530 replies to this topic

[Razor444]

Another blog post. Less complementary:

 

Nicotinamide Riboside — Where’s the Beef?

[midas]

Another blog post. Less complementary:

 

Nicotinamide Riboside — Where’s the Beef?

 

What he says makes sense if you are looking at NR for lifespan extension. But if like me you were attracted to NR because it may help with illness/disease and give better quality of life in later years. then i don't agree with what he is saying.

Not everyone is looking to live longer, some just want to make the later years as problem free as possible. A longer lifespan would be a welcome bonus.

 

He says in his blog.. "CoQ10 has been found to improve heart health, but it has failed to extend life span in mice."..............Well, for someone that has heart problems that Q10 helps heal or alleviate, then by default Q10 DOES actually extend lifespan in those people....

[Tom Andre F. (ex shinobi)]

Another blog post. Less complementary:

 

Nicotinamide Riboside — Where’s the Beef?

 

He forget some important information we have about the biochemistry process with NR and NAD+ and their method of action. But I couldnt agree more with him about the whole picture : we can discuss and speculate here about the potential of such component, but I dont accept companies who use our speculation for their marketing campaign. They have money to proven what they want to claim. We are speaking about company such as chromadex. Same thing for PQQ, the big companies never came out with life extension result. I do believe as well as the author, that bad result are just not published when they are sponsored by such companies. Thats the problem

[Vastmandana]

 

Another blog post. Less complementary:

 

Nicotinamide Riboside — Where’s the Beef?

 

He forget some important information we have about the biochemistry process with NR and NAD+ and their method of action. But I couldnt agree more with him about the whole picture : we can discuss and speculate here about the potential of such component, but I dont accept companies who use our speculation for their marketing campaign. They have money to proven what they want to claim. We are speaking about company such as chromadex. Same thing for PQQ, the big companies never came out with life extension result. I do believe as well as the author, that bad result are just not published when they are sponsored by such companies. Thats the problem

 

First, I'd like to say I enjoyed the article on antiaging firewalls ( http://www.anti-agin...he-nad-world-2/) and found lots to absorb... Thanks, Kevin....however, the negative NR "beef"  article is crude, very sketchy and incomplete, and comments related to the article by recent posters here  are speculation...such as questioning whether the product is just marketing hype as reflected above....Oh, and MY pet peeve... by people NOT revealing their age... hmmmm me thinks ur all young...

 

While the validity of claims is often questionable in the capitalistic rape pillage plunder world in which we live (just look at climate collapse vs oil propaganda), research to flush this all out is ramping up.  Don't agree with the reference to PQQ at all.... it's not like anyone has the corner on this market and the fact is our research funding models are highly controlled by big pharma.... more so with each cut/reduction in federal r&d support (huge issue impacting lots of shit)...

 

I admire the Sinclairs and Duarte's of the world... and choose not to wait for us to totally understand the complex realities of human biochemistry...to fully explore this avenue...I'll be decrepid and probably dead long before we sort out all the elements of longevity.

 

I have devoted a relatively large share of my meager disposable income to NR/micronized resveratrol/pqq and a wide number of other longevity strategies... just added curcuwin to my regimine... why?  so I can hopefully operate more effectively in these crucial moments when humanities' survival may be decided.

 

Despite a long supplement stack, nothing has impacted my eyesight/physiological condition as much as since starting NR/resveratrol (duarte feals they're synergistic).  As a garden artist, I move boulders, dig holes, terraform spaces and am in better shape than most in my age bracket... but my body has been slowely unwinding and I truely feal something is happening... things are waking up... I feel it a bit more every day.   Personally I don't care about "EXTENDING" my life anywhere as much as making the most out of every moment I'm here.... 

 

You can poo poo things all you want and choose to await data as it unfolds, but your insinuations are speculation.   I've spent most of my life trying to discern what is really going on....everywhere...and this issue is no different.  I respect my information synthesizing, fallible as it is, and whenever I've exercised due diligence, I've generally moved in positive and constructive directions...Have I wasted lots of money??? Sure! Hell, every beer and coffee "laitee" is a waste of money.... At 64,  with a huge agenda to complete planetwise, I choose not to wait till we nail down the complete biochemistry of longevity...as I'll be long gone by then... time is too precious and I will continue exploring promising avenues...just like Duarte...

 

If you are my age, and sitting on the sideline chucking darts I question your wisdom... If you're young/younger, sit back and wait... it is as simple as that...

 

 

Edited by Vastmandana, 19 November 2014 - 05:36 AM.

[midas]

Team discovers that a derivative of vitamin B3 prevents liver cancer in mice.

 

"The results, published in the prestigious journal Cancer Cell, indicate that diets rich in nicotinamide riboside, a derivative of vitamin B3, protect these mice from developing HCC (hepato-cellular carcinoma) in its most initial stage, when genotoxic stress is damaging cellular DNA. They also show a curative effect of the diet in those mice that had previously developed the disease."

 

http://medicalxpress...=daily-nwletter

Edited by midas, 24 November 2014 - 10:30 AM.

[M-K]

Recent speech by David Sinclair:

 

His part starts about 44 minutes in, but I found the opening presentation (starting at about 14 minutes) by Steve Simpson equally worthwhile.  

[sthira]

Thank you for posting this. I like David Sinclair. I believe he's doing important work, he seems to be compassionate and to care, I like what he says about his mom, and I like how he breaks the complicated science down well for a general audience. Toward the end of the panel discussion he mentions metformin, rapamycin, and of course resveratrol, and NAD promoters and potentially new drugs that are many times more effective than what we currently have to halt and perhaps reverse "ageing."

If you were sitting in that audience, what would you ask him? Do you think he would put his mom on the current crop of NAD promoters (like Niagen)? Or ... is he just another slick scam artist looking to buy more expensive houses or clothes or whatever... ?

[M-K]

I don't think he's a scam artist.  He strikes me as quite genuine.  However, he does seem concerned about his personal accomplishments and image; perhaps a little reluctant to promote others and competing approaches.  I think he's said his parents were taking resveratrol.  

 

I would have asked what else he's learned about NAD et al in the last year.

[albedo]

Recent speech by David Sinclair:

 

His part starts about 44 minutes in, but I found the opening presentation (starting at about 14 minutes) by Steve Simpson equally worthwhile.  

 

Thank you for sharing. I was surprised by what he said (at about 1:28) about resveratrol plus exercise which might turn to be deleterious based on one study.

[Asor]

That video isnt really new (Published on Nov 4, 2014)

[midas]

That video isnt really new (Published on Nov 4, 2014)

 

Yes, that was made around the time that NR first hit the headlines.....

 

Here is another short 18 minute video from earlier this month at Chicago Ideas Week, no new information here either really....There are a few more videos on the same page below this one if you scroll down that might be of interest but I have not had time to watch them yet...

 

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

Edited by midas, 22 February 2015 - 11:59 AM.

[M-K]

 

That video isnt really new (Published on Nov 4, 2014)

 

Yes, that was made around the time that NR first hit the headlines.....

 

Here is another short 18 minute video from earlier this month at Chicago Ideas Week, no new information here either really....There are a few more videos on the same page below this one if you scroll down that might be of interest but I have not had time to watch them yet...

 

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

 

Midas, thanks for the link.  "Recent" is relative, and compared to other Sinclair videos on YouTube, the one I posted is recent.  The point is valid, though, and I'll try to include dates in the future.  NAD first hit the headlines in December, 2013; not sure when NR did, unless it was the recent Elysium flurry.

[midas]

 

 

That video isnt really new (Published on Nov 4, 2014)

 

Yes, that was made around the time that NR first hit the headlines.....

 

Here is another short 18 minute video from earlier this month at Chicago Ideas Week, no new information here either really....There are a few more videos on the same page below this one if you scroll down that might be of interest but I have not had time to watch them yet...

 

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

 

Midas, thanks for the link.  "Recent" is relative, and compared to other Sinclair videos on YouTube, the one I posted is recent.  The point is valid, though, and I'll try to include dates in the future.  NAD first hit the headlines in December, 2013; not sure when NR did, unless it was the recent Elysium flurry.

 

Sorry M-K,  I should correct what I said in that last post I made.....NR hit the headlines just after the Sinclair paper in December 2013 and not as I stated in my last post....I misunderstood Asor's  post and thought he had said the video was from November 2013 instead of 2014, I apologise for any misunderstanding....

 

 

 

[APBT]

 

Recent speech by David Sinclair:

 

His part starts about 44 minutes in, but I found the opening presentation (starting at about 14 minutes) by Steve Simpson equally worthwhile.  

 

Thank you for sharing. I was surprised by what he said (at about 1:28) about resveratrol plus exercise which might turn to be deleterious based on one study.

 

 

 

See this and this

[Darryl]

GSK researchers report the first synthetic CD38 inhibitors with nanomolar affinity (human IC₅₀ 7.3 nM for compound 78c)

 

Haffner, C. D., Becherer, D., Boros, E. E., Cadilla, R., Carpenter, T., Cowan, D., ... & Ulrich, J. (2015). Discovery, Synthesis and Biological Evaluation of Thiazoloquin (az) olin (on) es as Potent CD38 Inhibitors. Journal of Medicinal Chemistry.

 

A series of thiazoloquin(az)olinones were synthesized and found to have potent inhibitory activity against CD38. Several of these compounds were also shown to have good pharmacokinetic properties and demonstrated the ability to elevate NAD levels in plasma, liver and muscle tissue. In particular, compound 78c was given to diet induced obese (DIO) C57Bl6 mice elevating NAD > 5-fold in liver and > 1.2-fold in muscle versus control animals at a 2 hour time point. The compounds described herein possess the most potent CD38 inhibitory activity of any small molecules described in the literature to date. The inhibitors should allow for a more detailed assessment of how NAD elevation via CD38 inhibition affects physiology in NAD deficient states.

 

[Fafner55]

Watson and Giuliano's recent blog  Part 4 of the NAD world: the NQ01 gene, the Warburg effect, SIRT 1 and inflammation, and possible interventions makes the critical point that the NQ01 gene drives the NAD+/NADH ratio.  Beta-lapachone direct activates NQO1, but this compound is hard to source.  Epicatechin indirectly upregulates NQO1 by activating Nrf2, the transcription factor that turns on the NQO1 gene.

 

It might not be coincidental that Jeanne Calment, who lived to the age of 122 years, is reported to have eaten nearly a kilogram of chocolate every week.  Cocoa is a major source of epicatechin.  Mdm Calment’s intake of epicatechin can be estimated to be (assuming a 60% cocoa content and the measured epicatechin content of cocoa)

 

(1000 gm/ 7 days)(0.6 cocoa content est.)(46.1 mg epicatechin content/40 g cocoa) = 99 mg epicatechin/day

 

[ymc]

I am new to this NMN/NR thing. I know NMN has some mice studies to demonstrate effectiveness. What about NR? Did it show similar effects in mice studies?

[Darryl]

I've been investigating methylsulfonylmethane (aka MSM, dimethyl sulfone, methyl sulfone, oxidized DMSO), an OTC arthritis / joint pain supplement, and potential chemotherapy adjuvant active through suppressing inflammatory signaling. Of some note to this thread, MSM appears to inhibit the major NAD+ase PARP.

 

Karabay AZ et al. 2014. Methylsulfonylmethane modulates apoptosis of LPS/IFN-γ-activated RAW 264.7 macrophage-like cells by targeting p53, Bax, Bcl-2, cytochrome c and PARP proteins. Immunopharmacology and immunotoxicology, 36(6), 379-389.

Kim JH et al. 2014. Methylsulfonylmethane suppresses hepatic tumor development through activation of apoptosis. World journal of hepatology, 6(2), 98.

 

 

[Tom Andre F. (ex shinobi)]

I've been investigating methylsulfonylmethane (aka MSM, dimethyl sulfone, methyl sulfone, oxidized DMSO), an OTC arthritis / joint pain supplement, and potential chemotherapy adjuvant active through suppressing inflammatory signaling. Of some note to this thread, MSM appears to inhibit the major NAD+ase PARP.

 

Karabay AZ et al. 2014. Methylsulfonylmethane modulates apoptosis of LPS/IFN-γ-activated RAW 264.7 macrophage-like cells by targeting p53, Bax, Bcl-2, cytochrome c and PARP proteins. Immunopharmacology and immunotoxicology, 36(6), 379-389.

Kim JH et al. 2014. Methylsulfonylmethane suppresses hepatic tumor development through activation of apoptosis. World journal of hepatology, 6(2), 98.

 

It seems in inflammation / cancer cell line test only. Sulfur is really necessary for every cell viability, without it there is no life and our modern dietary style dont give us enough sulfur. I think supplement ourself with some MSM is a good idea

[tunt01]

I'm having trouble following one section of Sinclair's paper.  If anyone can shed light on this section and the Figure 6 results, I'd appreciate it.

 

• Fig. 6C.  I'm not following what is driving the nuclear encoded subunits if AMPK is negatively effected by the adenovirus and SIRT1 is induced KO.
• Fig 6D-6F.  Any clarification on what the paper is explaining in 6D-6F would be helpful.

 

 

Gomes/Sinclair - Declining NAD+ Induce Pseudohypoxic State Disrupting Nuclear-Mitochondrial Communication During Aging

 

Re: Section (Figure) 6 Results.

 

AMPK Functions as a Switch between PGC1a-Dependent and -Independent Pathways Driven by SIRT1

 

Next, we determined the mechanisms that determine whether SIRT1 utilizes the PGC-1a-dependent or -independent pathways.  Under conditions of low energy, AMPK-mediatedphosphorylation of PGC-1a allows it to be deacetylated and activated by SIRT1 (Canto´ et al., 2009; Gerhart-Hines et al.,  2007; Rodgers et al., 2005), whereas under basal conditions, acetylation status is primarily regulated by the acetyltransferase GCN5 (Fernandez-Marcos and Auwerx, 2011). We speculated that the biphasic decline in OXPHOS subunits (in Figure 1L) might be due to AMPK. In time course experiments following SIRT1 deletion, AMPK activation occurred after 48 hr, well after the decline in VHL-TFAM and mitochondrial genes (Figures 1L– 1M and 6A) but coincident with the decline in nuclear-encoded OXPHOS genes and mitochondrial mass (see Figures 1L–1M).  

 

An AMPK dominant-negative adenovirus (AMPK-DN) prevented the decline of nuclear OXPHOS mRNAs at 48 hr (Figures 6B and 6C), whereas forced maintenance of TFAM prevented AMPK activation (Figures 6D, 5D, and 5E). Together, these results strongly suggest that AMPK is the switch between the

PGC-1a-dependent and -independent pathways. In this model, AMPK activation occurs in the absence of SIRT1 only when ATP levels fall below a threshold. Consistent with this, AMPK was unchanged under fed conditions in the SIRT1 iKO mice and 22month-old wild-type mice but was markedly increased in fasting

animals, when we observe changes in both nuclear- and mitochondrially encoded OXPHOS genes (Figure 6E and 6F).

 

 

 

Figure 6

 

 

Edited by prophets, 08 July 2016 - 03:16 PM.

[Logic]

Trance said: My main complaint [on NADH] was insatiable and miserable constant feeling of hunger. My girl friend of the time experienced the same effect

Your experience seems to confirm the research and anecdotal consensus (of forums) that consistent nictinamide use can induce a pronounced insulin resistant state. This insulin resistant state is also likely indicative of the hypoxic state that NAD inducing strategies are designed to ameliorate. Anything that has the potential to produce a state of long term energy deficiency in the cell should be looked at with suspicion, even if it temporarily increases NAD.

We have to parse the strategies that may temprarily upregulate pathways at the cost of long term downregulation and strategies that will cause semi-permanent or permanent increase in, in the case of this model of aging, the NAD/NADH ratio at baseline. SIRT activating strategies seem to fall in the latter category. Niacinamide seems to fall in the former. However, niacin related compounds seem to be varied in action with some being seemingly opposite in their net effect than other similar compounds. Getting to the bottom of the net long term effects on energy metabolism of all relevant niacin related compounds should be a priority.
 

It would be interesting to know what the NAD/NADH ratio was, after return to homeostasis, in relation to the prior baseline.

Nad+ is thought to drive SIRT activation. Here's an article to add some more context:

http://www.ncbi.nlm....les/PMC3764375/

excerpt:
 

So, we can see here how niacinamide supplementation may act as such a potent SIRT inhibitor and likely a potent downregulating agent for NAD+.
 

Nicainamide is the 'anti-calorie restriction' mimetic and likely a strong net inhibitor of NAD+.

Other relevant excerpts:
 
Aside: revisit L-Serine and caffeine as a method to improve the NAD+/NADH ratio.
 

Surprisingly, CR reduces neurodegeneration in animal models of both PD and AD, possibly via upregulation of SIRT3 (Zhu et al., 1999; Mattson, 2000). Furthermore, overexpression of SIRT3 has been shown to significantly increase neuronal lifespan (Weir et al., 2012). ...

the effect of resveratrol on Sirtuin expression remains controversial. In one study, mice on a 30% CR diet exhibited increased Sirt3 mRNA levels, while treatment with resveratrol did not affect Sirt3 expression levels. In light of this finding, resveratrol may be ineffective in mimicking CR-mediated health benefits (Tauriainen et al., 2011). However, not all hope is lost for the polyphenol compounds. A recent report found that a resveratrol derivative, trans-(-)-ε-viniferin, is able to increase SIRT3 expression and provide protection in cell models of Huntington’s disease (HD). Specifically, viniferin treatment of striatal precursor cells overexpressing mutant huntingtin resulted in increased SIRT3 expression, increased the NAD⁺/NADH ratio, reduced intracellular ROS accumulation, and decreased acetylated MnSOD levels. Additionally, treatment with viniferin increased levels of activated AMPK and decreased acetylated LKB1, effects which were shown to require the presence of SIRT3. Thus, Sirt3 is required for viniferin-mediated neuroprotection in HD models

This has all mostly been prior discussed or alluded to at sometime or another, with the exception of maybe viniferin, but it's worthwhile to rehash in light of Sinclair's research.

 

 
This is all very IIRC.  I haven't been here in ages!

The problem with resveratrol is the difference between in-vitro and in-vivo results. (and some confusion on this count)

When you look at the metabolites of Resveratrol after the liver you'll find the in-vivo effects we get from them are the same as their in-vitro results...
(Some good things IIRC)

If you want the in-vitro effects of Resveratrol in-vivo: Pterostillbene.
In-vivo Pterostillbene metabolites are the closest to in-vitro Resveratrol (molecules) you can get.
(Unless things have progressed?)

It activates SIRT1 and NAD in-vivo, just as Resveratrol does in-vitro.
IIRC 

 

Edited by Logic, 29 December 2024 - 09:03 PM.