471 replies to this topic

[Tom Andre F. (ex shinobi)]

 

Here is the patent list regarding niagen: https://chromadex.co...ts/Patents.html

 

does that mean that no one else can synthesis NR without being under the patent law ??

 

I think they patented their own particular process to make NR.

Others can eventually come up with a different process.

 

 

It seems they bought some univeristy patents and have a knd of the full range to synthesised it. I would like to offer some NR pure for cheap but then i can come under their patent... I will need to look deeper into that. Its weird because NR is found naturally in nature.

[smithx]

NR is not protected. NR-Cl is protected if you use their patented process (and if the patents are valid).

 

 

[Tom Andre F. (ex shinobi)]

NR is not protected. NR-Cl is protected if you use their patented process (and if the patents are valid).

 

what is your source to say that ? When you look at this page, you can see at least 2 patent which protect the route of synthesis for NR:

 

https://chromadex.co...ts/Patents.html

 

for exemple they patented a method to get NR from Saccharomyces strain by making them produce NR via culture into a media..

 

Thats crazy but they bought most of their patent from old one from university etc..

 

BUT I will keep looking to produce my own NR. Since its in nature, im sure it exist some other alternative to produce it in a cost effective way. Lets see

[Bryan_S]

Good luck . . . It is produced in nature but not in quantities you'd find adequate to supplement your NAD needs. They did an outstanding job of taking trace amounts created and excreted by yeast and disabling those same yeast cells from utilizing the NR they produced. Now if you could genetically modify a yeast cell to do the same, feed it Niacin or Niacinamide as a feedstock mixed in the growth media you might find yourself on the proper path.

 

This as close as I can point you, most of us don't have these resources. This was the result of several years of trial and error and they deserve the rewards of their efforts.

Nrt1 and Tna1-Independent Export of NAD+ Precursor Vitamins Promotes NAD+ Homeostasis and Allows Engineering of Vitamin Production

 

Edited by Bryan_S, 29 August 2015 - 11:57 PM.

[Tom Andre F. (ex shinobi)]

Good luck . . . It is produced in nature but not in quantities you'd find adequate to supplement your NAD needs. They did an outstanding job of taking trace amounts created and excreted by yeast and disabling those same yeast cells from utilizing the NR they produced. Now if you could genetically modify a yeast cell to do the same, feed it Niacin or Niacinamide as a feedstock mixed in the growth media you might find yourself on the proper path.

 

This as close as I can point you, most of us don't have these resources. This was the result of several years of trial and error and they deserve the rewards of their efforts.

Nrt1 and Tna1-Independent Export of NAD+ Precursor Vitamins Promotes NAD+ Homeostasis and Allows Engineering of Vitamin Production

 

NR is not only produced by yeast. Thats why I think we can check other ways to produce it. and chromadex didnt made directly the patents, actually they just bought it to some university. I sould have an answer soon of its possible or not to turn around these patents anyway

 

 

[curious_sle]

 

ACTIVATION OF AMP-PROTEIN ACTIVATED KINASE BY OXALOACETATE COMPOUNDS

 

United States Patent Application 20150238450 http://www.freepaten...15/0238450.html

 

Not sure if anyone else noticed this on the radar today, I think it deserves a little side research. Oxaloacetate also seems to be listed as a Caloric restriction mimetic and a AMPK Booster. There were some studies done on oxaloacetate and C. elegans. Now Caenorhabditis elegans are a rather easy organism to work with. It seems like we see a number of compounds increasing their life span. However it appears later studies included mouse models so there might be something to take note of after all.

 

I also found a little discussion on it here on LongeCity but it seems to have lost momentum.

 

At any rate anything that activates mitochondrial biogenesis and acts as a AMPK booster is topic on this thread.

 

 

I wonder if Oxaloacetate ( see benagene.org for more, it's been comercialized a while ago already) and NR are synergetic. Any insights?

[bluemoon]

This isn't intended as a vendor plug, but rather as what I consider to be news: The company I buy Niagen from (Live Cell Research) called me on the phone and offered me a multi-bottle sale at 40-50% off, which gets the cost for a bottle of 30 250 mg capsules down to $20-25. That's about $3/gram, which still isn't cheap, but it's a lot cheaper than it has been! (This was a direct offer and not available through their website--at least not presently.)

 

So, this might be a sign of the long-hoped-for price drop, and hopefully it will begin to spread to all vendors.

 

There has been a price drop at Elysium as well, which adds 50mg of pterostilbene to 250mg of NR (60 capsules of 125mg bottles), and started selling 6 month and 12 month subscriptions for $45 and $40 a bottle, down from the previous plan of $60/ one time bottle and  $50 for a monthly subscription. I think this is fairly recent. 

Edited by bluemoon, 31 August 2015 - 10:07 AM.

[smithx]

They seem to have patents I wasn't aware of. Either they listed them or obtained them after I last checked, or I missed it. Taken at face value, they have the market locked up, and even more than locked up (see the last patent below).

 

One of their patents covers any "pharmaceutical" use of NR. I think that could be vulnerable on the grounds of being obvious. (http://patft.uspto.g...RS=PN/8,383,086)

 

A second patent covers any use as a pill if in combination with "one or more of tryptophan, nicotinic acid, or nicotinamide". Probably most preparations would be contain impurities, some of which would be likely to be nicotinic acid or nicotinamide, so this would seem to protect most pills. Again, maybe vulnerable because of the fact that these are likely impurities and not material to utility. http://patft.uspto.g...RS=PN/8,197,807

 

A third patent may be the most troubling, because it appears to protect anything which increases "sirtuin activity in diseased and/or injured neurons and supporting cells in an amount effective to decrease axonal degeneration". Since this is probably true of anything that increases SIRT, this patent would appear to control every type of Sirutin activation!

Again, I think it may be vulnerable, this time because of prior art in that there were other known sirutin activators before the filing date of the patent. http://patft.uspto.g...RS=PN/7,776,326

 

 

 

 

 

NR is not protected. NR-Cl is protected if you use their patented process (and if the patents are valid).

 

what is your source to say that ? When you look at this page, you can see at least 2 patent which protect the route of synthesis for NR:

 

https://chromadex.co...ts/Patents.html

 

for exemple they patented a method to get NR from Saccharomyces strain by making them produce NR via culture into a media..

 

Thats crazy but they bought most of their patent from old one from university etc..

 

BUT I will keep looking to produce my own NR. Since its in nature, im sure it exist some other alternative to produce it in a cost effective way. Lets see

 

 

 

[resveratrol_guy]

 

 

ACTIVATION OF AMP-PROTEIN ACTIVATED KINASE BY OXALOACETATE COMPOUNDS

 

United States Patent Application 20150238450 http://www.freepaten...15/0238450.html

 

Not sure if anyone else noticed this on the radar today, I think it deserves a little side research. Oxaloacetate also seems to be listed as a Caloric restriction mimetic and a AMPK Booster. There were some studies done on oxaloacetate and C. elegans. Now Caenorhabditis elegans are a rather easy organism to work with. It seems like we see a number of compounds increasing their life span. However it appears later studies included mouse models so there might be something to take note of after all.

 

I also found a little discussion on it here on LongeCity but it seems to have lost momentum.

 

At any rate anything that activates mitochondrial biogenesis and acts as a AMPK booster is topic on this thread.

 

 

I wonder if Oxaloacetate ( see benagene.org for more, it's been comercialized a while ago already) and NR are synergetic. Any insights?

 

 

Kudos to Bryan for reintroducing this incredible substance. I'm now taking it based on the impressive (and largely ignored, apparently) science behind it.

 

So to your question, there is, as we know, a clear connection between NR and caloric restriction in terms of the NAD+/NADH ratio. It turns out that oxaloacetate is as close as it gets to CR in a bottle. See the interview linked in my post here on the Benagene thread, which is probably a better place to discuss oxaloacetate.
 

Edited by resveratrol_guy, 02 September 2015 - 11:32 AM.

[Bryan_S]

Revolutionary New Nutrients? Part 1 - Dr. Ronald Hoffman

 

Podcast

 

http://drhoffman.com...trients-part-1/

 

http://drhoffman.com...trients-part-2/

 

"Could these supplements be the CoQ10s and resveratrols of tomorrow? Frank Jaksch, founder and CEO of ingredient-manufacturer Chromadex, discusses nicotinamide riboside (Niagen, Niacel) and pterostilbene (PteroPure), two novel nutraceuticals with enormous promise. Could nicotinamide ribosome revolutionize our approach to mitochondrial disorders? Why is NADH important to the human body? Does nicotinamide riboside deliver benefits for energy, neurological support, blood sugar regulation, cholesterol optimization, or sports performance? Could it provide anti-aging benefits? What about its potential for hearing protection and tinnitus? New human trials are underway, and dozens of researchers are exploring its applications worldwide. Pterolstilbine, found in blueberries, is an antioxidant compound that may support brain and circulatory health. Will these promising but little-known nutrients be mainstreamed?"

[resveratrol_guy]

Revolutionary New Nutrients? Part 1 - Dr. Ronald Hoffman

 

Podcast

 

http://drhoffman.com...trients-part-1/

 

http://drhoffman.com...trients-part-2/

 

"Could these supplements be the CoQ10s and resveratrols of tomorrow? Frank Jaksch, founder and CEO of ingredient-manufacturer Chromadex, discusses nicotinamide riboside (Niagen, Niacel) and pterostilbene (PteroPure), two novel nutraceuticals with enormous promise. Could nicotinamide ribosome revolutionize our approach to mitochondrial disorders? Why is NADH important to the human body? Does nicotinamide riboside deliver benefits for energy, neurological support, blood sugar regulation, cholesterol optimization, or sports performance? Could it provide anti-aging benefits? What about its potential for hearing protection and tinnitus? New human trials are underway, and dozens of researchers are exploring its applications worldwide. Pterolstilbine, found in blueberries, is an antioxidant compound that may support brain and circulatory health. Will these promising but little-known nutrients be mainstreamed?"

 

 

For what it's worth, I'm taking 300-500 mg/d of PteroPure, in case I can be of use as a guinea pig. This is a huge dose which carries some risk of acute hypoglycemia, GRAS status notwithstanding. I'm doing this because it seems to be the single most effective way to reduce phosphotau (see APBT's full text above), which is IMO the most dangerous aspect of Alzheimer's, especially while a vaccine is still in phase 2 trials. At this dose, in combination with 100 mg/d Benagene oxaloacetate (thank you, Bryan), I've noticed outrageously strong hunger tolerance in just the few days that I've been on both. I'm down to about 1000 calories/d and I only seem to get hungry for half an hour or so in the evening. Granted, my idea of exercise is maybe 15 minutes/d, low intensity aerobic or light weights. Probably I'll need to move up to 1400 or so once all my fat is burned. In any event, the combination seems to work, unless there's some coincidence going on which I haven't considered.

[Bryan_S]

For what it's worth, I'm taking 300-500 mg/d of PteroPure, in case I can be of use as a guinea pig. This is a huge dose which carries some risk of acute hypoglycemia, GRAS status notwithstanding. I'm doing this because it seems to be the single most effective way to reduce phosphotau (see APBT's full text above), which is IMO the most dangerous aspect of Alzheimer's, especially while a vaccine is still in phase 2 trials. At this dose, in combination with 100 mg/d Benagene oxaloacetate (thank you, Bryan), I've noticed outrageously strong hunger tolerance in just the few days that I've been on both. I'm down to about 1000 calories/d and I only seem to get hungry for half an hour or so in the evening. Granted, my idea of exercise is maybe 15 minutes/d, low intensity aerobic or light weights. Probably I'll need to move up to 1400 or so once all my fat is burned. In any event, the combination seems to work, unless there's some coincidence going on which I haven't considered.

 

 

 (see APBT's full text above)

 

Your link went missing. I searched and found a post about "Low-dose pterostilbene, but not resveratrol, is a potent neuromodulator

in aging and Alzheimer’s disease" I trust this is the correct one. Thank you APBT for finding that.

 

Which vender's product containing PteroPure are you taking? I'm also searching for the best value as I take 100mg/d and felt this was on the low side.

 

I hadn't considered starting a Benagene oxaloacetate regiment yet. My interest was peaked some months back from research produced by Professor Hayashi who if proven correct then glycine supplementation may also be an additional stopgap measure.

 

http://www.longecity...-12#entry741005

 

I've gone back further and found some other interest on this thread and others.

http://www.longecity...e-7#entry730229

 

http://www.longecity...e-7#entry730669

 

http://www.longecity...lf/#entry736069

 

http://www.longecity...e-be-taking-it/

 

As I've mentioned I'm looking for root interventions and with many of these I see them as secondary or further down the stream. NAD boosting is right at the pinnacle Metabolic respiration/Cellular respiration. If Professor Hayashi is correct than part of the aging problem might be in 2 genes that regulate Glycine.

 

"The researchers then looked for genes that might be controlled epigenetically resulting in these age-associated mitochondrial defects. Two genes that regulate glycine production in mitochondria, CGAT and SHMT2, were found. The researchers showed that by changing the regulation of these genes, they could induce defects or restore mitochondrial function in the fibroblast cell lines. In a compelling finding, the addition of glycine for 10 days to the culture medium of the 97 year old fibroblast cell line restored its respiratory function. This suggests that glycine treatment can reverse the age-associated respiration defects in the elderly human fibroblasts.

These findings reveal that, contrary to the mitochondrial theory of aging, epigenetic regulation controls age-associated respiration defects in human fibroblast cell lines. Can epigenetic regulation also control aging in humans? That theory remains to be tested, and if proven, could result in glycine supplements giving our older population a new lease of life."

[resveratrol_guy]

 

For what it's worth, I'm taking 300-500 mg/d of PteroPure, in case I can be of use as a guinea pig. This is a huge dose which carries some risk of acute hypoglycemia, GRAS status notwithstanding. I'm doing this because it seems to be the single most effective way to reduce phosphotau (see APBT's full text above), which is IMO the most dangerous aspect of Alzheimer's, especially while a vaccine is still in phase 2 trials. At this dose, in combination with 100 mg/d Benagene oxaloacetate (thank you, Bryan), I've noticed outrageously strong hunger tolerance in just the few days that I've been on both. I'm down to about 1000 calories/d and I only seem to get hungry for half an hour or so in the evening. Granted, my idea of exercise is maybe 15 minutes/d, low intensity aerobic or light weights. Probably I'll need to move up to 1400 or so once all my fat is burned. In any event, the combination seems to work, unless there's some coincidence going on which I haven't considered.

 

 

 (see APBT's full text above)

 

Your link went missing. I searched and found a post about "Low-dose pterostilbene, but not resveratrol, is a potent neuromodulator

in aging and Alzheimer’s disease" I trust this is the correct one. Thank you APBT for finding that.

 

Which vender's product containing PteroPure are you taking? I'm also searching for the best value as I take 100mg/d and felt this was on the low side.

 

I hadn't considered starting a Benagene oxaloacetate regiment yet. My interest was peaked some months back from research produced by Professor Hayashi who if proven correct then glycine supplementation may also be an additional stopgap measure.

 

http://www.longecity...-12#entry741005

 

I've gone back further and found some other interest on this thread and others.

http://www.longecity...e-7#entry730229

 

http://www.longecity...e-7#entry730669

 

http://www.longecity...lf/#entry736069

 

http://www.longecity...e-be-taking-it/

 

As I've mentioned I'm looking for root interventions and with many of these I see them as secondary or further down the stream. NAD boosting is right at the pinnacle Metabolic respiration/Cellular respiration. If Professor Hayashi is correct than part of the aging problem might be in 2 genes that regulate Glycine.

 

"The researchers then looked for genes that might be controlled epigenetically resulting in these age-associated mitochondrial defects. Two genes that regulate glycine production in mitochondria, CGAT and SHMT2, were found. The researchers showed that by changing the regulation of these genes, they could induce defects or restore mitochondrial function in the fibroblast cell lines. In a compelling finding, the addition of glycine for 10 days to the culture medium of the 97 year old fibroblast cell line restored its respiratory function. This suggests that glycine treatment can reverse the age-associated respiration defects in the elderly human fibroblasts.

These findings reveal that, contrary to the mitochondrial theory of aging, epigenetic regulation controls age-associated respiration defects in human fibroblast cell lines. Can epigenetic regulation also control aging in humans? That theory remains to be tested, and if proven, could result in glycine supplements giving our older population a new lease of life."

 

 

Yes, that's the study. You can see from the HPLC results how pterostilbene was able to reduce phosphotau. I don't know of any more effective (or cost-effective, for that matter) means of doing so. But I'm all ears if anyone else knows how to dissolve tau oligomers while we wait and hope that tau vaccine works.

 

I got mine as bulk powder direct from Chromadex. Their process control is impressive. They can even provide intricate detail regarding solvent contamination levels per-batch.

 

I think oxaloacetate is basically as much of a root intervention as NR. It's right there in the citric acid cycle. Now that I'm paying more attention, I'm noticing a few hours of improved mental clarity starting about an hour after ingestion. I'm so familiar with brain fog (unfortunately) that I'm quite confident that this is above the placebo threshold. But according to Alan Cash, it's "as toxic as vitamin C", so IMO the benefits outweigh the risks.

 

I think glycine supplementation is probably hopeless. We presumably get grams of the stuff per day just from ordinary protein sources, right? Supplementing it might unnecessarily stimulate IGF1, like protein does generally. It sounds like what we really care about is using CRISPR or something to tweak CGAT and SHMT2. Maybe someone should tell Bioviva to look into this.
 

[Bryan_S]

 

I got mine as bulk powder direct from Chromadex. Their process control is impressive. They can even provide intricate detail regarding solvent contamination levels per-batch.

 

I think glycine supplementation is probably hopeless. We presumably get grams of the stuff per day just from ordinary protein sources, right? Supplementing it might unnecessarily stimulate IGF1, like protein does generally. It sounds like what we really care about is using CRISPR or something to tweak CGAT and SHMT2. Maybe someone should tell Bioviva to look into this.
 

 

Epigenetic regulation of the nuclear-coded GCAT and SHMT2 genes confers human age-associated mitochondrial respiration defects

http://www.nature.co...icles/srep10434

 

Being that we are talking about Epigenetic regulation of the nuclear-coded GCAT and SHMT2 genes we likely don't need CRISPR and some other intervention is likely to be discovered and administered to ones whole body. 

 

The main point is Professor Hayashi may have identified the actual cause of the Age-associated respiration defects with these experiments. The fact that they got respiratory improvements by treating the cells with Glycine is enormously encouraging. Of course I would like to see this experiment duplicated. The fact that in vitro supplementation of Glycine restored mitochondrial respiration without the step of resetting the epigenome of the GCAT and SHMT2 genes suggests we have a possible oral supplementation path, even if they fail in fixing the epigenetic coding of these 2 genes. They point out that the underlying DNA is not mutated. Then the next step should be animal studies and if those results reflect the in vitro results human trials should follow.

 

We do produce it but if falls off with age as suggested in the articles. We also consume anywhere from 2-10 grams/day. Its also regarded as a nonessential nutrient but that opinion may change. 
 

 

Scientists reverse aging in human cell lines and give theory of aging a new lease of life

http://www.viewzone.com/glycine.html

Edited by Bryan_S, 07 September 2015 - 02:42 AM.

[ceridwen]

It seems to me that as soon as a health warning comes out about something the food industry counters this with opposing research saying it is actually good for us. We have just been warned about AGES and now we are told to eat pork scratchings which must be full of AGES it is nice and crispy yum. We are also told to eat all sorts of other skins from meat and gelatine everyone seems to have forgotten the BSE scare and now suddenly meat is said to be healthy. I would really like glycine to work and shall probably buy some pork scatchings tomorrow to see if they help but at the same time I don't hold out much hope. I'd have to try this for 10 days to see an improvement? What is the optimal amount of glycine one is supposed to take?

[Bryan_S]

I think what I like about Professor Hayashi is he's saying the accepted mitochondrial theory of aging is wrong and for an academic to lay it on the line like this deserves our respect or at least your attention until proven wrong. "The mitochondrial theory of aging, proposes that age-associated mitochondrial defects are controlled by the accumulation of mutations in the mitochondrial DNA." He is a total maverick defying this general consensus and lays out a compelling argument for us in support of his study. As I mentioned above I would like to see some additional study confirmation.

 

As to dosage he hasn't given us a therapeutic range but that doesn't mean there isn't any data on it's safety or experimental dosages.

Here is the general safety white paper.

http://www.onboces.o...cine_315.00.pdf

 

Now I'm not suggesting we all go out and buy some glycine. I am saying we need to watch this work and it may prove to be an additional stopgap measure. If you are like me and actively boosting NAD levels to increase your mitochondrial activity then fixing them or bypassing the epigenetic impediments they've accumulated with glycine supplementation is of special interest.

 

For those who jump the gun however it appears to be relatively safe but don't take this as an endorsement to experiment.

https://research.amn...sds/Glycine.pdf

http://examine.com/s...ements/glycine/

 

As the previous article suggests it has been studied for its ability to help with sleep problems.

http://onlinelibrary...E44F67C1.d01t02

http://www.ncbi.nlm....les/PMC3328957/

 

Glycine is also an approved sweetener and currently added to foods we eat.

 

Here is a complete list of clinical trials. https://clinicaltria...e&Search=Search

Now as far as large dosages I've found clinical studies on Schizophrenia where the dosages were in the 30-40 gram/day range. I am not suggesting this dosage but it does help lay out previously used quantities. 

 

Glycine is also manufactured synthetically, so don't confuse it with gelatin which contains a high percentage of Glycine but is an animal derivative.

 

Edited by Bryan_S, 07 September 2015 - 08:37 AM.

[ceridwen]

Glycine tastes very sweet followed by a salty after taste? Do I have real glycine?
Glycine tastes very sweet followed by a salty after taste? Do I have real glycine?

[resting]

It is sweet.

[ceridwen]

Yes it is used as a sweetener. Thanks

[Bryan_S]

Here is an article from Feb 23, 2015 which we missed.  The author missed a few comparative precursor points but does a OK job of pulling most of the relevant facts together as an introduction to the concept of NAD+ Boosting. In the end he plugs another product that claims to be superior to resveratrol and we take no stand on its claims.  

 

Sorting Out the Science Behind Modern Medicines Newest Anti-Aging Pills

http://www.resveratr...ing-pills/1180/

[Tom Andre F. (ex shinobi)]

Here is an article from Feb 23, 2015 which we missed.  The author missed a few comparative precursor points but does a OK job of pulling most of the relevant facts together as an introduction to the concept of NAD+ Boosting. In the end he plugs another product that claims to be superior to resveratrol and we take no stand on its claims.  

 

Sorting Out the Science Behind Modern Medicines Newest Anti-Aging Pills

http://www.resveratr...ing-pills/1180/

 

very interesting Bryan, i think i will use his chart about the PARP activity (NAD+ consuming). I think when we consider that part, it clearly show that it is not possible to reverse aging by only feeding NAD+ precursor such as NR.. And you come always to the same conclusion, we need also to control the PARP activity, wich comes to the NO1 topic, that I spoke about ( http://www.beta-lapa...f-healthy-life/ ), beta-lapachone is surely one of the best candidate to date.

 

EDIT: the supplement is is speaking longevinex is actually: resveratrol supplemented with 5% quercetin and 5% rice bran phytate (commercially known as Longevinex). These ingredients were micronized to increase the bioavailability.

 

its interesting to see that this supplement increase SIRT3 in a very good manner

Edited by Tom Andre F. (ex shinobi), 07 September 2015 - 08:39 PM.

[Bryan_S]

Tom,

 

Thanks for the contribution on β-lapachone. I've looked over the link you provided and while most of that I would agree is supported by study, how these metabolic states are reached gives me reason for pause.

 

Most of what I've read about β-lapachone is in the context of β-lapachone-induced cell death and in the realm of Cancer therapy. I read one mouse study where administration of β-lapachone created conditions resembling Calorie Restriction with raised NAD levels and extended mouse lifespan, so I'll be fair in saying they got a 17% increase and with CR only 10%. We also know with such short lived organisms often small shifts in metabolism can produce significant results. Since we are only talking about weeks or months those gains can also represent metabolic sacrifices in longer lived organisms which could shorten overall life-span where reaching the distant finish line takes a different strategy.  Lets examine how they got there.

 

The recognized mechanism attributed to the increased NAD+ levels seems to be connected to the Inhibition of poly(ADP-ribose) polymerase activation. PARP Poly ADP ribose polymerase. Now depending on the degree of inhibition this can have far reaching effects. This compound also raised ROS and produced conditions were (superoxide and hydrogen peroxide are then generated.) This compound can also stress the cell into activating NQO1 gene expression in an attempt to shift the NAD+/NADH ratio to react to a perceived stress. I would also expect it might also raise AMPK levels. We typically associate these last 2 changes as positive but the devil is in the details. Now in a mouse/rat that only lives 3-months to 2-years sacrificing some DNA maintenance by inhibiting PARP obviously extended life-span and the accumulated DNA errors were not significant enough to pose a problem in the limited time span of the study. Lets take this scenario out another 60-80 years and this PARP sacrifice might at first provide short-lived benefits but is going to manifest its own tolls in ways I can't comprehend. Our bodies are forever moving towards cellular entropy but we have a regenerative capacity to forestall the inevitable and PARP plays part of the repair roll.

 

So on one hand it can raise NAD levels and on the other it can stress the repair of DNA and bring about cell death which might be the desired outcome in cancer treatments where this induced stress can weed out cancer cells. I believe this is where this compound has its true value.

 

Now I have just combed thru multiple studies and may have missed details outside the main theme of PARP inhibition. I don't see these things as a negative in the context they are written. They appear to be valid cancer attack vectors and depending on dose they can be used to weed out the diseased tissue from the healthy. Personally I don't think I want to experiment with anything to attenuate or subdue my Poly ADP ribose polymerase activity. In fact I want to feed this pathway as much NAD+ as it demands, not limit its use unless there is a desired goal such as killing rogue cancer cells.

 

Is there a perspective I'm missing? I don't mind being proven wrong but I don't see a longterm benefit outside of cancer treatments. I think you and I had this conversation once before.

 

 

http://www.nature.co...is2014202a.html

[resveratrol_guy]

I think what I like about Professor Hayashi is he's saying the accepted mitochondrial theory of aging is wrong and for an academic to lay it on the line like this deserves our respect or at least your attention until proven wrong. "The mitochondrial theory of aging, proposes that age-associated mitochondrial defects are controlled by the accumulation of mutations in the mitochondrial DNA." He is a total maverick defying this general consensus and lays out a compelling argument for us in support of his study. As I mentioned above I would like to see some additional study confirmation.

 

As to dosage he hasn't given us a therapeutic range but that doesn't mean there isn't any data on it's safety or experimental dosages.

Here is the general safety white paper.

http://www.onboces.o...cine_315.00.pdf

 

Now I'm not suggesting we all go out and buy some glycine. I am saying we need to watch this work and it may prove to be an additional stopgap measure. If you are like me and actively boosting NAD levels to increase your mitochondrial activity then fixing them or bypassing the epigenetic impediments they've accumulated with glycine supplementation is of special interest.

 

For those who jump the gun however it appears to be relatively safe but don't take this as an endorsement to experiment.

https://research.amn...sds/Glycine.pdf

http://examine.com/s...ements/glycine/

 

As the previous article suggests it has been studied for its ability to help with sleep problems.

http://onlinelibrary...E44F67C1.d01t02

http://www.ncbi.nlm....les/PMC3328957/

 

Glycine is also an approved sweetener and currently added to foods we eat.

 

Here is a complete list of clinical trials. https://clinicaltria...e&Search=Search

Now as far as large dosages I've found clinical studies on Schizophrenia where the dosages were in the 30-40 gram/day range. I am not suggesting this dosage but it does help lay out previously used quantities. 

 

Glycine is also manufactured synthetically, so don't confuse it with gelatin which contains a high percentage of Glycine but is an animal derivative.

 

First off, thanks for pointing out that this is an epigenetic tweak we're talking about, so you're clearly right that we don't need to do any DNA editing, provided that we can find a way of flipping the switches in the right direction on expression of both genes.

 

OTOH I think supplementation is a nonstarter, if you're correct that we already get several grams a day dietarily, and a useful intervention dose might be north of 30 g/d. That's total daily protein intake for some people. And there are various essential (unsynthesizable) amino acids, so we need to reserve some protein grams for them. It seems quite unlikely that we could do both without (1) upregulating IGF1 and all its evil cascades or (2) migrating to a protein-dominated diet, which even the case of CR, implies rampant gluconeogenesis, AKA AGEy glucose metabolism.
 

It sounds like what might work is some form of targetted (lipidated? pyruvated?) glycine, given the low likelihood that we'll have access to the required epigenetic tweaks anytime soon.

[Bryan_S]

I would like to see Professor Hayashi's results duplicated and his glycine insights confirmed.

 

The epigenetic path might be feasible to up-regulate production but currently no one is working on this, at least yet.

 

If this proves out, supplementation might tip the scales filling the deficit and this has already been suggested in his research.

 

I make no inference into what quantity might be needed to fill this deficit but the clinical trials on Schizophrenia suggest tolerable upper limits in the 30-40gram/day range which appears high at first glance. My past experience with glycine tells me I likely couldn't take that much anyway. From my perspective it acted as an appetite suppressant, so at some point you wouldn't want to consume levels past a certain point. From what I've read one teaspoon of glycine powder provides 2.8 grams of glycine and it is readily available at a nominal cost either in powder of capsule so its not difficult to obtain. 

 

I don't think we've heard the last of this challenge to the accepted mitochondrial theory of aging but if confirmed we might see a relatively easy path of intervention to strengthen aging mitochondrial respiration.

 

On that note I read a recent comparative article that suggests how the normal mitochondrial metabolism changes with age. (Young vs Old) http://medicalxpress...nction-age.html So even if we stimulate mitochondrial biogenesis along with sirtuin activation with our NAD boosting, my question is; "are we still faced with duplicating aging mitochondria that don't easily switch from lipid oxidation to glucose oxidation?" If this is the case then glycine supplementation may also be an additional stopgap measure to restore functionality.

 

So I'm still very much in the question phase but see this as a possible adjuvant therapy to NAD boosting.

[docmaas]

one teaspoon is 4.568 gm according to the bag I have from Bulk Supplements on Amazon.com.  I'm taking 15-20 gms/day in @5gm chunks with meals to reduce blood sugar.  Seems to be helping but my next a1c should give me a better idea of how much.  I've noticed nothing other than the taste.  I usually mix a tsp with crystalized lime juice (True Lime) and carbonated water.  Makes a nice soda.

 

Mike

[Bryan_S]

one teaspoon is 4.568 gm according to the bag I have from Bulk Supplements on Amazon.com.  I'm taking 15-20 gms/day in @5gm chunks with meals to reduce blood sugar.  Seems to be helping but my next a1c should give me a better idea of how much.  I've noticed nothing other than the taste.  I usually mix a tsp with crystalized lime juice (True Lime) and carbonated water.  Makes a nice soda.

 

Mike

 

Most interesting, the A1C test is a common blood test used to diagnose type 1 and type 2 diabetes. Have you approached glycine as a treatment for diabetes? Obviously you have glucose concerns or you wouldn't be following this regiment and watching levels.

 

Indeed as I read more I see glycine is involved in gluconeogenesis.  I also see "The metabolic response to ingested glycine" showing that supplementation is a documented management tool for blood sugar problems. I also see papers reaching back many decades so this isn't just a coincidence suggesting a mitochondrial connection. I'm beginning to see a recognized inter-relationship here adding further credibility to this glycine mitochondrial connection as Professor Hayashi suggests.

 

Mike let us know about the effectiveness of your glucose response? I also expect since you are posting on the "Nicotinamide Riboside Current News and Updates" forum you are already taking NR and looking for synergistic compounds to augment your glucose management, correct?

[resveratrol_guy]

So maybe plain old glycine supplementation is effective, after all. But I really think it's inefficient at fasting glucose reduction as compared to a 100 mg to 1 g of oxaloacetate per day. While I recommend watching the entire video, definitely check out the graph at 14:21 if you have glucose management problems.

 

 

[Tom Andre F. (ex shinobi)]

 

Tom,

 

Thanks for the contribution on β-lapachone. I've looked over the link you provided and while most of that I would agree is supported by study, how these metabolic states are reached gives me reason for pause.

 

Most of what I've read about β-lapachone is in the context of β-lapachone-induced cell death and in the realm of Cancer therapy. I read one mouse study where administration of β-lapachone created conditions resembling Calorie Restriction with raised NAD levels and extended mouse lifespan, so I'll be fair in saying they got a 17% increase and with CR only 10%. We also know with such short lived organisms often small shifts in metabolism can produce significant results. Since we are only talking about weeks or months those gains can also represent metabolic sacrifices in longer lived organisms which could shorten overall life-span where reaching the distant finish line takes a different strategy.  Lets examine how they got there.

 

The recognized mechanism attributed to the increased NAD+ levels seems to be connected to the Inhibition of poly(ADP-ribose) polymerase activation. PARP Poly ADP ribose polymerase. Now depending on the degree of inhibition this can have far reaching effects. This compound also raised ROS and produced conditions were (superoxide and hydrogen peroxide are then generated.) This compound can also stress the cell into activating NQO1 gene expression in an attempt to shift the NAD+/NADH ratio to react to a perceived stress. I would also expect it might also raise AMPK levels. We typically associate these last 2 changes as positive but the devil is in the details. Now in a mouse/rat that only lives 3-months to 2-years sacrificing some DNA maintenance by inhibiting PARP obviously extended life-span and the accumulated DNA errors were not significant enough to pose a problem in the limited time span of the study. Lets take this scenario out another 60-80 years and this PARP sacrifice might at first provide short-lived benefits but is going to manifest its own tolls in ways I can't comprehend. Our bodies are forever moving towards cellular entropy but we have a regenerative capacity to forestall the inevitable and PARP plays part of the repair roll.

 

So on one hand it can raise NAD levels and on the other it can stress the repair of DNA and bring about cell death which might be the desired outcome in cancer treatments where this induced stress can weed out cancer cells. I believe this is where this compound has its true value.

 

Now I have just combed thru multiple studies and may have missed details outside the main theme of PARP inhibition. I don't see these things as a negative in the context they are written. They appear to be valid cancer attack vectors and depending on dose they can be used to weed out the diseased tissue from the healthy. Personally I don't think I want to experiment with anything to attenuate or subdue my Poly ADP ribose polymerase activity. In fact I want to feed this pathway as much NAD+ as it demands, not limit its use unless there is a desired goal such as killing rogue cancer cells.

 

Is there a perspective I'm missing? I don't mind being proven wrong but I don't see a longterm benefit outside of cancer treatments. I think you and I had this conversation once before.

 

 

http://www.nature.co...is2014202a.html

 

 

the fact that the result in life extension is better in the beta lapachone group than the CR group, is what is really impressive. Im not sure to have even seen sch result, even in the C60 study (it was only control group versus olive oil versus C6Ooo)

 

which study do you use to say BL increase ROS production please ? Are you sure its not in a cancer cell line only ?

 

about the metabolic sacrifice part, im not sure to follow you... I will look deeper into what you say and come back to you. i think feed the NAD+ precursor is clearly not enough, and the studies showing parp activity increase with age by a lot comes in that sense. We need to control parp. The repair activity of parp you are speaking about doesnt make sense knowing the role of NAD+ into cells. I really want to move forward with that. Thanks

I would like to see Professor Hayashi's results duplicated and his glycine insights confirmed.

 

The epigenetic path might be feasible to up-regulate production but currently no one is working on this, at least yet.

 

If this proves out, supplementation might tip the scales filling the deficit and this has already been suggested in his research.

 

I make no inference into what quantity might be needed to fill this deficit but the clinical trials on Schizophrenia suggest tolerable upper limits in the 30-40gram/day range which appears high at first glance. My past experience with glycine tells me I likely couldn't take that much anyway. From my perspective it acted as an appetite suppressant, so at some point you wouldn't want to consume levels past a certain point. From what I've read one teaspoon of glycine powder provides 2.8 grams of glycine and it is readily available at a nominal cost either in powder of capsule so its not difficult to obtain. 

 

I don't think we've heard the last of this challenge to the accepted mitochondrial theory of aging but if confirmed we might see a relatively easy path of intervention to strengthen aging mitochondrial respiration.

 

On that note I read a recent comparative article that suggests how the normal mitochondrial metabolism changes with age. (Young vs Old) http://medicalxpress...nction-age.html So even if we stimulate mitochondrial biogenesis along with sirtuin activation with our NAD boosting, my question is; "are we still faced with duplicating aging mitochondria that don't easily switch from lipid oxidation to glucose oxidation?" If this is the case then glycine supplementation may also be an additional stopgap measure to restore functionality.

 

So I'm still very much in the question phase but see this as a possible adjuvant therapy to NAD boosting.

 

This is exactly for what im concern too.. Otherwize PQQ should extend lifespan, and it does not.

For the "glycine therapy", why you want to feed us with extra dosage while the food already contains enough ? Maybe not enough but still why do not rather: control / regulate the two genes involved with the production of glycine (CGAT and SHMT2), because maybe im wrong, but the addition of glycine to reverse the aging is only seen into a medium so we do not take care the vivo and absorption part for exemple wich can be related to the aging process. I think we should rather be able to control the 2 genes, for me it looks more promising isnt ?

Edited by Tom Andre F. (ex shinobi), 09 September 2015 - 06:02 PM.

[Tom Andre F. (ex shinobi)]

From the study:

 

"defects in glycine metabolism in the mitochondria as a result of a reduction in SHMT2 and GCAT expression would be partly responsible for the reduction in mitochondrial translation, resulting in the expression of age-associated respiration defects. Because continuous glycine treatment restored respiration defects in elderly human fibroblasts (Supplementary Fig. 6), glycine supplementation may be effective in preventing age-associated respiration defects and thus benefiting the health of elderly human subjects."

 

so by supplementing in glycine (if we forget all the absorption and pharmakokinetics process) you dont really reverse aging, you just benefit elerderly people (wich is still good..) but SHMT2 and GCAT are what matters. We need now to focus on that pathway too.

Edited by Tom Andre F. (ex shinobi), 09 September 2015 - 07:37 PM.

[Bryan_S]

 

 

1) the fact that the result in life extension is better in the beta lapachone group than the CR group, is what is really impressive.

 

2) which study do you use to say BL increase ROS production please ? Are you sure its not in a cancer cell line only ?

 

3) about the metabolic sacrifice part, im not sure to follow you...

 

4) For the "glycine therapy", why you want to feed us with extra dosage while the food already contains enough ? Maybe not enough but still why do not rather: control / regulate the two genes involved with the production of glycine (CGAT and SHMT2)

 

 

I just had some oral surgery and I'm not 100% with the pain killers but here are my thoughts.

 

#1 yes I agree it was very impressive and and the β-lapachone group lived longer. 

 

#2 yes I was looking at the cancer data.

 

#3 I will have to go back an look at the data again, here is why. I was reading a study that clearly stated it was a PARP inhibitor. "DNA damage and cytotoxicity induced by beta-lapachone: relation to poly(ADP-ribose) polymerase inhibition." and another article suggesting "excessive poly(ADP-ribose) polymerase (PARP) activation and subsequent depletion of intracellular NAD(+) and ATP were seen in beta-lapachone-treated U2-OS cells." Clearly we can't have it both ways. Inhibitor and/or excessive activator.

 

The best explanation I've uncovered on the β-lapachone mechanisms of action comes from cancer studies, like in this link. "The selective necrotic cell death in cancer cells following PARP1 activation induced by β-lapachone may involve a difference in either the magnitude of, or the response to PARP1 activation. Our preliminary data suggest that β-lapachone can activate PARP1 in normal cells, albeit to a lesser degree (Li W et al., unpublished data). Yet no necrotic cell death is induced in normal cells in the absence of unrepairable or lethal DNA damage. We hypothesize that cancer cells or cells with unrepairable DNA damage may be hypersensitive to PARP activation, leading to apoptotic or necrotic cell death." 

 

So again as to #3, since I see studies at adds with each other maybe we have a selective situation. If it is a PARP inhibitor this would help raise NAD levels in heathy tissue. This would be a sacrifice to normal PARP activity. In cancer cells it appears to accelerate PARP activation leading to depleted NAD levels and cell death. In the longevity mouse study they attribute the life extension benefits to increased NQO1 gene expression and increasing NAD+/NADH ratio.

 

I still come back to my original statement "how these metabolic states are reached gives me reason for pause."

 

Since I can't fairly determine if my earlier β-lapachone assessments were correct because the data points both ways, I'm going to a neutral corner and wait this one out. It looks like a selective cancer tool, that much I'm pretty convinced of because of multiple studies spanning over 10-years. As far as a longevity tool I'm going to wait for more than one study because it appears to be a powerful PARP modifier. With a 17% increase in lifespan it should have reverberated thru the scientific community and with a publication date of October 11, 2012 we should have seen this life-extension aspect of β-lapachone revisited in a follow-up study by now to confirm the findings and mechanisms of action.

 

#4 yes I think a (CGAT and SHMT2) epigenetic modifier would be the most desirable path. There is no mention of CGAT and SHMT2 in the sirtuin activators this is new territory. So a pathway to modify these genes hasn't been identified yet. However since measurable glucose results have been obtained thru Glycine supplementation this might be a viable path until a CGAT and SHMT2 modifier is found. I think this deserves further consideration to supplement our mitochondrial functionality. Its cheap, appears to be safe which is a priority and as I mentioned I'd like to see follow up studies to confirm Professor Hayashi's results.

 

Now this recent interest in oxaloacetate by resveratrol_guy after we found the patent application has me thinking.

 

ACTIVATION OF AMP-PROTEIN ACTIVATED KINASE BY OXALOACETATE COMPOUNDS

 

So what about safety, absorption and availability. If we can shift the NAD+/NADH ratio this would be of benefit to add to our NAD boosting. Tip of the hat to resveratrol_guy for the Alan Cash oxaloacetate video.

Edited by Bryan_S, 10 September 2015 - 02:19 AM.