471 replies to this topic

[follies]

You have it. Particularly what you bolded at the end. I am ignorant on biochem , when it says nicotinamide does that include NR, or is NR different from plain old nicotinamide?

[Bryan_S]

You have it. Particularly what you bolded at the end. I am ignorant on biochem , when it says nicotinamide does that include NR, or is NR different from plain old nicotinamide?

 

Nicotinamide Riboside (NR) is Nicotinamide (NAM) bonded to a ribose sugar. Its a cheat in the “NAD salvage cycle” and enters the cycle before NMN (and is subsequently converted into NAD). The author is correct in that "no longterm studies have verified how long elevated NAD levels can be maintained." He makes a valid point. At least I haven't seen a study directly aimed at that question. Maybe someone else reading here has seen such a study and can comment?

[to age or not to age]

I filmed Leonard Guarente on April 7th and 8th (Tuesday and Wednesday this week) and I have spoken at length with

Vince Giuliano on this issue and am aware of his and Watson's recent blog entry.

I don't have time now to go deep but here is my 2 cents:

1) With regard to dose of NR, it turns out that in Chromadex's initial dosing study of 100mg, 200mg and 1000mg doses

of NR, 200mg created the highest response.  More may not be better.

2) Lenny admitted that we don't know if NAD levels can be maintained, because we don't know precisely why it goes

down. There is a long chat here.

3) I asked a question concerning the body's tendency to return to equilibrium (feedback loops), and if the equilibrium is that NAD levels

and in slow decline, there may be that tendency. He admitted that point.

4) Not only is dosing a question mark, but so is the timing and frequency of dosing (vis a vis the circadian clock etc) 

5) I will be speaking with Vince this afternoon on other matters but will raise these questions.

 

3) "are in slow decline"

[Bryan_S]

I filmed Leonard Guarente on April 7th and 8th (Tuesday and Wednesday this week) and I have spoken at length with

Vince Giuliano on this issue and am aware of his and Watson's recent blog entry.

I don't have time now to go deep but here is my 2 cents:

1) With regard to dose of NR, it turns out that in Chromadex's initial dosing study of 100mg, 200mg and 1000mg doses

of NR, 200mg created the highest response.  More may not be better.

2) Lenny admitted that we don't know if NAD levels can be maintained, because we don't know precisely why it goes

down. There is a long chat here.

3) I asked a question concerning the body's tendency to return to equilibrium (feedback loops), and if the equilibrium is that NAD levels

and in slow decline, there may be that tendency. He admitted that point.

4) Not only is dosing a question mark, but so is the timing and frequency of dosing (vis a vis the circadian clock etc) 

5) I will be speaking with Vince this afternoon on other matters but will raise these questions.

 

3) "are in slow decline"

 

Thanks, these are important questions we would "all" like answered.

[Bryan_S]

As I inferred in the first post on this thread any topic related to NAD synthesis is fair game here. So along those lines:

 

Honokiol Blocks Cardiac Hypertrophic Response via Activation of SIRT3

So researchers uncovered another SIRT3 Activating substance.

 

http://circ.ahajourn...bstracts/A16685

"Treatment of primary cultures of neonatal rat cardiomyocytes with HKL dose dependently increased NAD/NADH ratio and SIRT3 mRNA and protein levels."

 

http://www.fiercebio...medy/2015-04-14

 

http://www.ncbi.nlm....les/PMC2842137/

 

Here is one of the best statments: http://medicalxpress...rsecardiac.html

"They found that honokiol reduced mitochondrial protein acetylation. When they tested it in the heart muscle cells from mice, they found that a small amount of honokiol nearly doubled SIRT3 levels within 24 hours."

 

There is a thread on the Honokiol Topic at http://www.longecity...okiol-magnolol/ but I haven't seen any activity there so far.

Edited by Bryan_S, 14 April 2015 - 11:11 PM.

[midas]

As I inferred in the first post on this thread any topic related to NAD synthesis is fair game here. So along those lines:

 

Honokiol Blocks Cardiac Hypertrophic Response via Activation of SIRT3

So researchers uncovered another SIRT3 Activating substance.

 

http://circ.ahajourn...bstracts/A16685

"Treatment of primary cultures of neonatal rat cardiomyocytes with HKL dose dependently increased NAD/NADH ratio and SIRT3 mRNA and protein levels."

 

http://www.fiercebio...medy/2015-04-14

 

http://www.ncbi.nlm....les/PMC2842137/

 

Here is one of the best statments: http://medicalxpress...rsecardiac.html

"They found that honokiol reduced mitochondrial protein acetylation. When they tested it in the heart muscle cells from mice, they found that a small amount of honokiol nearly doubled SIRT3 levels within 24 hours."

 

There is a thread on the Honokiol Topic at http://www.longecity...okiol-magnolol/ but I haven't seen any activity there so far.

 

Great find Bryan, you're a star
 

[Alex_G]

I have been taking 250mg per day and I am going to take 2,800mg per day for 2 weeks ( this should be equivalent to the dose given to the mouse in the experiments).  

Has anyone seen any studies on how NAD changes after going from a high dose to a low dose?

 

Thanks guys.

[Bryan_S]

The multifaceted mitochondrion: An attractive candidate for therapeutic strategies Available online 24 March 2015

http://www.sciencedi...043661815000468

 

Sorry I missed this one guys, I must be getting old.   and for those who can attend Charles M. Brenner - ACKERSON LECTURE

 

Apr. 29, 2015

 4:00 pm–5:00 pm

 Beadle Center Room: E103

Additional Info: BEAD

 Melanie Simpson, 402-472-9309, msimpson2@unl.edu

“How Nicotinamide Riboside Promotes Weight Loss” will be presented by Dr. Charles M. Brenner, PhD, Roy J. Carver Chair of Biochemistry & Professor of Internal Medicine, Carver College of Medicine, University of Iowa.

[Asor]

This is not about NIcotinamide Riboside but sort of, here they used nicotinic acid to restore NADH's levels and other drugs to control signaling pathways (including resveratrol).

The study is on worm but they are ready to perform the same experiment on humans with mitochondrial diseases.

 

http://medicalxpress...ses-humans.html

 

http://www.sciencedi...567724915000264

 

 

 

Edited by Asor, 18 April 2015 - 04:37 AM.

[midas]

 

The multifaceted mitochondrion: An attractive candidate for therapeutic strategies Available online 24 March 2015

http://www.sciencedi...043661815000468

 

Sorry I missed this one guys, I must be getting old.   and for those who can attend Charles M. Brenner - ACKERSON LECTURE

 

Apr. 29, 2015

 4:00 pm–5:00 pm

 Beadle Center Room: E103

Additional Info: BEAD

 Melanie Simpson, 402-472-9309, msimpson2@unl.edu

“How Nicotinamide Riboside Promotes Weight Loss” will be presented by Dr. Charles M. Brenner, PhD, Roy J. Carver Chair of Biochemistry & Professor of Internal Medicine, Carver College of Medicine, University of Iowa.

 

 

Thanks once again Bryan, you seem to have a nose for sniffing this stuff out.

 

And as a side note to the Muppet that left the "Pointless, Timewasting" tag at the bottom of my last post....I hardly think showing another forum member my appreciation for his hard work searching this stuff out for us is "Pointless, Timewasting".....
 

[Bryan_S]

Major Pathway Identified in Nerve Cell Death Offers Hope for Therapies

Released: 21-Apr-2015 2:05 PM EDT 
Source Newsroom: Washington University in St. Louis

 

http://www.newswise....es/view/633076/

 

 

Edited by Bryan_S, 22 April 2015 - 12:52 AM.

[Supierce]

Bryan_S, thank you for finding these. I'm still on the fence about NR so it's good to see study results. I imagine enough time has elapsed that studies begun a year or so ago are wrapping up. With new studies in the pipeline, I hope we'll see more of these.

[Bryan_S]

April 23, 2015 SIRT1-Mediated eNAMPT Secretion from Adipose Tissue Regulates Hypothalamic NAD⁺ and Function in Mice

http://www.sciencedi...550413115001576

 

Fat signals control energy levels in the brain

https://news.wustl.e...-the-brain.aspx

 

 

Washington University School of Medicine

Shin-ichiro Imai, MD, PhD is a big name along side Leonard Guarente and David Sinclair. Sorry I don't have the full article access. If one of you does please post the PDF for the rest of us.

[APBT]

The PDF file of SIRT1-Mediated eNAMPT Secretion from Adipose Tissue Regulates Hypothalamic NAD+ and Function in Mice exceeds the limit of a maximum single file size of 2MB that is allowed on Longecity. 

Edited by APBT, 27 April 2015 - 09:32 PM.

[APBT]

FULL TEXT IN TWO PARTS:

Attached Files

•  SIRT1-Mediated eNAMPT Secretion from Adipose Tissue Regulates Hypothalamic NAD+ and Function in Mice_Part1.pdf   1.8MB   20 downloads
•  SIRT1-Mediated eNAMPT Secretion from Adipose Tissue Regulates Hypothalamic NAD+ and Function in Mice_Part2.pdf   1.25MB   16 downloads

[Bryan_S]

Washington University Medical School Scientists Publish Results of Pre-Clinical Study Showing Nicotinamide Riboside is Effective in Rescuing Neurons Subjected to Trauma and Disease - See more at: http://globenewswire...nd-Disease.html

 

http://www.eurekaler...o-mpi042115.php

 

We posted something on this a week ago but ChromaDex included a 2nd study listed below about saving nerve cells by raising NAD+ levels.

Scripps Florida Scientists' 'Mad Cow' Discovery Points to Possible Neuron Killing Mechanism Behind Alzheimer’s and Parkinson’s Diseases

See link: http://www.scripps.e...12lasmesas.html

 

Failure and Rescue of Brain Cells

"In the new study, the scientists used a misfolded form of the prion disease protein, called TPrP, a model they had previously developed, to study misfolded protein-induced neurodegeneration in the laboratory. Misfolded proteins are the common cause of the group of diseases comprising prion, Alzheimer’s, Parkinson’s diseases, ALS and other conditions.

Using biochemical techniques, the researchers demonstrated that TPrP induces neuronal death by profoundly depleting NAD+ (nicotinamide adenine dinucleotide)—a metabolite well known as a coenzyme that is common to all cells and necessary for energy production and cellular homeostasis.

Restoring NAD+ proved to be the critical factor for the rescue of neurons subjected to TPrP injury. Even when added three days after TPrP exposure, an infusion of NAD+ reversed within only a few hours the fate of neurons that had been doomed to destruction.

“Our study shows for the first time that a failure of NAD+ metabolism is the cause of neuronal loss following exposure to a misfolded protein,” Lasmézas said.

The loss of NAD+ also triggers autophagy—a way cells rid themselves of damaged material such as misfolded proteins—and apoptosis, or programmed cell death, the last resort of the cell when everything starts to go wrong. However, the researchers demonstrated these mechanisms do not initiate the neuronal demise.

“We show that apoptosis or programmed cell death and autophagy are not primary players in the death cascade,” said Staff Scientist Minghai Zhou, the first author of the study. “Modulation of neither of these processes significantly alters the death of TPrP-exposed neurons. This is all caused by NAD+ disappearing—the cell cannot survive without it.”

Lasmézas noted the loss of NAD+ is suggestive of some other neurodegenerative diseases, such as Parkinson’s where NAD+ depletion could play a role in mitochondrial failure."

Edited by Bryan_S, 29 April 2015 - 06:37 PM.

[Bryan_S]

Leonard Guarente Massachusetts Institute of Technology RUN TIME: 1 hours 07 minutes

http://thesciencenet...eonard-guarente

[follies]

Excellent interview. It was 6 years ago. Are there any more recent interviews?

[Bryan_S]

Excellent interview. It was 6 years ago. Are there any more recent interviews?

 

I found this one to be very enlightening as well. I was searching for the latest Leonard Guarente interviews when this one turned up and it filtered to the top as if it was new. I also suspected it it might be older after I watched it but thought it was still worth sharing.

 

No the latest interviews on Leonard Guarente are from Robert Kane Pappas and he recently visited him and hopefully that will generate a new video. See https://www.youtube....Nv_Fs4SNKnZ8fyQ

 

Now if you want the latest interviews on the subject Harvard Professor Dr. David Sinclair loves the limelight and speaks prolifically where Leonard Guarente is a bit more reserved.

I found 2 recent videos from Sinclair one from the Chicago Ideas Week Oct 18, 2014 at the Cadillac Palace Theatre: 

https://www.chicagoi....com/videos/656

 

And a 2nd video from UNSW Medicine's Deans lecture 2014  Oct 21,  2014 See: 

 

I think since these 2 lectures were just days apart you essentially get the same presentation. I enjoyed watching both and found each to be enlightening.

 

These are the latest videos I've found but if you have more please post them. I am secretly wishing the lecture from yesterday “How Nicotinamide Riboside Promotes Weight Loss” by Dr. Charles M. Brenner will be posted, so keep an eye out.

[Bryan_S]

Mechanism Behind Nicotinamide Riboside Could Be Translated Into Future ALS, Neurodegerative Disease Therapy

http://mitochondrial...isease-therapy/

 

I think this stuff (NR) may have far reaching implications into ailments not previously considered. If you follow the thoughts of Dr. David Sinclair from the lectures above this stuff could be the fuel to power the epigenetic changes we are targeting for increased health.

[Bryan_S]

Nicotinamide Riboside & Rosacea

 

http://www.brainrinsing.org/?p=409

http://www.brainrinsing.org/?p=404

 

It might be time for researchers to look at the anecdotal evidence from this subgroup. I posted an observation about my own Rosacea last year getting better and a few with this skin condition took notice. For the most part the treatments that are available do little to curb the extreme severity of this condition. However some reports are suggesting (NR) might be another tool for some, which might be working better than their earlier treatments. Inflammatory skin conditions are more prevalent than many realize.

[Vastmandana]

http://www.futurity....y-axons-914382/

Interesting article
New research highlights how nerves—whether harmed by disease or traumatic injury—start to die.

The discovery unveils new targets for developing drugs to slow or halt peripheral neuropathies and devastating neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis (ALS).

Peripheral neuropathy damages nerves in the body’s extremities and can cause unrelenting pain, stinging, burning, itching, and sensitivity to touch. The condition is commonly associated with diabetes or develops as a side effect of chemotherapy.

Nerve cells talk to each other by transmitting signals along communication cables called axons. Such signals underlie vital activities, such as thinking and memory, movement, and language.

As part of a study published in Science, the researchers showed they could prevent axons from dying, a finding that suggests therapies could be developed to counteract the withering away of nerve axons.

“We have uncovered new details that let us piece together a major pathway involved in axon degeneration,” says senior author Jeffrey Milbrandt, professor in, and head of, the genetics department at Washington University School of Medicine in St. Louis.

“This is an important step forward and helps to identify new therapeutic targets. That we were able to block axon degeneration in the lab also gives us hope that drugs could be developed to treat patients suffering from a variety of neurological conditions.”

ENERGY SUPPLY
A common thread among many neurological disorders and traumatic nerve injuries is the degeneration of axons, which interrupts nerve signaling and prevents nerves from communicating with one another. Axon degeneration is thought to be an initiating event in many of these disorders. In fact, an unhealthy axon is known to trigger its own death, and researchers are keenly interested in understanding how this happens.

Working in cell cultures, fruit flies, and mice, Milbrandt and coauthor Aaron DiAntonio, professor of developmental biology, and their colleagues showed that a protein already known to be involved in axon degeneration acts like a switch to trigger axon degeneration after an injury.

Moreover, they found that this protein, once unleashed, causes a rapid decline in the energy supply within axons. Within minutes after the protein—called SARM1—is activated in neurons, a massive loss of nicotinamide adenine dinucleotide (NAD), a chemical central to a cell’s energy production, occurs within the axon.

“When a nerve is diseased or injured, SARM1 becomes more active, initiating a series of events that quickly causes an energetic catastrophe within the axon, and the axon undergoes self-destruction,” says first author Josiah Gerdts, an MD/PhD student in Milbrandt’s laboratory.

KEEPING AXONS ALIVE
Working in neurons in which SARM1 was activated, the researchers showed they could completely block axon degeneration and neuron cell death by supplementing the cells with a precursor to NAD, a chemical called nicotinamide riboside. The neurons were able to use nicotinamide riboside to keep the axons energized and healthy.

Nicotinamide riboside has been linked in animal studies to good health and longevity, but its benefits have not been shown in people. The researchers say much more research is needed to know whether the chemical could slow or halt axon degeneration in the body.

“We are encouraged by the findings and think that identifying a class of drugs that block SARM1 activity has therapeutic potential in neurological disorders,” Milbrandt says. “The molecular details this pathway provides give us a number of therapeutic avenues to attack.”

The National Institutes of Health (NIH) and Vertex Pharmaceuticals supported the work.

Source: Washington University in St. Louis

[Bryan_S]

New Paper

 

Calorie Restriction-Mediated Replicative Lifespan Extension in Yeast Is Non-Cell Autonomous

Szu-Chieh Mei, Charles Brenner

 

http://www.medicine....tent/Mei15a.pdf

 

I'm finding recent comments about this paper made elsewhere and can't help to think we might have missed the significance of this publication posted back in February. To that end I re-read this paper after reading a April 22, 2015 post from Maria Costanzo, Ph.D. http://www.yeastgeno...ring-the-health

 

What is this altruistic factor being exported by these cells into the growth medium? (NA) and (NR) seem to act as mimics restoring calorie restriction benefits as pointed out in the study but they seem to have found a yet unidentified mechanism.  Szu-Chieh Mei and Charles Brenner appear to be on the trail of a new life extension molecule. Will it offer us higher organisms any benefits, who's to say at this early stage.

 

Just when we thought yeast had given up all its life extension secrets another tantalizing mystery emerges "suggesting" another beneficial molecule.

 

Along these lines I also reviewed "Nrt1 and Tna1-Independent Export of NAD+ Precursor Vitamins Promotes NAD+ Homeostasis and Allows Engineering of Vitamin Production" and "Yeast strain and method for using the same to produce nicotinamide riboside" and cant help to think that what Charles Brenner, PhD has uncovered here is a very old evolutionary pathway where the extracellular export of certain molecules like (NR) benefits the success of the entire cellular community. The fact that the NMRK1 nicotinamide riboside kinase 1 and the NMRK2 nicotinamide riboside kinase 2 have been conserved across so many lifeforms (See NMRK1 & NMRK2 Lineage) suggests an early common origin still important to all of us today.

[ceridwen]

How much NR does 1 have to take in order to protect axons and neurons

[Bryan_S]

Study: Vitamin B3 May Help Prevent Certain Skin Cancers

http://abcnews.go.co...ancers-31024391

 

Guess this will be no surprise to this thread. It is at least encouraging that the DNA repair aspects of boosting NAD are being documented. 

 

http://www.nbcnews.c...er-risk-n358446

 

Obviously this benefit isn't confined to only the skin. 

Edited by Bryan_S, 13 May 2015 - 10:52 PM.

[Supierce]

Study: Vitamin B3 May Help Prevent Certain Skin Cancers
http://abcnews.go.co...ancers-31024391
 
Guess this will be no surprise to this thread. It is at least encouraging that the DNA repair aspects of boosting NAD are being documented. 
 
http://www.nbcnews.c...er-risk-n358446
 
Obviously this benefit isn't confined to only the skin.

HealthDay article on the same study:

http://consumer.heal...cer-699398.html

Edited by Supierce, 14 May 2015 - 12:08 AM.

[Bryan_S]

Busy day but these things flew across the Radar.

 

Nicotinamide Riboside Ameliorates Hepatic Metaflammation by Modulating NLRP3 Inflammasome in a Rodent Model of Type 2 Diabetes.

 

http://www.bioportfo...n-a-Rodent.html

 

 

Reduced Ssy1-Ptr3-Ssy5 (SPS) Signaling Extends Replicative Life Span by Enhancing NAD+ Homeostasis in Saccharomyces cerevisiae

 

http://www.jbc.org/c.../20/12753.short

 

Anticancer Activity of Nicotinamide on Lung Cancer

 

http://www.bioportfo...ung-Cancer.html

 

 

[Bryan_S]

Reagents and Methods for Detecting Sirtuin Enzymatic Activity and Screening Sirtuin Inhibitors

 

http://www.flintbox..../project/27398/

 

Anthony Sauve has done much to push (NR) and NAD research. 

[Bryan_S]

ChromaDex's (CDXC) CEO Frank Jaksch on Q1 2015 Results

http://seekingalpha....call-transcript

 

For those wanting some insight on where ChromaDex is taking its NAD precursor in the world marketplace. 

[midas]

http://online.lieber...9/jmf.2015.3439

 

Nicotinamide Riboside Ameliorates Hepatic Metaflammation by Modulating NLRP3 Inflammasome in a Rodent Model of Type 2 Diabetes