2255 replies to this topic

[Nate-2004]

 

Are you suggesting I wash out for a week, get blood work done, then take NR, get blood work done, then take apigenin with the NR and get blood work done again to gets pre NR, post NR and post Apigenin levels of NAD? Has anyone here done this for NR?

 

Since starting Apigenin with NR two days ago I do feel I have even more energy than I had with just the NR. I'm not sure if that's placebo or what. That aside, apigenin is also said to be an aromatase inhibitor which sounds good to me as I'd definitely like to boost my testosterone levels.

 

 

The entire topic of whether something is beneficial is in my view really difficult. Personally I have concluded that I can probably do regime changes every 2-3 months if I want to conclude anything. Short term effects like more or less energy I am not taking too serious anymore. So I watch:

- memory recall. How welll can I remember numbers for a short time. For work I regularly dial into conference calls with 9 digit ID codes, so do I remember better or not...either I dial wrong or right after looking at the number couple times.

- physical appearence. I have a pretty standard gym routine so is my body changing more or less

- hair. My hairline is on a slow recovery. Does it stay on track or stall

- eyesight. This has improved but still intermittent. I suspect lens stiffening cannot be easily overcome...

- skin, the ultimate challenge in my view. ECM in the face, wrinkless, elasticity

 

But all of those will only show changes in longer term. Just as example skin epidermal cells renew every 15-30 days. So if you want to see impact for example from epigenetic changes my guess is you would need couple months before something becomes visible. I have noticed people make fast changes to regimes but the body renewal doesn't go that fast in my opinion.

 

Personally I am very satisfied with NR, but I have added some polyphenols on the hypothesis to tamp inflammation for example. I have added those over time. It is not easy to say what each item does but I am fairly sure that the combination work. Of course each person in different and I am also convinced that other factors like the amount you eat and the exercise you do are other critical components. Exercise activates 100s of genes for example. Anyways I am 46 years old and last week I got offered a student card for a nightclub :-) that would not have happened 1-2 years ago so yeah I am not in a hurry to tweak my CD38s....I go for long and slow improvement just like aging which is long and slow but then resversed.

 

 

This is all very good info. I've not changed my regimen much in the last 40-45 days since I began NR. I plan to stick with this beyond another 60 days for sure. Those are good markers to keep track of. I've been watching skin over the past 30 days now. I've not seen much yet but I'm holding out for a few months like you say before deciding what works. I have been exercising for at least 30 mins at target heart rate (161) four times a week for quite a while now.

 

I'm learning that apigenin has a very long half life of 91 hours according to most reliable sources. I may end up reducing the dose back to once a week at that rate. It's got a sedative effect in higher amounts and I'm feeling it today, so I'll be skipping it. Some sources I linked above say that food bound apigenin is more stable. There's no telling how much of it is required to reduce CD38, your diet may include it Stefan, but mine probably doesn't. I haven't been eating oranges, celery, grapefruit or any of the food sources listed except perhaps a small amount of onion with other foods on occasion. I eat a lot of apples, bananas, strawberries and blueberries but it's not in those. I hate grapefruit and while I might add oranges back into my diet I may just stick with chamomile tea instead of taking the supplement. I will let everyone know if this speeds things up in terms of reversing age in any way. 

Edited by Nate-2004, 23 June 2016 - 02:57 PM.

[Harkijn]

 

 

 

Yes, please let's keep some focus here. The very essence of this thread, you could say, is how to boost NAD+ while avoiding NAMPT. So far we have two approaches: NMN and NR.  Now the interview I linked to earlier today speaks of spectacular succes by involving TFAM. Perhaps it sinks in better if a paste a quote:

 

'Now your lab showed that there is a very exciting gene engineering alternative involving TFAM (Transcription Factor A, Mitochondrial). Why is TFAM important, and what have you done with it?

Church: TFAM is a key regulatory protein that is in this pathway of NMN and NAD+. It allows cells to manufacture the NMN precursor on their own, so you don't have to manufacture it outside the cell and then try to get it into the cell from outside. Ideally, you don't want to have to take NMN for the rest of your life, you want to fix the body's ability to make its own NMN and buy yourself rejuvenation for at least a few decades before you have to worry about NMN again. In order to accomplish this on a single cell level, we've used CRISPR to activate a TFAM activator, and we made it semi-permanent. 

Fahy: With this technique, you were able to increase TFAM levels in the cell by 47-fold. This resulted in restored ATP levels, increased NAD+, and an increased NAD+/NADH ratio. It also increased total mitochondrial mass and reversed several other age-related changes.

Church: Yes. We have a number of ways to measure mitochondrial function and age-related losses of those functions. When we activated TFAM, these changes returned to what you would expect of a younger cell state. And we built this anti-aging ability into the cell, so it's self-renewing and eliminates the need to take pills or injections. (Italics mine)

However, I looked up TFAM this afternoon and did find nothing as yet about involvement in NADproduction. The info I saw referred to a role more 'downstream'. Anyone aware of useful sources?

 

While this is certainly promising I think at best this is many years out in the future. Even if approved it would require all your current mitochondria to be replaced, not sure how realistic that is. Perhaps this could be a seperate thread?

 

Don't hold your breath, but clinical trials expected within one year. Wish we could say that for NR! They do not want to replace mitochondria piece by piece, it works differently...

 

 

I am not holding my breath, if you read the entire interview then its clear that there is quite a bit of speculation in the claims...also I assume you noticed this piece "On January 7, 2016, Dr. Church's company, Editas Medicine, filed papers to launch a $100 million IPO,". Nevertheless the study around aging factors is interesting but it didnt get clear to me who is actually doing those. Also using my entirely non-scientific evaluation on his appearance in pictures in the internet I concluded that he looks at least his age so whatever he talks about he is either not using himself already or then it doesnt work.

 

I will dig a bit too into TFAM nevertheless....

 

I will now stop posting about TFAM just because it turns out to be such a central factor. It is probably discussed already in other threads like the  C60 or Telomere threads by people more qualified than me. However for those few who want to take a very first look at the slightly bigger picture, a nice start is:

http://www.anti-agin...o-faces-of-p53/

Yes, it's Giuliano again. Scroll to paragraph 16.

[stefan_001]

 

 

 

 

 

 

This is all very good info. I've not changed my regimen much in the last 40-45 days since I began NR. I plan to stick with this beyond another 60 days for sure. Those are good markers to keep track of. I've been watching skin over the past 30 days now. I've not seen much yet but I'm holding out for a few months like you say before deciding what works. I have been exercising for at least 30 mins at target heart rate (161) four times a week for quite a while now.

 

I'm learning that apigenin has a very long half life of 91 hours according to most reliable sources. I may end up reducing the dose back to once a week at that rate. It's got a sedative effect in higher amounts and I'm feeling it today, so I'll be skipping it. Some sources I linked above say that food bound apigenin is more stable. There's no telling how much of it is required to reduce CD38, your diet may include it Stefan, but mine probably doesn't. I haven't been eating oranges, celery, grapefruit or any of the food sources listed except perhaps a small amount of onion with other foods on occasion. I eat a lot of apples, bananas, strawberries and blueberries but it's not in those. I hate grapefruit and while I might add oranges back into my diet I may just stick with chamomile tea instead of taking the supplement. I will let everyone know if this speeds things up in terms of reversing age in any way. 

 

 

That will be interesting to see how it goes. I am just guessing here but if the body is far down the aging curve aggressive inhibition of NAD+ consumers for a while may make sense to nudge the system in the right direction.

[Kirito]

I too have had that issue with apigenin. I will probably stick to taking it whenever I get anxiety flares-ups. Last year, I tried Swanson ProC3G (black rice extract) but it appears to have been discontinued. I seemed to have positive results with it, such as an energy and endurance increases (Not sure if placebo). HPN appears to sell it, but it doesn't come cheap...

 

With the future of Chromadex up in the air, I suppose it's a good idea to have a list of alternatives laid out. Just in case the worst happens or if we want to stack them with NR.

 

Theobromine increases NAD⁺/Sirt-1 activity and protects the kidney under diabetic conditions.

http://www.ncbi.nlm....pubmed/25411384

 

I thought of the idea to cook some black rice with dark chocolate melted onto it. An NAD boosting dessert rice of sorts. I tried it and loved it.

[Asor]

In my opinion Chromadex isnt going anywhere. It cant be a pump and dump stock, as hypothesized by that Seeking Alpha smear article, you dont need to be an expert to understand that Chromadex has a more than legit business, with Nobel laureates on the board, some great patents, ton of promising human trials on their main product going on and animal trials as well already concluded.

 

 

 

[Bryan_S]

Boosting NAD+ for the prevention and treatment of liver cancer

http://www.ncbi.nlm....les/PMC4905329/

 

 

"Interestingly, inhibitors against nicotinamide phosphoribosyltransferase (NAMPT), the enzyme implicated in boosting NAD+ pools via the salvage pathway, are currently being used in several phase II clinical trials as anticancer therapy. Based on our data, this kind of therapy should be considered with caution because reducing NAD+ levels might be harmful through exposing healthy cells to genotoxic stress. To revolutionize cancer treatment, we instead propose that NAD+ boosters in combination with chemotherapeutic drugs might be useful to protect healthy cells against DNA damage and transformation into cancerous cells.

 

A defect in cell metabolism is therefore a fundamental characteristic for acquiring genomic instability and certainly other hallmarks of cancer. Thus, therapeutic intervention against metabolic alterations prior to development of genomic instability warrants further attention in the prevention and treatment of tumorigenesis. Facilitating the development of more efficient and stable NAD+ “boosters” would offer innovative new avenues and mechanism-based therapeutics to maintain human health and prevent and cure cancer and various associated metabolic dysfunctions."

 

Sometimes I miss a few publications and I apologize for this one. I believe I read the title and thought I'd already posted it. However this study was a paper written a year after one I'd first posted here about these authors. 

 

Team discovers that a derivative of vitamin B3 prevents liver cancer in mice

November 20, 2014

http://medicalxpress...n-b3-liver.html

 

Some months ago we were discussing if NAD Repletion/boosting could be contraindicated in cancer patients. Here is a study example where it might be indicated. However I'll add a word of caution if you or someone you know is in treatment, fully disclose to your oncologist any NAD boosting supplements you may be taking because some cancer treatments are designed to starve cells of NAD to weaken cancer. This starvation approach itself also has risks because reducing NAD+ levels might be harmful through exposing healthy cells to genotoxic stress.

 

I think what studies like these point out is NAD+ can help correct cellular instability in some instances. I would like to see this NAD boosting technique studies across a number of human cancer types in the coming years.

Edited by Bryan_S, 24 June 2016 - 09:30 AM.

[Bryan_S]

Study to Evaluate the Effect of Nicotinamide Riboside on Immunity

First received: June 23, 2016

https://www.clinical...&show_rss=Y

Background:

 

The immune system controls how the body responds to infection or injury. Researchers want to see what effect a dietary supplement called nicotinamide riboside (NR) has on the immune system. A study showed that fasting has a good effect on immune cell health in healthy people. And when immune cells were exposed to NR they had a similar positive response as with fasting. Researchers want to see if healthy people have the same effects from NR and fasting, and if those effects last.

 

Objectives:

 

To see if taking nicotinamide riboside will have the same healthy immune system effects as fasting. To see if these good effects continue even after eating again.

 

Eligibility:

 

Healthy volunteers ages 18 39

 

Design:

 

Participants will be screened with medical history, physical exam, and blood tests. Women will have a urine pregnancy test.

 

Participants will take 4 pills of either NR or a placebo once a day for 1 week.

 

On day 6, they will not eat or drink anything.

 

On day 7, they will have a study visit to give a blood sample before and after eating a meal at the clinic.

 

They will also give a urine sample.

 

Participants will stop taking the pills for 1 2 weeks.

 

Participants will take either NR or a placebo once a day for 1 week.

 

They will repeat day 6 and day 7 of the first week.

 

Participants will get NR once and placebo once, but will not know which they are taking.

 

This brings the total count for Human Clinical testing of (NR) to 8 listed studies.

Edited by Bryan_S, 24 June 2016 - 05:07 PM.

[ironfistx]

So is CD38 good actually?

[Bryan_S]

So is CD38 good actually?

 

There will be more research on this in the months to come. I personally feel this will launch a new path in the NAD repletion story. No one can say what that will entail at the moment and we need study confirmation of these findings and other labs to untangle its underpinnings.

Post 631

 

Function

CD38 is a multifunctional ectoenzyme that catalyzes the synthesis and hydrolysis of cyclic ADP-ribose (cADPR) from NAD+ to ADP-ribose. These reaction products are essential for the regulation of intracellular Ca2+.[5]

 

https://en.wikipedia.org/wiki/CD38

 

 

ironfistx I took down the stock charts because although the continued supply of Nicotinamide Riboside is of interest to our readers we've received some criticism about posts about the short selling of the stock.  

Edited by Bryan_S, 25 June 2016 - 01:08 AM.

[Bryan_S]

mTORC1 and SIRT1 Cooperate to Foster Expansion of Gut Adult Stem Cells during Calorie Restriction

Masaki Igarashi, Leonard Guarente

Publication stage: In Press Corrected Proof

Publication History

Published: June 23, 2016

DOI: http://dx.doi.org/10...ell.2016.05.044

http://www.cell.com/...8674(16)30595-5

 

Highlights

•Calorie restriction induces mTORC1 and SIRT1 in intestinal stem cells to increase their number

•The mTORC1 inhibitor rapamycin blocks the effects of calorie restriction on intestinal stem cells

•Paneth cell signaling increases NAD synthesis in intestinal stem cells during calorie restriction

•Intestinal stem cells are insulated from directly sensing reduced caloric intake

 

Summary

Longevity-promoting caloric restriction is thought to trigger downregulation of mammalian target of rapamycin complex 1 (mTORC1) signaling and upregulation of SIRT1 activity with associated health benefits. Here, we show that mTORC1 signaling in intestinal stem cells (ISCs) is instead upregulated during calorie restriction (CR). SIRT1 deacetylates S6K1, thereby enhancing its phosphorylation by mTORC1, which leads to an increase in protein synthesis and an increase in ISC number. Paneth cells in the ISC niche secrete cyclic ADP ribose that triggers SIRT1 activity and mTORC1 signaling in neighboring ISCs. Notably, the mTOR inhibitor rapamycin, previously reported to mimic effects of CR, abolishes this expansion of ISCs. We suggest that Paneth cell signaling overrides any direct nutrient sensing in ISCs to sculpt the observed response to CR. Moreover, drugs that modulate pathways important in CR may exert opposing effects on different cell types.

 

Edited by Bryan_S, 24 June 2016 - 05:54 PM.

[Bryan_S]

NMN - The Latest Anti-Aging Drug to be Tried on Humans

http://www.worldheal...mononucleotide/

 

Researchers are planning to test nicotinamide mononucleotide (NMN) on a small group of 10 healthy people.

 

NMN - The Latest Anti-Aging Drug to be Tried on Humans

"Nicotinamide mononucleotide (NMN), a compound that has shown to slow the aging process in animals, is now going to be used in a clinical study to test its safety and effectiveness in humans. Keio University’s Research Ethics Committee is going to explore the appropriateness of the idea, and if the plan is accepted, Washington University in St. Louis and Keio University will begin this study in Japan next month. The researchers will then give the compound, nicotinamide mononucleotide to ten healthy people and study whether NMN can improve bodily functions. A research group including Prof. Shinichiro Imai of Washington University found NMN could potentially extend people’s life spans by activating a gene known for its anti-aging effects called sirtuin. Sirtuins are able to silence certain genes, including ones that promote aging. When mice were given NMN, it was found that the compound can reverse age-related eyesight and metabolism deteriorations. “We’ve confirmed a remarkable effect in the experiment using mice, but it’s not clear yet how much [the compound] will affect humans,” Imai said. “We’ll carefully conduct the study, which I hope will result in important findings originating in Japan.” Next fiscal year, the government will contribute full-fledged support to anti-aging studies, promoting research in this field and benefiting the NMN clinical trial."

 

I say let the NAD+ precursor competition begin. Let the best man (precursor) win!

http://www.businessw...ent-Specialized Also guys if you do plan on purchasing NMN there is a booming market in FAKE NMN as there is in FAKE NR, so Caveat Emptor or buyer beware.

 

We've been following Prof. Shinichiro Imai of Washington University work for some time on the (NR) threads. He has been one of the major contributors to the NAD+ Repletion/Boosting concept. In fact you will see Prof. Shinichiro Imai, David Sinclair and Leonard Guarantee's names appear regularly on this topic. Here is a video of him with Leonard Guarantee.

 

Edited by Bryan_S, 24 June 2016 - 07:05 PM.

[APBT]

ARTICLE:

Attached Files

•  NAD+ Declines during Aging - It's Destroyed.pdf   265.92KB   17 downloads

[Tom Andre F. (ex shinobi)]

I say let the NAD+ precursor competition begin. Let the best man (precursor) win!

Hi bryan,

If you want to know what is the best precursor then you have to add both nicotinic acid and nicotinic acid riboside and play with dosage.
In my opinion its what have to be compared. We know nmn has to be converted back to nr prior to enter the cell and is just much more expensive.
Nicotinic acid also doesnt work via nampt and some person here even report better result compared to nr..

[Tom Andre F. (ex shinobi)]

And just to quote back daryl about something we should be concerned:

NR isn't rate-limited by NAMPT, and doesn't cause flushing, but only some tissues (in animals) express NR kinases to utilize it.

[...]

From Bogan, K. L., & Brenner, C. (2008). Nicotinic acid, nicotinamide, and nicotinamide riboside: a molecular evaluation of NAD+ precursor vitamins in human nutrition. Annu. Rev. Nutr., 28, 115-130.

Daryl also mentioned a study that showed Na was better than Nr to increase NAD+ in vivo in many tissue

[Nate-2004]

Also guys if you do plan on purchasing NMN there is a booming market in FAKE NMN as there is in FAKE NR, so Caveat Emptor or buyer beware.

 

This concerned me. Has HPN's NR been tested for label accuracy? I'm assuming that all comes from Chromadex. 

[Harkijn]

And just to quote back daryl about something we should be concerned:

NR isn't rate-limited by NAMPT, and doesn't cause flushing, but only some tissues (in animals) express NR kinases to utilize it.

[...]

From Bogan, K. L., & Brenner, C. (2008). Nicotinic acid, nicotinamide, and nicotinamide riboside: a molecular evaluation of NAD+ precursor vitamins in human nutrition. Annu. Rev. Nutr., 28, 115-130.

Daryl also mentioned a study that showed Na was better than Nr to increase NAD+ in vivo in many tissue

Tom, i just read through the study you mentioned. They are a lot more upbeat about NR than you think:

 

The most fundamental use of NAD+ precursor molecules, Na and Nam, is in the prevention of pellagra. Like Na and Nam, NR is a natural product found in milk (14), which is incorporated into the intracellular NAD+ pool (94), and thus could be used as a general supplement, potentially for people who have adverse reactions to Na or Nam. More significantly, however, the specific utilization of NR by neurons may provide qualitative advantages over niacins in promoting function in the central and peripheral nervous system.

[Tom Andre F. (ex shinobi)]

 

And just to quote back daryl about something we should be concerned:

NR isn't rate-limited by NAMPT, and doesn't cause flushing, but only some tissues (in animals) express NR kinases to utilize it.

[...]

From Bogan, K. L., & Brenner, C. (2008). Nicotinic acid, nicotinamide, and nicotinamide riboside: a molecular evaluation of NAD+ precursor vitamins in human nutrition. Annu. Rev. Nutr., 28, 115-130.

Daryl also mentioned a study that showed Na was better than Nr to increase NAD+ in vivo in many tissue

Tom, i just read through the study you mentioned. They are a lot more upbeat about NR than you think:

 

The most fundamental use of NAD+ precursor molecules, Na and Nam, is in the prevention of pellagra. Like Na and Nam, NR is a natural product found in milk (14), which is incorporated into the intracellular NAD+ pool (94), and thus could be used as a general supplement, potentially for people who have adverse reactions to Na or Nam. More significantly, however, the specific utilization of NR by neurons may provide qualitative advantages over niacins in promoting function in the central and peripheral nervous system.

 

 

Yes because:

 

The use of NR as a precursor in mammalian cell types was first demonstrated in DRG neurons, which induce the NRK2 transcript when damaged by axotomy (71). The ubiquitous expression of Nrk1 in mammalian tissues (80) suggests utilization of NR and/or NaR (83) in a diverse array of cell types. The fact that DRG neurons cannot be protected from damage induced neuropathy by Na or Nam without concurrent gene expression of Na or Nam salvage genes suggests that NR is a uniquely useful precursor to the nervous system (71) when de novo synthesis of NAD+ from Trp is not sufficient.

 

Means: the missing link here was NRK2 that is also used by.. NaR (nicotinic acid riboside).  So you expect exact same result using this one. Second, NaR would be even better since it is also converted into Na that is not NRK1/2 specific.

 

Problem with NR is it can only use the NRK1/2 or being converted by hydrolisis into Nam directly..

 

Why is that a problem ? because:

 

Nrk2 is present in heart, brain, and skeletal muscle, and is notably absent in kidney, liver, lung, pancreas, and placenta (48, 71)

 

So, its very clear now that we need both NRK and press handler specific molecule, since NaR does use both, and since there is also not the direct release into Nam like happen with NR, (because NAD+ release already some Nam due to NAD+ consuming enzyme, Nam use Nampt that we know now is weak due to aging.), NaR looks a better supplement to me on the paper. But we dont have source for now.. so we should go for low dose NR and Na for the combo effect, but this is just my opinion, rest are facts.

 

Finally, in this study: http://www.cell.com/...4131(12)00192-1 figure 1 D ( vivo result), you can see they compared NA and NR to increase NAD+ in liver and muscle . The result confirm in liver almost no effect from NR (and the result is very lickely due to Nam from NR, since NMN even gave more poor result) while the increase in NAD+ was twice for Na. In muscle however, where NRK is present, NR gave same result in NAD+ boosting as Na

 

 

 

 

 

 

 

 

Edited by Tom Andre F. (ex shinobi), 25 June 2016 - 06:09 PM.

[Steve H]

I think in all honesty the real solution to the NAD/NADH ratio can only be tackled to a substantive degree by CRISPR or similar technology. George Church plans to roll out a therapy that targets TFAM directly upregulating NAD+ in the cell. They have taken the research data of Sinclair who used NMN and now have a way to apply this to a AAV based CRISPR edit.



This is really the way forward in my view and George Church is saying it should be underway in human trials in the next year. I am not convinced by the NR data personally and I think only very robust gene edits will lead to long term solutions to age related NAD decline. Supplements can sometimes be useful of course but I am waiting on Church to deliver far more robust solutions.

Edited by Steve H, 25 June 2016 - 07:59 PM.

[Nate-2004]

I think in all honesty the real solution to the NAD/NADH ratio can only be tackled to a substantive degree by CRISPR or similar technology. George Church plans to roll out a therapy that targets TFAM directly upregulating NAD+ in the cell. They have taken the research data of Sinclair who used NMN and now have a way to apply this to a AAV based CRISPR edit.



This is really the way forward and George Church is saying it should be underway in human trials in the next year. I am not convinced by the NR data personally and I think only very robust gene edits will lead to long term solutions to age related NAD decline. Supplements can sometimes be useful of course but I am waiting on Church to deliver far more robust solutions.

 

I am really looking forward to that but bioethicists are getting in the way of things with bad arguments and the FDA will be a big hurdle that may delay this for years. I'm not counting on this any time soon. It's taken 3 years for the High Frequency Ultrasound surgery to even get in the queue for FDA approval on treatments for movement disorders and it's still not approved after nearly 8 months now, meanwhile everyone is suffering in the U.S. while other countries have already approved it. This amazing non invasive surgery machine does far less than CRISPR, which I am hoping will do more than just end aging, but cure a lot of non-age related genetic disorders.

[Steve H]

It is a valid point though Church is apparently already setting up human testing so he must know something we do not. I will see what I can find out about this as we have friends in his lab and he might give us some further indication of the situation. TFAM is an excellent way to boost NAD and the data support NMN certainly in mice. Of course a lot of hucksters are selling supplements off the back of David Sinclairs work and making BS claims that other related compounds can do the same when there is just none or not enough data to justify that. 

[Harkijn]

It is a valid point though Church is apparently already setting up human testing so he must know something we do not. I will see what I can find out about this as we have friends in his lab and he might give us some further indication of the situation. TFAM is an excellent way to boost NAD and the data support NMN certainly in mice. Of course a lot of hucksters are selling supplements off the back of David Sinclairs work and making BS claims that other related compounds can do the same when there is just none or not enough data to justify that. 

Thanks for weighing in here Steve. I was beginning to doubt this thread a little bit when I posted about TFAM a few days back and noone seemed to notice...

[Bryan_S]

Daryl also mentioned a study that showed Na was better than Nr to increase NAD+ in vivo in many tissue

 

I don't know this Daryl and haven't seen the study. Niacin (NA) is cheap, Nicotinamide (NAM) is also, Nicotinamide mononucleotide (NMN) is not, at least the real stuff. There's no way I could take the Niacin in the quantities I'd need. Plus there is chance of liver damage longterm in the higher quantities. "Niacin’s safety record is equally impressive. However, a brief foray into the use of very-slow-release niacin preparations in the 1980s taught us an important lesson: niacin is very safe, if the liver is exposed to it for only a few hours at a time. Niacin is, after all, just vitamin B3. However, 24-hour, day-after-day exposure to niacin over an extended period can be toxic to the liver. Thus, the very-slow-release niacin preparations that yielded sustained, high blood levels of niacin caused liver toxicity in 10-20% of people who used these preparations in the 1980s. Unfortunately, this learning experience left some physicians fearful of recommending niacin to their patients. For this reason, very-slow-release niacin should be avoided."

http://www.lifeexten...7/3/atd/Page-01

 

This isn't the case with NAM and I've seen longterm studies with up to 9 grams per day however 3 is generally considered the limit. 

http://www.nejm.org/...197311292892208

 

This concerned me. Has HPN's NR been tested for label accuracy? I'm assuming that all comes from Chromadex. 

I would PM maxwatt and ask him to send you the name of the lab he uses to test NR.

 

I think in all honesty the real solution to the NAD/NADH ratio can only be tackled to a substantive degree by CRISPR or similar technology.

 

Guys back up a few posts and read the latest posts, please.  NAD+ Declines during Aging - It's Destroyed.pdf This also speaks to the CRISPER DNA editing as well. If CD38 is killing the NAD+ why would we want to monkey with the NAD/NADH ratio? Why make permanent changes to our DNA to change the ratio or churn out more NAD when something else is wrong? This what that study is suggesting, our carburetor settings might be fine in a manner of speaking.

 

"Thanks for weighing in here Steve. I was beginning to doubt this thread a little bit when I posted about TFAM a few days back and noone seemed to notice..." Sometimes we don't respond to questions or side topics that have previously been answered. TFAM is very exciting and we've discussed it before within the topic of Nicotinamide Riboside

http://www.ncbi.nlm....pubmed/24410488

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

 

And someone mentioned something about which tissues use NR. We've been down this road before and as I'm suggesting answers to many previous questions asked here can be found with the LongeCity search engine in the top right hand corner of your browser.

http://www.longecity...e-7#entry731929

 

Guys we have this wonderful resource. Many of the questions being asked here have been painstakingly answered before, and as you might imagine some of them require a full afternoon to answer through research. We have the latest papers collected here and some of the best and most frequent questions/answers are just a few key strokes away if you know how to look. 

[stefan_001]

 

It is a valid point though Church is apparently already setting up human testing so he must know something we do not. I will see what I can find out about this as we have friends in his lab and he might give us some further indication of the situation. TFAM is an excellent way to boost NAD and the data support NMN certainly in mice. Of course a lot of hucksters are selling supplements off the back of David Sinclairs work and making BS claims that other related compounds can do the same when there is just none or not enough data to justify that. 

Thanks for weighing in here Steve. I was beginning to doubt this thread a little bit when I posted about TFAM a few days back and noone seemed to notice...

 

 

You dont need to wait for any crispr tooling if you believe TFAM is the way to go, just start taking fingerroot:

 

BPE also elevated the mRNA expression of key factors of mitochondrial biogenesis and function, which are activated by PGC-1α, such as estrogen-related receptor α (ERRα), nuclear respiratory factor 1 (NRF-1), and mitochondrial transcription factor A (Tfam).

http://www.ncbi.nlm....pubmed/27331877

[stefan_001]

 

 

 

Yes because:

 

The use of NR as a precursor in mammalian cell types was first demonstrated in DRG neurons, which induce the NRK2 transcript when damaged by axotomy (71). The ubiquitous expression of Nrk1 in mammalian tissues (80) suggests utilization of NR and/or NaR (83) in a diverse array of cell types. The fact that DRG neurons cannot be protected from damage induced neuropathy by Na or Nam without concurrent gene expression of Na or Nam salvage genes suggests that NR is a uniquely useful precursor to the nervous system (71) when de novo synthesis of NAD+ from Trp is not sufficient.

 

Means: the missing link here was NRK2 that is also used by.. NaR (nicotinic acid riboside).  So you expect exact same result using this one. Second, NaR would be even better since it is also converted into Na that is not NRK1/2 specific.

 

Problem with NR is it can only use the NRK1/2 or being converted by hydrolisis into Nam directly..

 

Why is that a problem ? because:

 

Nrk2 is present in heart, brain, and skeletal muscle, and is notably absent in kidney, liver, lung, pancreas, and placenta (48, 71)

 

So, its very clear now that we need both NRK and press handler specific molecule, since NaR does use both, and since there is also not the direct release into Nam like happen with NR, (because NAD+ release already some Nam due to NAD+ consuming enzyme, Nam use Nampt that we know now is weak due to aging.), NaR looks a better supplement to me on the paper. But we dont have source for now.. so we should go for low dose NR and Na for the combo effect, but this is just my opinion, rest are facts.

 

Finally, in this study: http://www.cell.com/...4131(12)00192-1 figure 1 D ( vivo result), you can see they compared NA and NR to increase NAD+ in liver and muscle . The result confirm in liver almost no effect from NR (and the result is very lickely due to Nam from NR, since NMN even gave more poor result) while the increase in NAD+ was twice for Na. In muscle however, where NRK is present, NR gave same result in NAD+ boosting as Na

 

 

Hey Tom, good observation. What I really like is figure 5 showing the chronic NR administration case. It demonstrates NR keeps doing the job but also a much better NAD+ increase caused by NR in the liver as compared to the Figure 1D which was a short term test.

Edited by stefan_001, 25 June 2016 - 09:44 PM.

[Tom Andre F. (ex shinobi)]

 

Daryl also mentioned a study that showed Na was better than Nr to increase NAD+ in vivo in many tissue

 

I don't know this Daryl and haven't seen the study. Niacin (NA) is cheap, Nicotinamide (NAM) is also, Nicotinamide mononucleotide (NMN) is not, at least the real stuff. There's no way I could take the Niacin in the quantities I'd need. Plus there is chance of liver damage longterm in the higher quantities. "Niacin’s safety record is equally impressive. However, a brief foray into the use of very-slow-release niacin preparations in the 1980s taught us an important lesson: niacin is very safe, if the liver is exposed to it for only a few hours at a time. Niacin is, after all, just vitamin B3. However, 24-hour, day-after-day exposure to niacin over an extended period can be toxic to the liver. Thus, the very-slow-release niacin preparations that yielded sustained, high blood levels of niacin caused liver toxicity in 10-20% of people who used these preparations in the 1980s. Unfortunately, this learning experience left some physicians fearful of recommending niacin to their patients. For this reason, very-slow-release niacin should be avoided."

http://www.lifeexten...7/3/atd/Page-01

 

This isn't the case with NAM and I've seen longterm studies with up to 9 grams per day however 3 is generally considered the limit. 

http://www.nejm.org/...197311292892208

 

I think in all honesty the real solution to the NAD/NADH ratio can only be tackled to a substantive degree by CRISPR or similar technology.

 

Guys back up a few posts and read the latest posts, please.  NAD+ Declines during Aging - It's Destroyed.pdf This also speaks to the CRISPER DNA editing as well. If CD38 is killing the NAD+ why would we want to monkey with the NAD/NADH ratio? Why make permanent changes to our DNA to change the ratio or churn out more NAD when something else is wrong? This what that study is suggesting, our carburetor settings might be fine in a manner of speaking.

 

"Thanks for weighing in here Steve. I was beginning to doubt this thread a little bit when I posted about TFAM a few days back and noone seemed to notice..." Sometimes we don't respond to questions or side topics that have previously been answered. TFAM is very exciting and we've discussed it before within the topic of Nicotinamide Riboside

http://www.ncbi.nlm....pubmed/24410488

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

 

And someone mentioned something about which tissues use NR. We've been down this road before and as I'm suggesting answers to many previous questions asked here can be found with the LongeCity search engine in the top right hand corner of your browser.

http://www.longecity...e-7#entry731929

 

Guys we have this wonderful resource. Many of the questions being asked here have been painstakingly answered before, and as you might imagine some of them require a full afternoon to answer through research. We have the latest papers collected here and some of the best and most frequent questions/answers are just a few key strokes away if you know how to look. 

 

Hi Bryan,

 

your link in bold, state :

 

nicotinic acid, which is the dietary form of the vitamin, has occasionally been associated with abnormalities of liver function when used in large doses in the treatment of hypercholesterolemia (3 to 10 g per day).^{45678910111213} The following case demonstrates that nicotinamide may cause major hepatic injury.

 

No one would use such large dose of Na knowing the RDA for a adult is around 20mg. And the effect on liver is logic since it posses the preiss handler pathway and nicotinamide will indeed also have some bad effect on liver like that but to a lesser extend since it will play via Nampt. I replied to almost all of that and also covered wich tissue possess what here :

 

 

 

Yes because:

 

The use of NR as a precursor in mammalian cell types was first demonstrated in DRG neurons, which induce the NRK2 transcript when damaged by axotomy (71). The ubiquitous expression of Nrk1 in mammalian tissues (80) suggests utilization of NR and/or NaR (83) in a diverse array of cell types. The fact that DRG neurons cannot be protected from damage induced neuropathy by Na or Nam without concurrent gene expression of Na or Nam salvage genes suggests that NR is a uniquely useful precursor to the nervous system (71) when de novo synthesis of NAD+ from Trp is not sufficient.

 

Means: the missing link here was NRK2 that is also used by.. NaR (nicotinic acid riboside).  So you expect exact same result using this one. Second, NaR would be even better since it is also converted into Na that is not NRK1/2 specific.

 

Problem with NR is it can only use the NRK1/2 or being converted by hydrolisis into Nam directly..

 

Why is that a problem ? because:

 

Nrk2 is present in heart, brain, and skeletal muscle, and is notably absent in kidney, liver, lung, pancreas, and placenta (48, 71)

 

So, its very clear now that we need both NRK and press handler specific molecule, since NaR does use both, and since there is also not the direct release into Nam like happen with NR, (because NAD+ release already some Nam due to NAD+ consuming enzyme, Nam use Nampt that we know now is weak due to aging.), NaR looks a better supplement to me on the paper. But we dont have source for now.. so we should go for low dose NR and Na for the combo effect, but this is just my opinion, rest are facts.

 

Finally, in this study: http://www.cell.com/...4131(12)00192-1 figure 1 D ( vivo result), you can see they compared NA and NR to increase NAD+ in liver and muscle . The result confirm in liver almost no effect from NR (and the result is very lickely due to Nam from NR, since NMN even gave more poor result) while the increase in NAD+ was twice for Na. In muscle however, where NRK is present, NR gave same result in NAD+ boosting as Na

 

 

And I would also add this: http://www.jbc.org/c...664458.full.pdf

 

In this study we tested whether NR or NAR can be generated in human cells and thereby represent an integral part of NAD metabolism. Our findings indicate that previously identified  human cytoplasmic 5'-nucleotidases are capable of dephosphorylating NAMN and (to a lesser extent) NMN thereby generating a pool of  ribosides in human cells. Thus, NAR can be  generated from NA via NAMN formation (by NAPRT). NAMN, in turn, is then dephosphorylated to NAR by 5’-NTs(cf. Fig. 1A). Strikingly, we observed that the generation and release of NAR from a fraction of cells in the culture is sufficient to maintain viability of neighboring cells that are unable to utilize NAD precursors other than ribosides. These results indicate that NAR and NR represent an integral part of the human NAD metabolome. Moreover, they suggest that different cell types might support each other's NAD pools by providing ribosides as NAD precursors.

 

So conclusion is Na is much more important than NR to cover the full function.

[Nate-2004]

 

Daryl also mentioned a study that showed Na was better than Nr to increase NAD+ in vivo in many tissue

 

I don't know this Daryl and haven't seen the study. Niacin (NA) is cheap, Nicotinamide (NAM) is also, Nicotinamide mononucleotide (NMN) is not, at least the real stuff. There's no way I could take the Niacin in the quantities I'd need. Plus there is chance of liver damage longterm in the higher quantities. "Niacin’s safety record is equally impressive. However, a brief foray into the use of very-slow-release niacin preparations in the 1980s taught us an important lesson: niacin is very safe, if the liver is exposed to it for only a few hours at a time. Niacin is, after all, just vitamin B3. However, 24-hour, day-after-day exposure to niacin over an extended period can be toxic to the liver. Thus, the very-slow-release niacin preparations that yielded sustained, high blood levels of niacin caused liver toxicity in 10-20% of people who used these preparations in the 1980s. Unfortunately, this learning experience left some physicians fearful of recommending niacin to their patients. For this reason, very-slow-release niacin should be avoided."

http://www.lifeexten...7/3/atd/Page-01

 

Completely avoided? I mean, what happens if you just take it every other day instead of every day or perhaps taken every couple of days or once a week? 

 

I'd take niacin in addition to NR if it weren't for the flush. I'm not sure if I could deal with the flushing.

Edited by Nate-2004, 25 June 2016 - 09:53 PM.

[airplanepeanuts]

 

Also guys if you do plan on purchasing NMN there is a booming market in FAKE NMN as there is in FAKE NR, so Caveat Emptor or buyer beware.

 

 

Hi Bryan. About the fake NR, do you mean seller that claim to sell the Niagen branded product? 

[Tom Andre F. (ex shinobi)]

 

 

Hey Tom, good observation. What I really like is figure 5 showing the chronic NR administration case. It demonstrates NR keeps doing the job but also a much better NAD+ increase caused by NR in the liver as compared to the Figure 1D which was a short term test.

 

 

Hey Stefan,

 

Well im not sure if you read the amount, they was above 0,25mmol /kg for fig 1D and below 0,2 for fig 5 (chronic). Also dont forget both NAD+ and NR will release Nam that will get the enzyme in the liver  Nampt to increase a bit its NAD+. So maybe the result is justified as the Nampt was poor after some time of use
 

[sthira]

Of course a lot of hucksters are selling supplements off the back of David Sinclairs work and making BS claims that other related compounds can do the same when there is just none or not enough data to justify that.

To narrow focus, are you saying this is what's happening here with Niagen?

[bluemoon]

A few weeks ago,chemist blogger who writes on the pharmaceutical industry,slammed part of Elysiums's marketing for Basis. April 26, 2016:

 

Subtle Changes Can Be Yours, for Fifty Dollars a Month

by Derek Lowe

 

Several people have sent me a link to Elysium Health, and I can’t say that it’s improved my morning. This is a supplement company founded by (among others) Leonard Guarente of MIT, who is of course well-known for his work in the study of longevity and aging. The company advertises a large and impressive board of advisers, and states that it:

 

. . .serves as a novel platform for Lenny and 30+ scientific advisors, doctors, and researchers to shorten the time between discovery and impact on human health. This collaboration allows Elysium to leverage the latest technologies and most significant research to pioneer a new approach to health in our everyday lives.

 

By “shorten the time”, I think that they mean “set ourselves up in the supplements space so that we don’t have to go through the FDA so much”. That may sound uncharitable, but when I start reading about the company’s first product, “Basis” for “metabolic repair and optimization”, my mood darkens (and see below – that actually is the whole reason). Here’s how Basis is described:

 

Science has enabled us to intervene at the cellular level to achieve optimal health, beyond what can be accomplished with diet and exercise. Basis focuses on NAD+ levels and sirtuin function in our cells to support vital metabolic processes like detoxification, inflammatory response, energy production, and DNA repair.

 

Detoxification? Really? There’s one of my biggest objections to this whole venture, summed up in one word. In general – and this has been long noted – anyone who starts talking about “detoxification” and “toxins” is likely to be a quack. It’s a buzzword, something that plays to peoples’ mistaken ideas about medicine and biochemistry, that there are all these toxins from the environment that have to be flushed out somehow for you to be healthy. And I know that Guarente is an excellent scientist, and that the people on the company’s board are, too, which is what upsets me. Why go there? Why sound like something advertised in the back of a cheap magazine?

 

Reading further, one finds that Basis contains nicontinamide riboside and pterostilbene. The first is an NAD precursor, and is already on sale at your local vitamin shop. (On the scientific end of things, I’m certainly willing to believe that NAD levels could be involved in aging, by the way – I just don’t know what the best way to go about dealing with that might be). And pterostilbene is a close cousin of our old friend resveratrol, and it’s also available down at the shop, too. (This is one of my lesser problems with Elysium, that so far its products are already on sale from other people. I have not compared prices, nor purities).

 

 

This article at MIT’s Technology Review lays things out pretty well:

 

The problem, Guarente says, is that it’s nearly impossible to prove, in any reasonable time frame, that drugs that extend the lifespan of animals can do the same in people; such an experiment could take decades. That’s why Guarente says he decided to take the unconventional route of packaging cutting-edge lab research as so-called nutraceuticals, which don’t require clinical trials or approval by the FDA. . .

 

. . .“You have high-end prescription drugs up here, which are expensive,” says Guarente, gesturing upward. “And you have the nutraceuticals down there, which are a pig in a poke—you don’t know what you’re getting and you don’t know a lot about the science behind them. There’s this vast space in between that could be filled in a way that’s useful for health maintenance.”

 

As the article mentions, Guarente has been down the small-biotech route before in this area – the sirtuin story is a long, complicated one (and can be partially explored by going backwards in this archive). And I can understand his point about clinical trials in this area. But it still seems like a big leap from that to the nutraceuticals industry (here’s more on the company’s founding). To quote from the web site: “Subtle changes in overall feeling of well-being, sleep quality, energy consistency, cognitive function, and skin health are often reported within 4-16 weeks of starting. . .” and that’s about as specific as the law will allow you to get. That, and talk about “detoxification”, I guess. When Guarente says that “you have the nutraceuticals down there”, he’s pretty much right about the direction – and now he’s down there with them. It just seems sad, somehow. It makes the legitimate research in this field seem a bit less respectable, which isn’t good, and it makes the supplement hawkers seem a bit more respectable by association, and that’s probably not what Elysium was planning on, either.

 

48 comments, and most are harsh:

 

http://blogs.science...dollars-a-month