mouse models and human failing hearts in this study, we provide strong evidence that a similar mechanism applies to human heart failure, and indicate a highly translatable therapeutic strategy. Although NMN has poor oral bioavailability, oral administration of nicotinamide riboside, a recently approved nutritional supplement, is effective in rising blood NAD+ levels in healthy volunteers (Airhart et al, unpublished). Additional study of the safety and tolerability of expanding NAD+ pool in patient population is thus highly warranted."

[Black Fox]

 

 

Apologies to everyone in advance as I'm far from being an expert in field of longevity, but I've trying to educate myself through lotta lurking and reading.

As I skimmed the whole Samuel A.J. trammel's papers and the following statements caught my eyes.

"The ability of milk to bind and preserve the integrity of NR makes dairy products potentially good sources of supplementing NR along with, specially non organic sources"

Will it be advisable to chug down a glass of milk along with NR? As we want it to reach our gut as stable as possible , even though I was recommended by HPN's owner Sean Torbati to avoid fats while taking NR.


"Though current data is highly suggestive that NMN utilization requires dephosphorylation by CD73 to NR or hydrolysis to Nam by CD38"

If CD38 is involved in the process of NMN =>>NAM, why does it get outta hand with age? Will it be such a good idea to inhibit it for the long run as we don't know the role that it plays? What about keeping their levels to a youth stage, so it does what it suppose to do?

CD38 has been implicated in the secretion and function of hormones such as oxytocin and ACTH and may modulate maternal and social behavior and also CD38 plays a key role in the mechanism by which the organism fights bacterial infection... And God knows what else...

Cuz some people are supplementing with quercetin and this is being identified as a Sirt 1 inhibitor along with CD38.In fact, SIRT1 and CD38 have several similarities in their enzymatic and catalytical properties.

http://www.ncbi.nlm....les/PMC2883294/

Wouldn't it be better to use. Apigenin over quercetin?http://www.ncbi.nlm....pubmed/23172919


"NMN depends upon CD38, CD73, and NRK"

Will this explain why Sinclair was able to bring the clock back on those old mice's muscles in such short period of time? I'm guessing that old mouse had high levels of CD38

Because according to the paper it shows that NR superior than NMN and yet we have not seen the results of NMN had in such short period of time.

"NR contributed to the intracellular NAD metabolome more rapidly than NMN and increased NAD+ by more than 2 fold after 24 hours, indicating NR is kinetically superior to NMN"

Regarding the discussion between Bryan and Tom, it looks like NR is superior to NA and NAM at hepatic levels even though NA produced the least increase in hepatic NAD+ but also was 4-6 hours faster than NR and Nam in the kinetics of hepatic NAD+ accumulation. They also used NAAD as biomarker to state that NR is superior , but what's the role of NAAD , is it a pool to raise NAD+ over time?

NR is a superior liver precursor to NAD+ compared to Nam and NA and the increase in NAD+ correlated with NAAD... But is it that superior?


Thoughts?

Torbati advised you to avoid eating fat and NR at the same time. Did he give you a reason for this?Perhaps a reference?

Would love to know the answer to this one.

I'd luv to know the answers to all of that.... As per Torbati , I wrote him an e-mail regarding my homocysteine levels ; asking him if he knew any relationship between high levels of HCY and NR intake and he replied back telling me he didn't have any knowledge about it and to avoid fats while taking g NR, NO references provided!

Honestly speaking I'm doing opposite ( healthy fats though) ramping up my fat intake while ditching most of the unhealthy carbs.

Btw I've found the email, I've attached a screenshot of it, I was also asking him about taking it subligually

Edited by YOLF, 28 September 2016 - 09:42 AM.