2255 replies to this topic

[midas]

 

What about make a topic to speak in a more general way about NAD+ ?  because i think we still need to consider an holisitic approach to speak about that theme

 

Good idea as there are a number of ways of increasing NAD+ that the NR disciples here don't want in the bible!  

 

BL = Beta-Lacaphone

1st mention here?:

http://www.longecity...beta-lacaphone/

 

Toms  Blog:

http://www.beta-lapachone.com/

 

 

BL is a mute subject in this topic because it is unavailable to the public......I really do not see why it should be relevant as far as the NR topic goes.

Tom Andre seems to be obsessed with it, which is fine, maybe he should start his own thread on the subject instead of inserting it on this thread at every opportunity...
 

[Alex_G]

thanks Logic.

and I agree with Tom on starting a NAD+ topic.

[Logic]

 

 

What about make a topic to speak in a more general way about NAD+ ?  because i think we still need to consider an holisitic approach to speak about that theme

 

Good idea as there are a number of ways of increasing NAD+ that the NR disciples here don't want in the bible!  

 

BL = Beta-Lacaphone

1st mention here?:

http://www.longecity...beta-lacaphone/

 

Toms  Blog:

http://www.beta-lapachone.com/

 

 

BL is a mute subject in this topic because it is unavailable to the public......I really do not see why it should be relevant as far as the NR topic goes.

Tom Andre seems to be obsessed with it, which is fine, maybe he should start his own thread on the subject instead of inserting it on this thread at every opportunity...
 

 

 

 

I think I've just been punched with a NR bible!  

My humble apologies for blaspheming in your holy NR book!   
If I've increased your blood pressure,  you may want to look into Telmisartan!   

 

Seriously:
Note that I quoted Tom as saying exactly what you recommend! 

 

I wouldn't be so anti NR if it was reasonably priced  ....Midas...

[Bryan_S]

There are many roads to Rome. I don't discount any of them, however some are more direct paths to NAD+ boosting than others. Since NAD levels are in part controlled by a variety of feedback loops it's possible to re-stack the deck in your favor and I concede to that. As far as the NAD precursor path is concerned this is the most direct NAD intervention currently on the table and the central topic of this thread. It is also relatively benign (NAD boosting with its precursors) and the least likely approach to do harm because we've seen over 70-years of research and human trials with these B3 supplements. Now I'm not an alarmist and these other NAD boosting paths may hold promise but I'm not going to recommend a path with scant research, support and limited history.

 

I keep track of this threads traffic and on average 140 people per day visit here researching the topic of nicotinamide riboside, so we need to stay true to our readership. A few of you are serious researchers and not shy about posting and you found your way here because this topic interests you. Just try and keep in mind there are many, many silent thread lurkers browsing here to read about nicotinamide riboside.

 

To support this readership we discuss the broad medical benefits of NAD boosting, the proven NAD precursors which NR is apart of and the surrounding molecular and epigenetic changes that stem from supplementation. We can mention alternatives but don't overwhelm us.

 

Now no one here is trying to subdue the alternatives. You can still find your posts about them through out this thread. My contention is when several of you start heading down these alternate paths I get complaints about this thread going off topic. I also have general safety concerns on some of the bleeding edge alternatives and can't in good conscience recommend them. So if you feel you need a thread to expand out on the alternate boosting topics I've encouraged that here from the very beginning, just don't swamp this topic. So if you ever need to review what's appropriate in this forum please review the first thread post. 

[midas]

 

 

 

 

I wouldn't be so anti NR if it was reasonably priced  ....Midas...

 

 

I feel you.....it isn't cheap for me to buy it from the UK either.......Purchase price, shipping and then import taxes pretty much double the USA cost.

 

By the way, it was not me who marked down your last post.
 

[Tom Andre F. (ex shinobi)]

 

 

What about make a topic to speak in a more general way about NAD+ ?  because i think we still need to consider an holisitic approach to speak about that theme

 

Good idea as there are a number of ways of increasing NAD+ that the NR disciples here don't want in the bible!  

 

BL = Beta-Lacaphone

1st mention here?:

http://www.longecity...beta-lacaphone/

 

Toms  Blog:

http://www.beta-lapachone.com/

 

 

BL is a mute subject in this topic because it is unavailable to the public......I really do not see why it should be relevant as far as the NR topic goes.

Tom Andre seems to be obsessed with it, which is fine, maybe he should start his own thread on the subject instead of inserting it on this thread at every opportunity...
 

 

 

Im not obsessed with it.. I m just a pure passionate anti aging research like everyone here

 

And I dont think NR is the holy grail we are looking for and the evidence given by chromadex seems to confirm it.. The ratio turn back very fast to normal and the only strategy given reading all the pages here seems to be feed ourselve even more forgiven possible serious side effect. Also, still no single study showing life extension using NR or any precursor because i think this effect is not enough, so i come back to an holistic approach and molecule which control the NQO1 gene are very limited, at least i know only the one midas think im obessed with..

 

Sorry for the off topic, i will start another thread then where discution could take the NAD+ target in a more large way

 

 

 

 

[Logic]

I feel you.....it isn't cheap for me to buy it from the UK either.......Purchase price, shipping and then import taxes pretty much double the USA cost.
 
By the way, it was not me who marked down your last post.

  I'm glad to know you took my teasing so well midas.

 

If Tom doesn't start a new thread on alternate NAD+ boosting methods, I will Bryan_S.

The previous one WAS closed with a link to HERE btw..!?

To those who want to believe they have found the fountain of youth in a single substance and thus save themselves the trouble (or impossibility?) of independent research and conclusions:  

Complaining about other research and alternate means to the same end here!?!! Shame on you!

Please stay TF away from the Alternate NAD+ boosting methods thread!

 

http://www.anti-agin...-interventions/

Will get you started IF you have the inclination and ability, but won't tell you why you age.

For that you will have to figure out why NF-kB and co. increase with AGE.  

[stefan_001]

Wow a NR war :-) .... Relax...!

[Bryan_S]

If Tom doesn't start a new thread on alternate NAD+ boosting methods, I will Bryan_S.

The previous one WAS closed with a link to HERE btw..!?

To those who want to believe they have found the fountain of youth in a single substance and thus save themselves the trouble (or impossibility?) of independent research and conclusions:  

Complaining about other research and alternate means to the same end here!?!! Shame on you!

 

Its all good Logic and we go back a few posts and you know I respect your opinions.

 

I don't think NR is the end all molecule either. Many have seen the sideline topics I post on and I contribute in other areas as well. I have an interest in Cellular senescence and the related senolytics drugs to help clear out Zombie cells. I don't speak openly about this but last year after a 4-day trial I'm here to say some care needs to be observed when experimenting with some of these bleeding edge treatments. I think there is some real potential for doing good by clearing out senescence cells but you can make yourself sick as I did. So I'm in a watch, read and see mode as more progress in them is made and solid treatment plans are devised.

 

I'm also keen to read developments in cell signaling proteins to bring back to life to our aging stem cells. I don't want to be one of those individuals who dies with a 30-year stem cell supply still unused. There is a whole new related horizon of epigenetics opening up and this fascinates me that we can potentially reactivate dormant genes of youth. For the first time I think we can begin to grasp the fundamentals of what genes get down-regulated with age and bring back their function. This is at the crux of why our regenerative abilities begin to fail with age. We stand a chance of ameliorating many aspects of aging with the existing tools already found within our own bodies and a few key molecules to activate these genes.

 

Sidelining this interest I see Epigenetic and disease targets by polyphenols as an entry point into this realm. Some of you know of my interest in Honokiol and it parallels NR in its ability to stimulate SIRT3. It also has direct antiangiogenic and antitumor properties. It has been shown to reduce cardiac hypertrophy and relax smooth muscle tissue. It also brings about benzo like calming properties. It's believed all this is happening at molecular level by activating conserved pathways within our genome. There are other plant polyphenols that are also exciting and much of our medicine started with plants but I diverge.

 

To be true to this thread as moderator I have to bring this Off-Topic rant back to NR and to that end I see a huge crossover from the NAD boosting strategy we all follow into many health frontiers and pathways mentioned above. Bottom line we have a whole array of NAD consuming enzymes that simple ATP will not fuel. These include but are not limited to the PARP's and sirtuins. So I'm not NR centric, I see NR as one spoke in the wheel and it's a player among several treatment paths that are emerging to treat our declining metabolism and cellular upkeep that brings on this condition we call aging.

Edited by Bryan_S, 04 February 2016 - 02:58 AM.

[Logic]

Its all good Logic and we go back a few posts and you know I respect your opinions.
 
I don't think NR is the end all molecule either. Many have seen the sideline topics I post on and I contribute in other areas as well. I have an interest in Cellular senescence and the related senolytics drugs to help clear out Zombie cells. I don't speak openly about this but last year after a 4-day trial I'm here to say some care needs to be observed when experimenting with some of these bleeding edge treatments. I think there is some real potential for doing good by clearing out senescence cells but you can make yourself sick as I did. So I'm in a watch, read and see mode as more progress in them is made and solid treatment plans are devised.
 
I'm also keen to read developments in cell signaling proteins to bring back to life to our aging stem cells. I don't want to be one of those individuals who dies with a 30-year stem cell supply still unused. There is a whole new related horizon of epigenetics opening up and this fascinates me that we can potentially reactivate dormant genes of youth. For the first time I think we can begin to grasp the fundamentals of what genes get down-regulated with age and bring back their function. This is at the crux of why our regenerative abilities begin to fail with age. We stand a chance of ameliorating many aspects of aging with the existing tools already found within our own bodies and a few key molecules to activate these genes.
 
Sidelining this interest I see Epigenetic and disease targets by polyphenols as an entry point into this realm. Some of you know of my interest in Honokiol and it parallels NR in its ability to stimulate SIRT3. It also has direct antiangiogenic and antitumor properties. It has been shown to reduce cardiac hypertrophy and relax smooth muscle tissue. It also brings about benzo like calming properties. It's believed all this is happening at molecular level by activating conserved pathways within our genome. There are other plant polyphenols that are also exciting and much of our medicine started with plants but I diverge.
 
To be true to this thread as moderator I have to bring this Off-Topic rant back to NR and to that end I see a huge crossover from the NAD boosting strategy we all follow into many health frontiers and pathways mentioned above. Bottom line we have a whole array of NAD consuming enzymes that simple ATP will not fuel. These include but are not limited to the PARP's and sirtuins. So I'm not NR centric, I see NR as one spoke in the wheel and it's a player among several treatment paths that are emerging to treat our declining metabolism and cellular upkeep that brings on this condition we call aging.

My rant wasn't aimed at you Brian_S
Rather @ the people complaining to you when anything besides NR is mentioned in the thread. 

You have let this thread go ...'off topic' according to some, on numerous occasions.

 

I don't know that I want to comment on the other points in your post here, but SIRT3 is relevant, so would like to mention HGW and PQQ:

http://www.longecity...ndpost&p=565043

 

 

Edited by Logic, 04 February 2016 - 08:31 AM.

[Bryan_S]

That's all good but what I'm attempting to do is draw some of you out. You guys want a full fledged NAD boosting discussion? I'm game but I'm only good for one or 2 well thought out posts per day because I hold a job and can only dedicate so many hours per day to research and fact checking my opinions. So just to give this attempt a chance to draw some of you out let me comment on Tom's post to get some discussion going.

 

 

 

And I dont think NR is the holy grail we are looking for and the evidence given by chromadex seems to confirm it.. The ratio turn back very fast to normal and the only strategy given reading all the pages here seems to be feed ourselve even more

 

Maybe not the Holy Grail. One point Tom makes is if you discontinue NR NAD levels return to your previous levels in a matter of time. So from this perspective you are not fixing the problem. He goes on to say;

 

 

 

Also, still no single study showing life extension using NR or any precursor because i think this effect is not enough

 

I can find no problem in that reasoning and no life extension studies have "yet" demonstrated a lifespan increase.

 

Except we do find raising NAD levels can increase the survival of stressed or injured neurons and cardiac tissue. And by increasing NAD levels, a cells ability to maintain and repair its microtubules (cytoskeleton) increases dramatically. We could also include the the ability of NAD dependent enzymes in the endoplasmic reticulum and they are responsible for maintaining a number of protein related functions. Now mind you I'm just scratching the surface but I would be remiss if I didn't mention the results of raising NAD levels in mice prone to liver cancer. Some might say but this wasn't humans and I would turn around and say what about non-melanoma skin cancers. So these results don't necessarily indicate a lifespan increase but healthspan certainly and for some of us that could increase lifespan.

 

Now can the alternatives fix the gradual decline of NAD which seems to be tied to the gradual reduction of NAMPT which recycles the residual nicotinamide after the elections have been depleted from the NAD? What causes this decline? My hunch (opinion) is it's being downregulated somewhere in the epigenome and this is where the fix likely hides. So I agree NR supplementation isn't a fix for this problem but by the same token can these alternatives produce as much or more NAD to maintain NAD's downstream functions that are dependent on having an adequate pool to function properly?

 

So there is the question.

 

This is a forum about NAD boosting and if there is a fix to this leaky bucket scenario, where we can fix and keep up with with our NAD demand without constant NR supplementation let's have that discussion! We are all in the same boat and NR is a cost burden to many. ChromaDex is our drug dealer and if we stop taking it we go back to the way we were.

 

As I've said before some of these Non-NAD-Precurcer regiments aren't proven and some have cytotoxic effects which need to be publicly disclosed upfront. I mention this because Beta-Lacaphone is one such agent. I've read it can increase the short lifespans of mice longer than calorie restriction but at what cost? A short lived mammal isn't going to have to worry about accumulated DNA damage many years down the line but I will. So if you want to tell us about something that beats the pants off the B3's for correcting this gradual NAD depletion I'm willing to entertain research that makes this point but keep it real because some of these approaches aren't ready for primetime yet. 

Edited by Bryan_S, 04 February 2016 - 11:03 AM.

[Tom Andre F. (ex shinobi)]

That's all good but what I'm attempting to do is draw some of you out. You guys want a full fledged NAD boosting discussion? I'm game but I'm only good for one or 2 well thought out posts per day because I hold a job and can only dedicate so many hours per day to research and fact checking my opinions. So just to give this attempt a chance to draw some of you out let me comment on Tom's post to get some discussion going.

 

 

 

And I dont think NR is the holy grail we are looking for and the evidence given by chromadex seems to confirm it.. The ratio turn back very fast to normal and the only strategy given reading all the pages here seems to be feed ourselve even more

 

Maybe not the Holy Grail. One point Tom makes is if you discontinue NR NAD levels return to your previous levels in a matter of time. So from this perspective you are not fixing the problem. He goes on to say;

 

 

 

Also, still no single study showing life extension using NR or any precursor because i think this effect is not enough

 

I can find no problem in that reasoning and no life extension studies have "yet" demonstrated a lifespan increase.

 

Except we do find raising NAD levels can increase the survival of stressed or injured neurons and cardiac tissue. And by increasing NAD levels, a cells ability to maintain and repair its microtubules (cytoskeleton) increases dramatically. We could also include the the ability of NAD dependent enzymes in the endoplasmic reticulum and they are responsible for maintaining a number of protein related functions. Now mind you I'm just scratching the surface but I would be remiss if I didn't mention the results of raising NAD levels in mice prone to liver cancer. Some might say but this wasn't humans and I would turn around and say what about non-melanoma skin cancers. So these results don't necessarily indicate a lifespan increase but healthspan certainly and for some of us that could increase lifespan.

 

Now can the alternatives fix the gradual decline of NAD which seems to be tied to the gradual reduction of NAMPT which recycles the residual nicotinamide after the elections have been depleted from the NAD? What causes this decline? My hunch (opinion) is it's being downregulated somewhere in the epigenome and this is where the fix likely hides. So I agree NR supplementation isn't a fix for this problem but by the same token can these alternatives produce as much or more NAD to maintain NAD's downstream functions that are dependent on having an adequate pool to function properly?

 

So there is the question.

 

This is a forum about NAD boosting and if there is a fix to this leaky bucket scenario, where we can fix and keep up with with our NAD demand without constant NR supplementation let's have that discussion! We are all in the same boat and NR is a cost burden to many. ChromaDex is our drug dealer and if we stop taking it we go back to the way we were.

 

As I've said before some of these Non-NAD-Precurcer regiments aren't proven and some have cytotoxic effects which need to be publicly disclosed upfront. I mention this because Beta-Lacaphone is one such agent. I've read it can increase the short lifespans of mice longer than calorie restriction but at what cost? A short lived mammal isn't going to have to worry about accumulated DNA damage many years down the line but I will. So if you want to tell us about something that beats the pants off the B3's for correcting this gradual NAD depletion I'm willing to entertain research that makes this point but keep it real because some of these approaches aren't ready for primetime yet. 

 

Hi Bryan,

 

First Im just saying that we need to take this topic in an holistic way because B3s action still limited, and we already have a lot of B3s in our diet.. And still age here. NR is of course in a better position in diagram from NAD+ but still not that impressive. We pointed out a lot of study showing a lot of biochemical reaction increased with age and still here while supplementing with NR.

I dont say again NR is ineffective, and the NAD+ is very important of course. I just say for instance resveratrol do a lot of "such actions" and still fail to increase lifespan.. Same for PQQ, and worst for Acid alpha lipoic wich is good in many research in vitro but very bad in vivo (decrease lifespan), same for TA65 > decrease lifespan too..

 

Thats why indeed we need to be careful. I never seen any study showing BL was toxic in normal cell line, even the most recent study you point out conclude: "beta-Lapachone killed cells in a tumorselective manner" and increase lifespan in mamals is what im looking for most often.

 

I will come up deeper into that topic

 

 

[Bryan_S]

Axon Self-Destruction: New Links among SARM1, MAPKs, and NAD+ Metabolism

 

Wallerian axon degeneration is a form of programmed subcellular death that promotes axon breakdown in disease and injury. Active degeneration requires SARM1 and MAP kinases, including DLK, while the NAD+ synthetic enzyme NMNAT2 prevents degeneration. New studies reveal that these pathways cooperate in a locally mediated axon destruction program, with NAD+ metabolism playing a central role. Here, we review the biology of Wallerian-type axon degeneration and discuss the most recent findings, with special emphasis on critical signaling events and their potential as therapeutic targets for axonopathy.

 

http://www.cell.com/...(15)01125-3.pdf

 

This review was just released today and nicotinamide riboside gets a mention.

 

Update: http://www.sciencedi...896627315011253

Edited by Bryan_S, 07 February 2016 - 08:44 AM.

[Bryan_S]

Hi Bryan,

 

First Im just saying that we need to take this topic in an holistic way because B3s action still limited, and we already have a lot of B3s in our diet.. And still age here. NR is of course in a better position in diagram from NAD+ but still not that impressive. 

 

Tom I'm not sure you read the therapeutic areas where NAD boosting has already proven itself.

 

 injured neurons and cardiac tissue

 repair its microtubules (cytoskeleton) increases dramatically

 NAD dependent enzymes in the endoplasmic reticulum 

 NAD levels in mice prone to liver cancer

 non-melanoma skin cancers.

 

NAD boosting is the whole point of this thread. This thread is about extending healthspan and no our diets don't have enough B3 in them to bring about these benefits. The point I made several posts ago was our cells slowly begin to mismanage the B3 we do consume as we grow older. When we are young we do a pretty good job of recycling the available B3 from our diets and this ability declines with age leading to a NAD deficit.

 

Now as you browse the forums on LongeCity you will find the latest life extension topics as our readers follow the trend of the day. Some of these topics fade away pretty fast and the more promising ones last the test of time. I like to think NR and NAD boosting is one of those that will stick around for awhile because it addresses a number health issues stemming from NAD depletion which if you live long enough will grip you as well. If the benefits of NAD+ don't impress you I don't know what you are looking for because nothing else at this time has this many downstream beneficial effects.

 

So if you want to lay down and compare point by point the research on these alternatives where NAD boosting research is already producing results I'm pretty sure this has anything you can bring to the table already beat. I'm not saying NR or NAD boosting in general is the end all solution but it's here today, relatively safe and has already racked up an impressive resumé.

Edited by Bryan_S, 05 February 2016 - 09:04 AM.

[Tom Andre F. (ex shinobi)]

 

Hi Bryan,

 

First Im just saying that we need to take this topic in an holistic way because B3s action still limited, and we already have a lot of B3s in our diet.. And still age here. NR is of course in a better position in diagram from NAD+ but still not that impressive. 

 

Tom I'm not sure you read the therapeutic areas where NAD boosting has already proven itself.

 

 injured neurons and cardiac tissue

 repair its microtubules (cytoskeleton) increases dramatically

 NAD dependent enzymes in the endoplasmic reticulum 

 NAD levels in mice prone to liver cancer

 non-melanoma skin cancers.

 

NAD boosting is the whole point of this thread. This thread is about extending healthspan and no our diets don't have enough B3 in them to bring about these benefits. The point I made several posts ago was our cells slowly begin to mismanage the B3 we do consume as we grow older. When we are young we do a pretty good job of recycling the available B3 from our diets and this ability declines with age leading to a NAD deficit.

 

Now as you browse the forums on LongeCity you will find the latest life extension topics as our readers follow the trend of the day. Some of these topics fade away pretty fast and the more promising ones last the test of time. I like to think NR and NAD boosting is one of those that will stick around for awhile because it addresses a number health issues stemming from NAD depletion which if you live long enough will grip you as well. If the benefits of NAD+ don't impress you I don't know what you are looking for because nothing else at this time has this many downstream beneficial effects.

 

So if you want to lay down and compare point by point the research on these alternatives where NAD boosting research is already producing results I'm pretty sure this has anything you can bring to the table already beat. I'm not saying NR or NAD boosting in general is the end all solution but it's here today, relatively safe and has already racked up an impressive resumé.

 

 

Bryan,

 

Sorry but Im not sure the way you read my last post or how you could say I think NAD+ is not that important because we all know it is critical as the ratio NAD+ /NADH is also critical, and i point that also in my blog everywhere i can since it also regulate sirtuins for instance..

 

However my point is just that NR studies show it break down very fast and as per your recomandation we should supplement ourselve maybe twice a day to have any therapeutic effect, means after only couple hours maybe all the benefit is lost.. Also, no study show there is not the same effect that the one you point with classic B3: with age maybe the NR is less and less absorbed also + possible hhttp://www.longecity...0956abbituation effect.

 

Its look like fill a pierced bottle with water for me if we dont take this in a more large way than just supplement ourselve with NR.

 

But again NAD+ level and the ratio NAD+/NADH are criticial, the question is how to get back this to young level in a permanent manner

 

[Kirito]

One thing commonly overlooked is the effects of CD38 on NAD+

 

5.1. CD38 and NAD Metabolism

As discussed above, CD38 is an enzyme that has been implicated on the generation of the second messenger cyclic- ADP-ribose (cADPR) [12–26]. However, its main enzymatic activity is the hydrolysis of NAD to nicotinamide and ADPR. We postulated that CD38 is the major NADase in mammalian cells and that it regulates intracellular NAD and nicotinamide levels. In fact, our recent publications indicate that in CD38 deficient mice, tissue levels of NAD are several folds higher than in wild type animals [17]. In addition, we observed that NADase activity is essentially absent in several tissues from CD38 deficient mice [17].

5.2. CD38, a Regulator of SIRT1 Activity?

We proposed that by modulating availability of NAD and nicotinamide to the SIRT1 enzyme, CD38 regulates SIRT1 activity. These findings have strong implications for the understanding of the basic mechanisms that modulate obesity, metabolic syndrome, energy homeostasis, longevity, and aging.

 

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

 

Also, there is this: http://www.longecity...e-2#entry631288

 

Just a little something that can be expanded upon in an alternative NAD thread.

 

NR can still be very useful, but it is one spoke in the wheel, as mentioned above.

 

[Bryan_S]

Needing more NAD as time goes by is just the reality of ageing. To bring about a permanent "fix" to this situation I think it's still just beyond our reach at the moment. Something at a gene signaling level is downregulated with time. Since these are very old metabolic processes conserved thru our evolution whatever it proves to be is likely found in all higher animals. So if it can be identified in worms and mice, we likely would possess it as well. So right now I'm not sure who is doing research aimed at mapping epigenetic change with aging but I would bet this is where we will get the answers.

 

I made mention of this article last year "Repression of the Heat Shock Response Is a Programmed Event at the Onset of Reproduction" The title doesn't sugest the ramifications contained within and on the surface it looks unrelated.

 

http://phys.org/news...-longevity.html

 

http://upriser.com/p...e-aging-process

 

So this is the kind of research I'm speaking about. It's not headline stuff, there are no direct interventions for us to use just yet and we need to give it some time to develop. Otherwise we are just taking potshots in the dark.

 

So this is an unrelated topic from this thread but if this research continues to yield fruit I see a day when our focus will move away nicotinamide riboside and NAD boosting.

Edited by Bryan_S, 05 February 2016 - 05:16 PM.

[niner]

There's been a lot of talk of sublingual dosing of NR, but I suspect that it's not working as well as people may think.   There are a number of requirements for successful SL dosing that are not met by NR:

• Total dose should be less than 20 mg.
• Compound should be at least partially non-ionized.  NR is fully ionized.
• Oil/water partition coefficient between 40 and 2000 (i.e. logP between 1.5 and 3.3) is optimal, but calculated logP for NR is -6. 

In other words, it's a pretty poor candidate for the SL route.  Certainly a little bit will squeak through, but I think that the vast majority of it is getting swallowed.  Unless you like the taste, you're probably better off just taking it as a pill, since the oral bioavailability is good.

[Bryan_S]

you're probably better off just taking it as a pill, since the oral bioavailability is good.

 

Thanks niner, any sublingual references you can share about optimization?  I came across one article that outlined some methods. http://www.pharmtech...ablets-overview

[Bryan_S]

Weight loss is associated with increased NAD/SIRT1 expression but reduced PARP activity in white adipose tissue

 

http://press.endocri...10/jc.2015-3054

 

Guess it pays to keep the weight off.

[Logic]

Needing more NAD as time goes by is just the reality of ageing. To bring about a permanent "fix" to this situation I think it's still just beyond our reach at the moment.

Isn't reaching what this forum is all about?
ie: Following the epigenetic changes upstream, looking for the common denominator/s..?

The AntiAgingFirewalls posts have been doing some reaching:

The NQ01 gene which drives the NAD+/NADH ratio, and factors related to its activation and expression: BET proteins, the 20S proteasome, BET inhibitors, NQ01 regulation of PGV-1alpha, Nrf2 regulation, etc
 

The two “epigenetic readers” that suppress the Nrf2-induction of the NQO1 gene are called “Bromodomain and Extraterminal Proteins” (or BET proteins).  Specifically, Brd2 and Brd4 proteins “sit on top” of the histone protein acetylated lysines at the promoters of the Nrf2-dependent genes.  As a consequence, Nrf2 and the other transcription factors that “turn on” NQO1 gene cannot turn the gene on.  (This is why BET inhibitors like JQ1are so exciting).

http://www.anti-agin...-interventions/

 

Lets "reach" a little further, following one lead; Nrf2 upstream:

 

As people age and their metabolic problems increase, the levels of this regulator, Nrf2, should be increasing, but in fact they are declining....
The reason for this decline is increasing levels of a microRNA called miRNA-146a.
http://www.longecity...-nrf2-in-aging/

 

It looks like miRNA-146a might increase with age as a means of downregulating the inflammation caused by high glucose and glycation to me?

http://www.longecity...ndpost&p=755625

 

Please feel free to "reach" a little people, as the exceptional members who used to frequent this forum and did so seem to have moved on, or no longer bother to post!?

Probably due to getting sick and tired of 'spoon feeding' everyone else!?

 

TheGoogleSiteSearch option in the search dropdown menu (top right) is a good place to start joining some dots.

How to slow, stop and even reverse AGEs would be a good next step don't you... think?

 

 

Edited by Logic, 07 February 2016 - 09:47 AM.

[Bryan_S]

JQ1 is a possible solution but as far as I know no human clinical trials have been put together because of its extremely short half-life. There is a similar molecule (OncoEthix – OTX015) in clinical trials https://clinicaltria...how/NCT01713582 I am not familiar with the results but here is more on that:

http://www.the-scien...Clears-Phase-I/

 

http://oncologydisco...omatin-readers/

 

OncoEthix – OTX015 

OncoEthix, a Swiss oncology company, is the current leader in the BET inhibitor space, with a potential first-in-class BRD4 program. OTX015 is being developed as an oral small-molecule inhibitor of BRD2/3/4, and has a similar chemical structure and in-vitro potency profile to the chemical probe JQ1 (Figure 7). This shouldn’t be surprising, since both of these molecules share the same DNA, originating from the Mitsubishi Tanabe patent literature. In fact, OncoEthix negotiated the rights for OTX015 in 2012 from Mitsubishi Tanabe Pharmaceuticals. Importantly, although OTX015 has similar binding affinity and in-vitro potency to the chemical probe JQ1, its pharmacokinetic properties are superior with a drug half-life of approximately 5 hrs.

 

 

As I suggested a few posts ago the "fix" will likely be on an epigenetic level and these are the first few steps into this new class of drugs.

 

Logic, Spoon feeding can't be avoided and if you really want to promote a topic like NAD boosting you have to revisit the same material over and over again for the new readers. As you look back on this thread you will see a lot of new study material makes it to the thread on a regular basis. However the study implications are rarely discussed. So you are right many have moved on and a few of us keep repeating the old points as we add new material to hopefully bring new blood aboard. 

 

and Yes I still think it's "just beyond our reach at the moment."

Edited by Bryan_S, 07 February 2016 - 11:05 AM.

[stefan_001]

Somehow this discussion is getting a bit distorted. NR is a nice hack to attempt to circumvent a systematic problem for which we have no solution. So perhaps the thread should be seen as a place to develop further and validate the efficacy of hack while the entire board can be seen as the discussion searching for the root cause.

[Bryan_S]

It's still a NR news and updates thread covering NAD boosting, however it was my hope that as new developments came to light we might discuss where these ideas were leading. I know what contributors like Logic want and he summed it up "Isn't reaching what this forum is all about?" He appears to want to parse out the very latest research on this front and the BET inhibitors are in the bleeding edge "group." We also have the activators and we've already seen some development there. So if you guys want to tackle more I'm game but I feel I need to keep my focus on the news and updates thread moving forward with posts on the most current developments. If I don't do it who will?

 

What I think this thread is . . . a stepping off point for many. I'm going to think about this some more.

[stefan_001]

It's also a stepping in point....at least it was for me. I do think it could be a bit wider, in particular around what NR does not fix.....but that is just my own interest in my hope to find a good stack. If the thread has a 140 readers a day it seems to me to be in a sweet spot.

Edited by stefan_001, 07 February 2016 - 09:50 PM.

[Bryan_S]

February 15th will mark the 12th HPN Niagen Nicotinamide Riboside group buy for our members.

​HPN gives our members 3 categories based on quantity. There is a 3 plus bottle code which is not driven by any calendar date (buy anytime.) A 6 thru 11 category and the best value at 12 plus bottles.

[Skyguy2005]

What are the effects of Nicotinamide Riboside on autophagy? And compared to Nicotinic Acid etc. 

[Bryan_S]

Good question and I'm asking this very same question Skyguy2005.

 

Just so we have a context for this, autophagy can take different forms. Most commonly it involves the recycling of damaged cell organelles and proteins within living cells. Here I see NR benefiting the the process. In this situation the recycling of damaged organelles delays senescence extending a cell's life. In this context increased cellular housekeeping should result in slower aging. Then we have an area attached to this, autophagy-enabled senescence whereby the entire cell has reached the end of its replicative life. Cellular senescence is considered a stable form of cell cycle arrest and it's believed that limits the proliferation of damaged cells.

 

There was a nice article in fightaging.org on At the Intersection of Autophagy and Cellular Senescence worth reading.

 

This is not to be confused with Apoptosis which is programmed cell death which can be triggered if all else fails. Here is a pretty good picture describing Senescence, Autophagy and Apoptosis. As pointed out some postmitotic cells like neurons or cardiomyocytes cannot become senescent since they are already terminally differentiated. So to survive they have to clear away or isolate whatever is damaging the cell and NAD boosting would most certainly help them to survive.

 

If you are asking this question you likely read my post on NR and Senolytics and this is where it this topic gets more complicated. This is a topic followed by those who would like to clear way senescence cells and the toxins they are thought to produce. This question hasn't been directly asked by researchers studying NR but my thought is that it would #1 slow our path towards cellular senescence. (a good thing) #2 we know that targeting NAD+ salvage pathways induces autophagy and recent studies have suggested that NAD + treatment can prevent not only necrosis but also apoptotic changes and autophagy. 

 

Now provided everything is working probably some cells escape death due to senescence and can continue to contribute. Now there is research to support that the surviving senescence cells may contribute to healing in cases of injury but I and others feel this is offset by their toxic cell signaling byproducts. Now on the flip side NAD+ boosting can also lead to an inhibition of inflammation produced by those byproducts so a reversal in senescence function may be indicated. Evidence also suggests that at least 16 separate autophagy genes (Atg) are ultimately required for the formation of the autophagosome and the subsequent induction of autophagy. Now we also know that SIRT1 activity is induced by NAD+ boosting and SIRT1 activates autophagy by several different mechanisms, the 4 major ones being deacetylation of multiple cytoplasmic proteins including several involved with autophagy, such as ATG5, ATG7, and ATG8/LC3. So while research would seem to indicate increased cell survival with general NAD+ boosting is will also help enable the machinery of autophagy.

 

So the question I believe you read on the Senolytics thread was proposed to elicit much of what I've mentioned above. If your goal is to remove senescence cells thru senolytics (which is untested bleeding edge medical tech with no clinically documented human testing) I would at this point in time Feb, 2016 recommend discontinuing NAD+ boosting (all the NAD precursors) before the a senolytic treatment begins and resume them again after the treatment was completed. (Note I am not advocating Senolytic treatments at this time, it's a bit early and the compounds available at this time appear tissue specific.)

 

Here is the tread where the question was proposed.

http://www.longecity...-10#entry761554

 

Be aware this is all speculative based on suggestive clinical study findings. Until this notion is lab tested (which hasn't happened) I suspect there is a net net effect where the autophagy machinery is enabled helping to prolong cell survival but once the cell death cascade is initiated "Apoptosis" nothing stops it. I have to look at the overall effects of NAD boosting and conclude the benefits far would outweigh the uncertainties of rescuing senescence cells.  

Edited by Bryan_S, 10 February 2016 - 07:45 PM.
autophagy background added some opinions removed or re-edited

[Castiel]

 

 

. I've read it can increase the short lifespans of mice longer than calorie restriction but at what cost? A short lived mammal isn't going to have to worry about accumulated DNA damage many years down the line but I will. So if you want to tell us about something that beats the pants off the B3's for correcting this gradual NAD depletion I'm willing to entertain research that makes this point but keep it real because some of these approaches aren't ready for primetime yet. 

 

Hi Bryan,

 

First Im just saying that we need to take this topic in an holistic way because B3s action still limited, and we already have a lot of B3s in our diet.. And still age here. NR is of course in a better position in diagram from NAD+ but still not that impressive. We pointed out a lot of study showing a lot of biochemical reaction increased with age and still here while supplementing with NR.

I dont say again NR is ineffective, and the NAD+ is very important of course. I just say for instance resveratrol do a lot of "such actions" and still fail to increase lifespan.. Same for PQQ, and worst for Acid alpha lipoic wich is good in many research in vitro but very bad in vivo (decrease lifespan), same for TA65 > decrease lifespan too..

 

Thats why indeed we need to be careful. I never seen any study showing BL was toxic in normal cell line, even the most recent study you point out conclude: "beta-Lapachone killed cells in a tumorselective manner" and increase lifespan in mamals is what im looking for most often.

 

I will come up deeper into that topic

 

 

 

 

Resveratrol increases the lifespan of fruit flies, yeast, mitochondrially disfunctional rodents, obese rodents, think worms, and even some short lived fish iirc.   Now that we know that NAD+ has age related decrease in rodents, and probably longer lived species too, this can seriously affect if not negate resveratrol's effect in late age, if the effect is pronounced enough as it seems.  The sirtuins depend on NAD+ to work, resveratrol works by boosting the activity of multiple sirtuins, primarily sirt1, iirc.   But if aging in longer lived species depletes NAD+ enough, then resveratrol can't work as there won't be enough NAD+ to allow for adequate sirtuin activity.

 

My bet is that if NAD+ and the ratio can be restored to more youthful levels, then resveratrol supplementation will increase lifespan in longer lived vertebrates just like it did in shorter lived species.

 

As for alpha lipoic acid, it affects telomerase activity, in some rodents it can positively affect disease states like atherosclerosis, but in highly cancer prone species this might very well not be a good idea and could reduce lifespan.  
 

Edited by Castiel, 14 February 2016 - 07:10 PM.

[Tom Andre F. (ex shinobi)]

 

 

 

. I've read it can increase the short lifespans of mice longer than calorie restriction but at what cost? A short lived mammal isn't going to have to worry about accumulated DNA damage many years down the line but I will. So if you want to tell us about something that beats the pants off the B3's for correcting this gradual NAD depletion I'm willing to entertain research that makes this point but keep it real because some of these approaches aren't ready for primetime yet. 

 

Hi Bryan,

 

First Im just saying that we need to take this topic in an holistic way because B3s action still limited, and we already have a lot of B3s in our diet.. And still age here. NR is of course in a better position in diagram from NAD+ but still not that impressive. We pointed out a lot of study showing a lot of biochemical reaction increased with age and still here while supplementing with NR.

I dont say again NR is ineffective, and the NAD+ is very important of course. I just say for instance resveratrol do a lot of "such actions" and still fail to increase lifespan.. Same for PQQ, and worst for Acid alpha lipoic wich is good in many research in vitro but very bad in vivo (decrease lifespan), same for TA65 > decrease lifespan too..

 

Thats why indeed we need to be careful. I never seen any study showing BL was toxic in normal cell line, even the most recent study you point out conclude: "beta-Lapachone killed cells in a tumorselective manner" and increase lifespan in mamals is what im looking for most often.

 

I will come up deeper into that topic

 

 

 

 

Resveratrol increases the lifespan of fruit flies, yeast, mitochondrially disfunctional rodents, obese rodents, think worms, and even some short lived fish iirc.   Now that we know that NAD+ has age related decrease in rodents, and probably longer lived species too, this can seriously affect if not negate resveratrol's effect in late age, if the effect is pronounced enough as it seems.  The sirtuins depend on NAD+ to work, resveratrol works by boosting the activity of multiple sirtuins, primarily sirt1, iirc.   But if aging in longer lived species depletes NAD+ enough, then resveratrol can't work as there won't be enough NAD+ to allow for adequate sirtuin activity.

 

My bet is that if NAD+ and the ratio can be restored to more youthful levels, then resveratrol supplementation will increase lifespan in longer lived vertebrates just like it did in shorter lived species.

 

As for alpha lipoic acid, it affects telomerase activity, in some rodents it can positively affect disease states like atherosclerosis, but in highly cancer prone species this might very well not be a good idea and could reduce lifespan.  
 

 

 

Im not sure to agree with that and resveratrol I think was shown to activate sirt1 in an independent manner. Im not sure more NAD+ wil influence it.

 

However, a point interesting enough is that sirt1 block parp1. Bryan can you confirm this ?

 

Im trying to connecting the dots, and would like to make a pics the more complete as we can where we show the main pathways

 

EDIT: about sirt1 activity while we age: http://journals.plos...ne.0042357.t001 as you can see there is no strong difference and we can even say no statistical difference. Female do not have decrease in sirt1..

 

However, its even more clear that the main problem remain the loss of NAD+ due to PARP1 activity. Again and again, this is the main problem: DNA damage.

 

Edited by Tom Andre F. (ex shinobi), 15 February 2016 - 01:16 PM.