2255 replies to this topic

[stefan_001]

I first heard about NQO1 gène here: http://www.anti-agin...-interventions/

 

He explained very well because at this time, we dint have the niagen data release. And he already speculated that the NAD+ would fastly return back to original due to the NQO1 gène..

 

Then I also wrote a topic more specialised with beta-lapachone here: http://www.beta-lapa...f-healthy-life/

 

You can found many studies wich show beta lapachone increase all biomarker in mamals of NAD+ and also increase lifespan more than CR. I contacted the author and they are sure you can even get better result by playing with the dosage, but would have cost them lot of time

 

You have also direct result on the mitochondria structure and its really impressive the way it protect it and even return them to normal

 

Ok thanks I will do some reading. I did notice the anti-aging firewalls topic but I am not convinced by that. Perhaps there is some increased "resistance" over time but I dont think that it will be able to scale to a level that rapidly would remove the NAD+ back. If the body could scale removal up that well I never would get drunk either for example and the liver would simply grow as far as needed....Anekdotal evidence doesnt support it either. Personally I am using NR (2 days / day) for over 6 months now and I dont have at all the perception that its effect is diminishing. Ok twice a day is a pulsating increase and perhaps the author is right if the supplementation is truly continuous --> so should be avoided till we know more?
 

Edited by stefan_001, 01 December 2015 - 05:46 PM.

[Bryan_S]

 

Since the 300mg dose generated the +50% I see this as max target to work around but your suggestions are worth charting. No matter the dose we are going to eliminate some down the drain. Would like to write some more but I've got to head into work, will log back in later.

 

At this point, with so little info, seems like a strategy that keeps one between about +30 and +50% for 12 hours may be a good compromise between cost and effectiveness, and 3 doses of 125 mg, spaced 4 hours apart, may get you pretty close to that, depending how exactly one sums the overlapping dose effects.  Even using your method, which applies the half life to the dose mass, after the first 4 hours we would have 62.5 mg left from the first dose to be added to the second dose of 125 mg = 187.5 mg, which probably gets us to at least +40% (and not much different from simply adding +15% remaining from 1st dose and +30% from 2nd dose = +45%).

 

 

Sorry it took me so long but I needed to write a graphing half-life chart so we could visualize the results. Here is "3 doses of 125 mg, spaced 4 hours apart."

 

Attached Files

•  3 doses of 125 mg, spaced 4 hours apart.png   325.66KB   1 downloads

Edited by Bryan_S, 02 December 2015 - 07:20 AM.

[Tom Andre F. (ex shinobi)]

 

Ok thanks I will do some reading. I did notice the anti-aging firewalls topic but I am not convinced by that. Perhaps there is some increased "resistance" over time but I dont think that it will be able to scale to a level that rapidly would remove the NAD+ back. If the body could scale removal up that well I never would get drunk either for example and the liver would simply grow as far as needed....Anekdotal evidence doesnt support it either. Personally I am using NR (2 days / day) for over 6 months now and I dont have at all the perception that its effect is diminishing. Ok twice a day is a pulsating increase and perhaps the author is right if the supplementation is truly continuous --> so should be avoided till we know more?
 

 

 

Well, its not my point: I think the problem is same as your exemple with hangover and alcool, the body wash itself even if its take some time of course. Return back to the normal NAD+ level at age 25 and normal level at age 85 is the problem. We dont cheat enough the cell, its not real hacking. I believe its enough to temporary cure some desease maybe, but not interesting enough from a pure anti aging point of view. We should play on others factor. Im not sure we can have life extension study on mamals using NR alone.

 

Using NR still interesting if used in a combo, because supply with precursor is very important, but we need also to allow our body to keep it and function as it was when it was young. I would like to see a study using both NR and BL.

 

Finally, consuming NR would also be a problem if we dont take care our homocysteine level (if the effect is similar to niacin of course..). Homocysteine is not only a cardiovascular desease biomarker, its also proven to make telomere shrinking by 3 fold faster

[warner]

 

 

Yes, that would be the less expensive, "no waste" approach to dosing, keeping you between +30 and +45% for most of the 12 hours (improved a bit if first dose was 250 mg, as in your proposed scheme).  (And assuming that 250 mg gets you to +50%.)

 

Then we're back talking about the falling NAD+ levels with age, and how much one really needs to boost NAD+ to get a measurable effect on health, and where I'm not as convinced as you are that levels need to be much greater than +50% (from perspective of a 60 year old).  We'll see!

[warner]

I guess conceptually simplest "no waste" approach would be 250/4hr/125/4hr/125 producing 3 peaks of 250 (near +50%) with dips to 125 (> +30%), if half-life is applied to dose mass.  (Hmm... perhaps this accounts for both the original 125 or 250 mg capsule sizes and noises about actually needing 500 mg per day... they may have known about 250 mg likely producing maximum response, and the 4-hour half-life, for quite some time.)

Edited by warner, 02 December 2015 - 04:05 PM.

[Bryan_S]

I guess conceptually simplest "no waste" approach would be 250/4hr/125/4hr/125 producing 3 peaks of 250 (near +50%) with dips to 125 (> +30%), if half-life is applied to dose mass.  (Hmm... perhaps this accounts for both the original 125 or 250 mg capsule sizes and noises about actually needing 500 mg per day... they may have known about 250 mg likely producing maximum response, and the 4-hour half-life, for quite some time.)

 

Since we now have a templet to plug these scenarios into we can create a library of dosing options. Seeing these results drives home the idea of a time released version. One of the most interesting lower cost profiles covering a 12-hour period that still keeps within the 30-50% parameters is: 250 followed by 3 125's taken every 4-hours.

 

Not to throw a monkey wrench into our thinking but we are considering single "one time" dose data. If the mouse studies are correct increased mitochondrial biogenesis should increase the conversion process over time, so I really want to see the long-term human data when it becomes available.

 

Attached Files

•  250_followed_by_3_125s.png   313.52KB   1 downloads

[warner]

Since we now have a templet to plug these scenarios into we can create a library of dosing options. Seeing these results drives home the idea of a time released version. One of the most interesting lower cost profiles covering a 12-hour period that still keeps within the 30-50% parameters is: 250 followed by 3 125's taken every 4-hours.

Thanks for the graphs Bryan!  

 

Also, simply taking 125 mg every 4 hours, 6x per day, would give you the +30 to +50% for the entire day, totaling just 750 mg/d (costing at least $3/d or $1000/yr at current best prices).  But we don't know what long-term effects would be of continual dosing.  So good advice currently might be to simply suggest taking 125 mg every 4 hours or so, for as long as one can afford it (between $1 and $3/d), or thinks is prudent based on circadian or other concerns.

 

For me, the 24 hour timing would be pretty easy:  6AM (wake), 10AM (brunch), 2PM, 6PM (dinner), 10PM (break before bed), 2AM (up briefly for other reasons).  After I have enough data at my current dosage, I may try that for awhile just to see what happens.  (Heck, as B3, that would still be less than the amount of NAM, 2x500 mg/d, recently found to help prevent non-melanoma skin cancers.)

 

(btw, I don't know if applying the half-life to the dose mass makes the most sense, but the simplicity of adding half as much (125) as the target dose (250) after each 4-hour half-life is easy to explain, and likely gets us close enough to what we're trying to achieve, while minimizing cost.)

[Logic]

Finally, consuming NR would also be a problem if we dont take care our homocysteine level (if the effect is similar to niacin of course..). Homocysteine is not only a cardiovascular desease biomarker, its also proven to make telomere shrinking by 3 fold faster

 

 

Some useful leads:

 

Homocysteine levels may increase in relation to Niacin, as Niacin metabolism in the liver places a strain on the Methyl cycle.  Specifically, SAMe is used up, methylating Niacin.  It appears that the metabolic side effects of Niacin (elevated liver chemistries and blood sugar), and the rise in Homocysteine sometimes observed with Niacin treatment, are related to Methyl group depletion.  In animals, Niacin wastes B6 and elevates Homocysteine, but these side effects do not occur, and Niacin’s lipid lowering benefit is maintained, if B6 is given along with Niacin.  In humans, Methionine 1000 mg twice a day prevented the rise in blood glucose and liver chemistries seen in a control group that received Niacin alone.  Homocysteine metabolism and Methyl cycle supplementation is discussed on the heartfixer.com website, but all of our patients are advised to take a broad-spectrum 6 tab/day multi that contains B6, folic acid, and B12, and if  Homocysteine does rise, then additional steps can be taken (methylated B12, folate, or SAMe).

http://www.heartfixe...cs - Niacin.htm

 

ie: you need all the Bs in the correct ratios...

 

Note that I still believe that the Nicotinamide part of NR increases NAD+ by downregulating NAD+ consuming, DNA repairing PARP...
I still think Ribose is a limiting factor in the production of NAD+ and that its slow release by  the slow cleaving of NR by the intestinal lining is what we should be looking for/at?

[Bryan_S]

 

Since we now have a templet to plug these scenarios into we can create a library of dosing options. Seeing these results drives home the idea of a time released version. One of the most interesting lower cost profiles covering a 12-hour period that still keeps within the 30-50% parameters is: 250 followed by 3 125's taken every 4-hours.

Thanks for the graphs Bryan!  

 

Also, simply taking 125 mg every 4 hours, 6x per day, would give you the +30 to +50% for the entire day, totaling just 750 mg/d (costing at least $3/d or $1000/yr at current best prices).  But we don't know what long-term effects would be of continual dosing.  So good advice currently might be to simply suggest taking 125 mg every 4 hours or so, for as long as one can afford it (between $1 and $3/d), or thinks is prudent based on circadian or other concerns.

 

For me, the 24 hour timing would be pretty easy:  6AM (wake), 10AM (brunch), 2PM, 6PM (dinner), 10PM (break before bed), 2AM (up briefly for other reasons).  After I have enough data at my current dosage, I may try that for awhile just to see what happens.  (Heck, as B3, that would still be less than the amount of NAM, 2x500 mg/d, recently found to help prevent non-melanoma skin cancers.)

 

(btw, I don't know if applying the half-life to the dose mass makes the most sense, but the simplicity of adding half as much (125) as the target dose (250) after each 4-hour half-life is easy to explain, and likely gets us close enough to what we're trying to achieve, while minimizing cost.)

 

 

True we don't know what the long-term effects of continual use will be. However there are some of us who are approaching or have passed the 2-year mark now. 

 

For me I make a $4.27 investment per day and accept not everyone can do this. So this is where I think we can use the "available" data to develop more cost effective dosing strategies and as we get better data from the long-term human research we can focus better on how, when and where that money should be spent. For now we can just wait for the data but seeing the NIH, P&G and increased academic interest is encouraging.

 

As far as the 24-hour thing you talked about I tried that. Having BPH, which is now almost a memory, I was up frequently to void. So I tried dosing in the wee hours. For me I became too alert and found a better strategy was to keep my NR consumption confined to my active hours. That's not to say you cant sleep while taking it, I found on days where I was very active and I was mildly exhausted I could get back to sleep fine but not every day is like that. Now I use plain Nicotinamide for the AM hours and haven't slept better. It has some sedative association with the GABA receptor.

 

As far as the non-melanoma skin cancers, yes the NR is a smaller dose but it hasn't been proven effective in a study yet. I suspect however since NR promotes the CR response this state encourages one to believe it might be better than nicotinamide working along other paths. In the end its eventually converted to nicotinamide so you get a secondary benefit as well.

 

Here is the 1000mg chart I'm dosing under. In practice I'm not hitting my doses precisely on time but I can tell you my energy levels have been more constant with the NR spread out over the course of a day like this than all at once.

 

Attached Files

•  NR-graph-1000mg.png   298.62KB   3 downloads

Edited by Bryan_S, 03 December 2015 - 04:42 AM.

[Bryan_S]

The Proposed Effects of Nicotinamide Adenine Dinucleotide (NAD) Supplementation on Energy Metabolism

http://pubs.sciepub..../5/3/index.html

 

Abstract

 

Energy metabolism is a process that is essential in the maintenance of life and has obvious roles with regards to sporting performance. Oxygen’s role in aerobic respiration is to act as the final hydrogen/electron accepter to form water. If oxygen is not present the whole aerobic pathway cannot occur and so the body will rely on energy produced anaerobically. The question instantly raised is to whether oxygen is ever in short supply, does it become a limiting factor for energy metabolism? The body will adapt to training in a variety of manners so that only under extreme conditions is oxygen a limiting factor. All of these adaptations are beneficial from an exercise performance standpoint and increase the efficiency of the complex metabolic process. There are still however questions surrounding the idea that NAD+ plays a key role in this process and whether increasing the synthesis/concentration would be advantageous for the trained individual. Nicotinamide, nicotinic acid, tryptophan and nicotinamide riboside are all natural substances that are acquired in the diet. Due to the protein and other biosynthetic uses of tryptophan it may not be as efficient or indeed practical to use tryptophan as a supplement. Supplementation of nicotinamide and nicotinic acid appears to increase NAD+ biosynthesis and the intracellular NAD+ pool. Whether these effects can aid in sporting performance is currently unanswered with no research in this area.

[Bryan_S]

NAD+ in aging, metabolism, and neurodegeneration

http://www.sciencema...6265/1208.short

 

• ABSTRACT

Nicotinamide adenine dinucleotide (NAD⁺) is a coenzyme found in all living cells. It serves both as a critical coenzyme for enzymes that fuel reduction-oxidation reactions, carrying electrons from one reaction to another, and as a cosubstrate for other enzymes such as the sirtuins and poly(adenosine diphosphate–ribose) polymerases. Cellular NAD⁺ concentrations change during aging, and modulation of NAD⁺ usage or production can prolong both health span and life span. Here we review factors that regulate NAD⁺ and discuss how supplementation with NAD⁺ precursors may represent a new therapeutic opportunity for aging and its associated disorders, particularly neurodegenerative diseases.

Eric Verdin in this paper was pretty broad in NAD's scope relating it to a host of aging disorders. Its clear to me that the concept of NAD depletion is becoming a much more accepted condition related to aging among Gerontologists. Its funny how some researchers fully accept NAD's roll in aging while others are slower to adopt this idea. In terms of compensating for age related NAD decline Nicotinamide Riboside was mentioned repeatedly. He explored how NAD+ precursors may be useful against aging and its chronic diseases. Eric Verdin also asked many of the same questions we have in this forum including dosage. It will be interesting to see what the Gladstone Institutes turn up.

 

In all Eric Verdin has a very good grasp of geriatrics and aging. His perspective wraps around many topics we've discussed on this forum. He spoke recently representing the Gladstone Institutes and shared some of those insights.

Edited by Bryan_S, 09 December 2015 - 08:24 AM.

[Bryan_S]

I still believe that the Nicotinamide part of NR increases NAD+ by downregulating NAD+ consuming, DNA repairing PARP...

 

 

references?

[stefan_001]

I still believe that the Nicotinamide part of NR increases NAD+ by downregulating NAD+ consuming, DNA repairing PARP...

 
references?

At least in mice it does not seem to work like that:
- To further solidify our data, we also wondered whether the enhanced NAD+ levels upon NR treatment could derive from alterations in the NAD+ salvage pathway or PARP activity. However, we could not see any change in Nampt mRNA or protein content in response to NR treatment (Fig.1G). Similarly, PARP activity and PARP-1 content were not affected by NR (Fig.1H). Altogether, these results suggest that NR increases NAD+ by direct NAD+ biosynthesis rather than by indirectly affecting the major NAD+ salvage (Nampt) or consumption (PARPs) pathways. Importantly, this increase in NAD+ was not linked to changes in cellular glycolytic rates or ATP levels (data not shown), which would be expected if NAD+/NADH ratios had been altered to the point of compromising basic cellular functions.

http://www.ncbi.nlm....les/PMC3616313/

Edited by stefan_001, 05 December 2015 - 06:55 AM.

[Logic]

 

 

I still believe that the Nicotinamide part of NR increases NAD+ by downregulating NAD+ consuming, DNA repairing PARP...

 
references?

At least in mice it does not seem to work like that:
- To further solidify our data, we also wondered whether the enhanced NAD+ levels upon NR treatment could derive from alterations in the NAD+ salvage pathway or PARP activity. However, we could not see any change in Nampt mRNA or protein content in response to NR treatment (Fig.1G). Similarly, PARP activity and PARP-1 content were not affected by NR (Fig.1H). Altogether, these results suggest that NR increases NAD+ by direct NAD+ biosynthesis rather than by indirectly affecting the major NAD+ salvage (Nampt) or consumption (PARPs) pathways. Importantly, this increase in NAD+ was not linked to changes in cellular glycolytic rates or ATP levels (data not shown), which would be expected if NAD+/NADH ratios had been altered to the point of compromising basic cellular functions.

http://www.ncbi.nlm....les/PMC3616313/

 

I stand corrected.
Thx Stefan; good to know!

[platypus]

Are there any dosing half-life calculators online? I was planning to learn Python and write one myself but life intervened..

[TaiChiKid]

Signaling from dysfunctional mitochondria induces cellular senescence with a distinct secretory phenotype.  Source:  Buck Institute Dec 1o/2015: https://www.buckinst...tinct-secretory

 

“The senescent phenotype only occurred when we eliminated the mitochondrial sirtuins,” said Wiley. In addition, Wiley saw that the senescent cells secreted a different SASP (senescence-associated secretory phenotype) than expected – one that lacks the IL-1-dependent inflammatory arm – a major factor in the SASP originally identified in the Campisi lab in 2008.  The authors dubbed this new phenomenon MiDAS – mitochondrial dysfunction-associated senescence. 

 

Along with identifying MiDAS, Wiley also found that mitochondrial dysfunction upset the balance of NAD+ (an enzyme that is a co-factor for sirtuins), which arrested cell growth and prevented the IL-1-associated SASP. “The NAD+ balancing act happens outside the mitochondria in the cytoplasm of the cell,” said Wiley. “This really highlights a signaling role for mitochondria, something understudied in the context of disease. And it identifies a new type of SASP, underscoring the existence of different types of senescence.”

[Bryan_S]

Are there any dosing half-life calculators online? I was planning to learn Python and write one myself but life intervened..

 

http://www.calculato...calculator.html

 

Google half-life-calculator and you'll find a lot of help.

 

I made mine in Excel and it was a fairly easy to check the results against the online calculators. Keep in mind however if you want to plot the results for more than a single dose you'll have to calculate the overlapping decay for the previous doses to show the accumulated results. Also as you assemble a graphing plot consider plotting the residual just before the next does is taken to see how low the residuals fell just before a new dose was administered. Once you wade in you'll see what I mean.

 

For instance its 2 pm and I'm about to take my next dose, at what level is the last dose residual just before I take that next dose. If you don't account for this time interval and plot it prior to the next dose it will throw off the lows that were reached as you plot your main dosage points which represent the highs in the chart.

 

 

By the way guys Nature, Cell and Science Magazine all did nice aging spreads this month. Also Nat Geo did a nice show about Aging in their series called Breakthroughs. If you have On-Demand cable services its worth reviewing this show. While NR wasn't a main theme in all this media aging as a target for treatment to help alleviate or postpone the development of other age related conditions was. I think 2015 was a great year for advancements in our understanding and beyond the scientific journals the Popular Media is now onboard popularizing the results that have shown promise. I also think the FDA's decision to clear a path for the Metformin trials shows a positive shift in thinking which will help draw in more funding to this cause. JMHO

[Logic]

Signaling from dysfunctional mitochondria induces cellular senescence with a distinct secretory phenotype.  Source:  Buck Institute Dec 1o/2015: https://www.buckinst...tinct-secretory

 

“The senescent phenotype only occurred when we eliminated the mitochondrial sirtuins,” said Wiley. In addition, Wiley saw that the senescent cells secreted a different SASP (senescence-associated secretory phenotype) than expected – one that lacks the IL-1-dependent inflammatory arm – a major factor in the SASP originally identified in the Campisi lab in 2008.  The authors dubbed this new phenomenon MiDAS – mitochondrial dysfunction-associated senescence. 

 

Along with identifying MiDAS, Wiley also found that mitochondrial dysfunction upset the balance of NAD+ (an enzyme that is a co-factor for sirtuins), which arrested cell growth and prevented the IL-1-associated SASP. “The NAD+ balancing act happens outside the mitochondria in the cytoplasm of the cell,” said Wiley. “This really highlights a signaling role for mitochondria, something understudied in the context of disease. And it identifies a new type of SASP, underscoring the existence of different types of senescence.”

 

 

Back to C60oo and the other interesting mito anti-oxidants.

 

Joining some dots here: (Hopefuly!   )
Telomerase will also migrate from the nucleus where its supposed to be to lengthen Telomeres, to the mitochondria to protect them when they produce too many free radicals etc.
Long telomeres have a positive epigenetic effect on cells.  Its not just a case of losing DNA info when they get too short.

ie: Telomeres are shortened by ROS including Mito ROS.
ROS is caused by inflammation, which is caused by AGEs etc....?
An AGE blocking, breaking and reversing regimen is where it all points to IMHO...?

 

http://www.longecity...ndpost&p=750568
etc. there.





 

[Multivitz]

The cell activity around the NAD is limited by the cells alkali components.
I think all these observations are very intresting, but there's a magnified cell life effect when Magnesium ions are present. Cells can go dormant for many reasons, I wouldn't want too many excited at once as my organs can only process so much food!
Some parasites consume Tryptophan and release Heroine, does the Niacin type compounds become bio available to parasites? Thanks in advance.

[Bryan_S]

A new group-buy offer for our Longecity members. See link

 

This is an ongoing offer for our members to bridge the gap between our main 60-day discounts.

Edited by Bryan_S, 14 December 2015 - 08:42 AM.

[warner]

Before placing my next order for NR, I was curious as to why James P. Watson posting on http://www.anti-agingfirewalls.com/ had concluded that NR supplementation was probably a waste of time, so I waded through his detailed series of NAD world posts here.  In a nutshell, he thinks that the complex system governing NAD+/NADH can be transiently modified with NR supplementation, but that it will simply return to its original/normal state over a sufficiently long period of NR supplementation.  [Meaning, I guess, that even if supplementation continues to spike intraday NAD+ levels, that over a long time, whatever benefit these spikes may have had will eventually be offset by other long-term changes to the system.]

 

However, I think this is a somewhat arbitrary conclusion, considering,

 

- Watson also considers NAM (nicotinamide) supplementation to be ill-advised, but not because it will produce no change, but because it will produce a long-term modification of the system (supressing SIRT1 activity, etc.).  But why assume that NAM is effective at modifying the system, but NR is not?

 

- There is a lot of evidence, both acute and long-term, associating increased PARP activity (and its NAD+ consumption) with decreased NAD+ levels.  So if a significant consumer of NAD+ can have a long-term effect on NAD+ levels, then why can't a significant supplier of NAD+ (like NR) also have a long-term effect on the system?

 

- Bryan has spent a lot of time on this and other threads documenting the unique properties of NR that make it likely to be a good candidate for being an effective raiser of NAD+ levels (gets through digestive system, finds its way into cells, enters the cycle at just the right spot, etc.).

 

- I suspect that the folks at Chromadex who have already documented +50% levels of NAD+ with modest NR supplementation also already know something more about long-term effects, and will soon let us know about that, one way or the other.

 

- NR is likely to at least be a better B3 vitamin, with fewer side effects.  So it probably makes more sense to encourage than discourage its use, esp. by those already taking B3 supplements, so we can get on with determining in what cases it should be replacing NA or NAM.  (For example, I already take NR in preference to NA, since NR does not raise my eye pressures like NA does.  I'll also determine whether it has lipid profile effects, etc.)

 

So, anyway, I went ahead and ordered more NR. 

Edited by warner, 19 December 2015 - 03:42 AM.

[sthira]

I wonder when ChromaDex will release the PK-data that was completed more than a year ago? And why they've not yet released it? Anyone speculating on this?

[Bryan_S]

Just a brief note I spoke with Chromadex 2-days ago because I've been pushing for additional data. I'm told at this stage; "is a little too early to really engage on the PK/PD story, as the NAD+ metabolome is complicated." I'm also told; "We will learn a lot more about NR during the second human clinical we have just started, and I think that will bring a lot more clarity to the questions you are asking." They also added; "More of the existing clinical data will be published soon by Charlie Brenner and there are a lot more peer review published studies coming."

 

So I don't read anything nefarious in those statements and feel they have allot at stake and just want to be sure they get the preliminary details right. So no one is more hungry than myself to build on the data we already have but as I've mentioned with interest from players like P&G there is more to this story than is being released. They are looking at the long game and have paid experts to vet this opportunity.

 

Before placing my next order for NR, I was curious as to why James P. Watson posting on http://www.anti-agingfirewalls.com/ had concluded that NR supplementation was probably a waste of time, so I waded through his detailed series of NAD world posts here.  In a nutshell, he thinks that the complex system governing NAD+/NADH can be transiently modified with NR supplementation, but that it will simply return to its original/normal state over a sufficiently long period of NR supplementation.  [Meaning, I guess, that even if supplementation continues to spike intraday NAD+ levels, that over a long time, whatever benefit these spikes may have had will eventually be offset by other long-term changes to the system.]

 

However, I think this is a somewhat arbitrary conclusion, considering,

 

- Watson also considers NAM (nicotinamide) supplementation to be ill-advised, but not because it will produce no change, but because it will produce a long-term modification of the system (supressing SIRT1 activity, etc.).  But why assume that NAM is effective at modifying the system, but NR is not?

 

As far as Vince Giuliano and James P. Watson on NAD boosting they said; "For a number of years it has been proposed in research publications that promoting NAD levels in humans could be an effective preventative and/or therapeutic strategy.for multiple disease processes  Also, it is a proven strategy for extending the lifespans of c-elegans worms. However, this strategy has never entered our mainline medical or health maintenance system." They also say "I am now confidence that supplementation with a NAD+ precursor like NMN or NR transiently increased the ratio of NAD+  to NADH (NAD/NADH), but the ratio returns to normal in the course of continued supplementation." This is opinion without a reference and specifically mentions the ratio. We can look up the (NAD/NADH) ratio and it does not tell us the NAD pool returns to a pre-NR-state with continued use and Giuliano and Watson do not say this. The Ratio does not express the total increase just the balance. We are talking about the ratio as if it was the total cell volume or capacity. Yes the (NAD/NADH) ratio will balance itself as it has evolved but in an aging NAD deficient state that is at 15 or 30% of a young NAD profile we aren't even talking about surpassing normal youthful levels in this (NAD/NADH) ratio context. The (NAD/NADH) ratio makes no reference to increasing or maintaining the total NAD pool just the balance of NAD to NADH which will seek its balance.

 

Lets look at the ratio like a fuel to air mixture. We are actually talking about 2 forms of the same enzyme but in a strict ratio context. Now if I could increase at will the total number of active engine cylinders (or Mitochondria) from 4 to 8 does that change my fuel to air mixture/ratio? No and as we look at boosting this enzyme with NR in a biological sense we can get an effect called mitochondrial biogenesis. This is like increasing the number of engine cylinders. What we understand in biological systems is the cell and tissues are designed to meet our needs limited by our internal or external environment, so we aren't talking about building unnecessary Mitochondria to waste bodily resources. Our Age-associated Mitochondrial decline is a well accepted fact driven by a cascade of effects related to our NAD decline and the environment it helps produce. So if we do nothing like in the engine concept our cells are slowly reducing the number of active engine cylinders in relation to the total NAD pool. By inducing mitochondrial biogenesis we are in effect increasing the capacity we can utilize NAD closer to more youthful levels and we haven't violated any (NAD/NADH) ratio laws.

 

In my opinion at present with the mitochondrial damage we accumulate I don't think we can reach the NAD utilization rates we had as children. So I'm not holding my breath. Pushing the utilization capacity back a just few years I think is a worth wild expectation but the results will depend on our health and age. 

 

As far as how long elevated levels can be maintained we have seen nicotinamide riboside in mice studies for 12 or 16 weeks where high NAD levels were maintained. Now that's about to change with a human time equivalent study.

 

As far as nicotinamide (NAM) SIRT1 fears we've been studying plain (NAM) since the 1930's in clinical tests so its metabolic functioning is more familiar and well tested in humans than most molecules. Plus we also have to consider where the SIRT1 comments originated.

 

Its funny that David Sinclair's study was one to say Nam downregulates SIRT1, he's also came around 180 degrees and defended Niacinamide, have you read that? This sounds odd but he makes a good point but you don't see academics pointing to Sinclair's restatement, reframing his published statement. http://www.alzforum....anism-involving "One must be careful when calling nicotinamide an "inhibitor" in this experiment. While it is true that our lab showed that nicotinamide is a direct inhibitor of SIRT1 enzyme, it is also a precursor of NAD+, and NAD+ is a co-substrate (i.e., activator) of SIRT1.

 

In vivo, there is an abundant enzyme called Nampt in cells and serum that initiates the conversion of nicotinamide to NAD+. Therefore we should entertain the possibility that nicotinamide is activating SIRT1 in vivo, not inhibiting it. This would fit with other papers showing that SIRT1 is neuroprotective." He defines in vitro and in vivo, in a test tube and in a living organism. I don't worry about it now and have added Pterostilbene for SIRT1 insurance anyway (150mg), also nicotinamide is generated after our NAD is used, so you cant avoid it anyway you cut this, so I embrace it.

 

Its all good discussion but once you publish that sort of thing in a paper without illuminating the flip side of nicotinamide (NAM) authors like Vince Giuliano and James P. Watson aren't going to challenge David Sinclair's study or locate where he tried to set the record straight.

 

I just bought another 12 bottles as well and think if this was just a placibo effect it would have worn off after nearly 2-years. group-buy offer for our Longecity members Keep us posted on the eye pressure.

Edited by Bryan_S, 19 December 2015 - 09:19 AM.

[warner]

Thanks again Bryan for bringing all that research together.  Anyone considering NR supplementation should definitely take the time to read all your posts regarding the matter. 

 

My general take on Watson/Giuliano was that although they hung their hat on the NAD/NADH ratio (and NQO1, etc.) as the reason things might return to "normal" after extended NR supplementation, I think they too probably recognize that "the NAD+ metabolome is complicated", and that, given the relative lack so far of well-documented benefits in humans, they simply wouldn't be surprised if most NR supplementation effects are transient, for one complex reason or another.  And so until we have more data, the decision to try NR supplementation remains controversial and personal, although likely harmless, and possibly of great benefit.

Edited by warner, 19 December 2015 - 10:38 AM.

[Tom Andre F. (ex shinobi)]

 

Signaling from dysfunctional mitochondria induces cellular senescence with a distinct secretory phenotype.  Source:  Buck Institute Dec 1o/2015: https://www.buckinst...tinct-secretory

 

“The senescent phenotype only occurred when we eliminated the mitochondrial sirtuins,” said Wiley. In addition, Wiley saw that the senescent cells secreted a different SASP (senescence-associated secretory phenotype) than expected – one that lacks the IL-1-dependent inflammatory arm – a major factor in the SASP originally identified in the Campisi lab in 2008.  The authors dubbed this new phenomenon MiDAS – mitochondrial dysfunction-associated senescence. 

 

Along with identifying MiDAS, Wiley also found that mitochondrial dysfunction upset the balance of NAD+ (an enzyme that is a co-factor for sirtuins), which arrested cell growth and prevented the IL-1-associated SASP. “The NAD+ balancing act happens outside the mitochondria in the cytoplasm of the cell,” said Wiley. “This really highlights a signaling role for mitochondria, something understudied in the context of disease. And it identifies a new type of SASP, underscoring the existence of different types of senescence.”

 

 

Back to C60oo and the other interesting mito anti-oxidants.

 

Joining some dots here: (Hopefuly!   )
Telomerase will also migrate from the nucleus where its supposed to be to lengthen Telomeres, to the mitochondria to protect them when they produce too many free radicals etc.
Long telomeres have a positive epigenetic effect on cells.  Its not just a case of losing DNA info when they get too short.

ie: Telomeres are shortened by ROS including Mito ROS.
ROS is caused by inflammation, which is caused by AGEs etc....?
An AGE blocking, breaking and reversing regimen is where it all points to IMHO...?

 

http://www.longecity...ndpost&p=750568
etc. there.





 

 

 

If it was true, then carnosine wich is a pure AGE breaker would really extend lifespan in mamals and it does not unfortunately

 

 

Just a brief note I spoke with Chromadex 2-days ago because I've been pushing for additional data. I'm told at this stage; "is a little too early to really engage on the PK/PD story, as the NAD+ metabolome is complicated." I'm also told; "We will learn a lot more about NR during the second human clinical we have just started, and I think that will bring a lot more clarity to the questions you are asking." They also added; "More of the existing clinical data will be published soon by Charlie Brenner and there are a lot more peer review published studies coming."

 

So I don't read anything nefarious in those statements and feel they have allot at stake and just want to be sure they get the preliminary details right. So no one is more hungry than myself to build on the data we already have but as I've mentioned with interest from players like P&G there is more to this story than is being released. They are looking at the long game and have paid experts to vet this opportunity.

 

Before placing my next order for NR, I was curious as to why James P. Watson posting on http://www.anti-agingfirewalls.com/ had concluded that NR supplementation was probably a waste of time, so I waded through his detailed series of NAD world posts here.  In a nutshell, he thinks that the complex system governing NAD+/NADH can be transiently modified with NR supplementation, but that it will simply return to its original/normal state over a sufficiently long period of NR supplementation.  [Meaning, I guess, that even if supplementation continues to spike intraday NAD+ levels, that over a long time, whatever benefit these spikes may have had will eventually be offset by other long-term changes to the system.]

 

However, I think this is a somewhat arbitrary conclusion, considering,

 

- Watson also considers NAM (nicotinamide) supplementation to be ill-advised, but not because it will produce no change, but because it will produce a long-term modification of the system (supressing SIRT1 activity, etc.).  But why assume that NAM is effective at modifying the system, but NR is not?

 

As far as Vince Giuliano and James P. Watson on NAD boosting they said; "For a number of years it has been proposed in research publications that promoting NAD levels in humans could be an effective preventative and/or therapeutic strategy.for multiple disease processes  Also, it is a proven strategy for extending the lifespans of c-elegans worms. However, this strategy has never entered our mainline medical or health maintenance system." They also say "I am now confidence that supplementation with a NAD+ precursor like NMN or NR transiently increased the ratio of NAD+  to NADH (NAD/NADH), but the ratio returns to normal in the course of continued supplementation." This is opinion without a reference and specifically mentions the ratio. We can look up the (NAD/NADH) ratio and it does not tell us the NAD pool returns to a pre-NR-state with continued use and Giuliano and Watson do not say this. The Ratio does not express the total increase just the balance. We are talking about the ratio as if it was the total cell volume or capacity. Yes the (NAD/NADH) ratio will balance itself as it has evolved but in an aging NAD deficient state that is at 15 or 30% of a young NAD profile we aren't even talking about surpassing normal youthful levels in this (NAD/NADH) ratio context. The (NAD/NADH) ratio makes no reference to increasing or maintaining the total NAD pool just the balance of NAD to NADH which will seek its balance.

 

Lets look at the ratio like a fuel to air mixture. We are actually talking about 2 forms of the same enzyme but in a strict ratio context. Now if I could increase at will the total number of active engine cylinders (or Mitochondria) from 4 to 8 does that change my fuel to air mixture/ratio? No and as we look at boosting this enzyme with NR in a biological sense we can get an effect called mitochondrial biogenesis. This is like increasing the number of engine cylinders. What we understand in biological systems is the cell and tissues are designed to meet our needs limited by our internal or external environment, so we aren't talking about building unnecessary Mitochondria to waste bodily resources. Our Age-associated Mitochondrial decline is a well accepted fact driven by a cascade of effects related to our NAD decline and the environment it helps produce. So if we do nothing like in the engine concept our cells are slowly reducing the number of active engine cylinders in relation to the total NAD pool. By inducing mitochondrial biogenesis we are in effect increasing the capacity we can utilize NAD closer to more youthful levels and we haven't violated any (NAD/NADH) ratio laws.

 

In my opinion at present with the mitochondrial damage we accumulate I don't think we can reach the NAD utilization rates we had as children. So I'm not holding my breath. Pushing the utilization capacity back a just few years I think is a worth wild expectation but the results will depend on our health and age. 

 

As far as how long elevated levels can be maintained we have seen nicotinamide riboside in mice studies for 12 or 16 weeks where high NAD levels were maintained. Now that's about to change with a human time equivalent study.

 

As far as nicotinamide (NAM) SIRT1 fears we've been studying plain (NAM) since the 1930's in clinical tests so its metabolic functioning is more familiar and well tested in humans than most molecules. Plus we also have to consider where the SIRT1 comments originated.

 

Its funny that David Sinclair's study was one to say Nam downregulates SIRT1, he's also came around 180 degrees and defended Niacinamide, have you read that? This sounds odd but he makes a good point but you don't see academics pointing to Sinclair's restatement, reframing his published statement. http://www.alzforum....anism-involving "One must be careful when calling nicotinamide an "inhibitor" in this experiment. While it is true that our lab showed that nicotinamide is a direct inhibitor of SIRT1 enzyme, it is also a precursor of NAD+, and NAD+ is a co-substrate (i.e., activator) of SIRT1.

 

In vivo, there is an abundant enzyme called Nampt in cells and serum that initiates the conversion of nicotinamide to NAD+. Therefore we should entertain the possibility that nicotinamide is activating SIRT1 in vivo, not inhibiting it. This would fit with other papers showing that SIRT1 is neuroprotective." He defines in vitro and in vivo, in a test tube and in a living organism. I don't worry about it now and have added Pterostilbene for SIRT1 insurance anyway (150mg), also nicotinamide is generated after our NAD is used, so you cant avoid it anyway you cut this, so I embrace it.

 

Its all good discussion but once you publish that sort of thing in a paper without illuminating the flip side of nicotinamide (NAM) authors like Vince Giuliano and James P. Watson aren't going to challenge David Sinclair's study or locate where he tried to set the record straight.

 

I just bought another 12 bottles as well and think if this was just a placibo effect it would have worn off after nearly 2-years. group-buy offer for our Longecity members Keep us posted on the eye pressure.

 

 

Bryan, I dont think its that black and white story. NR may be very useful but it looks like feeding a perforated bag. The NQO1 story they bring into the game is interesting because overexpressing of it, increase lifespan of all animal models tested. Maybe if we low dose ourself with NQO1 modulator + NR we get the perfect mix ? We dont touch PARP in that  way.

 

So  we have a study where we see a lifespan increase more impressive than CR using beta-lapachone, imagin what we can do if we now play with dosage.

We know that NR will increase NAD+ in vivo, but fastly return back to normal. What if we feed the mices with BL + NR ? They will recreate the perfect pool and ratio you are speaking about isnt ? So Im really wonder what woud be then the lifespan increase score of the 2 as a combo

Finally, I would also add some very known anti ROS and glutathione booster such as pterostilbene in order to decrease in an indirect way the PARP activity as well wich is proven to be overactivated by ROS.

 

Chromadex are rich enough to provide data on many animal model for a possible lifespan increase of NR standalone and they do not..

[albedo]

.....

By the way guys Nature, Cell and Science Magazine all did nice aging spreads this month. Also Nat Geo did a nice show about Aging in their series called Breakthroughs. If you have On-Demand cable services its worth reviewing this show. While NR wasn't a main theme in all this media aging as a target for treatment to help alleviate or postpone the development of other age related conditions was. I think 2015 was a great year for advancements in our understanding and beyond the scientific journals the Popular Media is now onboard popularizing the results that have shown promise. I also think the FDA's decision to clear a path for the Metformin trials shows a positive shift in thinking which will help draw in more funding to this cause. JMHO

 

Thank you for the heads-up and agree. The Science special section on Aging has a review on NR by Eric Verdin:

 

NAD+ in aging, metabolism, and neurodegeneration

 

"Nicotinamide adenine dinucleotide (NAD+) is a coenzyme found in all living cells. It serves both as a critical coenzyme for enzymes that fuel reduction-oxidation reactions, carrying electrons from one reaction to another, and as a cosubstrate for other enzymes such as the sirtuins and poly(adenosine diphosphate–ribose) polymerases. Cellular NAD+ concentrations change during aging, and modulation of NAD+ usage or production can prolong both health span and life span. Here we review factors that regulate NAD+ and discuss how supplementation with NAD+ precursors may represent a new therapeutic opportunity for aging and its associated disorders, particularly neurodegenerative diseases."

 

"...These concerns notwithstanding, the studies reviewed here have ignited considerable interest in manipulating NAD+ concentrations in therapeutic efforts aimed at disease prevention and life-span extension. Future rigorous clinical testing in humans will tell us whether this early promise will become a reality..."

 

 NAD+ biosynthesis.PNG   98.85KB   9 downloads

 

 NAD Science.PNG   98.16KB   6 downloads

 

Apologizes if already seen and you know already all about it, I am learning :-)

[Logic]

Signaling from dysfunctional mitochondria induces cellular senescence with a distinct secretory phenotype.  Source:  Buck Institute Dec 1o/2015: https://www.buckinst...tinct-secretory
 
“The senescent phenotype only occurred when we eliminated the mitochondrial sirtuins,” said Wiley. In addition, Wiley saw that the senescent cells secreted a different SASP (senescence-associated secretory phenotype) than expected – one that lacks the IL-1-dependent inflammatory arm – a major factor in the SASP originally identified in the Campisi lab in 2008.  The authors dubbed this new phenomenon MiDAS – mitochondrial dysfunction-associated senescence. 
 
Along with identifying MiDAS, Wiley also found that mitochondrial dysfunction upset the balance of NAD+ (an enzyme that is a co-factor for sirtuins), which arrested cell growth and prevented the IL-1-associated SASP. “The NAD+ balancing act happens outside the mitochondria in the cytoplasm of the cell,” said Wiley. “This really highlights a signaling role for mitochondria, something understudied in the context of disease. And it identifies a new type of SASP, underscoring the existence of different types of senescence.”

 

 
Back to C60oo and the other interesting mito anti-oxidants.
 
Joining some dots here: (Hopefuly!   )
Telomerase will also migrate from the nucleus where its supposed to be to lengthen Telomeres, to the mitochondria to protect them when they produce too many free radicals etc.
Long telomeres have a positive epigenetic effect on cells.  Its not just a case of losing DNA info when they get too short.
ie: Telomeres are shortened by ROS including Mito ROS.
ROS is caused by inflammation, which is caused by AGEs etc....?
An AGE blocking, breaking and reversing regimen is where it all points to IMHO...?
 
http://www.longecity...ndpost&p=750568
etc. there.

 
If it was true, then carnosine wich is a pure AGE breaker would really extend lifespan in mamals and it does not unfortunately

Michael:
"...a recent study in humans finds that only 8 out of 25 subjects administered 60 mg/kg carnosine (4200 mg in a lean 70 kg adult male) exhibited a detectable increase in plasma carnosine, which was largely over in an hour in most subjects and totally gone by two)..."
http://www.longecity...ndpost&p=619279

Carnosinase inhibitors?

[Bryan_S]

 

.....

By the way guys Nature, Cell and Science Magazine all did nice aging spreads this month. Also Nat Geo did a nice show about Aging in their series called Breakthroughs. If you have On-Demand cable services its worth reviewing this show. While NR wasn't a main theme in all this media aging as a target for treatment to help alleviate or postpone the development of other age related conditions was. I think 2015 was a great year for advancements in our understanding and beyond the scientific journals the Popular Media is now onboard popularizing the results that have shown promise. I also think the FDA's decision to clear a path for the Metformin trials shows a positive shift in thinking which will help draw in more funding to this cause. JMHO

 

Thank you for the heads-up and agree. The Science special section on Aging has a review on NR by Eric Verdin:

 

NAD+ in aging, metabolism, and neurodegeneration

 

"Nicotinamide adenine dinucleotide (NAD+) is a coenzyme found in all living cells. It serves both as a critical coenzyme for enzymes that fuel reduction-oxidation reactions, carrying electrons from one reaction to another, and as a cosubstrate for other enzymes such as the sirtuins and poly(adenosine diphosphate–ribose) polymerases. Cellular NAD+ concentrations change during aging, and modulation of NAD+ usage or production can prolong both health span and life span. Here we review factors that regulate NAD+ and discuss how supplementation with NAD+ precursors may represent a new therapeutic opportunity for aging and its associated disorders, particularly neurodegenerative diseases."

 

"...These concerns notwithstanding, the studies reviewed here have ignited considerable interest in manipulating NAD+ concentrations in therapeutic efforts aimed at disease prevention and life-span extension. Future rigorous clinical testing in humans will tell us whether this early promise will become a reality..."

 

NAD+ biosynthesis.PNG

 

NAD Science.PNG

 

Apologizes if already seen and you know already all about it, I am learning :-)

 

 

albedo, You were the only one to followup and look. These weren't public articles and you needed a subscription so I didn't copy and past them, however I have no problem pointing to someone who did. http://mindblog.deri...agazine-on.html

 

 

Guys let try and keep this thread focused on NR and NAD boosting. Everyone keeps interjecting other alternatives and I agree they are interesting but the main research push is surrounding NAD boosting. So just shifting the NAD to NADH ratio with alternative paths isn't going to supply the cell anymore raw precursor resources to build more NAD to make up for the deficit we develop. And if these alternative paths are that good let's see the research making this case that this new approach is superior. The way I see it NAD boosting already has a 10-year head start and the tissue specific protective effects are well documented in animals and with these observations they are now beginning human trials and considering treatment for specific ailments. The same can not be said about these other areas and most of us want what we can touch today, not 10-years from now.  

 

NIH Testing Way to Boost Mitochondrial Health

Plans studies of ChromaDex's NIAGEN, a NR supplement, in rare neurodegenerative diseases

http://mitochondrial...ondrial-health/

 

 

Eliciting the mitochondrial unfolded protein response by nicotinamide adenine dinucleotide repletion reverses fatty liver disease in mice

http://onlinelibrary.../hep.28245/full

Publication History

• Article first published online: 16 December 2015
• Accepted manuscript online: 24 September 2015
• Manuscript Accepted: 22 September 2015
• Manuscript Received: 18 March 2015

 

Edited by Bryan_S, 24 December 2015 - 06:16 AM.

[Tom Andre F. (ex shinobi)]

 

 

 

Signaling from dysfunctional mitochondria induces cellular senescence with a distinct secretory phenotype.  Source:  Buck Institute Dec 1o/2015: https://www.buckinst...tinct-secretory
 
“The senescent phenotype only occurred when we eliminated the mitochondrial sirtuins,” said Wiley. In addition, Wiley saw that the senescent cells secreted a different SASP (senescence-associated secretory phenotype) than expected – one that lacks the IL-1-dependent inflammatory arm – a major factor in the SASP originally identified in the Campisi lab in 2008.  The authors dubbed this new phenomenon MiDAS – mitochondrial dysfunction-associated senescence. 
 
Along with identifying MiDAS, Wiley also found that mitochondrial dysfunction upset the balance of NAD+ (an enzyme that is a co-factor for sirtuins), which arrested cell growth and prevented the IL-1-associated SASP. “The NAD+ balancing act happens outside the mitochondria in the cytoplasm of the cell,” said Wiley. “This really highlights a signaling role for mitochondria, something understudied in the context of disease. And it identifies a new type of SASP, underscoring the existence of different types of senescence.”

 

 
Back to C60oo and the other interesting mito anti-oxidants.
 
Joining some dots here: (Hopefuly!   )
Telomerase will also migrate from the nucleus where its supposed to be to lengthen Telomeres, to the mitochondria to protect them when they produce too many free radicals etc.
Long telomeres have a positive epigenetic effect on cells.  Its not just a case of losing DNA info when they get too short.
ie: Telomeres are shortened by ROS including Mito ROS.
ROS is caused by inflammation, which is caused by AGEs etc....?
An AGE blocking, breaking and reversing regimen is where it all points to IMHO...?
 
http://www.longecity...ndpost&p=750568
etc. there.

 

 
If it was true, then carnosine wich is a pure AGE breaker would really extend lifespan in mamals and it does not unfortunately

 

Michael:
"...a recent study in humans finds that only 8 out of 25 subjects administered 60 mg/kg carnosine (4200 mg in a lean 70 kg adult male) exhibited a detectable increase in plasma carnosine, which was largely over in an hour in most subjects and totally gone by two)..."
http://www.longecity...ndpost&p=619279

Carnosinase inhibitors?

 

 

it doesnt make sense, i thought carnosinase was only able to decrease carnosie by a rate of 250mg per 5 hours or so.. Other way should be supplement with beta-alanyn but I know we are off topic here :/
 

[Logic]

Guys let try and keep this thread focused on NR and NAD boosting. Everyone keeps interjecting other alternatives and I agree they are interesting but the main research push is surrounding NAD boosting. So just shifting the NAD to NADH ratio with alternative paths isn't going to supply the cell anymore raw precursor resources to build more NAD to make up for the deficit we develop. And if these alternative paths are that good let's see the research making this case that this new approach is superior. The way I see it NAD boosting already has a 10-year head start and the tissue specific protective effects are well documented in animals and with these observations they are now beginning human trials and considering treatment for specific ailments. The same can not be said about these other areas and most of us want what we can touch today, not 10-years from now.

From previous posts of yours; I am under the impression that you benefit financially from the sale of NR Bryan_S. Am I correct?