54 replies to this topic

[MikeDC]

Are there published human studies yet on NR?

And let's grant you that maybe NMN is 20% less effective at raising NAD+ (plasma?) levels. So what? What effectively matters is the cost ($) to produce a certain NAD+ increase. Given that as far as I know there isn't a company out there claiming to have an exclusive patent on synthesizing NMN, in the long run it is likely to be cheaper (if it isn't now).

I agree that increasing NAD+ seems like a good idea. It appears that we have a couple of routes to achieve that. In the long run the most cost effective route will likely win out.

Not sure how long you have been away. There have been many human clinical trials published already using NR. There are 33 clinical trials registered for NR while only one registered for NMN. Even though NR is protected by patent, it will always be less expensive than NMN because it is more complex to make NMN. All the legit sources of NMN cost over $100 per month on 250mg dose. All the cheaper NMNs on amazon are not legit. Probably produced by some labs in China with no quality control.

Elysium did a small trial on als with basis. The results are significantly better than existing drugs.

Edited by MikeDC, 21 February 2019 - 09:15 PM.

[MikeDC]

Fast forward to 5:07 and watch the mice crossing the beam. NR has cross generational benefits.

https://m.youtube.co...eature=youtu.be

[able]

Let’s take the results of a recent mice study comparing NR and NMN on ataxia mice models. It was posted in another thread. The mice were fed NR and NMN on molar bases. Since NMN is 31% heavier than NR, mice were fed 31% more NMN than NR based on weight. But NMN only increased NAD+ 5% more than NR. If you adjust the results based on equal weight, NR is over 20% better than NMN.
Of course increasing NAD+ is not the only factor that demonstrate effectiveness. There are large number of NR users who reports rejuvenation effects like younger skin, hair color change and disappearing age spots. But I have not heard many NMN users with similar effects.
Lastly there is not a single publication of human study on NMN.

 

Maybe your vision is bad, or math.  Or just being blatantly dishonest on purpose?

 

the difference between NR and NMN in chart a looks to be from 1.0 to 1.2.  for WT, about 20%.  A bit less for the sick animals. 

 

Most definitely not 5%.

 

Edited by able, 21 February 2019 - 10:57 PM.

[MikeDC]

Maybe your vision is bad, or math. Or just being blatantly dishonest on purpose?

the difference between NR and NMN in chart a looks to be from 1.0 to 1.2. for WT, about 20%. A bit less for the sick animals.

Most definitely not 5%.

I was looking at the wild type mice. It is 5.6%. For sick mice it is 16%. For our purpose, we are more like wild type mice than sick mice.

[OP2040]

If I'm not mistaken MikeDC is quite open about the fact that he owns Chromadex stock.

 

I did not know that, so I guess I have to give him credit for that amount of openness.  It's hard enough for someone to be unbiased when they are financially tied to an outcome.  But he doesn't even make an attempt to be unbiased.  I'm not sure he's been caught in an outright lie.  But everything is "spin" to the point of distortion.

 

You might say that same for David Sinclair, except for a few key differences.  He explicitly states that he will not endorse any supplement.  He is not just a businessman, but a basic scientist with a great job at Harvard that is tied up closely with his reputation as a scientist.  He never gives off a slimy used car salesman vibe.

 

Perhaps Chromadex should spend some of it's money on something other than price gouging patents.  Maybe develop better delivery systems, which are sorely needed in that industry.  In the times we live in, a company cannot just be successful by holding onto a patent or some mysterious formula.  There's just too much science out there, too many options, and both are growing by the day.  They will go down in flames due to disruptive innovation, probably sooner rather than later.  Lets just take a recent article from their company news section that demonstrates how this troll of a company decides to spend it's money while David Sinclair diligently tries to defeat aging (paraphrasing his own statements)

 

 

01/22/19ChromaDex Prepared to Proceed with Patent Infringement Action Against Elysium Health

 

Perhaps they are completely right in this dispute, but it doesn't matter.  They are still part of the problem, not part of the solution.  People like George Church, Sinclair, de Grey, and many more are part of the solution.  And many of them have spinoff companies as well.

 

So I guess we can add "terrible investor" to the list of character traits for this constant annoyance.
 

[Robert Seitz]

 Thanks, "OP2040", for posting the link: https://www.newswise...ular-senescence that kicks off this thread.  A few thoughts come to mine.

First, we're not alone. Chromadex, Elysium, and AliveByNature must surely be assessing this news, along with David Sinclair and his father. 

Can we reduce our loads of senesecent cells enough to offset the enhanced cancer-promotion effects of taking, say, 750 mg./day of sublingual NMN, sublingual NAD+ and/or TRUniagen/BASIS?

Can we compile a list of studies that quantify the benefits of NAD+ restoration in old animals and humans? Does the gain outweigh the pain? Does NAD+ restoration increase the average lifespans of old animals? If not, is it because of a higher incidence of cancer in NR-supplemented animals?

With respect to reducing our loads of senescent cells, how much can different senolytic protocols, such as dasatinib + quercetin, quercitin + fisetin + theaflavins, fox04-dri, ubx0101, etc., reduce our senescent cell loads? It's my understanding that senolytic agents are tissue-specific.

Maybe an organization like Calico could perform a relatively low-cost service by rounding up this kind of data? It would be much appreciated (at least by me)(:-))

[Robert Seitz]

Hm-m-m. If senescent cell loads increase exponentially with advancing age, then, I guess, so would the purported risk (per the Wistar news release) of taking NAD+ promoters increase one's risk of promoting cancer development.. If I suppose that our senescent cell loads double every 8 years, then they would roughly 10-fold every 26.5 years. Following that logic, David Sinclair's father would have something like 10 times his son's risk of cancer promotion per unit time.

On the other hand, the benefits of NAD+ precursors presumably also rise with age.

Until I have an inkling of the magnitude of this NAD+ influence on cancer promotion, I guess my tins of NAD+ and NMN, and my bin of NR will stay on the shelf.

[Robert Seitz]

I guess I should amend what I just wrote to say that what I'd like to know is the net effect of high NAD+ as a senescent cell cancer promoter versus the cancer prevention effects that high NAD+ levels may afford.

 

 

[stefan_001]

For once I agree with MikeDC. Cancer cells have a plethora of unpredictable nuclear mutations (or sometimes none at all!), but one thing that is common to all is that they have damaged mitochondria. Therefore they have to make energy in the cytoplasm (primarily through glycolysis). This is also related to how they become immortal (overcome replicative senescence).

 

Therefore increasing the selective pressure on mitochondria, i.e. through exercise, fasting, keto, and yes - higher NAD+ levels through supplements, will REDUCE the chance of getting cancer.

 

If you've already got cancer, all bets are off; higher NAD+ probably wouldn't make it worse, unless it somehow reduces the effectiveness of your cancer medication.

 

Here's some more information on the mitochondrial theory of cancer genesis:

 

https://www.ncbi.nlm...les/PMC4493566/

 

I am also inline with the above. I once checked do cancer cells have higher expression of the NRKs but could not find conclusive data on that so I speculated that is not a path that fuels cancer growth. Also if you look at the amounts of energy cancer needs to grow its doubtful in my view that supplementation can have any difference on cancer growth rate. I do however also think that when you use cancer medication you should go off the NR/NMN as the NRK path is not dead and as in my my view supplementation may not accelerate growth it may help cancer cells survive when you try to kill them. Personally I always take one polyphenol or another when using NR. For example I regularly use Fisetin that will tamp down senescence.
 

[LawrenceW]

And then there is this from page 12 of this study: https://doi.org/10.1...ell.2018.02.008

 

"The ability of NMN to promote angiogenesis raises the question of whether it might stimulate tumor growth. Mice treated with NMN or NR for extended periods show no evidence of increased tumor burden (Mills et al., 2016; Zhang et al., 2016).  Indeed, during the course of our studies, no increase in tumor burden was seen with NMN-treatment or in a DEN-induced model of hepatocarcinoma (Figures S7J and S7K), although more study is warranted."

Edited by Michael, 01 July 2019 - 04:52 PM.
Removing sci-hub link

[QuestforLife]

 

And then there is this from page 12 of this study: https://doi.org/10.1...ell.2018.02.008

 

"The ability of NMN to promote angiogenesis raises the question of whether it might stimulate tumor growth. Mice treated with NMN or NR for extended periods show no evidence of increased tumor burden (Mills et al., 2016; Zhang et al., 2016).  Indeed, during the course of our studies, no increase in tumor burden was seen with NMN-treatment or in a DEN-induced model of hepatocarcinoma (Figures S7J and S7K), although more study is warranted."

 

 

What dose of NMN are you on again, LawrenceW; wasn't it something like 6g?

Edited by Michael, 01 July 2019 - 04:55 PM.
Removing sci-hub link

[LawrenceW]

What dose of NMN are you on again, LawrenceW; wasn't it something like 6g?

 

That was 3 years ago.  Currently I take 400 mg of NMN with Activator in capsules twice per day interspersed with six 30 mg sublinguals a minimum of 1 hour between each sublingual. 

[OP2040]

 

And then there is this from page 12 of this study: https://doi.org/10.1...ell.2018.02.008

 

"The ability of NMN to promote angiogenesis raises the question of whether it might stimulate tumor growth. Mice treated with NMN or NR for extended periods show no evidence of increased tumor burden (Mills et al., 2016; Zhang et al., 2016).  Indeed, during the course of our studies, no increase in tumor burden was seen with NMN-treatment or in a DEN-induced model of hepatocarcinoma (Figures S7J and S7K), although more study is warranted."

 

 

That is nice to see.  The best strategy definitely involves cycling on and off between regenerative supplements and senolytic supplements.  This should cause a positive upward spiral over time.  Less senescent cells provide a healthier micro-environment for regenerative therapies to operate more effectively.  And at the other end of the equation, an environment awash with regenerative potential will lead to much healthier cells that never get to a point of senescence.  So basically: Rejuvenate > Clear Damage > Rejuvenate.  Wash, Rinse, Repeat. 

 

The caveat here is that the science is nowhere near good enough yet to play this game with supreme confidence.  There are two missing ingredients here.  

 

One is immunosenescence, which we have no definitive answer for yet.  It is presumably one of the main reasons for the increase in senescent cells to begin with.  It is also incredibly complex, even by the standards of biology. 

 

The second is the senolytics themselves.   While the advances in the past few years have been breathtaking, it is still not enough.  There are many senolytics, but they lack comprehensiveness.  Some are more comprehensive than others, but most seem to be senolytic for only a subset of cells.  I think comprehensive senolytics are not tat far off.  But in the meantime this is another judgement call.  I take Fisetin and Quercetin, and a mix is probably better to get more coverage.  But any current mix is likely to miss many cell types. 

 

One way we could mitigate this latter problem is simply by gathering the data.  We know certain cancers are many times more prevalent than others, lung cancer for example.  So knowing which senolytics for whatever lung cells are involved in lung cancer is vastly more important and actionable than knowing which ones are senolytic for the cells involved in brain cancer, fpr example.  Brain cancer, scary as it is, happens to be fairly rare.  And there are other very rare cancers that don't even merit our attention at this point because the risk so low.  Over half of all cancers are in just four regions: lung, breast, bowel and prostate.  Senolytics that we know work for thee cell types of these cancers would be a very auspicious starting point. 

Edited by Michael, 01 July 2019 - 04:56 PM.
removing sci-hub url

[OP2040]

I would also like to see some evidence for why certain things act as a regenerative and cancer preventative at the same time.  Things like exercise and calorie restriction have presumably been shown to do both.  I am assuming this, and no one would be less surprised than me if they found out that vigorous exercise  or CR promote some forms of cancer or chronic disease.   But for a moment, lets assume that exercise and/or CR reduce risk of both classes of disease by a substantial amount.  By what mechanism?  Hormesis?  Both presumably act more as signalling mechanisms telling the body to initiate repair programs.  But isn't that precisely what Sirtuins do as well?  Shouldn't the same concern about cancer be evident for exercise and CR if in fact they are initiating a cascade of repair processes?

[Michael]

 

And then there is this from page 12 of this study: https://doi.org/10.1...ell.2018.02.008

 

"The ability of NMN to promote angiogenesis raises the question of whether it might stimulate tumor growth. Mice treated with NMN or NR for extended periods show no evidence of increased tumor burden (Mills et al., 2016; Zhang et al., 2016).  Indeed, during the course of our studies, no increase in tumor burden was seen with NMN-treatment or in a DEN-induced model of hepatocarcinoma (Figures S7J and S7K), although more study is warranted."

 

First: LawrenceW and others: please do not post links to sites designed to evade c0py-right laws. Whatever one thinks of the ethics of such sites, you could bring a whole world of pain onto Longecity if a publisher decided to crack down on us for such. It was also not necessary in this case: as you can see from the direct link with which I've replaced the offending one, the paper is already free in full text.

 

Anyway: This statement is a mixture of things that aren't true and that are not actually as informative as one might think. It's just not true that the NR late-life life extension study (Zhang et al., 2016) "show[ed] no evidence of increased tumor burden:" I specifically asked the authors about pathology and cause of death, and they didn't do necropsies — they just counted dead mice.

 

It's true that the Imai long-term NMN study (Mills et al., 2016) showed no evidence of increased tumor burden, but this isn't very convincing: these were still young adult mice when the study ended, well before the ages at which cancer becomes evident in in reasonably well-husbanded wild-type mice. What you want to look for is an effect starting a few months out from then, during and after the 'knee' in the survival curve, and preferably to the end of life.

 

As far as their own substudy goes:

"DEN (diethylnitrosamine)-induced hepatocellular carcinoma model: WT mice were treated with DEN (25 mg/kg) at 14 days of age via intraperitoneal injection. Mice were weaned at 21 days of age, fed normal chow diet and treated with NMN (2 g/L) via drinking water for 20 weeks. Mice were killed and the number of surface tumors per liver was counted. Pictures of liver with tumor nodes and number of surface liver tumors (n = 10). "

 

That's certainly evidential, but I'm not sure how convincing it is: it's artificial, and very short-term. Also, if they're just looking at the number of surface tumors per liver, they wouldn't catch any metastases (which might be expected to increase from angiogenesis or increased SASP), You might also expect any effect on the original tumor to be most likely in a tumor type where NAMPT is commonly expressed, but this review does not mention the liver as amongst these: "colorectal, ovarian, breast, gastric, prostate, well-differentiated thyroid cancer, melanoma, glioma, and endometrial carcinoma."

[Harkijn]

Reawakening this thread, just in case you missed today's post by Michael in the News section. I keep taking my NR but I have to say I am bit more worried than before that higher NAD may turn against us.

 

https://www.cell.com...2765(20)30904-7

 

 

[Heisok]

Hi Harkijn,

 

I can not find Michael's post in News.

 

Would you share a link?

 

Thanks.

[Hebbeh]

https://www.longecit...sk/#entry902591

[Mind]

While it is always good to be cautious, this was an in vitro investigation in cells and mice injected with cancerous cells (not endogenous cancer), which makes me cautious about these results as well.

 

For the last 20 years I have read many cautious statements about any substance or therapeutic that generically increases some aspect of metabolism or growth. The fear is always that these treatments will cause cancer cells to proliferate. My layman reasoning as to why this is not always the case is that you are also most likely going to increase internal cancer defenses. For people who have higher cancer resistance into old age, it seems there would still be a net benefit to increasing some aspect of metabolism (to rebuild or regenerate broken down systems).

 

However, as an alternative, the SENS approach of "repairing damage" does not seem to carry along the "fear of cancer" baggage.

Edited by Mind, 22 January 2021 - 07:55 PM.

[MikeDC]

Four or five studies on mice in vivo has already shown that increasing NAD+ reduce cancer migration and growth. B3 can significantly increase cancer therapy by a few folds.

[MikeDC]

You are also much less likely to get cancer by maintaining high NAD+ levels so DNA damage can be repaired and your immune cells are healthy.

[Daniel Cooper]

Four or five studies on mice in vivo has already shown that increasing NAD+ reduce cancer migration and growth. B3 can significantly increase cancer therapy by a few folds.

 

Can you give us some links to those studies?

[MikeDC]

https://www.nature.c...1590-020-0793-3

[Michael]

The last 3 posts (on stopping cancer by getting pregnant) are quite clearly off-topic; unless someone cogently objects, I'm going to cleave them off into a separate thread. Please put votes "for" by way of "agree" tags on this post; if you disagree, please instead make a post explaining your objection.

[osris]

The study cited in the first post in this thread, relies on mouse models of pancreatic and ovarian cancers and this may limit the generalizability of the findings to other cancer types or human populations. Also, the translation of these findings to clinical settings, particularly the proposed use of NAMPT inhibitors to mitigate the pro-tumorigenic effects of NAD+ augmentation, requires validation in human trials.