529 replies to this topic

[Kevnzworld]

Regarding Sirt1 enducers,activators like resveratrol and nicotinamide riboside. I m reading an article an came upon this paragraph.
" In this context, Sirt1 is being found to interact with a variety of non-histone proteins whose functions significantly impact longevity. Just one example should make the point here: p53. Deacetylation of p53 suppresses its transcriptional activity and renders cells resistant to DNA damage and oxidative stress-induced apoptosis. However p53 deacetylation could potentially be a double-edged sword since suppression of p53, another of whose functions is to act as a tumor suppressor, could promote oncogenesis. ".
http://www.smart-pub...lifespan-part-i
I also take Metformin which depletes NAD but up regulates p53, what some surmise is its MOA in cancer suppression.
Is anyone concerned about this side effect of Sirt1 activation?

[PWAIN]

Talk about overselling....

Aging Successfully Reversed in Mice; Human Trials to Begin Next

http://guardianlv.co...-to-begin-next/

[blood]

ChromaDex apparently secured almost 70 million worth of advance orders for NR in the 2013 financial year.
(For reference, the world resveratrol market is currently worth about 20 million - this stat from a recent article by Bill Sardi).

Article: http://www.nutraingr...agen-ingredient

[1thoughtMaze1]

Talk about overselling....

Aging Successfully Reversed in Mice; Human Trials to Begin Next

http://guardianlv.co...-to-begin-next/

Yeah we know

[follies]

Is anyone concerned about Ukko's comments about NR actually reducing NAD+?
Reading Vince's comments following the article linked by Ukko, he states that he wants to further research the negative effects but I did not find a follow up.
BTW, thank you Ukko for pointing me to Vince's blog, it seems to be a great resource.

[tunt01]

Is anyone concerned about this side effect of Sirt1 activation?

This is a primary concern I have, as brought up previously.

Is anyone concerned about Ukko's comments about NR actually reducing NAD+?

He's talking about Nicotinamide, not NR. NR raises NAD+. I don't know if it is possible to say whether or not there is some negative homeostatic feedback mechanism that would ultimately lower baseline NAD+ levels (akin to a drug addict) with repeated NR use. I think there just isn't enough data and we might not know for another 2-3 years until we can really see some long-term mouse studies (which hopefully someone is doing....)


I have used 3 doses of my Niagen bottle. I think I will use the rest of it on an abnormal schedule of say once a week on a Saturday or something.

[APBT]

Regarding Sirt1 enducers,activators like resveratrol and nicotinamide riboside. I m reading an article an came upon this paragraph.
" In this context, Sirt1 is being found to interact with a variety of non-histone proteins whose functions significantly impact longevity. Just one example should make the point here: p53. Deacetylation of p53 suppresses its transcriptional activity and renders cells resistant to DNA damage and oxidative stress-induced apoptosis. However p53 deacetylation could potentially be a double-edged sword since suppression of p53, another of whose functions is to act as a tumor suppressor, could promote oncogenesis. ".
http://www.smart-pub...lifespan-part-i
I also take Metformin which depletes NAD but up regulates p53, what some surmise is its MOA in cancer suppression.
Is anyone concerned about this side effect of Sirt1 activation?

I posted this in the "Niagen group buy" thread started by PWAIN, in response to prophets (legitimate) concerns. I'll re-post it here, as this seems a more appropriate thread to discuss. Post #35: http://www.longecity...side-group-buy/page__st__30

The consensus of the role of sirtuins seems to be in flux:

The Dual Role of Sirtuins in Cancer
http://gan.sagepub.c...nt/2/6/648.full
SIRT1, Is It a Tumor Promoter or Tumor Suppressor?
http://www.ijbs.com/v05p0147.htm
The ups and downs of SIRT1
http://chmwww.rutger...~kyc/pdf/12.pdf

Possible P53 upregulators
Vitamin D Analogues Increase p53, p21, and Apoptosis in a Xenograft Model of Human Retinoblastoma
http://www.iovs.org/...44/10/4192.full
Expression of the p53 Tumor Suppressor Gene Is Up-Regulated by Depletion of Intracellular Zinc in HepG2 Cells
http://jn.nutrition....130/7/1688.long

[APBT]

I'm not clear on how they concluded NR is effective at lower concentrations than NMN. They seem to have dosed the mice with the same 400 mg/kg/day.

FULL TEXT: http://www.sciencedi...550413112001921

DISCUSSION
Furthermore, NR protects against metabolic dysfunction at lower concentrations than those reported for NMN, and we proved that it is effective after oral administration when mixed with food, in contrast to NMN, which is injected intraperitoneally (Yoshino et al., 2011)

RESULTS
We next evaluated the efficacy of NR, NMN, and NA to increase NAD⁺ in vivo by supplementing mouse chow with NR, NMN, or NA at 400 mg/kg/day for 1 week. All compounds increased NAD⁺ levels in liver, but only NR and NA significantly enhanced muscle NAD⁺ content.

[tunt01]

I think the key to this SIRT1/P53 NMR issue is a circadian rhythm effect. I'd really like to see a longevity study in mice that has them taking this NMR upon wake, checking the half-life clearance (Niagen claims 4 hrs in humans), and hopefully giving the mice time to bring back some P53 activity before/during sleep.

I don't know enough about the circadian rhythm aspects of SIRT1/P53 and that's personally one of my biggest concerns. I really don't like the idea of X supplement inhibits P53 and Y supplement is a P53 agonist, so just take X and Y you'll be fine. The human body/metabolism is really complex and throwing more unnatural wrenches into the system seems risky to me.

I see people on these forums who take 30+ supplements (truth be told, I take about 8) and it just seems insane to me.

[APBT]

http://www.slideshar...entation-120313 Scroll down to 5 to read the quote in context.

ChromaDex is in the final stages of completing the design of its 1st human clinical study. This study is very important. It shows that in animals, the use of NR offers the health benefits of a low calorie diet and exercise; without doing either one

?

Apologies if this wasn't clear. The emphasis was that ChromaDex was going to be doing a human clinical study with NR; this was news to me. The link was simply where I harvested the quote from.

[midas]

I really don't like the idea of X supplement inhibits P53 and Y supplement is a P53 agonist, so just take X and Y you'll be fine. The human body/metabolism is really complex and throwing more unnatural wrenches into the system seems risky to me.

I see people on these forums who take 30+ supplements (truth be told, I take about 8) and it just seems insane to me.

It would be interesting to hear what those 8 supplement are after reading your post.

The reason I say that is no matter what we consider taking we seem to be able to find as much bad said about it as you can find that is good....My point being, their seems to be an element of risk in anything we decide to take.

I cant really think of one single thing that I have ever looked into where their isn't someone somewhere saying something negative about it...

In my opinion, it all boils down to doing your research as best you can and making an informed decision as to whether you think it is safe or not.

I think NR is the most promising thing that has appeared for a long time, and am hoping it lives up to 40% of the hype surrounding it......Anything over 40% would be a bonus!

I am pretty sure we are on the edge of making massive discoveries on ageing and I am hoping that NR is the beginning of something special.

Apologies if this wasn't clear. The emphasis was that ChromaDex was going to be doing a human clinical study with NR; this was news to me. The link was simply where I harvested the quote from.

Thanks for the clarification on that....

As I see it, ChromaDex are looking at Niagen (NR) as something very special and they obviously have a lot of confidence in that.

The next step for them, having a very high confidence level in the product, is to move on to clinical human trials. If the trials are successful, which I think they will be, it was their product that was used and proved to be efficient. Which gives them a huge amount of credibility, and more importantly, gives the population a massive amount of confidence in that particular product....As it is a patented, measured and controlled.

More to the point is, if it works in human clinical trials for any one of a few different illnesses that I think it will be tested for, it then ends up in the realms of a treatment for a specific illness/or illnesses, and they have hit the jackpot.........They are taking a risk (human trials cost a lot of money) but I am sure they wouldn't even be contemplating it unless they already know something we don't...

I also think that there is something big yet to come in the not to distant future from Mr Sinclair and friends....

[tunt01]

It would be interesting to hear what those 8 supplement are after reading your post.

carnosine, vitamin d, lactoferrin, zinc, telmisartan (pharmaceutical, not technically a supplement), probiotic, vitamin k2, kelp (iodine), stem cell 100 (multi

I think NR is the most promising thing that has appeared for a long time, and am hoping it lives up to 40% of the hype surrounding it......Anything over 40% would be a bonus!

I am pretty sure we are on the edge of making massive discoveries on ageing and I am hoping that NR is the beginning of something special.

I kind of think you are right. It certainly feels like it when I take it. I'd just like to see more studies. I worry about what we don't know.

[niner]

Ok, I finally found where I saw this. It was written by the guy who designed Niagen and I don't see any reason for him to exaggerate the amount found in milk, quite the opposite.

"We recieve calls and emails daily stating much the same. Of course quantity is important, There is about 12mg of nicotinamide riboside in an 8pz glass of milk, our daily serving is 20x more than this."

Actually, he does have a reason to exaggerate the amount of NR in milk. It buttresses the claim that it's an existing component of food which allows it to be sold as a supplement, and perhaps more importantly gives people the impression that it's as safe as drinking a lot of milk. If Johan Auwerx can't quantify it in milk, I really don't know how a supplement developer could pull it off. Unless he could provide some evidence that there is such a massive quantity in milk (really, to an analytical chemist, 12 mg in a quarter liter is a massive quantity) then I think he's either mistaken or making stuff up.

[APBT]

Study material regarding SIRT1 and the circadian clock:

MIT study finds that a gene associated with longevity also regulates the body�s circadian clock
http://newsoffice.mi...-and-aging-0620

SIRT1 Mediates Central Circadian Control in the SCN by a Mechanism that Decays with Aging
http://www.sciencedi...092867413005941

Pharmacological modulation of circadian rhythms by synthetic activators of the deacetylase SIRT1
http://www.pnas.org/...266110.full.pdf

SIRT1 controls circadian clock circuitry and promotes cell survival: a connection with age-related neoplasms
http://www.fasebj.or...ntent/23/9/2803

The Time of Metabolism: NAD+, SIRT1, and the Circadian Clock
http://symposium.csh.../76/31.full.pdf

https://www.sciencem...nt/324/5927/654

Abstract

Many metabolic and physiological processes display circadian oscillations. We have shown that the core circadian regulator, CLOCK, is a histone acetyltransferase whose activity is counterbalanced by the nicotinamide adenine dinucleotide (NAD⁺)�dependent histone deacetylase SIRT1. Here we show that intracellular NAD⁺ levels cycle with a 24-hour rhythm, an oscillation driven by the circadian clock. CLOCK:BMAL1 regulates the circadian expression of NAMPT (nicotinamide phosphoribosyltransferase), an enzyme that provides a rate-limiting step in the NAD⁺ salvage pathway. SIRT1 is recruited to the Nampt promoter and contributes to the circadian synthesis of its own coenzyme. Using the specific inhibitor FK866, we demonstrated that NAMPT is required to modulate circadian gene expression. Our findings in mouse embryo fibroblasts reveal an interlocked transcriptional-enzymatic feedback loop that governs the molecular interplay between cellular metabolism and circadian rhythms.

[APBT]

Study material (search results) for: circadian rhythm aspects of P53
https://www.google.c...thm aspects ofP53

[APBT]

I kind of think you are right. It certainly feels like it when I take it. I'd just like to see more studies. I worry about what we don't know.

I'm glad you're more conservative and cautious than many here. While we all would love to be able to take a handful of pills (with guaranteed safety and efficacy) and truly be bulletproof - it's important to broach these topics and raise these types of questions. It's very easy to get caught up in the group frenzy of a "new find." Opposing or questioning views, creates new dialog, which nudges cogitation, which creates growth and learning. That's one of the things I enjoy about Longecity; that there are folks from all over the world, with manifold backgrounds and motivations, contributing.

[APBT]

What I have learned is that the science is a moving target, multi-factorial in nature
and implication. My interest has not flagged and I am creating an ongoing series.

Indeed, I've coined the term, "dynamic conjecture" to describe exactly that. I look forward to your future efforts.

[APBT]

The is the response I received from LEF regarding the half-life of NR.

Dear Customer,
Thank you for your recent correspondence.
Unfortunately, the pharmacokinetic profile of nicotinamide riboside has not yet been determined. Here is a good overview of nicotinic acid, nicotinamide, and nicotinamide ribose as precursors to human NAD+ (nicotinamide adenine dinucleotide) production:
http://www.schulenbe...rticles/NAD.pdf
As nicotinamide riboside acts as a precursor to NAD+, its half-life may follow a similar pattern to that of NAD+.
According to the following literature review, NAD+ may have a half-life of approximately 10 hours in the liver:
http://jpet.aspetjou.../324/3/883.full

[midas]

Regarding Sirt1 enducers,activators like resveratrol and nicotinamide riboside. I m reading an article an came upon this paragraph.
" In this context, Sirt1 is being found to interact with a variety of non-histone proteins whose functions significantly impact longevity. Just one example should make the point here: p53. Deacetylation of p53 suppresses its transcriptional activity and renders cells resistant to DNA damage and oxidative stress-induced apoptosis. However p53 deacetylation could potentially be a double-edged sword since suppression of p53, another of whose functions is to act as a tumor suppressor, could promote oncogenesis. ".
http://www.smart-pub...lifespan-part-i
I also take Metformin which depletes NAD but up regulates p53, what some surmise is its MOA in cancer suppression.
Is anyone concerned about this side effect of Sirt1 activation?

Regarding Sirt1 enducers,activators like resveratrol and nicotinamide riboside. I m reading an article an came upon this paragraph.
" In this context, Sirt1 is being found to interact with a variety of non-histone proteins whose functions significantly impact longevity. Just one example should make the point here: p53. Deacetylation of p53 suppresses its transcriptional activity and renders cells resistant to DNA damage and oxidative stress-induced apoptosis. However p53 deacetylation could potentially be a double-edged sword since suppression of p53, another of whose functions is to act as a tumor suppressor, could promote oncogenesis. ".
http://www.smart-pub...lifespan-part-i
I also take Metformin which depletes NAD but up regulates p53, what some surmise is its MOA in cancer suppression.
Is anyone concerned about this side effect of Sirt1 activation?

I posted this in the "Niagen group buy" thread started by PWAIN, in response to prophets (legitimate) concerns. I'll re-post it here, as this seems a more appropriate thread to discuss. Post #35: http://www.longecity...side-group-buy/page__st__30

The consensus of the role of sirtuins seems to be in flux:

The Dual Role of Sirtuins in Cancer
http://gan.sagepub.c...nt/2/6/648.full
SIRT1, Is It a Tumor Promoter or Tumor Suppressor?
http://www.ijbs.com/v05p0147.htm
The ups and downs of SIRT1
http://chmwww.rutger...~kyc/pdf/12.pdf

Possible P53 upregulators
Vitamin D Analogues Increase p53, p21, and Apoptosis in a Xenograft Model of Human Retinoblastoma
http://www.iovs.org/...44/10/4192.full
Expression of the p53 Tumor Suppressor Gene Is Up-Regulated by Depletion of Intracellular Zinc in HepG2 Cells
http://jn.nutrition....130/7/1688.long

I think the key to this SIRT1/P53 NMR issue is a circadian rhythm effect. I'd really like to see a longevity study in mice that has them taking this NMR upon wake, checking the half-life clearance (Niagen claims 4 hrs in humans), and hopefully giving the mice time to bring back some P53 activity before/during sleep.

I don't know enough about the circadian rhythm aspects of SIRT1/P53 and that's personally one of my biggest concerns. I really don't like the idea of X supplement inhibits P53 and Y supplement is a P53 agonist, so just take X and Y you'll be fine. The human body/metabolism is really complex and throwing more unnatural wrenches into the system seems risky to me.

I see people on these forums who take 30+ supplements (truth be told, I take about 8) and it just seems insane to me.

Not sure if this will give you more up to date info on the P53 question but here you go......... https://www.landesbi...2014CC5568R.pdf

I read most of it but its a bit over my head, so if any of you understand it please let me know roughly what it is saying in a way that I might understand it better..

I know its not really NR related specifically but its on that track......(NMN, nicotinamide mononucleotide, amongst others)

Edited by midas, 02 April 2014 - 04:30 AM.

[eighthman]

I use niacin and Acipimox ( synthetic niacin analogue) to fast once a week for 20 hours (I'd like to stretch that to 24 soon). This is straight out of the Bergamini experiments in which lipids are shut off from the blood stream and your body has to 'fish' for bad proteins. A Dentist told me my gum tissue was "phenomenal" as I got a couple implants (I'm retirement age)

Looking at evolution in some whales and possibly a few other ageless animals, this sort of management of autophagy appears to me to offer the biggest results. If there are any anecdotal claims about NAD/Niacin or whatever is similar as to slowing or reversing aging, I'd like to know because so far I'm not aware of any.

[to age or not to age]

Here is the 1st part of my interview with Dr. Leonard Guarente of MIT. It runs 7 minutes.
Sinclair was one of his post docs at MIT in the 90's.

[malbecman]

Nice video, thanks for posting....

[midas]

Thanks once again.....I do love to listen to a balanced educated man

[midas]

http://www.thorne.co...h/prd~SP642.jsp

[niner]

http://www.thorne.co...h/prd~SP642.jsp

In case you don't like clicking on mystery links, This is Thorne's version of Chromadex NR. 60 caps, 125 mg, $59.00. Their marketing name for it is "NiaCel".

Anyone know what price and minimum purchase Chromadex has set for NR? Are they going to carefully dole it out in order to keep the price up? I suspect they will try to avoid saturating the market and undercutting their large customers.

[Hebbeh]

http://www.thorne.co...h/prd~SP642.jsp

In case you don't like clicking on mystery links, This is Thorne's version of Chromadex NR. 60 caps, 125 mg, $59.00. Their marketing name for it is "NiaCel".

Anyone know what price and minimum purchase Chromadex has set for NR? Are they going to carefully dole it out in order to keep the price up? I suspect they will try to avoid saturating the market and undercutting their large customers.

The group buy is $33.60 (or about half) for the same thing...

http://www.longecity...side-group-buy/

[midas]

In case you don't like clicking on mystery links,

Wasn't difficult was it!

The group buy is $33.60 (or about half) for the same thing...

http://www.longecity...side-group-buy/

And we have to pay $81+shipping for the same thing over here in the UK and Europe..

http://www.supersmar...de-125-mg--0632

Edited by midas, 04 April 2014 - 02:45 AM.

[niner]

In case you don't like clicking on mystery links,

Wasn't difficult was it!

Some people don't like clicking on unidentified links. I've scrubbed enough malware from my machine for one lifetime, ya know? So I spent two minutes to save twenty thousand people the bother of deciding if it was worth a click or not. Sorry to be a PITA / grouch. Pet peeve...

[to age or not to age]

I will post another excerpt from my interview with Dr. Leonard Guarente soon. I decided not to include an on
camera verification of what the longecity group has already deduced about the precursors. I am having off the
record discussions about dose and frequency and will pass along the info when I can. Much like c60, it seems these
compounds are hardly needed in young animals (humans), thus the effects are minimal. The 64 thousand dollar
questions are: to what degree will later in life administration delay or reverse things, and. how far reaching are the
effects of NAD. Scientists are excited about the possible intervention for neurological maladies, which up till now
have been intractable.

[midas]

I decided not to include an on
camera verification of what the longecity group has already deduced about the precursors.

Thanks for the update

Could you please clarify what we have actually got right up to now, as there have been a few different ideas floating around over the last month or two?


I mentioned in a previous post that I thought the effects would be different in older and younger users of NR.
My logic with that train of thought is purely that younger people are pretty well topped up with NAD+ (and anything else that gives us the spark of life for that matter) naturally, and it starts to decrease as we get older so logically the effects of any substance that helps, will be more prominent later in life.
My guess is that it starts to decrease to a point where it shows an increasing negative effect at around 30-35 years of age...So supplementation gradually would be a good idea from around that age. Just my opinion.

I also think that we will need to be careful if NR turns out to be as effective as I think it might be. Jumping in at the deep end with massive amounts of the compound could be a big mistake, in as far as, the body may not be able to cope with a big change in a short period of time and could cause all sorts of unknown problems. After all, the ageing process is gradual, and I'm sure that trying to slow it, halt it or even reverse it should be looked at in a similar way.
Again, just my opinion.