142 replies to this topic

[VERITAS INCORRUPTUS]

You are the one seeing some 'battle', as I have simply provided sound information.  

 

Perhaps NR is creating some degree of paranoia or making you a more antagonistic sort, lol ...

 

I certainly never directly attack anyone - and any bias I may have is certainly not for any gain of any note, and certainly less than those who seem to have 'conflict of interests'.

I am largely pitching the concept using the most cost effective means which is highly important to the majority.  

 

First and foremost it is clear I am emphasizing NAM/NA and an argument why they are the sound core basis that appear of most worth, within again the emphasis to the information Logic made us aware of the NR is broken down in the gut akin to SR-NAM and SR-Ribose.

 

Within (potential) conflict of interest I am referring to those doing the studies, not you, though people can come to their interpretation within your 'banter' as to any bias of any nature.

I know I have none, so that sits fine with me.

 

Can TLR create a NAD+ enhancement formulation that puts NR to shame in efficacy and cost effectiveness? - Absolutely - no two ways, but I am certainly not pitching that as it is not a focus and we do not have a 2.5M Dollar grant to do the studies people would want to see to support it.  

 

NR as stated appears to be a waste of money as an oral supplement, with some potential if used in a fashion to bypass the gut - as I prior stated.

NAD+ may survive the gut to some degree due to its stability in acidic media being relatively high and needs further study in this area - notably, it seems quite worthwhile via modes of administration that bypass the gut.

 

Those doing studies on NR appear from my perspective to be negligent in accord with bias (COI) - hey, this is the real world, and that's my perspective with rationale to back it, as so given.

 

Just trying to help

 

Peace

[Kevnzworld]

Chromadex is funding a third party study to evaluate the pharmakinetics of NR that is ingested orally. Others are in the process of doing similar work, which should answer some questions, but probably not definitively.
Veritus, I agree that as a vendor with a product, you should be pitching the attributes of it in another thread that has more transparency. Unquestionably there will be a variety of NAD+ boosting products, or those that claim to be arriving in our infomail box,web forum soon. Without some third party study or support it won't be easy to evaluate the efficacy of said products ( memo to True Life ).

[VERITAS INCORRUPTUS]

^

My friend, I am not pitching anything nor have any plans for a NAD+ related product of any consequence - I am solely interested in evolving the understanding of that area and the application of optimal supplementation taking into account all factors.  To create a new thread would be counterproductive to simply wanting to assist to get at the best means within what as stands is most optimally practically applicable.  This thread is about deriving the best means from 'what is now in hand'.

 

Does that not makes sense?

Have I not contributed to such?

 

I will be transparent to say if someone wants to impart an investment of significance there is no doubt a highly superior product to Niagen can readily be formulated with immediacy, but I doubt there is any significance to stating such.  As well, I would like to see a WHOLLY independent (not funded by Chromadex) study on oral bioavailability/pharmacokinetics of ALL worthwhile substrates, as well as other parameters.  Can be done for a reasonable amount - far less than some of the grant amounts I believe I have seen so noted.  

 

Look at the valuable (independent) work that was done in the study I posted above regarding eNAD+ -- did you read that?!?

 

100% independent studies please - I do not trust the track record I have seen thus far within NR related 'dynamics'

- they got a great, strong advantage patent for production of NR - it would suck big for them if NR was not the holy grail they have tried to make it out to be, to be blunt. Or am I wrong?  

And does pointing this out as I have, and within all else I have, not bear strong merit.

 

I love the spirit of this thread and the high level of true intellectual investigatory discourse, as well as the subject area at hand and its meritorious nature toward betterment.  With all I have said, honestly, I really do hope I have contributed (and believe I have to a great extent).  Such has been out of the passion and interest for the progress of science of a worthwhile nature that I have engaged such.  And that is as well the purpose of TLR, so call it a vendor if you must, but it is not at all just such as that.

 

I think many have done a lot of great worth here.  

I am thankful to all who have contributed meaningfully - including BryanS - please note I do respect his passion and dedication, within I may not agree with all manner and means.

 

Again, I am trying to weed out what is most practical as seems optimal to the goals of those who have interest in that which is within this thread.  

If you read back on what I wrote I'd say it may be a strong guide and evaluation to assist with doing just that.

 

Peace

 

 

Edited by VERITAS INCORRUPTUS, 03 December 2014 - 02:59 AM.

[Vastmandana]

Thank you, Bryan...
Veritis... you do nothing more than babble...repetitively...providing NO DATA OR LINKS to any research data which corroborates ANYTHING you babble on about.... we are seeking insights... not empty blahdeblahs...

Please quit cluttering up this thread with long winded repetative rhetoric that provides NO DATA in support of anything you go on about...

OY!

Edited by Vastmandana, 03 December 2014 - 04:03 AM.

[Bryan_S]

 

http://molpharm.aspe...073916.full.pdf

 

Have a Nice Day 

 

I read the entire paper thanks for the link. On specific tissue cultures they showed impressive results no doubt.

 

You know there is a "however" coming but let me slowly work my way into that . . . the body isn't just made up of a single cell/tissue type. The body is a complete interwoven system where we can not exclude certain tissues for the benefit or others. This whole eNAD (extracellular NAD) experiment you sent us on cells in suspension demonstrated certain tissues (not all) could absorb eNAD through the cell membrane. They make an excellent case to that point, I tip my hat to you for this find. You also corrected me on the second half of my argument about cellular absorption of NAD and I humbly conceded. I'll even go as far as to suggest "if" we could ovoid the whole cardiovascular system and only deliver NAD to the extracellular space between cells we'd have a total winner based on this study.

 

Let me take it to another level of understanding on a parallel study.

 

Extracellular nucleotides such as NAD+ are considered to be ideally suited as extracellular signal transmitters because they can be rapidly mobilized from intracellular stores and the signal is rapidly terminated by degradation by nucleotide catabolizing enzymes. NAD+ is supposed to be preferentially released from intracellular stores in conditions of cell stress or inflammation7. There are many cells that respond in several ways to extracellular NAD+ (Broetto-Biazon et al., 2008)

 

So yes this is an extremely important finding supported by a secondary study begging further research into this signaling mechanism.

 

However search the document you gave me for "rapid degradation by hepatocytes." They also quote the aforementioned study by (Broetto-Biazon et al., 2008) where they learned that the liver rapidly degraded NAD into its constituents (98% at 8 minutes). Mind you they are not talking about digestion of NAD, that is another hurdle for discussion in another thread that you are welcome to start.

 

We are all trying to arrive at the truth whatever that may be. Also there are no fast answers, often you have to read several referenced documents just to understand the context of the one you think has what you're looking for. Last spring I picked up a copy of "Molecular and Cell Biology for Dummies" just to refresh my old and forgotten biology. I still comb these studies using a dictionary, so it's not a quick process to absorb any of these papers for some of us.

 

So lets back up our opinions with references because we are all participating in this discussion to learn.

Edited by Bryan_S, 03 December 2014 - 07:06 AM.

[Bryan_S]

Chromadex is funding a third party study to evaluate the pharmakinetics of NR that is ingested orally. Others are in the process of doing similar work, which should answer some questions, but probably not definitively.
Veritus, I agree that as a vendor with a product, you should be pitching the attributes of it in another thread that has more transparency. Unquestionably there will be a variety of NAD+ boosting products, or those that claim to be arriving in our infomail box,web forum soon. Without some third party study or support it won't be easy to evaluate the efficacy of said products ( memo to True Life ).

 

The Weill Cornell Medical College study on NAD and hearing loss is the most recent study performed with orally administered NR, it was published yesterday. They also independently produced their own NR so no conflict of interest could be inferred.

 

With reasearch funding so scarce right now we'll be extremely lucky to see other studies conducted without corporate assistance. 

 

The US is experiencing a huge brain drain right now as researchers are leaving the United States to find funding. Congress needs to pull their head out of there @$$ and restore the National Institutes of Health (NIH) funding. 

Edited by Bryan_S, 03 December 2014 - 08:45 AM.

[VERITAS INCORRUPTUS]

Human physiology is so complex and certainly so is all that surrounds the complexity of NAD+ enhancement.  Within all that and within the information processed at hand has been the impetus for a current look at the methods that look most readily viable and this as well pertains to cost of course.  Hence my evaluations.

 

Within that which regards hepatic issues, which trust I have well considered on all counts, this is why avoiding first pass entirely is desired as within that it can be done to some degree with sublingual and i.n., and as I always hint to, though impractical, injection (simply as to a real curiosity as to just what high doses of injected NAD+ can do, as well as other conjugates, such as NR).  And this is why with oral supplementation, in belief all the conjugates may suffer from complete of near complete degradation in the gut and and subsequent first pass liver metabolism (if any of the conjugate even survived the gut) to look to go with NAM and NA as primary, among other suggestions supported by all evidence.  I can get into all the physiological complexities and intricacies, and make several hypothesis, but it seems prudent to go with what seems most established and apply lean to even a bit of the KISS mode (to some reasonable degree)

 

Really what is best needed is a simple comprehensive study on ALL substrates first and foremost as to basic pharmacokinetics (and go from there).  It's sad it has taken so long and will still be lacking within that with truly well targeted studies the main core issues could be ascertained very quickly and with a modest amount of money.   Within that never seems to happen is the reason I engage the type of research I do; to create some form of acceleration of the process of true and practical merit.  It may not be wholly optimal, but that's of course simply due to not having any funds, not for lack of true, progressive, insightful, and meaningful practical direction.

 

At a drop of the hat a product that is so far superior to a simple NR product is feasible, but these things take a lot of money to make practical as well.  Within this, cost effectiveness always has to be a high consideration of course as well.  If some 'angel humanitarian beneficiary' dropped out of the sky to fund such I would gladly put together a product that would be beyond anything anyone here is even aware could be as to efficacy and cost effectiveness, and one could conduct the true scientific studies to demonstrate such.  I'd certainly need not to even take a penny for personal gain - it's not about money (in the sense of 'monetary gain') - it's all about science and progress - betterment to humanity.  Everything in TLR goes back into scientific research and new items - all toward these goals, that's the Project.

 

There could of course never be a perfect product or perfect means of enhancement,... but perhaps there can be perfect intention.

 

Preach Out - Peace!

 

 

Edited by VERITAS INCORRUPTUS, 03 December 2014 - 02:38 PM.

[oppenheimer82]

@ veritas, will you guys also be selling itpp in the near future?

[M-K]

Someone, please tell us if Veritas says something new. I presume English is not his native language, but it just isn't worth the effort to wade through.

[Vastmandana]

No...repeat...with request for Angel investors for a magical secret something better than NR

Edited by Vastmandana, 04 December 2014 - 12:58 AM.

[ikon2]

 

 

http://molpharm.aspe...073916.full.pdf

 

Have a Nice Day 

 

I read the entire paper thanks for the link. On specific tissue cultures they showed impressive results no doubt. [...]

 

However search the document you gave me for "rapid degradation by hepatocytes." They also quote the aforementioned study by (Broetto-Biazon et al., 2008) where they learned that the liver rapidly degraded NAD into its constituents (98% at 8 minutes). Mind you they are not talking about digestion of NAD, that is another hurdle for discussion in another thread that you are welcome to start.

 

 

Forgive me if my comment is ignorant but would creating a liposomal NAD+ preparation be as/more effective than NR as a precursor?  Or in this case, a "protected from enzymatic attack" NAD+ delivery system?  This seems to work well for other compounds easily degarded by digestion before they reach their target cells, such as Glutathione.

 

[Edit: trimmed redundant quotation -Michael]

Edited by Michael, 05 February 2015 - 08:25 PM.

[Bryan_S]

 

Forgive me if my comment is ignorant but would creating a liposomal NAD+ preparation be as/more effective than NR as a precursor?  Or in this case, a "protected from enzymatic attack" NAD+ delivery system?  This seems to work well for other compounds easily degarded by digestion before they reach their target cells, such as Glutathione.

 

 

I've heard of Liposomes used with an injection method to deliver drugs directly to the cell membrane for absorption. From what I've read it melts into the target cell membrane and the contents are released in the cell. For those who don't know what we're talking about sensitive drug cargos can be encapsulated in a lipid membrane for direct cell delivery. I'm of course oversimplifying. See Liposome link For one I'm reluctant to perform daily injections to maintain high NAD levels. I do however think your idea has merit and it avoids 3 barriers (Digestion, possibly the liver and the extracellular nucleotide catabolizing enzymes). The sterilization and preparation alone sounds like a monumental task. I have to be honest it sounds expensive and not totally without risk.

 

ikon2 I think there are a few in this crowd who would think this was a reasonable solution. I pretty much want something I can put in my mouth and swallow. I think if the price of NR were lower we wouldn't be having this discussion but here we are exploring the scary alternatives.

Edited by Bryan_S, 05 December 2014 - 09:13 PM.

[Vastmandana]

If the price were lower it would change the discussion. Towards this end I assume/hope the currently patented process can/will be scaled up as demand grows which lowers costs. Simultaneous I'm sure other means of manufacture are being explored towards this end

Edited by Vastmandana, 05 December 2014 - 09:24 PM.

[meth_use_lah]

If the price were lower it would change the discussion. Towards this end I assume/hope the currently patented process can/will be scaled up as demand grows which lowers costs. Simultaneous I'm sure other means of manufacture are being explored towards this end

 

Niagens cost was 17-18$ before Sinclairs study was published, it's not that expensive for them to manufacture they are just making bank.

[Bryan_S]

I've been poking around looking at Weill Cornell Medical College NAD boosting research. These guys are at the forefront of NAD research generating a lot of results on this topic. Everyone will remember their most resent data on "Vitamin Supplement Successfully Prevents Noise-Induced Hearing Loss". They are currently running a $322,050 study which will conclude next year URL Study Link

 

One statement from one of their studies caught my eye, "The compound, called nicotinamide riboside (NR) — a natural NAD+ precursor found in foods like milk — as well as other NR derivatives have already been proven to protect against cell death and axonal degeneration in cultured cells and in models of spinal cord injury. In 2007, the authors reported results of laboratory experiments finding that NR can increase NAD+ concentrations as high as 270 percent when compared with untreated control cells. No other known agent has been shown to achieve these types of increases in cells." Researchers Explore New Ways to Prevent Spinal Cord Damage" 

 

So I began searching for the all compounds within the scope of their research and found another study inferring a 270 percent NAD increase and this study listed some compounds involved in the study. "Moreover, nicotinamide riboside, nicotinic acid riboside, O-ethylnicotinate riboside, O-methylnicotinate riboside, and several N-alkyl derivatives have also been developed that markedly increase NAD+ con- centrations (from 120% to 270%) in several mammalian cell lines [391]" Mimicking Calorie Restriction: A Strategy for Improving Healthy Aging and Longevity

 

From 120% to 270% really. They did name a few substances and at least 2 of them are available as previously discussed in this thread. 

 

Nicotinamide riboside: we already know about this one and it is readily available.

 

 

Nicotinic acid riboside: we just started to investigate this one 

 

 

O-ethylnicotinate riboside: Can't find much on this one Search link

 

O-methylnicotinate riboside: Can't find much on this one Search link

 

 

[mikey]

For NAD+ enhancement, niacinamide and ribose (less important to supplement, as may not be rate limiting as to normal endogenous supply) are the way to go, within best taking low dose through the day.

In the end it all goes through niacinamide, within this pathway, so niacin in the end will only be effectively yielding niacinamide indirectly for your purposes anyway.  With some liver stress as to the amidation so required (though as long as it is not SR it will not overburden the liver in any significant way; this is why as so explained prior only SR will yield a constant taxation of this high affinity/low capacity pathway, if such is at all accurate - RE: http://www.pharmacol...-hepatotoxicity )

 

Within that, they key is as well not to overload the conversion pathway to NAD+ as that will engender greater levels of niacinamide available for SIRT1 inhibition - obviously undesirable.

(to clarify if any confusion here, anything that gets one to excessive niacinamide, which has to happen to get to NAD+, will engender the SIRT1 inhibition)

 

The way to 'top it off' effectively, above this, within saturation of the pathway, and the need to avoid the aforementioned excessive levels of NAM, is to supplement with pure NAD+ (I think I heard someone say this before )

This is best done in a manner that bypasses the gut, as NAD+ may survive the gut to some degree (it does have some reasonably stability in acidic media), but certainly bypassing the gut, and first pass as well, would be most optimal.  That leaves injections (best, but less viable for most), intranasal, and subligual/buccal (as prior stated).  

 

NR in essence as to supplemental use is simply overpriced SR-niacinamide/(ribose) (as likely the ribose is in adequate supply, though perhaps it assists).  It is as seemed noted prior what Logic pointed out fully hydrolyzed in a SR fashion, so all seems pretty simple as to that. A lot to pay for sustained release of very inexpensive substrates.

 

Notably, I am aware of an entity that can make an orally bioavailable SR niacinamide/ribose/NAD+ product, if enough people have some heavy interest.  This entity already has a proprietary established technology to achieve this.  Likely be quite a bit more of course that just going by the aforementioned recommendation, albeit somewhat more effective and easy for compliance.

 

Anyway, again it appears NR itself can be effectively (and far more economically) mimicked by SR-niacinamide, or simply taking niacinamide throughout the day, perhaps best with some ribose, which certainly could not hurt, is cheap and available enough - a 'better safe than sorry' means to ensure an adequate supply.

 

Stated all this more or less before, but reiterating, in case anyone wishes to make a clear argument against it.

 

The problem with taking niacinamide throughout the day is that it is pretty much gone from the bloodstream about 90 minutes after you take it, unless it is a true SR form.

 

This is where I buy pharmaceutical-grade SR niacinamide, sold as Enduramide:

http://www.endur.com...ur-amide-500-mg

 

I know this product is of the highest quality, because it is being used in a human study at UC Irvine as a potential cure for Alzheimer's.

 

Niacinamide was shown to successfully treat the mouse version of Alzheimer's, so the Alzheimer's Association quickly initiated a human study at UC Irvine with niacinamide, as Enduramide.

 

I have been taking 3 x 500 mg before bedtime because niacinamide has a benzodiazepine-Iike effect. (Please see attachment.)

 

It has a perceptible effect on improving the length of sleep for me.

Attached Files

•  Niacinamide as a brain constituent with benzodiazepine-like actions_Page_1.jpg   424.14KB   1 downloads
•  Niacinamide as a brain constituent with benzodiazepine-like actions_Page_2.jpg   481.37KB   1 downloads
•  Niacinamide as a brain constituent with benzodiazepine-like actions_Page_3.jpg   405.33KB   1 downloads

Edited by mikey, 29 December 2014 - 01:23 AM.

[Ark]

picamilon boosts NAD levels in the brain, I wonder if it does the same elsewhere across the body?

[osris]

According to ChatGPT:
 

"Nicotinic acid (NA), also known as niacin or vitamin B3, is considered a more direct precursor of nicotinamide adenine dinucleotide (NAD+) compared to nicotinamide riboside (NR) or nicotinamide mononucleotide (NMN). NA can be converted into NAD+ through a relatively simple pathway involving fewer enzymatic steps [7].

 

NR and NMN, on the other hand, require additional enzymatic reactions to be converted into NAD+ [6][8][10]. NR is first converted into NMN by the enzyme NR kinase, and then NMN is further converted into NAD+ by NMN adenylyltransferase [6][10]. The conversion of NR and NMN to NAD+ involves more complex metabolic processes compared to the direct conversion of NA to NAD+ [7].

 

It's worth noting that while NA may be a more direct precursor of NAD+, the effectiveness of NAD+ elevation through NA supplementation alone might be limited due to potential side effects such as flushing, which can be attributed to the release of prostaglandins [1][2]. In contrast, NR and NMN supplementation have been shown to effectively increase NAD+ levels in various preclinical and clinical studies [4][9]."

[MikeDC]

Wrong. Niacin is on the same level as NAM. AI is still just a hype.

[osris]

NA takes a longer pathway to NAD than NAM does.

NA takes a longer pathway to NAD than NAM does.

[CynthesisToday]

 

According to ChatGPT:
 

"Nicotinic acid (NA), also known as niacin or vitamin B3, is considered a more direct precursor of nicotinamide adenine dinucleotide (NAD+) compared to nicotinamide riboside (NR) or nicotinamide mononucleotide (NMN). NA can be converted into NAD+ through a relatively simple pathway involving fewer enzymatic steps [7].

 

NR and NMN, on the other hand, require additional enzymatic reactions to be converted into NAD+ [6][8][10]. NR is first converted into NMN by the enzyme NR kinase, and then NMN is further converted into NAD+ by NMN adenylyltransferase [6][10]. The conversion of NR and NMN to NAD+ involves more complex metabolic processes compared to the direct conversion of NA to NAD+ [7].

 

It's worth noting that while NA may be a more direct precursor of NAD+, the effectiveness of NAD+ elevation through NA supplementation alone might be limited due to potential side effects such as flushing, which can be attributed to the release of prostaglandins [1][2]. In contrast, NR and NMN supplementation have been shown to effectively increase NAD+ levels in various preclinical and clinical studies [4][9]."

 

Unless you include the actual cites in a searchable format, these "According to ChatGPT" entries are pretty useless. What is the searchable cite for [4], etc.?

 

There is evidence that ChatGPT fabricates citations. Here is one example: https://www.scienced...165178123002846 (2023) From the abstract: "We describe our March 2023 exchange with ChatGPT, which generated thirty-five citations, two of which were real. 12 citations were similar to actual manuscripts (e.g., near-matched title with incorrect author lists, journals, or publication years) and the remaining 21, while plausible, were in fact a pastiche of multiple existent manuscripts."

 

Here is a recent review paper (which includes searchable cites) including a table for human results on various NAD precursors: "NAD metabolism: Role in senescence regulation and aging" (2023) DOI: 10.1111/acel.13920

 

Here is another recent (2022) review paper (including searchable cites). Section 14 "Which Precursor is Better" says "Currently, there are no studies that directly compare the efficiency of the different precursors to conclude which of the NAD+ boosters has the best therapeutic prospects." "Current Uncertainties and Future Challenges Regarding NAD+ Boosting Strategies" https://doi.org/ 10.3390/antiox11091637

 

Various components of the NAD cycle (NAD, NMN, NR) and precursors exist in different amounts and different concentrations in different tissues and cell components. Here is a mouse study (because you can chop up a mouse and measure things you can't in a human) that illustrates via isotope tracer methods: "Quantitative Analysis of NAD Synthesis-Breakdown Fluxes" (2018)  https://doi.org/10.3390/metabo12070630. Some really useful diagrams showing transport of different metabolites (NA,  Tryptophan and NAM) within and between tissues (Figure 6). Figure 5 shows the distribution of NAD metabolites after isotopic infusions of tryptophan, nicotinic acid, NAM, and NAD(H). If you ask the question "which is best" you have to say for what to get an answer (in mice).

 

​And then there's questioning the whole question of "which is best"... There seems to be evidence for an evolutionary purpose for all of the precursors. See this review (with searchable cites): "NAD+ Precursors: A Questionable Redundancy" (2022) https://doi.org/10.1...met.2018.03.018 "Here, we discuss the possibility that the conservation of all of these biosynthetic pathways through evolution occurred because the different NAD+ precursors might serve specialized purposes."

 

You don't get any of the above by reading what ChatGPT said and you can't follow the cites for the ChatGPT result provided. It fails to consider, for example, that different enzymes have different activation rates so a reaction with two enzymes is not necessarily slower than one with one enzyme in its pathway as implied by this statement from ChatGPT "NR and NMN, on the other hand, require additional enzymatic reactions to be converted into NAD+"

[CynthesisToday]

Sorry... some how got a double post. Emptied the second post of the same thing.

 

Edited by CynthesisToday, 21 July 2023 - 01:11 AM.

[osris]

 

There is evidence that ChatGPT fabricates citations. Here is one example: https://www.scienced...165178123002846 (2023) From the abstract: "We describe our March 2023 exchange with ChatGPT, which generated thirty-five citations, two of which were real. 12 citations were similar to actual manuscripts (e.g., near-matched title with incorrect author lists, journals, or publication years) and the remaining 21, while plausible, were in fact a pastiche of multiple existent manuscripts."

 

 

 

Regarding my post that you are replying to, I checked that the citations that ChatGPT provided were correct before I quoted ChatGPT's reply to my query.