2255 replies to this topic

[Bryan_S]

Bryan, sorry but do you still have your graph for NR NAD+ boosting activity / Time please ? and also to come back more early on this topic: what made you think NMN has to first being converted to NR to enter the cell ?

 

 

Hi Tom,

 

Charts http://www.longecity...e-5#entry757406 However I heard through the grapevine we might be getting better half-life data soon so these charts are likely obsolete and inaccurate. 

 

Nicotinamide Mononucleotide (NMN)

It appears for cell membrane transport the phosphate is removed, you should read about the PnuC transporters if this of interest to you.

 

Some of us have been looking for alternatives and have weighed the alternatives but they've proved more expensive than (NR). 

I'm at dinner but look at this: http://www.longecity...e-7#entry733468

 

Also see:

https://en.wikipedia...ke_transporters

 

Pathways and subcellular compartmentation of NAD biosynthesis in human cells: from entry of extracellular precursors to mitochondrial NAD generation.

http://www.ncbi.nlm....pubmed/21504897

"Our results demonstrate that, besides nicotinamide and nicotinic acid, only the corresponding nucleosides readily enter the cells. Nucleotides (e.g. NAD and NMN) undergo extracellular degradation resulting in the formation of permeable precursors."

 

also http://jb.asm.org/co.../13/4410.full "We characterized two enzymes, a nucleotide phosphatase encoded by the e(P4) outer membrane protein and NadN, an NAD⁺ nucleotidase located in the periplasm (23, 40, 44). In addition, we showed that NAD⁺ and NMN cross the outer membrane mainly via the OmpP2 porin (2). However, only NR can be utilized by the transport system located in the inner membrane (19, 42), which is encoded by a homologue of pnuC. We characterized the pnuC gene product as the protein that is responsible for the main flow of the NR substrate into the cytoplasm, and we also found that H. influenzae pnuC knockout mutants were not able to grow under in vivo conditions (there was not invasive growth in infected infant rats) (19)."

 

Also see Nicotinamide mononucleotide transporter PnuC. There is a family of transporters involved in moving extracellular NAD and NMN across the cell membrane. As far as the texts read it appears it has something to do with the phosphate being removed at the cell membrane and the molecule is reassembled after crossing into the cell.

 

So the idea isn't mine and the cell membrane transport action seems conserved across a number of cell types.

Edited by Bryan_S, 24 April 2016 - 05:05 AM.

[Tom Andre F. (ex shinobi)]

Hi and thanks a lot bryan ! I save all the info and will search more about the Pnuc transporter

 P

About NR half life, I think a more relevant info (and maybe we already have it) would be the net level of NAD+. Means if you increase by 30% NAD+ level, how many time it takes to come back to normal / initial. And a further question would be: is a combination of NR with NQO1 modulator would help to fix this ? if not, does a decrease in full inflammatory statut (maybe using willow bark ?) would also decrease the PARP activity in the safe way ?

 

 

Edited by Tom Andre F. (ex shinobi), 24 April 2016 - 09:22 AM.

[Bryan_S]

And a further question would be: is a combination of NR with NQO1 modulator would help to fix this ? if not, does a decrease in full inflammatory statut (maybe using willow bark ?) would also decrease the PARP activity in the safe way ?

 

Many questions still remain and at the moment we are still in uncharted waters.

 

I don't know if I would want to decrease my PARP activity in favor of higher NAD+ levels.

 

Its all a biological hack anyway until we discover the true epigenetic root of aging which still eludes us. Good news is we know more than we once did and the search is feeding into our understanding of other diseases of aging.

[Tom Andre F. (ex shinobi)]

 

And a further question would be: is a combination of NR with NQO1 modulator would help to fix this ? if not, does a decrease in full inflammatory statut (maybe using willow bark ?) would also decrease the PARP activity in the safe way ?

 

Many questions still remain and at the moment we are still in uncharted waters.

 

I don't know if I would want to decrease my PARP activity in favor of higher NAD+ levels.

 

Its all a biological hack anyway until we discover the true epigenetic root of aging which still eludes us. Good news is we know more than we once did and the search is feeding into our understanding of other diseases of aging.

 

well the PARP activity is uncertain at this point, what is fact however is that young human have more NAD+ and less PARP activity (probably directly linked to the inflammation statut) and that old person have very high PARP activity profile and of course the NAD+ depletion associated.

 

So my point is if you really want to be young again, you have to at the end, choosing the best root fot that, get back to your young profile in ALL points. So PARP included. Have a high NAD+ and low PARP activity is not discussion for me, its really what we have to achieve.

 

If direct PARP inhibition is bad knowing its role for dna repair, I would however use pure anti inflammatory molecules such as salicin in willow bark that increased 400% lifespan in yeast. It will decrease our inflammatory statut : decrease TNFa (and probably beta as well), COX, and NF kB: http://www.ncbi.nlm....pubmed/20570123

 

 

 

 

[Bryan_S]

Tom,

 

Good article, as you are aware I'm out to blunt inflammation where ever I can. Short term is one thing, however I have the same concerns for Willow Bark as I do taking long term aspirin. So there are problems with most of these once you begin treating long term inflammatory conditions. One of my favorites was Naproxen sodium which like aspirin is an oral medication that is part of a larger family of nonsteroidal anti-inflammatory drugs, or NSAIDs. So it seems the stuff that works really well has a down side if you take it long enough.

 

PARP activity and NAD+ have been central subjects to aging in the past few years. This is a timely topic considering the recent article in Nature. Nuclear DNA damage signalling to mitochondria in aging. I feel by supplementing our NAD+ levels with (NR) we are already producing this anti inflammatory environment you are seeking by reducing cellular stress. Certainly we can do more to help but the generation of ATP itself produces some cellular damage. A healthy cellular environment will cope with these conditions better than a NAD depleted landscape. 

 

Here was a similar article last year.

Nuclear DNA Repair Proteins in Mitochondrial Health and Aging

 

This was one I read in 2014. So this theme is gaining momentum and increasing NAD+ to combat decreasing levels is implied or directly stated in most of them.

Cellular Repair and Reversal of Aging: the Role of NAD

Edited by Bryan_S, 25 April 2016 - 01:38 AM.

[Nate-2004]

I've been reading through a lot of posts on this site about NR after having read a blog post about NR on Scientific American recently. 

 

I am always hesitant to buy anything new as far as supplements go because they can be a money pit for one thing, and are often snake oil for another.

 

As I posted in my intro thread my main concerns with NR was that Chromadex was selling Niagen before they had completed human trials and determined proper dosage. They're still conducting a trial as of March this year (2016) to determine dosage and have yet to publish the results on the dosage of the previous trial. They're selling $50 bottles of 250mg pills when the initial rat trials administered 400mg. From what I gather in all this reading, the proper dosage should be more along the lines of 2g, and either broken up into multiple times a day or time released throughout the day.

 

Brian_S responded saying that NR was just a hack anyway to keep NAD+ up and really did nothing to reverse aging anyway, that it's just one piece of the bigger puzzle.

 

What I don't understand fully is the question of niacinamide and nicotinamide. Both of these supplements can be found on Amazon for fairly cheap. Nacinamide is $5 a bottle from NOW for 100 tabs of 500mg. Nicotinamide (no flush) is the same amount for $29.

 

From what I gather, these two substances are also precursors for NAD+ but the problem is that unlike NR, instead of encouraging SIRT1 they inhibit it. Strange? WTF kind of catch 22 is that? Am I right in my understanding that the very same substance that is a precursor to that which encourages SIRT1 actually inhibits it?

 

Apparently there's also a lot of benefits to taking niacinamide. So I'm not sure if I should take some or not.

 

That said, I heard that NR is also in milk. I drink a LOT of milk and have for my entire 42 years. I'm wondering if this is what has kept people saying that I look and act like I'm 32, not 42. I don't feel old that's for sure, but I definitely don't want to start any time soon. Prevention is better than cure.  Grey hairs are definitely kicking in.

 

Any word about this latest Chromadex trial? Will any change in the dosage come of it? Does anyone believe they'd be selling more for less at some point if it shows successful?

 

I plan to go back and read this whole thread. There's so much to it.

[Bryan_S]

You have a lot of reading ahead. Niacinamide AKA nicotinamide AKA (NAM) is a NAD precursor and a cheap one at that. However NR jumps in line and does not require the Nicotinamide phosphoribosyltransferase (NAMPT) which is tightly regulated. This is where they diverge as (NR) takes a different path to NAD and doesn't work as an inhibitor. Its still better than not taking anything JMHO.

 

So when I say it doesn't turn back the clock it does reverse "some" aspects of aging or we wouldn't be here. Just don't believe all the marketing hype which is over the top, still amazing without calling it the fountain of youth. Your graying hair for instance isn't one of those things it reverses.

 

Got to get back to work.

Edited by Bryan_S, 25 April 2016 - 03:50 AM.

[stefan_001]

 They're selling $50 bottles of 250mg pills when the initial rat trials administered 400mg. From what I gather in all this reading, the proper dosage should be more along the lines of 2g, and either broken up into multiple times a day or time released throughout the day.

 

............................

 

That said, I heard that NR is also in milk. I drink a LOT of milk and have for my entire 42 years. I'm wondering if this is what has kept people saying that I look and act like I'm 32, not 42. I don't feel old that's for sure, but I definitely don't want to start any time soon. Prevention is better than cure.  Grey hairs are definitely kicking in.

 

 

I think the conclusion that the dosing should be around 2g is not something I have seen except that it is being used in some trials along other dosing levels.. I am using 375mg / day with sometimes a week of 500mg to see whether that makes a difference. At those levels I have experienced clear benefit. The Chromadex CEO stated in the last Q conf call for example that he uses 500mg / day. 

 

If you believe that 2g is the right level then milk drinking is really futile. There is a comparison in this article to the amount of milk to be drank compared to supplementation:

http://www.timelessl...de-in-cow-milk/

If I am doing it right it would mean 2500L a day.

Edited by stefan_001, 25 April 2016 - 04:32 AM.

[stefan_001]

Tom,

 

Good article, as you are aware I'm out to blunt inflammation where ever I can. Short term is one thing, however I have the same concerns for Willow Bark as I do taking long term aspirin. So there are problems with most of these once you begin treating long term inflammatory conditions. One of my favorites was Naproxen sodium which like aspirin is an oral medication that is part of a larger family of nonsteroidal anti-inflammatory drugs, or NSAIDs. So it seems the stuff that works really well has a down side if you take it long enough.

 

PARP activity and NAD+ have been central subjects to aging in the past few years. This is a timely topic considering the recent article in Nature. Nuclear DNA damage signalling to mitochondria in aging. I feel by supplementing our NAD+ levels with (NR) we are already producing this anti inflammatory environment you are seeking by reducing cellular stress. Certainly we can do more to help but the generation of ATP itself produces some cellular damage. A healthy cellular environment will cope with these conditions better than a NAD depleted landscape. 

 

Here was a similar article last year.

Nuclear DNA Repair Proteins in Mitochondrial Health and Aging

 

This was one I read in 2014. So this theme is gaining momentum and increasing NAD+ to combat decreasing levels is implied or directly stated in most of them.

Cellular Repair and Reversal of Aging: the Role of NAD

 

Willow bark sounds like a extract with interesting properties but with less research data than lets say honokiol. My impression is that many plant based supplements are acting in a similar direction so as such I personally would not jump on it but interesting to follow. Having said all that there is encouraging safety data on willowbark:

 

These data suggest that STW 33-I can be used as a basic treatment in the long-term therapy of painful musculoskeletal disorders and that it can be combined with NSAIDs and opioids if necessary.

http://www.ncbi.nlm....pubmed/23731658

 

Edited by stefan_001, 25 April 2016 - 06:24 AM.

[midas]

That said, I heard that NR is also in milk. I drink a LOT of milk and have for my entire 42 years. I'm wondering if this is what has kept people saying that I look and act like I'm 32, not 42. I don't feel old that's for sure, but I definitely don't want to start any time soon. Prevention is better than cure.  Grey hairs are definitely kicking in.

 

 

0.2144-1.3784 mg/L NR

 

Just on your point about milk, to get your 250mg per day which seems to be the norm for now you would have to drink 250 litres of milk or 66 US gallons per day, and that's if you were getting 1mg per litre...I know you say you drink a LOT of milk but I doubt you drink that much.
 

[Nate-2004]

 

 They're selling $50 bottles of 250mg pills when the initial rat trials administered 400mg. From what I gather in all this reading, the proper dosage should be more along the lines of 2g, and either broken up into multiple times a day or time released throughout the day.

 

............................

 

That said, I heard that NR is also in milk. I drink a LOT of milk and have for my entire 42 years. I'm wondering if this is what has kept people saying that I look and act like I'm 32, not 42. I don't feel old that's for sure, but I definitely don't want to start any time soon. Prevention is better than cure.  Grey hairs are definitely kicking in.

 

 

I think the conclusion that the dosing should be around 2g is not something I have seen except that it is being used in some trials along other dosing levels.. I am using 375mg / day with sometimes a week of 500mg to see whether that makes a difference. At those levels I have experienced clear benefit. The Chromadex CEO stated in the last Q conf call for example that he uses 500mg / day. 

 

If you believe that 2g is the right level then milk drinking is really futile. There is a comparison in this article to the amount of milk to be drank compared to supplementation:

http://www.timelessl...de-in-cow-milk/

If I am doing it right it would mean 2500L a day.

 

 

Good to know, I was not aware of exactly how much NR is in cow's milk. I was actually trying to find a link for that by Googling and could not find any info anywhere. Thanks. I drink a lot but not that much lol.

 

As far as the dosing, I was referring to the rat to human equation people have been posting about. I also read that during the last trials they were only able to boost NAD+ by 50% with the 250mg dosage and they did much better with 1g is that right?

 

Looking at the cost, 500mg per day at the HPM discount works out to ~$70 per month roughly. This is a nuts expensive supplement, and a bit of a gamble.

 

Has anyone lab tested the HPM stuff? Would you guys still recommend this as the best brand? I generally check Labdoor for supplement quality but they aren't testing NR yet.

[Bryan_S]

Venders

 

One of our members had HPN's Niagen independently tested. They were the first retailer when ChromaDex began building its retail supply chain. They have also been the recommended supplier for many of the academic studies. Its also the cleanest product of all of the retailers and is vegetarian friendly. They have also been responsive to the LongeCity Forums and eliminated all the objectionable encapsulation excipients. (we are a tough crowd to please) They will also willingly send you their 3rd party independent testing upon request, something other retails claim but won't make good on.

 

Today there are a number of venders being authorized so you have multiple choices, however HPN has helped grow the user base. They were also the the first to offer our members a Team Discount Buy and offer us the cheapest per gram price on multi bottle orders. (Their best offer is $4.14 per gram thru $4.88 depended upon quantity) So call me biased but if you change your product to please our user base and give me a product discount that beats all the others your likely to win my business.

 

We were running a venders page but it has been neglected lately. Its about time to update it, show who's doing what, list ingredients and who's opening themselves up to public scrutiny and those who have refused to comply. Some of us are sticklers for truth in marketing and don't like being lied to, so I say back up your customer assurances or retract those claims your not willing to prove and make public.

Edited by Bryan_S, 25 April 2016 - 05:58 PM.

[midas]

 

 

 They're selling $50 bottles of 250mg pills when the initial rat trials administered 400mg. From what I gather in all this reading, the proper dosage should be more along the lines of 2g, and either broken up into multiple times a day or time released throughout the day.

 

............................

 

That said, I heard that NR is also in milk. I drink a LOT of milk and have for my entire 42 years. I'm wondering if this is what has kept people saying that I look and act like I'm 32, not 42. I don't feel old that's for sure, but I definitely don't want to start any time soon. Prevention is better than cure.  Grey hairs are definitely kicking in.

 

 

I think the conclusion that the dosing should be around 2g is not something I have seen except that it is being used in some trials along other dosing levels.. I am using 375mg / day with sometimes a week of 500mg to see whether that makes a difference. At those levels I have experienced clear benefit. The Chromadex CEO stated in the last Q conf call for example that he uses 500mg / day. 

 

If you believe that 2g is the right level then milk drinking is really futile. There is a comparison in this article to the amount of milk to be drank compared to supplementation:

http://www.timelessl...de-in-cow-milk/

If I am doing it right it would mean 2500L a day.

 

 

 

 

As far as the dosing, I was referring to the rat to human equation people have been posting about. I also read that during the last trials they were only able to boost NAD+ by 50% with the 250mg dosage and they did much better with 1g is that right?

 

 

 

"The oral presentation and poster presented data which indicate that single doses of NIAGEN^® NR can elevate the co-enzyme NAD+ in the blood by as much as 2.7-fold. In the first-in-humans clinical trial which involved dosing twelve healthy adult subjects, the group showed that blood cell NAD+ increased with single 100 mg, 300 mg and 1 gram doses of NIAGEN^® NR. Average maximal increases in blood NAD+ were approximately 30% at the 100 mg dose and approximately 50% at the higher doses."

 

http://globenewswire...nd-is-Safe.html

 

I read that statement as there isn't much difference between the 300mg and 1000mg ((1 gram), both giving around 50% increase...

 

[Bryan_S]

 

As far as the dosing, I was referring to the rat to human equation people have been posting about. I also read that during the last trials they were only able to boost NAD+ by 50% with the 250mg dosage and they did much better with 1g is that right?

 

"The oral presentation and poster presented data which indicate that single doses of NIAGEN^® NR can elevate the co-enzyme NAD+ in the blood by as much as 2.7-fold. In the first-in-humans clinical trial which involved dosing twelve healthy adult subjects, the group showed that blood cell NAD+ increased with single 100 mg, 300 mg and 1 gram doses of NIAGEN^® NR. Average maximal increases in blood NAD+ were approximately 30% at the 100 mg dose and approximately 50% at the higher doses."

 

http://globenewswire...nd-is-Safe.html

 

I read that statement as there isn't much difference between the 300mg and 1000mg ((1 gram), both giving around 50% increase...

 

That's where these charts came from, oh and the half-life data they gave us. So if 300 mg is as high as you can push any dose before we start eliminating the excess (water soluble means you don't store the excess) it pays to dose thru the day and shoot for maintaining the maximum NAD threshold as levels fall do to its half-life.

[Tom Andre F. (ex shinobi)]

Tom,

 

Good article, as you are aware I'm out to blunt inflammation where ever I can. Short term is one thing, however I have the same concerns for Willow Bark as I do taking long term aspirin. So there are problems with most of these once you begin treating long term inflammatory conditions. One of my favorites was Naproxen sodium which like aspirin is an oral medication that is part of a larger family of nonsteroidal anti-inflammatory drugs, or NSAIDs. So it seems the stuff that works really well has a down side if you take it long enough.

 

PARP activity and NAD+ have been central subjects to aging in the past few years. This is a timely topic considering the recent article in Nature. Nuclear DNA damage signalling to mitochondria in aging. I feel by supplementing our NAD+ levels with (NR) we are already producing this anti inflammatory environment you are seeking by reducing cellular stress. Certainly we can do more to help but the generation of ATP itself produces some cellular damage. A healthy cellular environment will cope with these conditions better than a NAD depleted landscape. 

 

Here was a similar article last year.

Nuclear DNA Repair Proteins in Mitochondrial Health and Aging

 

This was one I read in 2014. So this theme is gaining momentum and increasing NAD+ to combat decreasing levels is implied or directly stated in most of them.

Cellular Repair and Reversal of Aging: the Role of NAD

 

Indeed Bryan but I think willow bark is safe enough. Some people use even normal aspirin on the long run. Maybe low dose or occasional supplementation in order to totally decrease the inflammation accumulation that increase day after day unfortunately.

 

Regarding sirtuin 1 for instance, I think resveratrol didnt extented lifespan in mice because.. actually I speculate resveratrol does not really increase sirt1.. simple as that. We only seen some sirt1 increase in some cells thats all. Here is a strange study: http://www.ncbi.nlm....pubmed/25924011 and cant found back a vitro study that showed resveratrol actually decreased sirt1. I never read similar things about pterostilbene that seems safer and can be used in lower dosage.

 

or to a less degree: http://journals.plos...al.pbio.1001603

 

 

 

I drink a LOT of milk and have for my entire 42 years.

 

Better to stop milk and dairy unlike what you used to be teached. Milk is full of pro inflammatory.. I really mean full: 32 hormones including estrogen such as estradiol, androgen such as DHT.. growth hormones and all of course in a ratio you dont want for human. Furthermore it contains lactose a very pro inflammatory compound, and even worst: casein. People who are looking to live long just cant drink eat dairy. No way. You will have more calcium in your blood vessel than on your bones actually. its called calcification

 

 

Tom,

 

Good article, as you are aware I'm out to blunt inflammation where ever I can. Short term is one thing, however I have the same concerns for Willow Bark as I do taking long term aspirin. So there are problems with most of these once you begin treating long term inflammatory conditions. One of my favorites was Naproxen sodium which like aspirin is an oral medication that is part of a larger family of nonsteroidal anti-inflammatory drugs, or NSAIDs. So it seems the stuff that works really well has a down side if you take it long enough.

 

PARP activity and NAD+ have been central subjects to aging in the past few years. This is a timely topic considering the recent article in Nature. Nuclear DNA damage signalling to mitochondria in aging. I feel by supplementing our NAD+ levels with (NR) we are already producing this anti inflammatory environment you are seeking by reducing cellular stress. Certainly we can do more to help but the generation of ATP itself produces some cellular damage. A healthy cellular environment will cope with these conditions better than a NAD depleted landscape. 

 

Here was a similar article last year.

Nuclear DNA Repair Proteins in Mitochondrial Health and Aging

 

This was one I read in 2014. So this theme is gaining momentum and increasing NAD+ to combat decreasing levels is implied or directly stated in most of them.

Cellular Repair and Reversal of Aging: the Role of NAD

 

Willow bark sounds like a extract with interesting properties but with less research data than lets say honokiol. My impression is that many plant based supplements are acting in a similar direction so as such I personally would not jump on it but interesting to follow. Having said all that there is encouraging safety data on willowbark:

 

These data suggest that STW 33-I can be used as a basic treatment in the long-term therapy of painful musculoskeletal disorders and that it can be combined with NSAIDs and opioids if necessary.

http://www.ncbi.nlm....pubmed/23731658

 

 

they tested over 10 000+ and none of them offered such an increase in both maximum and medium lifespan. Honokiol is for others pathway still very interesting. I use it myself too like you for sirt3.. Even if we dont know if it does same for all cells instead of only heart cells

[Bryan_S]

On the fence and waiting for data

 

https://www.geneticl...little-science/

[Bryan_S]

The CR Society considers the Michael Rae's article suggesting Nicotinamide Riboside is possibly harmful to our remaining "still-functional" Mitochondria.

 

Michael Rae's article

 

"Moreover, even if NR supplements do provide an immediate jolt to muscle mitochondrial metabolism in the way that the Harvard NMN studies suggest, it’s not clear that doing so is a good idea in the long term. NMN injections don’t improve mitochondrial function by repairing molecular damage wrought by the aging process in the organelles, nor in other cells and biomolecules whose damage with age results in a dampening-down of mitochondrial activity (see discussion in Question of the Month #11: “Are Mitochondrial Mutations Really All That Important?”). Instead, NMN injections leave the existing damage in place, and induce the still-functional mitochondria to work harder and pump out more energy. This is rather like pushing harder on the gas pedal when your car is not running at full power due to damage to its cams and push rods: it may make the car go faster in the short term, but the underlying damage hasn’t been fixed, and will likely get even worse from the excessive wear."

 

CR Society's Recent comments

(CR) Calorie Restriction

 

"Summary:

NR hasn't been shown to increase NAD (or even NMR - the compound that must be synthesized between NR and NAD).

It isn't clear boosting NAD benefits muscle strength even if you could elevate it,

In any case NAD doesn't benefit mitochondrial damage, if anything it boost the rate of MT damage accumulation by making the MT work harder.

Finally, the dosage used in animals is the human equivalent of 2000-4000 mg/day. Elysium has 250mg per day."

 

 

We also considered the Michael Rae article last November and found a few people who were also still on the fence.

Edited by Bryan_S, 27 April 2016 - 06:10 PM.

[Tom Andre F. (ex shinobi)]

Hi Bryan,

 

thanks a lot for this finding. It was my fear and actually it is very very bad news.. Even worst is that we are 100% nude against mutated mitochondria.. very nude and nothing can help with that including senolitics approach..

[Bryan_S]

Tom,
 
I'm not concerned because NAD Boosting encourages Mitochondrial biogenesis which has been well documented. We are not forcing the healthy Mitochondria to wear themselves out by any means. We are stimulating their ability to divide and multiply because they are not a finite resource. So in itself that produces more capacity to produce NAD+.
 
It's only when we openly subject ourselves to the criticism of others that we keep our opinions in line with the academic research. Now I'm not trying to chastise the indolent (guess I am actually) but opinions need to be researched and supported (academic citations, please) and I would expect if mine seemed as flimsy as Michael Rae's concerning NAD boosting some of you would step-in and challenge them.
 
Concerning ACADEMIC CITATIONS no-one here is expected to write like they are putting together a research paper. However the one thing that has defined the LongeCity forums is our members are considerate enough to include them to add validity to their opinions. Not a must but greatly appreciated and praised by our readers.
 
 

Hi Bryan,
 
thanks a lot for this finding. It was my fear and actually it is very very bad news.. Even worst is that we are 100% nude against mutated mitochondria.. very nude and nothing can help with that including senolitics approach..

Edited by Bryan_S, 27 April 2016 - 11:02 PM.

[stefan_001]

Hi Bryan,

 

thanks a lot for this finding. It was my fear and actually it is very very bad news.. Even worst is that we are 100% nude against mutated mitochondria.. very nude and nothing can help with that including senolitics approach..

 

you are kidding right? That's a terrible written article.

 

Please ask this somewhat frustated sounding researcher what is the link between Nr -> NAD+ -> SIRT3 -> FOXO3 -> mitochondrial homeostasis

Edited by stefan_001, 27 April 2016 - 07:36 PM.

[Tom Andre F. (ex shinobi)]

 

Tom,

 

I'm not concerned because NAD Boosting encourages Mitochondrial biogenesis which has been well documented. We are not forcing the healthy Mitochondria to wear themselves out by any means. We are stimulating their ability to divide and multiply because they are not a finite resource. So in itself that produces more capacity to produce NAD+.

 

It's only when we openly subject ourselves to the criticism of others that we keep our opinions in line with the academic research. Now I'm not trying to chastise the indolent but opinions need to be researched and supported (academic citations, please) and I would expect if mine seemed as flimsy as Michael Rae's concerning NAD boosting some of you would step-in and challenge them.

 

Concerning ACADEMIC CITATIONS no-one here is expected to write like they are putting together a research paper. However the one thing that has defined the LongeCity forums is our members are considerate enough to include them to add validity to their opinions. Not a must but greatly appreciated and praised by our readers.

 

 

Hi Bryan,

 

thanks a lot for this finding. It was my fear and actually it is very very bad news.. Even worst is that we are 100% nude against mutated mitochondria.. very nude and nothing can help with that including senolitics approach..

 

 

I understand Bryan, but just boosting mitochondria or increase their number is already possible for instance with PQQ, and still it didnt increased lifespan in mices. Thats why i think they at least point a good point about the mutated mitochondria. Some research even showed very bad result in vivo using coQ10 too. And dont forget some forum members experienced kind of tiredness in muscles after couple days of use NR in this forum

 

 

Hi Bryan,

 

thanks a lot for this finding. It was my fear and actually it is very very bad news.. Even worst is that we are 100% nude against mutated mitochondria.. very nude and nothing can help with that including senolitics approach..

 

you are kidding right? That's a terrible written article.

 

Please ask this somewhat frustated sounding researcher what is the link between Nr -> NAD+ -> SIRT3 -> FOXO3 -> mitochondrial homeostasis

 

FOXO3 is an interesting pathway, but I dont know the link with already mutated mitochondria.

Edited by Tom Andre F. (ex shinobi), 27 April 2016 - 07:46 PM.

[Tom Andre F. (ex shinobi)]

Its bit off topic but only strategy I see would be mitochondrial fusion:

 

• Fusion is essential for maintenance of mitochondrial DNA (mtDNA) levels
• Loss of mitochondrial fusion results in increased mtDNA mutations
• Fusion protects mitochondrial respiration in cells with high loads of mutated mtDNA

 

source: http://www.cell.com/...90?showall=true

 

• is able to control mitochondrial morphology and function

source: http://www.ncbi.nlm....2?dopt=Abstract

 

• mitochondrial hyperfusion is also able to prevent further reduction of mitochondria numbers and compensate mitochondrial activity lost due to mutations of mtDNA

source: http://www.ncbi.nlm....ial hyperfusion

 

and an interesting point to join stefen_001 about autophagy:

 

• During starvation, cellular cyclic AMP levels increase and protein kinase A (PKA) is activated. PKA in turn phosphorylates the pro-fission dynamin-related protein 1 (DRP1), which is therefore retained in the cytoplasm, leading to unopposed mitochondrial fusion. Elongated mitochondria are spared from autophagic degradation, possess more cristae, increased levels of dimerization and activity of ATP synthase, and maintain ATP production.

 

 

source: http://www.ncbi.nlm.... cell viability

 

 

And good news, resveratrol (so pterostilbene maybe also even better for vivo) modulate mitochondrial fusion and fission in senescent cells. It reduces the number of senescent cells with fragmented mitochondria as well as alterations of fusion and fission gene expression profiles.

 

source: http://journals.plos...104345-Rolland1

 

Maybe this is why Bryan pointed out numerous top scientist want the combination NR + Pt ?

 

 

[Bryan_S]

 

I understand Bryan, but just boosting mitochondria or increase their number is already possible for instance with PQQ, and still it didnt increased lifespan in mices. Thats why i think they at least point a good point about the mutated mitochondria. Some research even showed very bad result in vivo using coQ10 too. And dont forget some forum members experienced kind of tiredness in muscles after couple days of use NR in this forumzFOXO3 is an interesting pathway, but I dont know the link with already mutated mitochondria.

 

Tom that is if you buy into the "mitochondrial theory of aging." I for one like those scientists who are willing to go against grain and say things like "There is, however, a growing body of conflicting evidence that has raised doubts about the validity of this theory. The Tsukuba team in particular has performed some compelling research that has led them to propose that age-associated mitochondrial defects are not controlled by the accumulation of mutations in the mitochondrial DNA but by another form of genetic regulation."

 

That idea is of course being proposed by scientists like Professor Hayashi and his advocates go on to say "This led the researchers to propose that another form of genetic regulation, epigenetic regulation, may be responsible for the age-associated effects seen in the mitochondria." I can't tell you how much I enjoy seeing the status quo being challenged. So how does the SENS foundation suggest we fix these mitochondrial mutations anyway? Now there is more evidence mounting that the whole quality control process is mitigated by mitochondrial autophagy. 

 

 

and an interesting point to join stefen_001 about autophagy:

 

 

 

Maybe this is why Bryan pointed out numerous top scientist want the combination NR + Pt ?

 

 

That was only part of the story. But yes this is why I think SIRT1 and SIRT3 activators are so important. Its all about quality control and repair and we already have the innate tools within us, its all about learning to talk to our bio-machine and that language is slowly being revealed.

 

Its not like we need some SiFi Borg Nonobot to go to each cell to repair them, we already have that Technology built within us that's billions of years in the making.

 

[Tom Andre F. (ex shinobi)]

More about autophagy (here mitophagy) :

 

Mitophagy in cells with mtDNA mutations: being sick is not enough.

Abstract

Despite the emergence of autophagy as a key process for mitochondrial quality control, the existence and persistence of pathogenic mtDNA mutations in human disease suggests that the degradation of dysfunctional mitochondria does not occur widely in vivo. During macroautophagy, a double-membraned cup-shaped structure engulfs cytosolic content. This autophagic vesicle then fuses with lysosomes, allowing hydrolytic enzymes to degrade the contents. Mitochondrial autophagy, or mitophagy, is thought to degrade damaged or nonfunctioning mitochondria specifically. The Parkinson disease-related proteins PINK1 (a mitochondrially localized kinase) and PARK2 (PARKIN, a cytosolically-localized E3 ubiquitin ligase) are essential for targeting mitochondria for mitophagy. Upon chemical uncoupling of the mitochondrial transmembrane potential (Δψ(m)), PINK1 located in the mitochondrial outer membrane recruits PARK2 from the cytosol to the mitochondria, followed by delivery of the organelle to the autophagic machinery for degradation.

 

 

but in respect to both pathway:

 

Mitochondrial autophagy in cells with mtDNA mutations results from synergistic loss of transmembrane potential and mTORC1 inhibition.

Abstract

Autophagy has emerged as a key cellular process for organellar quality control, yet this pathway apparently fails to eliminate mitochondria containing pathogenic mutations in mitochondrial DNA (mtDNA) in patients with a variety of human diseases. In order to explore how mtDNA-mediated mitochondrial dysfunction interacts with endogenous autophagic pathways, we examined autophagic status in a panel of human cytoplasmic hybrid (cybrid) cell lines carrying a variety of pathogenic mtDNA mutations. We found that both genetic- and chemically induced loss of mitochondrial transmembrane potential (Δψ(m)) caused recruitment of the pro-mitophagic factor Parkin to mitochondria. Strikingly, however, the loss of Δψ(m) alone was insufficient to prompt delivery of mitochondria to the autophagosome (mitophagy). We found that mitophagy could be induced following treatment with the mTORC1 inhibitor rapamycin in cybrids carrying either large-scale partial deletions of mtDNA or complete depletion of mtDNA. Further, we found that the level of endogenous Parkin is a crucial determinant of mitophagy. These results suggest a two-hit model, in which the synergistic induction of both (i) mitochondrial recruitment of Parkin following the loss of Δψ(m) and (ii) mTORC1-controlled general macroautophagy is required for mitophagy. It appears that mitophagy can be accomplished by the endogenous autophagic machinery, but requires the full engagement of both of these pathways.

 

 

 

We know NAD+ play a role in autophagy :

 

The potential regulatory roles of NAD⁺ and its metabolism in autophagy

Abstract

(Macro)autophagy mediates the bulk degradation of defective organelles, long-lived proteins and protein aggregates in lysosomes and plays a critical role in cellular and tissue homeostasis. Defective autophagy processes have been found to contribute to a variety of metabolic diseases. However, the regulatory mechanisms of autophagy are not fully understood. Increasing data indicate that nicotinamide adenine nucleotide (NAD⁺) homeostasis correlates intimately with autophagy. NAD⁺ is a ubiquitous coenzyme that functions primarily as an electron carrier of oxidoreductase in multiple redox reactions. Both NAD⁺ homeostasis and its metabolism are thought to play critical roles in regulating autophagy. In this review, we discuss how the regulation of NAD⁺ and its metabolism can influence autophagy. We focus on the regulation of NAD⁺/NADH homeostasis and the effects of NAD⁺ consumption by poly(ADP-ribose) (PAR) polymerase-1 (PARP-1), NAD⁺-dependent deacetylation by sirtuins and NAD⁺ metabolites on autophagy processes and the underlying mechanisms. Future studies should provide more direct evidence for the regulation of autophagy processes by NAD⁺. A better understanding of the critical roles of NAD⁺ and its metabolites on autophagy will shed light on the complexity of autophagy regulation, which is essential for the discovery of new therapeutic tools for autophagy-related diseases

 

 

but not sure about mitophagy

[Tom Andre F. (ex shinobi)]

 

 

Tom that is if you buy into the "mitochondrial theory of aging." I for one like those scientists who are willing to go against grain and say things like "There is, however, a growing body of conflicting evidence that has raised doubts about the validity of this theory. The Tsukuba team in particular has performed some compelling research that has led them to propose that age-associated mitochondrial defects are not controlled by the accumulation of mutations in the mitochondrial DNA but by another form of genetic regulation."

 

That idea is of course being proposed by scientists like Professor Hayashi and his advocates go on to say "This led the researchers to propose that another form of genetic regulation, epigenetic regulation, may be responsible for the age-associated effects seen in the mitochondria." I can't tell you how much I enjoy seeing the status quo being challenged. So how does the SENS foundation suggest we fix these mitochondrial mutations anyway? Now there is more evidence mounting that the whole quality control process is mitigated by mitochondrial autophagy. 

 

 

 

That was only part of the story. But yes this is why I think SIRT1 and SIRT3 activators are so important. Its all about quality control and repair and we already have the innate tools within us, its all about learning to talk to our bio-machine and that language is slowly being revealed.

 

Its not like we need some SiFi Borg Nonobot to go to each cell to repair them, we already have that Technology built within us that's billions of years in the making.

 

 

 

 

I agree, and you can read my post just above. However, we have to make the difference between autophagy and mitophagy as explained above. But I think some points was already discussed here isnt ?

 

UPDATE:

 

Nicotinamide-induced mitophagy: event mediated by high NAD+/NADH ratio and SIRT1 protein activation.

Abstract

Active autophagy coupled with rapid mitochondrial fusion and fission constitutes an important mitochondrial quality control mechanism and is critical to cellular health. In our previous studies, we found that exposure of cells to nicotinamide causes a decrease in mitochondrial content and an increase in mitochondrial membrane potential (MMP) by activating autophagy and inducing mitochondrial fragmentation. Here, we present evidence to show that the effect of nicotinamide is mediated through an increase of the [NAD(+)]/[NADH] ratio and the activation of SIRT1, an NAD(+)-dependent deacetylase that plays a role in autophagy flux. The [NAD(+)]/[NADH] ratio was inversely correlated with the mitochondrial content, and an increase in the ratio by the mobilization of the malate-aspartate shuttle resulted in autophagy activation and mitochondrial transformation from lengthy filaments to short dots. Furthermore, treatment of cells with SIRT1 activators, fisetin or SRT1720, induced similar changes in the mitochondrial content. Importantly, the activators induced mitochondrial fragmentation only when SIRT1 expression was intact. Meanwhile, MMP did not increase when the cells were treated with the activators, suggesting that the change in MMP is not induced by the mitochondrial turnover per se and that elevation of the [NAD(+)]/[NADH] ratio may activate additional mechanisms that cause MMP augmentation. Together, our results indicate that a metabolic state resulting in an elevated [NAD(+)]/[NADH] ratio can modulate mitochondrial quantity and quality via pathways that may include SIRT1-mediated mitochondrial autophagy.

 

 

and older:

 

Nicotinamide enhances mitochondria quality through autophagy activation in human cells.

Abstract

Nicotinamide (NAM) treatment causes a decrease in mitochondrial respiration and reactive oxygen species production in primary human fibroblasts and extends their replicative lifespan. In the current study, it is reported that NAM treatment induces a decrease in mitochondrial mass and an increase in membrane potential (DeltaPsim) by accelerating autophagic degradation of mitochondria. In the NAM-treated cells, the level of LC3-II as well as the number of LC3 puncta and lysosomes co-localizing with mitochondria substantially increased. Furthermore, in the NAM-treated cells, the levels of Fis1, Drp1, and Mfn1, proteins that regulate mitochondrial fission and fusion, increased and mitochondria experienced dramatic changes in structure from filaments to dots or rings. This structural change is required for the decrease of mitochondrial mass indicating that NAM accelerates mitochondrial autophagy, at least in part, by inducing mitochondrial fragmentation. The decrease in mitochondria mass was attenuated by treatment with cyclosporine A, which prevents the loss of mitochondrial membrane potential by blocking the mitochondrial permeability transition, suggesting autophagic degradation selective for mitochondria with low DeltaPsim. All these changes were accompanied by and dependent on an increase in the levels of GAPDH, and are blocked by inhibition of the cellular conversion of NAM to NAD(+). Taken together with our previous findings, these results suggest that up-regulation of GAPDH activity may prolong healthy lifespan of human cells through autophagy-mediated mitochondria quality maintenance.

 

 

 

 

 

Edited by Tom Andre F. (ex shinobi), 28 April 2016 - 12:27 AM.

[Bryan_S]

"Nicotinamide (NAM) treatment causes a decrease in mitochondrial respiration" I believe with SIRT1 down regulation you might see a decrease in mitochondrial mass and (NAM) is a known inhibitor. On the other hand Nicotinamide is a NAD precursor so it should help maintain NAD if NAMPT levels can be maintained.

 

I've always felt for the mitochondria it was survival of the fittest. But we should also acknowledge their are true mitochondrial mutations and we have LongeCity members like Asor who are suffering as a result. We will see what research points us to in the coming months and years but its becoming more apparent that when everything is working properly the cell absorbs dysfunctional organelle like Mitochondria and promotes the biogenesis of the healthy ones. 

Edited by Bryan_S, 28 April 2016 - 06:48 AM.

[Nate-2004]

Better to stop milk and dairy unlike what you used to be teached. Milk is full of pro inflammatory.. I really mean full: 32 hormones including estrogen such as estradiol, androgen such as DHT.. growth hormones and all of course in a ratio you dont want for human. Furthermore it contains lactose a very pro inflammatory compound, and even worst: casein. People who are looking to live long just cant drink eat dairy. No way. You will have more calcium in your blood vessel than on your bones actually. its called calcification

 

I don't mean to derail this thread at all from NR but:

 

I've heard this before about DHT and milk but I've never been able to verify it. There are plenty of blog posts and message boards claiming as much out there on Google searches but nothing backing them up. I have been drinking specifically Horizon Organic milk for about 22 of those 42 years. It has no hormones of any kind, they don't give the cows IGF-1 or any antibiotics or anything. I still have all my hair, for now at least.

 

 

Anyway, back to the interesting discussion.

[Tom Andre F. (ex shinobi)]

 

Better to stop milk and dairy unlike what you used to be teached. Milk is full of pro inflammatory.. I really mean full: 32 hormones including estrogen such as estradiol, androgen such as DHT.. growth hormones and all of course in a ratio you dont want for human. Furthermore it contains lactose a very pro inflammatory compound, and even worst: casein. People who are looking to live long just cant drink eat dairy. No way. You will have more calcium in your blood vessel than on your bones actually. its called calcification

 

I don't mean to derail this thread at all from NR but:

 

I've heard this before about DHT and milk but I've never been able to verify it. There are plenty of blog posts and message boards claiming as much out there on Google searches but nothing backing them up. I have been drinking specifically Horizon Organic milk for about 22 of those 42 years. It has no hormones of any kind, they don't give the cows IGF-1 or any antibiotics or anything. I still have all my hair, for now at least.

 

 

Anyway, back to the interesting discussion.

 

 

Nope.. I get the info from a professor from the cancer department from Montpellier (France). He studied organic milk to understand why the prostate he see these days are twice the normal volume etc and he said all milk samples are positiv to hormones. And in unbalanced and high quantity compared to human. Naturally milk contain hormones but the non human ones have differents kind and ratio totally different. Human been is not made to drink milk of another species he concluded. Seems also confirmed by harvard: http://news.harvard....7/11-dairy.html (the more pregnant the more the hormones, and it is nothing related to the growth hormones some company can inject them). Naturally milk contains hormones its a fact. They are all necessary for the baby cow growth that has to grow at a rate totally different than the baby human. It is also confirmed (with all the references at the end) here: http://drhyman.com/b...use-acne/#close :

 

Here’s a short list of the 60-some hormones in your average glass of milk – even the organic, raw, and bovine growth hormone free milk:

• 20α-dihydropregnenolone
• progesterone (from pregnenolone)
• 5α-pregnanedione
• 5α-pregnan-3β-ol-20-one, 20α- and 20β-dihydroprogesterone (from progesterone)
• 5α-androstene-3β17β-diol
• 5α-androstanedione
• 5α-androstan-3β-ol-17-one
• androstenedione
• testosterone
• dehydroepiandrosterone sulphate acyl ester
• insulin like growth factors 1 and 2 (IGF-1 and IGF-2)
• insulin etc

 

 

And again, casein and lactose are 2 very potent pro inflammator that by themmselves make you age faster and faster (the mutation we all speak here etc)

 

Sorry but this topic really makes me wonder how in 2016 people can still continue with dairy while just normal logic is enough to understand why its a bad thing.

 

 

To come back to the topic:

 

Telomeres are directly linked to mito dysfunction via the P53-PGC mitochondrial/metabolic axis:

 

http://www.ncbi.nlm....les/PMC3718635/

 

and TGF beta 1 removal is a real target since then mito damage no longer in evidence, look the full study and this pathway: http://www.ncbi.nlm....7204/figure/F4/

 

Im now wondering to finally close the loop of NAD+ and telomeres
 

Edited by Tom Andre F. (ex shinobi), 28 April 2016 - 12:40 PM.

[Nate-2004]

 

Nope.. I get the info from a professor from the cancer department from Montpellier (France). He studied organic milk to understand why the prostate he see these days are twice the normal volume etc and he said all milk samples are positiv to hormones. And in unbalanced and high quantity compared to human. Naturally milk contain hormones but the non human ones have differents kind and ratio totally different. Human been is not made to drink milk of another species he concluded. Seems also confirmed by harvard: http://news.harvard....7/11-dairy.html (the more pregnant the more the hormones, and it is nothing related to the growth hormones some company can inject them). Naturally milk contains hormones its a fact. They are all necessary for the baby cow growth that has to grow at a rate totally different than the baby human. It is also confirmed (with all the references at the end) here: http://drhyman.com/b...use-acne/#close :

 

Here’s a short list of the 60-some hormones in your average glass of milk – even the organic, raw, and bovine growth hormone free milk:

• 20α-dihydropregnenolone
• progesterone (from pregnenolone)
• 5α-pregnanedione
• 5α-pregnan-3β-ol-20-one, 20α- and 20β-dihydroprogesterone (from progesterone)
• 5α-androstene-3β17β-diol
• 5α-androstanedione
• 5α-androstan-3β-ol-17-one
• androstenedione
• testosterone
• dehydroepiandrosterone sulphate acyl ester
• insulin like growth factors 1 and 2 (IGF-1 and IGF-2)
• insulin etc

 

 

And again, casein and lactose are 2 very potent pro inflammator that by themmselves make you age faster and faster (the mutation we all speak here etc)

 

Sorry but this topic really makes me wonder how in 2016 people can still continue with dairy while just normal logic is enough to understand why its a bad thing.

 

 

To come back to the topic:

 

Telomeres are directly linked to mito dysfunction via the P53-PGC mitochondrial/metabolic axis:

 

http://www.ncbi.nlm....les/PMC3718635/

 

and TGF beta 1 removal is a real target since then mito damage no longer in evidence, look the full study and this pathway: http://www.ncbi.nlm....7204/figure/F4/

 

Im now wondering to finally close the loop of NAD+ and telomeres
 

 

 

Sorry again about derailing this, perhaps we can move this to another thread if anybody has that ability.

 

From the harvard link: "But steps can be taken now to reduce the amount of hormones in milk, said Ganmaa. Because hormones reside in milk fat, drinking skim milk is one option. Getting calcium from green leafy vegetables is another."

 

All I have ever drank and all I ever drink is fat free skim milk btw. I also *hate* vegetables, worst tasting things ever, bitter as hell. I think I have that gene where veggies taste awful. Leafy green veggies are a low source of calcium by comparison.

 

As for why people still eat dairy, it's because a school newspaper post on a website design from 1999 (even if it is Harvard), Gwyneth Paltrow and ad ridden blog posts selling supplements aren't enough to convince anyone to stop the foods they love. It's unconvincing. Also people love it. I love diary. Cheese is one of my favorite foods. I can't get enough of it. It's delicious. Milk is probably in everything I love from my favorite kind of chocolate to my favorite kind of pizza and bread, though I avoid those things as much as I can. My latest bloodwork was fantastic, my bones are super strong, I have all my hair still. Maybe it is aging me, but not so sure about that. If it's skim milk, maybe not... according to that Harvard article you linked.

 

That blog post with the doctor by the way recommends probiotics, which is in yogurt, which is dairy, which is a contradiction because other anti-dairy blog posts say it has DHT in it. I dunno how to get around that one. I guess they're just trying to sell probiotic supplements. I have eaten tons of probiotics all the last year or so both in supplement form, yogurt and in sauerkraut. They're super good for social anxiety and depression and mood.

 

As for casein proteins, I know that they bind to anti-oxidants easily and that it's important to avoid them when eating anti-oxidant foods. Casein proteins have their own benefits when it comes to building muscles and bones. Scientists are also still in hot debate on anti-oxidants and have been for some time.

 

As for pro-inflammatory... I'm not super worried about that as I also take a lot of anti-inflammatory things. Not sure if they all cancel each other out or what. CBD is an anti-inflammatory, NSAIDS are anti-inflammatory, according to some sources non fat Yogurt /probiotics is/are anti-inflammatory in the gut, olive oil, etc...

 

I did just switch to non-fat yogurt after you pointed out the Harvard article, thanks for that.

Edited by Nate-2004, 28 April 2016 - 01:50 PM.

[stefan_001]

Nicotinamide Riboside reverses fatty liver disease in mice

 

http://www.timelessl...isease-in-mice/

 

NAD+ boosting by feeding animals with a diet enriched in nicotinamide riboside may prevent or reverse NAFLD by inducing the mitochondrial unfolded protein response (UPRmt) which in turn triggers a mitohormetic response.

 

Edited by stefan_001, 28 April 2016 - 02:52 PM.