Edited

[Mechanism]

Edited

Edited July 19, 2020 by Mechanism

[Dean Pomerleau]

Mechanism,

 

Let me google that for you. Oh lookie there. The #3 return is Michael Rae's recent SENS research blog post on Nicotinamide Riboside (NR) - the main ingredient in Elysium.

 

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.

 

--Dean (channeling Michael so he doesn't have to...)

[Mechanism]

Edited

Edited July 19, 2020 by Mechanism

[Dean Pomerleau]

Mechanism,

 

I'm glad you found Michael's post helpful, and my search strategy a useful tip.

 

While I don't always agree with Michael about everything, you really can't go wrong by checking what (if anything) he has said on a topic (particularly a supplement-related topic) before forming your own opinion.

 

--Dean

[Michael R]

Let me google that for you.

Oh, my — what a wonderful little snark-tool ...

 

Michael Rae's recent SENS research blog post on Nicotinamide Riboside (NR) ...

 

Summary:

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

 

I wouldn't actually go quite that far. I would say that it hasn't been shown to increase NAD in muscle, after oral administration. It's reasonably clear that it does so in the liver and the blood — although there hasn't IMO yet been enough work done using equimolar amounts of plain-assed niacin or nicotinamide as a positive control.

 

Dean (channeling Michael so he doesn't have to...)

Genuinely appreciated, Dean!

 

While I don't always agree with Michael about everything, you really can't go wrong by checking what (if anything) he has said on a topic (particularly a supplement-related topic) before forming your own opinion.

That is very high praise coming from anyone, and you in particular, sir ...

[Dean Pomerleau]

Michael,

Oh, my — what a wonderful little snark-tool ...

Yes, Let Me Google That for You is a nice little service. But I prefer to see it as a educational tool, rather than a means of chastising the indolent.

 

Mechanism seemed to interpret it in exactly in the spirit with which it was intended, as opportunity to learn a helpful search strategy - namely to append your name to any search query related to dietary supplements to see what you may have had to say on the topic.

 

That is very high praise coming from anyone, and you in particular, sir ...

See - I'm not always snarky :-).  Simply giving credit where credit is due.

 

--Dean

[Mechanism]

Edited

Edited July 19, 2020 by Mechanism

[notmuffy]

Thanks for this thread - I was seriously considering that "Basis" product before I read this. I won't waste my money.

[Sthira]

Thanks for this thread - I was seriously considering that "Basis" product before I read this. I won't waste my money.

Ahem, well, if you wanted to waste less money on "Basis" you could just take 50mg of pterostilbene (which is only like $12 bottle from Jarrow) and 250mg Niagen ($$$$), and that's pretty much what "Basis" equals. Not that you should or would or should not do such things, but such things are within collective gazes.

[Dean Pomerleau]

Wouldn't you know it. Two days after I get done trash-talking Nicotinamide Riboside (NR) as a supplement for health and longevity a new paper [1] (pop press article) comes out in the journal Science no less, apparently showing that NR supplementation extends lifespan in older mice by preventing their stem cells from turning senescent:

 

NR treatment of C57BL/6J mice slightly increased lifespan (chow diet, mean

829 ± 12.0; NR, mean 868 ± 12.4 days, p = 0.034) (Fig. 6G).

The beneficial effect of NR on survival was further confirmed

by Cox proportional hazards analysis (Fig. 6H). Although

the lifespan benefit is small, it was obtained with the

NR treatment commencing late in life at 24 months.

 

Here are the two survival curves for the NR-treated and control mice, in terms of how many days they lived after the treatment with NR (or placebo) began:

 

 

Here are some more impressive graphs from the full text, showing NAD+ was increased in both young and aged mice treated with NR, both groups had more viable muscle stem cells, ran longer and farther (when facing threat of shock), and had higher grip strength than controls:

 

 

 

Pretty impressive results, seeming to contradict Michael's contention that NR is not likely to be effective. Michael, did get (at least) one thing right in his analysis, these mice were fed a lot of NR - 400mg/kg-BW/day according to the paper's supplemental material (pdf), which is the human equivalent of 2000-4000 mg/day. To get that level, you'd have to consume a whole 30-capsule bottle of this 100mg LEF-brand NR supplements per day. At $25/bottle, that comes to $750/month. I'm sure you could get NR cheaper in bulk and/or from some less reputable supplement vendor, so Michael's estimate of $400-500/month is probably close to accurate - which is still a lot of money...

 

But I'm curious what Michael thinks about this new study. Hopefully he'll see this and share his thoughts and insights. Perhaps we should deploy the Bat Signal. 

 

 

--Dean

 

------------

[1] Science. 2016 Apr 28. pii: aaf2693. [Epub ahead of print]

NAD+ repletion improves mitochondrial and stem cell function and enhances life
span in mice.

Zhang H(1), Ryu D(1), Wu Y(2), Gariani K(1), Wang X(1), Luan P(1), D'Amico D(1),
Ropelle ER(3), Lutolf MP(4), Aebersold R(5), Schoonjans K(6), Menzies KJ(7),
Auwerx J(8).

Full text: http://sci-hub.cc/10.1126/science.aaf2693

Adult stem cells (SCs) are essential for tissue maintenance and regeneration yet
are susceptible to senescence during aging. We demonstrate the importance of the
amount of the oxidized form of cellular nicotinamide adenine dinucleotide
(NAD(+)) and its impact on mitochondrial activity as a pivotal switch to modulate
muscle SC (MuSC) senescence. Treatment with the NAD(+) precursor nicotinamide
riboside (NR) induced the mitochondrial unfolded protein response (UPR(mt)) and
synthesis of prohibitin proteins, and this rejuvenated MuSCs in aged mice. NR
also prevented MuSC senescence in the Mdx mouse model of muscular dystrophy. We
furthermore demonstrate that NR delays senescence of neural SCs (NSCs) and
melanocyte SCs (McSCs), and increased mouse lifespan. Strategies that conserve
cellular NAD(+) may reprogram dysfunctional SCs and improve lifespan in mammals.

Copyright © 2016, American Association for the Advancement of Science.

PMID: 27127236

[Sthira]

http://www.the-japan-news.com/news/article/0003030620

 

1st clinical trial set for ‘anti-aging compound’

 

The Yomiuri ShimbunKeio University and Washington University in St. Louis plan to begin a joint clinical study in Japan to test the safety and effectiveness in humans of a compound that is gradually being proved to retard the aging process in animals, scientists have said.

 

Keio University’s Research Ethics Committee will check the appropriateness of the plan and other factors. If approved, researchers plan to begin giving the compound — nicotinamide mononucleotide (see below) or NMN — to about 10 healthy people to confirm its safety. They will then examine whether NMN can improve functions of the human body.

 

The clinical study is scheduled to begin as early as next month.

 

A research group including Prof. Shinichiro Imai of Washington University, a gerontology expert, has found that NMN activates a gene called sirtuin, which is known for its anti-aging effects. An experiment giving NMN to mice found that the compound can reverse age-linked declines in metabolism and eyesight.

 

The study is planned to be conducted by researchers including Prof. Imai and Keio University, using NMN produced by a Japanese maker. The central government has decided to provide full-fledged support for anti-aging studies from next fiscal year, and is also paying attention to this clinical study.

 

“We’ve confirmed a remarkable effect in the experiment using mice, but it’s not clear yet how much [the compound] will affect humans,” Imai said. “We’ll carefully conduct the study, which I hope will result in important findings originating in Japan.”

 

Lower medical costs

 

By Takashi Ito / Yomiuri Shimbun Staff Writer

 

Progress in the study of a substance believed to help slow the aging process may reduce medical and nursing-care expenses, according to specialists.

 

How to prolong people’s healthy life span is an important task for Japan’s rapidly aging society. The study of the reportedly age-retarding substance may make it possible for elderly people to live their daily lives free of restrictions, they said.

 

A planned clinical study of the substance — Nicotinamide Mononucleotide (NMN) — by Keio University and Washington University in St. Louis has the possibility of extending the healthy life span of people in the future. An experiment using mice has shown that NMN is instrumental in slowing the aging process, thereby prolonging healthy life expectancy.

 

Starting next fiscal year, the government will make full-fledged efforts to promote projects aimed at slowing the aging process, using a large amount of budgetary appropriations for this endeavor. The move is expected to promote research activities in this field of study.

 

However, it is unknown what effect will NMN have on humans.

 

“The age-retarding effect of NMN has been only detected in such animals as mice. It’s necessary to carefully inspect the effects [of the substance],” said Prof. Daisuke Koya of Kanazawa Medical University, an expert in the aging process.

 

The planned clinical study will use NMN by treating it as food. If it is found to be safe for humans and has any benefits, NMN will likely be distributed as a product similar to “food with functional claims.”

 

■ NMN=Nicotinamide Mononucleotide

 

A chemical compound produced within the bodies of many living things, including people. NMN is also contained in food products. An experiment using mice is gradually showing that this compound activates sirtuin, whose functions are weakened due to aging, improving such things as symptoms of diabetes.

[Sthira]

Anyone here flirting with this expensive Niagen product yet?

 

Lookee, actual studies in humans:

 

https://clinicaltrials.gov/ct2/results?term=Nicotinamide+riboside&Search=Search

[Todd Allen]

I've been taking Nicotinamide Riboside (NR) since May.  The effect for me at the standard dosing of 125 mg 2x daily was pretty much unnoticeable.  But I started taking Nicotinic Acid (NA) in addition to NR and as I increased the dose of NA I got a measurable dose dependent boost in my endurance.  NA is cheaper, $30 a kilogram, compared $3+ per gram for NR, making higher dosing practical.  At 3 grams / day of NA I ran into issues with flushing, fast pulse and low blood pressure and I have backed off to 1.5 grams / day even though with each additional 500 grams daily through 3 grams daily I gained performance.

 

NA has been shown to boost NAD in the liver and muscle.  And I believe NR also boosts NAD in neurons.  When I run low on NR I will try suspending taking NR on alternate weeks and see if there is any measurable impact on performance.  If not, due to cost I will probably stop taking NR while continuing to take NA.  Note, my disease, SBMA, impairs mitochondrial function and appears to upregulate processes that consume NAD - which could contribute to mitochondrial dysfunction, so normal people may respond differently.

 

NA has been studied and used far more than NR.  NA is most often prescribed for hyperlipidemia with dosing as high as 5 or 6 grams daily though many experience a lot of flushing at that level and a few have liver issues/damage, especially when taking slow release forms that minimize flushing.  Myself, I've had a stunning improvement in the past 3 months between blood lipid tests with triglycerides dropping by more than half and hdl almost doubling resulting in greater than 4x improvement of my triglycerides to hdl ratio which is considered by some to be an excellent predictor of CVD risk.

[Sthira]

Pathway linked to slower aging also fuels brain cancer

 

http://m.medicalxpress.com/news/2016-12-pathway-linked-slower-aging-fuels.html

 

December 6, 2016

 

While a particular metabolic pathway shows potential to slow down the aging process, new research indicates a downside: That same pathway may drive brain cancer.

 

The pathway, known as the nicotinamide adenine dinucleotide (NAD+) pathway, is overactive in a deadly form of brain cancer known as glioblastoma, according to a study by researchers at Washington University School of Medicine in St. Louis. Glioblastoma is the most common and aggressive brain cancer in adults. Over 70 percent of patients with glioblastoma die within two years of diagnosis.

 

The new research showed that glioblastoma patients with high expression of an NAD+ pathway gene known as NAMPT died sooner. Tumors with elevated expression of the same gene grew rapidly when they were implanted in mice and shrank when NAMPT was inhibited.

 

The study, published Dec. 5 in Proceedings of the National Academy of Sciences, suggests that inhibiting the NAD+ pathway may improve the outlook for glioblastoma patients but also may affect other biological processes, such as aging.

 

NAMPT produces a molecule known as nicotinamide mononucleotide (NMN) that has been shown to reduce signs of aging in mice. While its safety in people has yet to be determined – a clinical trial is ongoing in Japan – NMN and other molecules along the NAD+ pathway are being marketed as anti-aging supplements.

 

"There's a lot of buzz about taking NAD+ precursors for their anti-aging effects, which is based on a lot of great science," said Albert H. Kim, MD, PhD, an assistant professor of neurological surgery and the senior author on the study. "We didn't directly demonstrate that taking NAD+ precursors makes tumors grow faster, but one implication of our work is that if you want to take anti-aging NAD+ precursors, you might want to keep in mind that we don't yet understand all the risks."

 

Using human glioblastoma cells, Kim, postdoctoral researcher Amit Gujar, PhD, and colleagues showed that NAMPT helped cancerous stem cells survive and proliferate, fueling the growth of existing tumors, while inhibiting NAMPT reduced the ability of the cancer stem cells to renew themselves.

 

Furthermore, the scientists found that glioblastoma cells responded to radiation therapy – a standard therapy used to treat the disease in people – by increasing expression of NAD+ pathway genes, and that inhibiting NAMPT before dosing the cells with radiation made them easier to kill.

 

"If you target the NAD+ pathway, you can disrupt the ability of the cancer stem cells to self-renew, and you can also make them more sensitive to radiation treatment," said Kim, who also treats patients with brain tumors at Siteman Cancer Center at Washington University School of Medicine and Barnes-Jewish Hospital. "In a patient, that could mean that if you suppress the pathway, the same dose of radiation may be more effective at destroying the tumor."

 

The NAD+ pathway involves many different genes and proteins, and its very complexity may be the key to having it both ways. Kim believes it may be possible to carefully modulate the pathway so as to suppress cancer without accelerating aging or interfering with other important biological processes.

 

"The question we are considering now is, 'How do we make an NAD+ strategy that is specific for cancer?'" Kim said. "Maybe there are some cancer-specific regulators, and we can disrupt those. Maybe we can change the expression of some key NAD+ pathway genes only in cancer cells, not healthy cells. There are many ways to look at this, and that's why we want to dig deeper into how this pathway works in glioblastoma."

 

More information: An NAD+-dependent transcriptional program governs self-renewal and radiation resistance in glioblastoma. Proceedings of the National Academy of Sciences. Dec. 5, 2016.

[Todd Allen]

Sthira,

 

Thanks much for posting the possible linkage between NAD+ and cancer.  Curiously there have been several studies of people with polyglutamine expansion disorders (such as my disease SBMA and Huntington's)  and it has been found that people with these diseases have significantly reduced rates of cancer although I don't believe a cause for it has been elucidated.  Mitochondrial impairment seems to be a factor in all the polyglutamine diseases and the role of mitochondria in many cancers is an increasingly hot topic.  There's some evidence that NAD depletion plays a role in my disease and I think it's also considered a potential factor in Huntington's and quite a few other neurological disorders.

 

All of these potential linkages are pretty fascinating.  Perhaps I'm increasing my risk of cancer by taking nicotinic acid and nicotinamide riboside.  I'm also probably increasing my cancer risk by trying to maximize IGF1 and MTOR.  But severe muscle wasting is highly correlated with early death not to mention the impact it has on quality of life.  So for myself, I'm going to stick with doing all of the things which appear to have reversed my muscle wasting, including taking the NAD precursors and cross my fingers that I don't push my luck too far with respect to cancer.

[Sthira]

All of these potential linkages are pretty fascinating. Perhaps I'm increasing my risk of cancer by taking nicotinic acid and nicotinamide riboside. I'm also probably increasing my cancer risk by trying to maximize IGF1 and MTOR. But severe muscle wasting is highly correlated with early death not to mention the impact it has on quality of life. So for myself, I'm going to stick with doing all of the things which appear to have reversed my muscle wasting, including taking the NAD precursors and cross my fingers that I don't push my luck too far with respect to cancer.

Maybe NAD balance is both a preventer and promoter of cancer? Is this study relevant to you?

 

http://www.scitechnol.com/peer-review/nad-in-cancer-prevention-and-treatment-pros-and-cons-zR4d.php?article_id=5285

 

Is a now nearly 4-years old mouse study relevant?

 

https://www.scripps.edu/newsandviews/e_20130225/felding.html

 

"..."To find out if the balance of NAD+ and NADH was critical for tumor cell behavior, the team proceeded to insert a yeast gene into cancer cells that caused a shift toward more NAD+. To the scientists’ amazement, this shift caused the tumor cells to become less aggressive..."

 

Scientists' amazement at 'nother mice study; but cute-whiskered mice (whatever their genetic histories) may bear little relevance to cancer in naked apes, and it's also about breast cancer, but, hey, you wrote somewhere else that we have more in common with chickens than we have differences with chickens, so if that observation holds straight for mice and humans, well, we've cured cancer decades ago. Meanwhile, let us keep dabbling with mice cancer rather than more intently studying the millions of women already are cursed with breast cancer.

 

Chin up, head high, ignore mouse studies.

Edited December 6, 2016 by Sthira

[Michael R]

I've been taking Nicotinamide Riboside (NR) since May. ... I started taking Nicotinic Acid (NA) in addition ... I got a measurable dose dependent boost in my endurance. NA is cheaper ... At 3 grams / day of NA I ran into issues with flushing, fast pulse and low blood pressure and I have backed off to 1.5 grams / day even though with each additional 500 grams daily through 3 grams daily I gained performance.

 

NA has been shown to boost NAD in the liver and muscle.

 

NA has been studied and used far more than NR. NA is most often prescribed for hyperlipidemia with dosing as high as 5 or 6 grams daily though many experience a lot of flushing at that level and a few have liver issues/damage

In addition to liver toxicity, there is pretty strong evidence for a significant risk of niacin-associated diabetes:

 

Niacin therapy and the risk of new-onset diabetes: a meta-analysis of randomised controlled trials

 

... We included trials with ≥50 non-diabetic participants and average follow-up of ≥24 weeks. Published data were tabulated and unpublished data sought from investigators. We calculated risk ratios (RR) for new-onset diabetes with random-effects meta-analysis. ...

 

Results In 11 trials with 26,340 non-diabetic participants, 1371 (725/13,121 assigned niacin; 646/13,219 assigned control) were diagnosed with diabetes during a weighted mean follow-up of 3.6 years. Niacin therapy was associated with a RR of 1.34 (95% CIs 1.21 to 1.49) for new-onset diabetes, with limited heterogeneity between trials (I²=0.0%, p=0.87). This equates to one additional case of diabetes per 43 (95% CI 30 to 70) initially non-diabetic individuals who are treated with niacin for 5 years. Results were consistent regardless of whether participants received background statin therapy (p for interaction=0.88) or combined therapy with [anti-flushing medication] laropiprant (p for interaction=0.52). ... [N]o difference was observed when comparing the trials that had or had not used background statin treatment (p=0.84 for interaction; see online supplementary eFigure 4). We performed an analysis with the largest trial, HPS2-THRIVE (which provided 65% of the overall weighting of the main analysis), excluded. In the remaining 10 trials, the RR of new-onset diabetes on niacin was similarly elevated at 1.38 ...

 

The mechanism that explains niacin's detrimental effect on glycaemic control and diabetes risk remains unclear. The observation that statins also increase diabetes risk and that this appears to be an on-target effect suggests that a specific lipid-modifying effect warrants particular attention. ... The data from HPS2-THRIVE also confirm that clinically significant deteriorations in glucose control in patients with diabetes are substantially increased on niacin. In those known to have diabetes at baseline in this major trial, there was a 55% increase in serious disturbances in glucose control for patients with diabetes, most of whom required hospital admission as a result. These findings contrast with earlier and smaller trials with shorter follow-up which suggested that the detrimental effect of niacin on glucose may only be temporary and therefore of potentially limited clinical importance. Additionally, the Coronary Drug Project showed that the relative risk of developing diabetes on niacin was similar regardless of whether patients had impaired fasting glycaemia (IFG) or normoglycaemia though the absolute risk was higher in IFG due to the increased rate of progression to diabetes.

 

Even with the discovery that statins modestly increase diabetes risk, their cardiovascular benefits still greatly outweigh any such metabolic risk. With niacin, the risk:benefit ratio appears far less favourable. Recent major niacin trials have now confirmed a lack of cardiovascular benefit when niacin is added to statin therapy ... In HPS2-THRIVE, gastrointestinal events, musculoskeletal events and infectious adverse events were increased on niacin. The results from HPS2-THRIVE and AIM-HIGH differ from the historical Coronary Drug Project, a clinical trial of niacin monotherapy which suggested modest cardiovascular benefit with similar effects across all glycaemic categories.

 

PMID: 26370223

 

A possible mechanism linked to lipid metabolism is niacin's effects on free fatty acids, which it initially suppresses but leads to a later rebound. Such a rebound would axially induce transient insulin resistance via the Randle cycle. That would seem to be more consistent with a transient, reversible effect.

 

A somewhat obscure second possible mechanism is through metabolic conversion of niacin to N-methylnicotinamide, a waste product of NAD⁺-consuming activities.

 

Diabetic subjects had significantly higher plasma N(1)-methylnicotinamide levels 5 h after a 100-mg nicotinamide load than the non-diabetic subjects (0.89 +/- 0.13 micromol/L vs 0.6 +/- 0.13 micromol/L, P < 0.001). Cumulative doses of nicotinamide (2 g/kg) significantly increased rat plasma N(1)-methylnicotinamide concentrations associated with severe insulin resistance, which was mimicked by N(1)-methylnicotinamide. Moreover, cumulative exposure to N(1)-methylnicotinamide (2 g/kg) markedly reduced rat muscle and liver NAD contents and erythrocyte NAD/NADH ratio, and increased plasma H(2)O(2) levels. Decrease in NAD/NADH ratio and increase in H(2)O(2) generation were also observed in human erythrocytes after exposure to N(1)-methylnicotinamide in vitro. Sweating eliminated excessive nicotinamide (5.3-fold increase in sweat nicotinamide concentration 1 h after a 100-mg nicotinamide load).

PMID 19960564

 

In human and rodent urine, it was previously found that 'species demonstrated profound changes in nucleotide metabolism, including that of NMN [here N-methylnicotinamide, not nicotinamide mononucleotide ...], which may provide unique biomarkers for following type 2 diabetes progression' In diabetic individuals, decreased urinary levels and slower plasma clearance of NMN after nicotinamide overload have been observed. Nicotinic acid and nicotinamide have been reported to induce insulin resistance and NMN is thought to trigger this effect. In light of these previous findings and our results, NMN might therefore represent an interesting biomarker for prednisolone-induced insulin resistance.

PMID 23199229

 

In a recent study on human and mouse nicotinamide riboside metabolism, 100 and 300 mg of oral NR had little effect on  levels of N-methylnicotinamide in human PBMC, but 1000 mg/d caused a substantial increase; in mouse liver, nicotinamide riboside elevated N-methylnicotinamide close to twice as much as niacin does. On the other hand, it has been shown to substantially blunt diabetes in mice, albeit at spectacular doses. It may be worth watching none the less.

 

Perhaps most mechanistically worrisome are the recent studies linking niacin's activation of the "niacin receptor" GPR109A/PUMA-G:

 

Eight-week niacin treatment elevated blood glucose concentration in obese mice with increased areas under the curve at oral glucose and intraperitoneal insulin tolerance tests. Additionally, niacin treatment significantly decreased glucose-stimulated insulin secretion (GSIS) but induced peroxisome proliferator-activated receptor gamma (Pparg) and GPR109a expression in isolated pancreatic islets; concomitantly, reactive oxygen species (ROS) were transiently increased, with decreases in GSIS, intracellular cyclic adenosine monophosphate (cAMP) accumulation and mitochondrial membrane potential (ΔΨm), but with increased expression of uncoupling protein 2 (Ucp2), Pparg and Gpr109a in INS-1E cells. Corroborating these findings, the decreases in GSIS, ΔΨm and cAMP production and increases in ROS, Pparg and GPR109a expression were abolished in INS-1E cells by GPR109a knockdown.

 

PMID 25622782

 

High levels of PUMA-G transcripts and protein were detected in all β cells, and about 40% of α cells. PUMA-G transcripts increased more than 3-fold in islets incubated with [the inflammatory cytokine] interferon γ. Cyclic adenosine monophosphate accumulation, induced by IBMX/forskolin, was inhibited by [nicotinic acid/niacin] .... Static incubation of islets with NA led to an approximately 30% reduction of GSIS. The results indicated that PUMA-G stimulation by NA in islet β cells inhibited GSIS likely via activation of the Gi signaling pathway.

PMID: 21441844

 

GPR109A was significantly reduced in islets from diabetic individuals and animal model of db/db mice as compared to their respective controls. Further, GPR109A levels in insulinoma were also reduced dramatically as compared to islets found in corresponding non-tumor normal tissues. Quantitative RT-PCR analysis demonstrated that GPR109A transcripts were severely down-regulated in rodent insulinoma cell lines as compared to that of freshly isolated islets from mice. Finally, human and murine GPR109A expression cassettes were transfected into INS-1 cells, which resulted in reduced accumulation of cAMP and insulin secretion after incubation with niacin.

 

PMID 27570060

 

If this is correct, then it's important to know that nicotinamide riboside does not engage the niacin receptor.

 

The effect of niacin on beta-cells could also be an acute and reversible effect, but seems more intuitively likely to be durable than something as clearly related to metabolic flux as an FFA-mediated effect, particularly granted that "GPR109A was significantly reduced in islets from diabetic individuals and animal model of db/db mice". It would be interesting to see islets from diet-induced diabetic mice transplanted into healthy syngeic mice to see if function recovered. On the other hand, this is evidence of impaired function, not actually of the death of beta-cells.

 

Everyone should be concerned about diabetes, of course; Todd, this may not apply to you — I'm not clear if you;re actually endeavoring to be CRed — but any impairment of beta-cell function may be of particular concern due to the possible role of beta-cell attrition (or even just downregulated function) in CR-associated impaired glucose tolerance.

 

Again, the core finding on niacin is worrisome to anyone, and irrespective of the mechanism; this last possible mechanism seems most worrisome for CR folk, and more likely niacin-specific.

[Todd Allen]

Michael, thanks for the info on niacin and diabetes.  I think it's very relevant to myself as I've come to believe I've been increasingly diabetic for the past 20 years.  I developed a wide range of symptoms consistent with diabetes such as peripheral and autonomic neuropathies and constant urination.  I've repeatedly brought it up with my doctors and been tested for it many times with the results showing increasing insulin resistance, at worst merely pre-diabetic but it never got to the point where they would diagnose me as being outright diabetic.  I've come to believe my neuromuscular disease has a synergistic effect and brings on the effects of diabetes at lower levels of blood glucose.

 

Anyway, for myself the fix has been to cut back on carbohydrates.  At 20-30 grams of digestible carbs per day my blood glucose rarely spikes badly and typically within a couple hours after a meal I'm back below 105.

 

All of the diabetes symptoms developed before I started taking niacin and all of them have been abating while taking niacin (and cutting carbs) and all of my biomarkers of metabolic syndrome have been getting dramatically better.  There is a strong measurable dose dependent improvement in my physical performance with niacin right up to the point where it crashes my blood pressure and makes me nauseated at 4-5 grams daily, but as soon as my heart rate and blood pressure stabilize I'm at my peak physically.  Somewhat arbitrarily I've been limiting myself to half that dosage to avoid the crash which is very unpleasant.

[Michael R]

All:

 

Wouldn't you know it. Two days after I get done trash-talking Nicotinamide Riboside (NR) as a supplement for health and longevity a new paper [1] (pop press article) comes out in the journal Science no less, apparently showing that NR supplementation extends lifespan in older mice by preventing their stem cells from turning senescent:

 

 

NR treatment of C57BL/6J mice slightly increased lifespan (chow diet, mean 829 ± 12.0; NR, mean 868 ± 12.4 days, p = 0.034) (Fig. 6G). The beneficial effect of NR on survival was further confirmed by Cox proportional hazards analysis (Fig. 6H). Although the lifespan benefit is small, it was obtained with the NR treatment commencing late in life at 24 months.

 

Here are the two survival curves for the NR-treated and control mice, in terms of how many days they lived after the treatment with NR (or placebo) began:

 

 

While there was a nominal difference between the two groups' median lifespans, both groups' median lifespans were still well within the normal zone for healthy mice. More significantly, while the authors don't report maximum (tenth-decile) survivorship (an increase in which relative to normal, healthy controls is the sine qua non of an anti-aging intervention), you can see right from the survival curves that this doesn't cut it: the very last control animal died at age ≈960 days (700 days (see legend to Figure 6) + an eyeballed 260 d from the graph)), and the last treated animal died at age ≈1010 days: ie, the controls were abnormally short-lived, and the treated animals on the low side of normal. This is already clear just from looking at the shape of the survival curve itself, which is clearly not rectangular: from ≈850 days onward, both groups were clearly suffering high death rates from middle age onward. It would have been nice to have been able to see the survival curves throughout the adult LS instead of just from initiation of treatment to see how exactly those normal-seeming median LSs could coexist with such relatively rapid death rates. Irrespective, this is obviously very unconvincing as a lifespan study.

 

Here are some more impressive graphs from the full text, showing NAD+ was increased in both young and aged mice treated with NR, both groups had more viable muscle stem cells, ran longer and farther (when facing threat of shock), and had higher grip strength than controls

The question is whether this would manifest in animals that weren't, apparently, rapidly failing in health starting from relatively early in the equivalent of human 60-70 year olds.

 

I should, however, say that the evidence supporting the benefits of NR certainly look better today than they did at the time I wrote my post for the SENS Research Foundation Blog. There's now evidence that NMN can work after oral administration, and the same study reported finding elevated NMN in plasma following oral gavage — and appeared to show benefits in aging mice. And a recent detailed study of NR and NMN metabolism seems to suggest that any benefits found in NMN should be translatable to NR.

 

The fact that all of these studies involve such extremely high doses, however, remains a significant question mark for people actually using the stuff and not ready to take such extremely high doses or shell out so much money to do so. And as noted above, I'd strongly urge caution about using the much cheaper and better-studied niacin as a companion NAD booster to NR.

 

[1] Science. 2016 Apr 28. pii: aaf2693. [Epub ahead of print]

NAD+ repletion improves mitochondrial and stem cell function and enhances life

span in mice.

 

Zhang H(1), Ryu D(1), Wu Y(2), Gariani K(1), Wang X(1), Luan P(1), D'Amico D(1),

Ropelle ER(3), Lutolf MP(4), Aebersold R(5), Schoonjans K(6), Menzies KJ(7),

Auwerx J

PMID: 27127236

[kpfleger]

This was a good thread and NAD+ is important, so I want to follow up with some things I've just learned. After not paying any attention to the whole world of NAD, NM, Sirtuins, resveratrol etc. due to all the disappointments in the area, I saw a great talk last week by Eric Verdin (long time researcher in the area and current head of the Buck Institute) summarizing a lot of stuff and making an important point.

 

High level summary: NAD+ is generally good and as Michael says NR supplementation to increase NAD+ has much better evidence recently that it did some years ago. However, CD38 is a substance that breaks NAD+ and CD38 increases with age. This seems to be a major reason why NAD+ declines (see paper below). Though NR supplementation helps recover the NAD+, it doesn't do anything about the CD38 so the degree to which NR can help is limited. CD38 inhibitors would solve the problem a level back and should be better than NR supplementation. Candidates to do that are actively being worked on. So watch this space.

 

Here's a 2015 review by Verdin on the area, though I didn't read it to see how similar it was to the talk:

REVIEW
NAD+ in aging, metabolism, and neurodegeneration
Eric Verdin
Science  04 Dec 2015: Vol. 350, Issue 6265, pp. 1208-1213
DOI: 10.1126/science.aac4854

full PDF found via Google Scholar: http://verdin.buckinstitute.org/s/2015-Science-review.pdf

 

Another big researcher in the area is Chini. Here is a paper that shows that CD38 causes the NAD decline with age:

CD38 Dictates Age-Related NAD Decline and Mitochondrial Dysfunction through an SIRT3-Dependent Mechanism
DOI: http://dx.doi.org/10.1016/j.cmet.2016.05.006

http://www.cell.com/cell-metabolism/fulltext/S1550-4131(16)30224-8

 

And a shorter intro that summarizes that message from the beginning of the special issues the above paper was part of:

Why NAD+ Declines during Aging: It’s Destroyed
DOI: http://dx.doi.org/10.1016/j.cmet.2016.05.022

http://www.cell.com/cell-metabolism/fulltext/S1550-4131(16)30244-3

 

For more maybe try searching Google for cd38 inhibitor....

[Mikecron]

Of course it's anecdotal evidence, but for what it's worth, I have tried NAD in the past, and experienced a general sense of malaise and weakness.

[Todd Allen]

On 12/17/2016 at 10:34 PM, Michael R said:

Diabetic subjects had significantly higher plasma N(1)-methylnicotinamide levels 5 h after a 100-mg nicotinamide load than the non-diabetic subjects (0.89 +/- 0.13 micromol/L vs 0.6 +/- 0.13 micromol/L, P < 0.001). Cumulative doses of nicotinamide (2 g/kg) significantly increased rat plasma N(1)-methylnicotinamide concentrations associated with severe insulin resistance, which was mimicked by N(1)-methylnicotinamide. Moreover, cumulative exposure to N(1)-methylnicotinamide (2 g/kg) markedly reduced rat muscle and liver NAD contents and erythrocyte NAD/NADH ratio, and increased plasma H(2)O(2) levels. Decrease in NAD/NADH ratio and increase in H(2)O(2) generation were also observed in human erythrocytes after exposure to N(1)-methylnicotinamide in vitro. Sweating eliminated excessive nicotinamide (5.3-fold increase in sweat nicotinamide concentration 1 h after a 100-mg nicotinamide load).

If the above is relevant it might explain why I've had good results with Niacin.  Before starting on nicotinic acid I had been taking 2 g / day of creatine monohydrate which probably reduced my methylation burden along with having previously corrected my B12 deficiency and taking an "activated" B  complex supplement with methylated forms of relevant B vitamins such as folic acid.  I also added 2 grams daily of trimethylglycine which might also help with niacin induced methyl consumption.  My nightly heat shock bath in 120+F water with a typical loss of 4 lbs weight though sometimes as high as 8 lbs (@ ~135 lbs body weight) probably helps purge excess methylnicotinamide.  And I added drinking Pau d' Arco/Lapacho tea and the Beta-Lapachone is supposed to provide substrate for NQO1 (NAD(P)H:quinone oxidoreductase) to boost the oxidation of NADH to NAD+.  Over time it seems my need for niacin has diminished.  I no longer notice any performance loss unless I suspend niacin for a week or more and 1 gram/day seems enough to maximize results.  For  the past month I've been doing great at 500 mg/day.

Co-administration of equimolar doses of betaine may alleviate the hepatotoxic risk associated with niacin therapy

Beta-Lapachone, a Modulator of NAD Metabolism, Prevents Health Declines in Aged Mice

And Lapacho has also recently been shown beneficial in a mouse model of Huntington's, a very similar disease with the same genetic mutation but on a different gene from the disease I used to have, SBMA.

Amelioration of Huntington's disease phenotypes by Beta-Lapachone is associated with increases in Sirt1 expression, CREB phosphorylation and PGC-1α deacetylation.

Here's an in depth recent review article about the interactions of NAD, diseases and aging:

Nicotinamide adenine dinucleotide (NAD+ ) metabolism and neurodegeneration 

[Sibiriak]

For a clear explanation of why niacin liver toxicity is primarily connected with extended release formulations   see:

Overview of niacin formulations: differences in pharmacokinetics, efficacy, and safety.

Pieper JA¹.

Am J Health Syst Pharm. 2003 Jul 1

 

https://www.researchgate.net/profile/John_Pieper2/publication/10627949_Overview_of_niacin_formulations_Differences_in_pharmacokinetics_efficacy_and_safety/links/59258717aca27295a8e3377b/Overview-of-niacin-formulations-Differences-in-pharmacokinetics-efficacy-and-safety.pdf?origin=publication_detail

 

[Todd Allen]

11 hours ago, Sibiriak said:

For a clear explanation of why niacin liver toxicity is primarily connected with extended release formulations   see:

Yes, because of that and related findings and because I like to economize I bought a kilo of powdered nicotinic acid (~$30 for 2+ years of supply depending on dose) which I dissolve in water and now take in a single dose daily typically after my evening exercise session.  I like the flavor, pleasantly tart, especially with TMG, fairly sweet but not sugary and sometimes add a little lime juice, elderberry puree or cranberry reduction.

I expect NR is somewhat a better choice than NA but probably less so than the 100 to 1 ratio in cost and I enjoy my NA beverage at a time of day when I'm often craving food which it satisfies for a while.  I also enjoy the niacin flush so long as it is mild, combined with my post-exercise flush it gives me satisfying sense of achievement/progress which often prompts me to take a few minutes to relax and bask mindfully in the sensations.  Perhaps it is just placebo effect but there are plenty of human studies suggesting placebo benefits can be real although we may be waiting a long time for scientific validation of placebo effect via mouse and rat studies.

[ferrisreva]

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Edited December 6, 2018 by ferrisreva